F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .","[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .","Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 ."],"string":"[\n \"___MASK74___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .\",\n \"Genetics and cardiovascular system : influence of human genetic variants on vascular function . Candidate gene association studies in cardiovascular diseases have provided evidence on the molecular basis of phenotypic differences between individuals . The comprehension of how inherited genetic variants are able to affect protein functions has increased the knowledge of how genes interact with environment in order to modulate a particular phenotype . Although it is known that the human genome contains more than 10 million SNPs , only a minor part of them are supposed to be functional . A causative SNP in a particular gene may confer a small to moderate effect in complex phenotypes , such as functions important to cardiovascular homeostasis . This paper is a selective review of the literature on the evidence for interactions between vascular function and naturally occurring genetic variants in endothelial nitric oxide synthase ( P29474 ) and beta - 2 adrenergic receptor ( P07550 ) , two genes among those influencing vascular phenotype and examples for which there is a strong evidence base . P29474 and P07550 will be characterized , as well as the mechanisms by which the enzyme and the receptor work to control vascular responses will be described . Understanding the molecular mechanisms underlying gene - mediated vascular function and their modification by genetic variants is expected to result in a better comprehension about individual ' s phenotypic differences .\",\n \"Additive role of tiotropium in severe asthmatics and Arg16Gly in P07550 as a potential marker to predict response . BACKGROUND : Recent findings have raised new interests about the use of anticholinergics , especially tiotropium , for the treatment of asthma . This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics , and to identify factors capable of predicting the response to tiotropium , using a pharmacogenetic approach . METHODS : A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited . DB01409 18 microg was added once a day and lung functions were measured every 4 weeks . Responders were defined as those with an improvement of > or = 15 % ( or 200 ml ) in the forced expiratory volume in 1 s ( FEV1 ) that was maintained for at least 8 successive weeks . Eleven single nucleotide polymorphisms ( SNPs ) in P11229 - 3 ( coding muscarinic receptors one to three ) which were identified by re - sequencing , and Arg16Gly and Gln27Glu in P07550 ( coding beta ( 2 ) adrenoreceptor ) were scored in 80 of the 138 asthmatics . RESULTS : Forty - six of the 138 asthmatics ( 33 . 3 % ) responded to tiotropium treatment . Logistic regression analyses ( controlled for age , gender , and smoking status ) showed that Arg16Gly in P07550 [ P = 0 . 003 , OR ( 95 % CI ) = 0 . 21 ( 0 . 07 - 0 . 59 ) in a minor allele - dominant model ] was significantly associated with response to tiotropium . CONCLUSIONS : As many as 30 % of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium . The presence of Arg16Gly in P07550 may predict response to tiotropium .\",\n \"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK5___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .\",\n \"Beta2 - adrenergic receptor signaling in P01730 + Foxp3 + regulatory T cells enhances their suppressive function in a PKA - dependent manner . Beta2 - adrenergic receptor ( P07550 ) signaling is known to impair Th1 - cell differentiation and function in a DB02527 - dependent way , leading to inhibition of cell proliferation and decreased production of P60568 and IFN - γ . P01730 (+) Foxp3 (+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self - tolerance . Nevertheless , very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function . Here we show that Foxp3 (+) Treg cells express functional P07550 . P07550 activation in Treg cells leads to increased intracellular DB02527 levels and to protein kinase A ( PKA ) - dependent CREB phosphorylation . We also found that signaling via P07550 enhances the in vitro suppressive activity of Treg cells . P07550 - mediated increase in Treg - cell suppressive function was associated with decreased P60568 mRNA levels in responder P01730 (+) T cells and improved Treg - cell - induced conversion of P01730 (+) Foxp3 (-) cells into Foxp3 (+) induced Treg cells . Moreover , P07550 signaling increased P16410 expression in Treg cells in a PKA - dependent way . Finally , we found that PKA inhibition totally prevented the P07550 - mediated increase in Treg - cell suppressive function . Our data suggest that sympathetic fibers are able to regulate Treg - cell suppressive activity in a positive manner through P07550 signaling .\",\n \"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK51___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .\",\n \"___MASK66___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .\",\n \"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK72___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK72___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK72___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK72___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK72___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .\",\n \"P10275 - mediated repression of novel target genes . BACKGROUND : The androgen receptor ( AR ) plays a pivotal role in prostate cancer ( PCa ) initiation and progression . To date , studies have focused disproportionately on androgen - stimulated genes such as prostate - specific antigen ( PSA ) , while repressed genes have gained little attention , even though they too may be involved in regulating cell growth , differentiation , and apoptosis . METHODS : ChIP Display was used to identify putative AR target genes in the ablation - resistant human PCa cell line , C4 - 2B . Quantitative real - time reverse transcription - PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone ( DB02901 ) timecourse and dose - response , as well as AR knock - down and bicalutamide - treatments . RESULTS : We report on three genes , Q5T5P2 , P11229 , and Q6UE05 , which were newly identified in a screen for AR - occupied regions in C4 - 2B PCa cells , and which were repressed by treatment with DB02901 . AR knock - down resulted in increased Q5T5P2 , P11229 , and Q6UE05 mRNA , indicating that , like PSA stimulation , AR represses these three genes even in the absence of added ligand . DB02901 decreased Q5T5P2 and P11229 pre - mRNA levels , suggesting AR - mediated transcriptional inhibition . Cycloheximide attenuated DB02901 - mediated repression of P11229 , suggesting the requirement of new protein synthesis . Furthermore , bicalutamide treatment did not mimic , but rather antagonized DB02901 - mediated Q5T5P2 repression . Unlike the handful of androgen - repressed genes studied thus far , AR occupancy at Q5T5P2 , P11229 , and Q6UE05 was mapped outside their respective 5 '- promoter regions . CONCLUSIONS : Many more genes likely share AR - mediated gene repression through distal regulatory elements . Further study of such targets and their transcriptional regulation may help explain the receptor ' s tumorigenicity in PCa .\",\n \"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK90___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .\",\n \"[ Relationship between genetic polymorphisms of β2 - adrenergic receptor gene and essential hypertension risk among the Han Chinese population : a Meta analysis ] . OBJECTIVE : To evaluate the relationship between A46G and C79G polymorphisms in the β2 - adrenergic receptor ( P07550 ) gene and the incidence of essential hypertension ( EH ) among the Han Chinese population . METHODS : We conducted a computer retrieval of PUBMED , EMBASE , CNKI , Wanfang and P01282 databases prior to May 2010 . Articles investigating the relationship of EH and P07550 gene polymorphism of Han group were found through literature search , including 15 articles on A46G and 10 articles on C79G . According to the including and excluding criteria , a Meta - analysis was conducted in EH and P07550 gene polymorphism of A46G and C79G . The association was examined by RevMan4 . 2 software through quantitative analysis . RESULTS : Eight articles on A46G polymorphism ( including 1078 EH cases and 788 control subjects ) and six articles on C79G polymorphism ( including 1367 EH cases and 1006 control subjects ) were included in the current study . Meta - analysis showed that there was a significant association between A46G polymorphism and EH : genotype GG / ( AA + AG ) ( fixed - effected model , OR = 1 . 35 , 95 % CI = 1 . 04 - 1 . 74 , P = 0 . 02 ) , genotype GG / AA ( fixed - effected model , OR = 1 . 41 , 95 % CI = 1 . 06 - 1 . 89 , P = 0 . 02 ) . No significant association was found between C79G polymorphism and EH of Han group in China : G / C allele comparison ( random - effected model , OR = 0 . 88 , 95 % CI = 0 . 55 - 1 . 39 , P = 0 . 57 ) . CONCLUSION : Significant association was found between A46G polymorphism of P07550 gene and EH , whereas no association could be found between C79G polymorphism and EH among Han Chinese population .\",\n \"___MASK70___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK70___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK70___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK70___ inhibits activated T cells . We show that in vitro , ___MASK70___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK70___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK70___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK70___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK70___ to treat chronic inflammatory disease .\",\n \"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .\",\n \"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . DB00734 non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .\",\n \"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .\",\n \"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK71___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .\",\n \"[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .\",\n \"Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK51___","___MASK5___","___MASK66___","___MASK70___","___MASK71___","___MASK72___","___MASK74___","___MASK75___","___MASK90___"],"string":"[\n \"___MASK51___\",\n \"___MASK5___\",\n \"___MASK66___\",\n \"___MASK70___\",\n \"___MASK71___\",\n \"___MASK72___\",\n \"___MASK74___\",\n \"___MASK75___\",\n \"___MASK90___\"\n]"},"answer":{"kind":"string","value":"___MASK51___"},"id":{"kind":"string","value":"MH_train_372"}}},{"rowIdx":373,"cells":{"query":{"kind":"string","value":"interacts_with DB00796?"},"supports":{"kind":"list like","value":["Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK27___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK27___ peptide content within the pituitary , and plasma ___MASK27___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK27___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK27___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK27___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK45___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","DB00796 inhibits Toll - like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll - like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT ( 1 ) R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti - inflammatory effects . Thus , we investigated whether an ARB exerts anti - inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0 . 05 vs . control ) along with decrease in the activity of NF - kappaB and the expression of IL - 1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti - inflammatory effects .","Unbalanced placental expression of imprinted genes in human intrauterine growth restriction . Imprinted genes control fetal and placental growth in mice and in rare human syndromes , but the role of these genes in sporadic intrauterine growth restriction ( IUGR ) is less well - studied . We measured the ratio of mRNA from a maternally expressed imprinted gene , Q53GA4 , to that from a paternally expressed imprinted gene , Q5EB52 , by Northern blotting in 38 IUGR - associated placentae and 75 non - IUGR placentae and found an increase in the Q53GA4 / Q5EB52 mRNA ratio in IUGR ( p = 0 . 0001 ) . Altered expression of Q53GA4 and Q5EB52 was not accompanied by changes in DNA methylation within their imprinting centers , and immunohistochemistry showed Q53GA4 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae . We next did a genome - wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under - perfusion compared to 15 non - IUGR placentae using Affymetrix U133A microarrays . In this series six imprinted genes were differentially expressed by Q9UNW9 with a Benjamini - Hochberg false discovery rate of 0 . 05 , with increased expression of Q53GA4 and decreased expression of Q5EB52 , Q9UI56 , P50440 , GNAS and Q9UM63 in IUGR placentae . At lower significance , we found P01344 mRNA decreased and P49918 mRNA increased in the IUGR cases . We confirmed the significant reduction in Q9UI56 non - translated RNA in IUGR placentae by Northern blotting . In addition to imprinted genes , the microarray data highlighted non - imprinted genes acting in endocrine signaling ( P41159 , P06850 , P15428 , P08476 ) , tissue growth ( IGF1 ) , immune modulation ( P14902 , PSG - family genes ) , oxidative metabolism ( P35754 ) , vascular function ( P30556 , P53805 ) and metabolite transport ( O00585 - family solute carriers ) as differentially expressed in IUGR vs . non - IUGR placentae .","[ ___MASK72___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK72___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .","Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .","Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK27___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .","Inhibitors of DB00171 - binding cassette transporters suppress interleukin - 12 p40 production and major histocompatibility complex II up - regulation in macrophages . DB00171 - binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and / or interferon ( IFN ) - gamma - induced interleukin ( IL ) - 12 p40 and tumor necrosis factor ( P01375 ) - alpha production , nitric oxide formation , as well as major histocompatibility complex II up - regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL - 12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4 , 4 '- diisothiocyanostilbene - 2 , 2 '- disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL - 12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2 , 2 '- iminodibenzoic acid failed to suppress the production of IL - 12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL - 12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL - 12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 / 44 mitogen - activated protein kinases or c - Jun kinase . ___MASK73___ also suppressed P01579 - induced up - regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and / or P01579 - induced macrophage activation .","Novel agents that potentially inhibit irinotecan - induced diarrhea . ___MASK11___ ( CPT - 11 , 7 - ethyl - 10 -[ 4 -( 1 - piperidino )- 1 - piperidino ] carbonyloxycamptothecin ) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting P11387 ( Topo I ) . However , severe and unpredictable dosing - limiting toxicities ( mainly myelosuppression and severe diarrhea ) hinder its clinical use . The latter consists of early and late - onset diarrhea , occurring within 24 hr or > or = 24 hr after CPT - 11 administration , respectively . This review highlights novel agents potentially inhibiting CPT - 11 - induced diarrhea , which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms . Early - onset diarrhea is observed immediately after CPT - 11 infusion and probably due to the inhibition of acetylcholinesterase activity , which can be eliminated by administration of atropine . Late - onset diarrhea appears to be associated with intestinal exposure to SN - 38 ( 7 - ethyl - 10 - hydroxycamptothecin ) , the major active metabolite of CPT - 11 , which may bind to Topo I and induce apoptosis of intestinal epithelia , leading to the disturbance in the absorptive and secretory functions of mucosa . CPT - 11 and SN - 38 may also stimulate the production of pro - inflammatory cytokines and prostaglandins ( PGs ) , thus inducing the secretion of Na (+) and Cl (-) . Early treatment of severe late - onset diarrhea with oral high - dose loperamide has decreased patient morbidity . Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models . These include intestinal alkalizing agents , oral antibiotics , enzyme inducers , P - glycoprotein ( PgP ) inhibitors , cyclooxygenase - 2 ( P35354 ) inhibitors , tumor necrosis factor - alpha ( P01375 ) inhibitors , or blockers of biliary excretion of SN - 38 . Further studies are needed to identify the molecular targets associated with CPT - 11 toxicity and safe and effective agents for alleviating CPT - 11 - induced diarrhea .","Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis . Chronic glomerulonephritis ( Q9P2M7 ) is one of the most severe kidney diseases . Genes of vascular reactivity are thought to play an important role in development and progression of Q9P2M7 . In this study , we analyzed association of genes of vascular homeostasis with hypertension and renal survival of Q9P2M7 patients . The study sample included 238 patients with Q9P2M7 and 304 healthy subjects of population control . Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction ( PCR ) , restriction fragment length polymorphism ( RFLP ) analysis and TaqMan assays . Association of the genotypes with renal survival was analyzed by the Kaplan - Meier estimator . Genotypes 311SC and 311SS of the Q15165 gene , (- 1166 ) AC and (- 1166 ) CC of the P30556 gene , (+ 46 ) AA of the P07550 gene , and 198KK and 198KN of the P05305 gene were associated with decreased rate of renal survival of the patients . Polymorphisms S311C Q15165 , (- 1166 ) A / C P30556 , (+ 46 ) G / A P07550 , and K198N P05305 were associated with the accelerated decline in kidney function in the Q9P2M7 patients .","Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK8___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .","Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 - activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) - alpha up - regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down - regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 )- IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA ( 2 )- IIA and extracellular signal - regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 )- IIA was quantitatively measured by an enzyme - linked - immunosorbent - assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 - kinase ) inhibitor LY294002 and the cholesterol - depleting drug methyl - beta - cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 )- IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA ( 2 )- IIA through the Q9UNN8 - dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 - mediated expression of sPLA ( 2 )- IIA through the cleavage of P25116 . The Q9UNN8 - dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1 / 2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA ( 2 )- IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 - kinase dependent protective activity for thrombin such that its cleavage of the lipid - raft localized P25116 inhibits the P01375 - mediated expression of sPLA ( 2 )- IIA in HUVECs .","Lessons learned from the irinotecan metabolic pathway . ___MASK11___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK11___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK11___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .","Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK86___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .","Cooperative regulation of extracellular signal - regulated kinase activation and cell shape change by filamin A and beta - arrestins . beta - Arrestins ( betaarr ) are multifunctional adaptor proteins that can act as scaffolds for G protein - coupled receptor activation of mitogen - activated protein kinases ( MAPK ) . Here , we identify the actin - binding and scaffolding protein filamin A ( P21333 ) as a betaarr - binding partner using Son of sevenless recruitment system screening , a classical yeast two - hybrid system , coimmunoprecipitation analyses , and direct binding in vitro . In P21333 , the betaarr - binding site involves tandem repeat 22 in the carboxyl terminus . betaarr binds P21333 through both its N - and C - terminal domains , indicating the presence of multiple binding sites . We demonstrate that betaarr and P21333 act cooperatively to activate the MAPK extracellular signal - regulated kinase ( P29323 ) downstream of activated muscarinic M1 ( M1MR ) and angiotensin II type 1a ( P30556 ) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr - P28482 complex formation by P21333 . In Hep2 cells , stimulation of M1MR or P30556 results in the colocalization of receptor , betaarr , P21333 , and active P29323 in membrane ruffles . Reduction of endogenous levels of betaarr or P21333 and a catalytically inactive dominant negative Q02750 , which prevents P29323 activation , inhibit membrane ruffle formation , indicating the functional requirement for betaarr , P21333 , and active P29323 in this process . Our results indicate that betaarr and P21333 cooperate to regulate P29323 activation and actin cytoskeleton reorganization .","P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK2___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .","Effect of polymorphisms on the pharmacokinetics , pharmacodynamics , and safety of risperidone in healthy volunteers . OBJECTIVE : To identify genetic markers capable of predicting the pharmacokinetics , pharmacodynamics , and adverse effects of risperidone . METHODS : Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone . ___MASK8___ and hydroxyrisperidone plasma levels were measured using high - performance liquid chromatography combined with tandem mass spectrometry . P01236 concentration was quantified by direct chemiluminescence . RESULTS : Poor P10635 metabolizers showed higher risperidone Cmax , area under the curve ( AUC ) , and t1 / 2 , as well as lower clearance . They also showed lower Cmax and AUC and higher t1 / 2 for hydroxyrisperidone . Furthermore , individuals with a mutant Q9BQB6 genotype had a lower risperidone AUC and t1 / 2 and higher clearance . The hydroxyrisperidone AUC was lower in individuals with the P21964 mutant genotype . ___MASK8___ increased prolactin levels ( iAUC and iCmax ) , which were higher in women than in men . The most frequent reactions were somnolence ( 47 . 1 % ) , headache ( 21 . 4 % ) , and dizziness ( 17 . 1 % ) . Women had neurological effects and headache more frequently than men . The incidence of headache was associated with polymorphisms in the P30556 and NAT2 ; neurological effects were associated with P33261 . CONCLUSIONS : Differences in the pharmacokinetics of risperidone are due to polymorphisms in P10635 , P21964 , and Q9BQB6 . Differences in adverse reactions can be explained by gender and polymorphisms in P33261 , P30556 , and NAT2 .","Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK64___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK72___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )","[ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin - converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin - converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy - proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non - nephrotic proteinuria ( protein , 0 . 5 to 3 . 5 g / day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8 - week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0 . 05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type - IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type - IV collagen excretion was recognized in patients with chronic glomerulonephritis .","Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .","Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK8___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .","A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .","Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .","Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity ."],"string":"[\n \"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK27___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK27___ peptide content within the pituitary , and plasma ___MASK27___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK27___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK27___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK27___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK45___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"DB00796 inhibits Toll - like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll - like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT ( 1 ) R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti - inflammatory effects . Thus , we investigated whether an ARB exerts anti - inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0 . 05 vs . control ) along with decrease in the activity of NF - kappaB and the expression of IL - 1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti - inflammatory effects .\",\n \"Unbalanced placental expression of imprinted genes in human intrauterine growth restriction . Imprinted genes control fetal and placental growth in mice and in rare human syndromes , but the role of these genes in sporadic intrauterine growth restriction ( IUGR ) is less well - studied . We measured the ratio of mRNA from a maternally expressed imprinted gene , Q53GA4 , to that from a paternally expressed imprinted gene , Q5EB52 , by Northern blotting in 38 IUGR - associated placentae and 75 non - IUGR placentae and found an increase in the Q53GA4 / Q5EB52 mRNA ratio in IUGR ( p = 0 . 0001 ) . Altered expression of Q53GA4 and Q5EB52 was not accompanied by changes in DNA methylation within their imprinting centers , and immunohistochemistry showed Q53GA4 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae . We next did a genome - wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under - perfusion compared to 15 non - IUGR placentae using Affymetrix U133A microarrays . In this series six imprinted genes were differentially expressed by Q9UNW9 with a Benjamini - Hochberg false discovery rate of 0 . 05 , with increased expression of Q53GA4 and decreased expression of Q5EB52 , Q9UI56 , P50440 , GNAS and Q9UM63 in IUGR placentae . At lower significance , we found P01344 mRNA decreased and P49918 mRNA increased in the IUGR cases . We confirmed the significant reduction in Q9UI56 non - translated RNA in IUGR placentae by Northern blotting . In addition to imprinted genes , the microarray data highlighted non - imprinted genes acting in endocrine signaling ( P41159 , P06850 , P15428 , P08476 ) , tissue growth ( IGF1 ) , immune modulation ( P14902 , PSG - family genes ) , oxidative metabolism ( P35754 ) , vascular function ( P30556 , P53805 ) and metabolite transport ( O00585 - family solute carriers ) as differentially expressed in IUGR vs . non - IUGR placentae .\",\n \"[ ___MASK72___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK72___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .\",\n \"Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .\",\n \"Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK27___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .\",\n \"Inhibitors of DB00171 - binding cassette transporters suppress interleukin - 12 p40 production and major histocompatibility complex II up - regulation in macrophages . DB00171 - binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and / or interferon ( IFN ) - gamma - induced interleukin ( IL ) - 12 p40 and tumor necrosis factor ( P01375 ) - alpha production , nitric oxide formation , as well as major histocompatibility complex II up - regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL - 12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4 , 4 '- diisothiocyanostilbene - 2 , 2 '- disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL - 12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2 , 2 '- iminodibenzoic acid failed to suppress the production of IL - 12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL - 12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL - 12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 / 44 mitogen - activated protein kinases or c - Jun kinase . ___MASK73___ also suppressed P01579 - induced up - regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and / or P01579 - induced macrophage activation .\",\n \"Novel agents that potentially inhibit irinotecan - induced diarrhea . ___MASK11___ ( CPT - 11 , 7 - ethyl - 10 -[ 4 -( 1 - piperidino )- 1 - piperidino ] carbonyloxycamptothecin ) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting P11387 ( Topo I ) . However , severe and unpredictable dosing - limiting toxicities ( mainly myelosuppression and severe diarrhea ) hinder its clinical use . The latter consists of early and late - onset diarrhea , occurring within 24 hr or > or = 24 hr after CPT - 11 administration , respectively . This review highlights novel agents potentially inhibiting CPT - 11 - induced diarrhea , which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms . Early - onset diarrhea is observed immediately after CPT - 11 infusion and probably due to the inhibition of acetylcholinesterase activity , which can be eliminated by administration of atropine . Late - onset diarrhea appears to be associated with intestinal exposure to SN - 38 ( 7 - ethyl - 10 - hydroxycamptothecin ) , the major active metabolite of CPT - 11 , which may bind to Topo I and induce apoptosis of intestinal epithelia , leading to the disturbance in the absorptive and secretory functions of mucosa . CPT - 11 and SN - 38 may also stimulate the production of pro - inflammatory cytokines and prostaglandins ( PGs ) , thus inducing the secretion of Na (+) and Cl (-) . Early treatment of severe late - onset diarrhea with oral high - dose loperamide has decreased patient morbidity . Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models . These include intestinal alkalizing agents , oral antibiotics , enzyme inducers , P - glycoprotein ( PgP ) inhibitors , cyclooxygenase - 2 ( P35354 ) inhibitors , tumor necrosis factor - alpha ( P01375 ) inhibitors , or blockers of biliary excretion of SN - 38 . Further studies are needed to identify the molecular targets associated with CPT - 11 toxicity and safe and effective agents for alleviating CPT - 11 - induced diarrhea .\",\n \"Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis . Chronic glomerulonephritis ( Q9P2M7 ) is one of the most severe kidney diseases . Genes of vascular reactivity are thought to play an important role in development and progression of Q9P2M7 . In this study , we analyzed association of genes of vascular homeostasis with hypertension and renal survival of Q9P2M7 patients . The study sample included 238 patients with Q9P2M7 and 304 healthy subjects of population control . Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction ( PCR ) , restriction fragment length polymorphism ( RFLP ) analysis and TaqMan assays . Association of the genotypes with renal survival was analyzed by the Kaplan - Meier estimator . Genotypes 311SC and 311SS of the Q15165 gene , (- 1166 ) AC and (- 1166 ) CC of the P30556 gene , (+ 46 ) AA of the P07550 gene , and 198KK and 198KN of the P05305 gene were associated with decreased rate of renal survival of the patients . Polymorphisms S311C Q15165 , (- 1166 ) A / C P30556 , (+ 46 ) G / A P07550 , and K198N P05305 were associated with the accelerated decline in kidney function in the Q9P2M7 patients .\",\n \"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK8___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .\",\n \"Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 - activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) - alpha up - regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down - regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 )- IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA ( 2 )- IIA and extracellular signal - regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 )- IIA was quantitatively measured by an enzyme - linked - immunosorbent - assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 - kinase ) inhibitor LY294002 and the cholesterol - depleting drug methyl - beta - cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 )- IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA ( 2 )- IIA through the Q9UNN8 - dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 - mediated expression of sPLA ( 2 )- IIA through the cleavage of P25116 . The Q9UNN8 - dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1 / 2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA ( 2 )- IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 - kinase dependent protective activity for thrombin such that its cleavage of the lipid - raft localized P25116 inhibits the P01375 - mediated expression of sPLA ( 2 )- IIA in HUVECs .\",\n \"Lessons learned from the irinotecan metabolic pathway . ___MASK11___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK11___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK11___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .\",\n \"Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK86___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .\",\n \"Cooperative regulation of extracellular signal - regulated kinase activation and cell shape change by filamin A and beta - arrestins . beta - Arrestins ( betaarr ) are multifunctional adaptor proteins that can act as scaffolds for G protein - coupled receptor activation of mitogen - activated protein kinases ( MAPK ) . Here , we identify the actin - binding and scaffolding protein filamin A ( P21333 ) as a betaarr - binding partner using Son of sevenless recruitment system screening , a classical yeast two - hybrid system , coimmunoprecipitation analyses , and direct binding in vitro . In P21333 , the betaarr - binding site involves tandem repeat 22 in the carboxyl terminus . betaarr binds P21333 through both its N - and C - terminal domains , indicating the presence of multiple binding sites . We demonstrate that betaarr and P21333 act cooperatively to activate the MAPK extracellular signal - regulated kinase ( P29323 ) downstream of activated muscarinic M1 ( M1MR ) and angiotensin II type 1a ( P30556 ) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr - P28482 complex formation by P21333 . In Hep2 cells , stimulation of M1MR or P30556 results in the colocalization of receptor , betaarr , P21333 , and active P29323 in membrane ruffles . Reduction of endogenous levels of betaarr or P21333 and a catalytically inactive dominant negative Q02750 , which prevents P29323 activation , inhibit membrane ruffle formation , indicating the functional requirement for betaarr , P21333 , and active P29323 in this process . Our results indicate that betaarr and P21333 cooperate to regulate P29323 activation and actin cytoskeleton reorganization .\",\n \"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK2___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .\",\n \"Effect of polymorphisms on the pharmacokinetics , pharmacodynamics , and safety of risperidone in healthy volunteers . OBJECTIVE : To identify genetic markers capable of predicting the pharmacokinetics , pharmacodynamics , and adverse effects of risperidone . METHODS : Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone . ___MASK8___ and hydroxyrisperidone plasma levels were measured using high - performance liquid chromatography combined with tandem mass spectrometry . P01236 concentration was quantified by direct chemiluminescence . RESULTS : Poor P10635 metabolizers showed higher risperidone Cmax , area under the curve ( AUC ) , and t1 / 2 , as well as lower clearance . They also showed lower Cmax and AUC and higher t1 / 2 for hydroxyrisperidone . Furthermore , individuals with a mutant Q9BQB6 genotype had a lower risperidone AUC and t1 / 2 and higher clearance . The hydroxyrisperidone AUC was lower in individuals with the P21964 mutant genotype . ___MASK8___ increased prolactin levels ( iAUC and iCmax ) , which were higher in women than in men . The most frequent reactions were somnolence ( 47 . 1 % ) , headache ( 21 . 4 % ) , and dizziness ( 17 . 1 % ) . Women had neurological effects and headache more frequently than men . The incidence of headache was associated with polymorphisms in the P30556 and NAT2 ; neurological effects were associated with P33261 . CONCLUSIONS : Differences in the pharmacokinetics of risperidone are due to polymorphisms in P10635 , P21964 , and Q9BQB6 . Differences in adverse reactions can be explained by gender and polymorphisms in P33261 , P30556 , and NAT2 .\",\n \"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK64___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK72___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"[ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin - converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin - converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy - proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non - nephrotic proteinuria ( protein , 0 . 5 to 3 . 5 g / day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8 - week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0 . 05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type - IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type - IV collagen excretion was recognized in patients with chronic glomerulonephritis .\",\n \"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .\",\n \"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK8___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .\",\n \"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .\",\n \"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .\",\n \"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .\"\n]"},"candidates":{"kind":"list like","value":["___MASK11___","___MASK27___","___MASK2___","___MASK45___","___MASK64___","___MASK72___","___MASK73___","___MASK86___","___MASK8___"],"string":"[\n \"___MASK11___\",\n \"___MASK27___\",\n \"___MASK2___\",\n \"___MASK45___\",\n \"___MASK64___\",\n \"___MASK72___\",\n \"___MASK73___\",\n \"___MASK86___\",\n \"___MASK8___\"\n]"},"answer":{"kind":"string","value":"___MASK8___"},"id":{"kind":"string","value":"MH_train_373"}}},{"rowIdx":374,"cells":{"query":{"kind":"string","value":"interacts_with DB00519?"},"supports":{"kind":"list like","value":["Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK48___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .","Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK8___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .","Immunohistochemical studies of the epididymal duct in Egyptian water buffalo ( Bubalus bubalis ) . Using immunohistochemistry ( IHC ) , this study aimed to evaluate the regional distribution pattern of some biologically active proteins in the epididymis of Egyptian water buffalo and to determine the structural - functional relationships of the different epididymal structures . Wax - embedded sections from different regions of the epididymal duct from adult , clinically healthy , buffalo bulls were used . Primary antibodies against angiotensin converting enzyme ( P12821 ) , S - 100 , galactosyltransferase ( GalTase ) , alpha smooth muscle actin ( α - SMA ) , connexin 43 ( P17302 ) and vascular endothelial growth factor ( P15692 ) were used for immunohistochemical studies . The results showed that , in addition to the well - known principal and basal cells , the epididymal epithelium , similar to that of other species , possessed apical cells and intraepithelial leukocytes . IHC showed that , with the exception of P15692 which reacted negatively , all antibodies used displayed variable reactivity in the different epididymal structures . Apical cells expressed a strong reaction with P12821 along the entire length of the duct . The principal cells in the caput epididymis exhibited a distinct reactivity with S - 100 and GalTase . The peritubular muscular coat displayed a marked immunostaining for α - SMA and for P17302 . In conclusion these findings showed a regional - specific distribution pattern , distinct from that in bovine bulls . Some potential functional capacities , especially absorptive and secretory ones , are discussed in relation to the different epididymal regions .","Inhibition of matrix metalloproteinase - 9 activity by trandolapril after middle cerebral artery occlusion in rats . We investigated whether an angiotensin - converting enzyme ( P12821 ) inhibitor could inhibit matrix metalloproteinase ( MMP ) activities in cerebral infarct lesions after middle cerebral artery occlusion ( MCAO ) in rats . After placebo or trandolapril ( 5 mg / kg per day ) was administered orally for 7 days , we permanently occluded the right middle cerebral artery . P12821 activity in extracts from the infarct side of placebo - treated rats was significantly higher than that in extracts from the non - infarct side from 5 days after MCAO , though they did not differ at 1 day . P12821 activities in extracts from both hemispheric segments in the trandolapril - treated group were significantly decreased compared with those in the placebo - treated group before MCAO , and this significant reduction persisted even at 7 days after MCAO . In the placebo - treated group , P14780 and P08253 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO , respectively . DB00519 treatment significantly reduced P14780 and P08253 activities to 68 . 5 % and 53 . 2 % , respectively . Seven days after MCAO , the ratios of infarct areas to the hemispheric sectional areas in placebo - and trandolapril - treated rats were 55 . 4 +/- 2 . 1 % and 30 . 9 +/- 2 . 9 % , respectively , and this difference was significant . Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril - treated rats . Cumulative survival in trandolapril - treated rats was significantly increased compared with that in placebo - treated rats . Thus , the inhibition of P14780 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia .","Gene polymorphisms impact the risk of rejection with hemodynamic compromise : a multicenter study . BACKGROUND : Rejection with hemodynamic compromise ( P18577 ) is associated with high mortality in heart recipients . This study investigates the association between genetic polymorphisms and P18577 in pediatric heart recipients . METHODS : Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to P18577 by recipient race , age at transplantation , and genotype at 13 genetic polymorphisms ( P01375 - α A - 308G , P05231 G - 174C , P27352 - γ T + 874A , P22301 G - 1082A , C - 819T , and C - 592A ; FAS A - 670G , P48023 C - 843T , and P12821 I / D ; and P15692 A - 2578C , C - 1451T , C + 405G , and - 2549 I / D ) . RESULTS : P18577 occurred in 126 ( 23 . 7 % ) patients during the study period . Adjusting for age and race , P22301 G - 1082A , FAS A - 670G , and P12821 I / D genotypes were associated with P18577 . P22301 G - 1082A GG genotype was associated with decreased risk of P18577 with an adjusted hazard ratio ( HR ) of 0 . 49 ( 95 % confidence interval [ CI ] , 0 . 27 - 0 . 90 ; P = 0 . 020 ) . FAS A - 670G AA genotype was associated with increased risk of P18577 with an adjusted HR of 1 . 84 ( 95 % CI , 1 . 25 - 2 . 69 ; P = 0 . 002 ) . P12821 II genotype was associated with decreased risk of P18577 with an adjusted HR of 0 . 58 ( 95 % CI , 0 . 36 - 0 . 95 ; P = 0 . 031 ) . CONCLUSIONS : Recipients with a high anti - inflammatory and immune - regulatory genetic profile ( high interleukin - 10 ) were protected from P18577 . Conversely , recipients with a pro - apoptotic genetic profile ( high Fas ) or high angiotensin - 1 - converting enzyme producing genotype were at increased risk of P18577 . This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients .","M ( 3 ) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation , hyperresponsiveness and remodeling in mice . M ( 3 ) muscarinic receptors are localized on inflammatory cells , airway smooth muscle , and submucosal glands , known to mediate bronchoconstriction , mucus secretion , and airway remodeling . It is hypothesized bencycloquidium bromide ( BCQB ) , a novel M ( 3 ) receptor antagonist , might have potential effects on airway hyperresponsiveness , inflammation and airway remodeling in a murine model of asthma . Mice sensitized and challenged with ovalbumin developed airway inflammation . Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts , and cytokine levels . Lung tissues were evaluated for cell infiltration , mucus hypersecretion , airway remodeling , and the expression of inflammatory biomarkers . Airway hyperresponsiveness was monitored by direct airway resistance analysis . Inhalation administration of BCQB significantly not only reduced ovalbumin - induced airway hyperresponsiveness comparing to methacholine , and prevented the ovalbumin - induced increase in total cell counts and eosinophil counts . Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin - induced mRNA expression of eotaxin , P05113 , P05112 and P14780 , and increased mRNA expression of IFN - γ and P01033 in a dose - dependent manner . Substantial IFN - γ / P05112 ( Th1 / Th2 ) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment . In addition , histological studies showed that BCQB dramatically inhibited ovalbumin - induced lung tissue eosinophil infiltration , airway mucus production and collagen deposition in lung tissues . Results reported in current paper suggest that M ( 3 ) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation , hyperresponsiveness and remodeling .","___MASK8___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK8___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .","Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK54___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .","Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .","[ Adjustment effects of Herba epimedii , Fructus ligustrilucidi on NO / ET , Q9Y251 axis in asthmatic rats ] . OBJECTIVE : To study the neuro - endocrine adjustment effects of Herba Epimedii and Fructus Ligustrilucidi on the asthmatic rats . METHOD : Rat asthma model was duplicated by OVA ( ovalbumin ) through sensitizing and challenging . Fifty male rats were randomly divided into normal group , model group , adjustment group of Herba Epimedii and Fructus Ligustrilucidi , Peibenfang group and Asimei capsule group . Investigating levels of ET ( Endothelin ) , NO , P35228 ( inducible NOS ) , and P29474 ( constitutive NOS ) in blood serum and BALF ( bronchoalveolar lavage fluid ) , O00230 ( corticotrophin ) in serum , DB01285 ( adrenocorticotropin hormone ) in plasma , CHR ( corticotropin release hormone ) in hypothalamus , protein expression of GCR ( glucocorticoid receptor ) in lung tissue . RESULT : The adjustment of Herba Epimedii and Fructus Ligustrilucidi could inhibit ET and NO content in BALF ( all P < 0 . 05 ) , decrease the level of P35228 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , and increase the level of P29474 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , raise the concentration of serum O00230 ( P < 0 . 01 ) , enhance the protein expression of GCR in lung tissue ( P < 0 . 05 ) . CONCLUSION : The preventive and therapeutic effect of Herba Epimedii and Fructus Ligustrilucidi on asthma relates to their adjustment effect on ET / NO and Q9Y251 axis .","Contribution of captopril thiol group to the prevention of spontaneous hypertension . We aimed to compare the effect of angiotensin converting enzyme ( P12821 ) inhibitors captopril ( containing thiol group ) and enalapril ( without thiol group ) on the development of spontaneous hypertension and to analyze mechanisms of their actions , particularly effects on oxidative stress and NO production . Six - week - old SHR were divided into three groups : control , group receiving captopril ( 50 mg / kg / day ) or enalapril ( 50 mg / kg / day ) for 6 weeks . At the end of experiment , systolic blood pressure ( SBP ) increased by 41 % in controls . Both captopril and enalapril prevented blood pressure increase , however , SBP in the captopril group ( 121 +/- 5 mmHg ) was significantly lower than that in the enalapril group ( 140 +/- 5 mmHg ) . Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group . ___MASK83___ and enalapril increased NO synthase activity in the heart and aorta to the similar level . Neither captopril nor enalapril was , however , able to increase the expression of P29474 . Both P12821 inhibitors increased the level of cGMP . However , cGMP level was significantly higher in the aorta of captopril group . We conclude that captopril , beside inhibition of P12821 , prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration .","Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis . DB00435 ( NO ) plays a central role in the pathogenesis of bacterial meningitis . However , the role of NO produced by endothelial NO synthase ( P29474 ) in meningitis is still unclear . We investigated the influence of P29474 depletion on the inflammatory host response , intracranial complications , and outcome in experimental pneumococcal meningitis . Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected P29474 - deficient mice than in infected wild type mice . This effect could be attributed to an increased expression of P16109 , macrophage inflammatory protein - 2 , keratinocyte - derived cytokine , and interleukin ( IL ) - 1beta in the brain of infected P29474 - deficient mice . However , no differences in the cerebral expression of intercellular adhesion molecule - 1 , tumor necrosis factor - alpha , and P05231 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice . In addition to enhanced leukocyte infiltration into the P04141 , meningitis - associated intracranial complications including blood - brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected P29474 - deficient mice . The aggravation of intracranial complications was paralleled by a worsening of the disease , as evidenced by a more pronounced hypothermia , an enhanced weight reduction , and an increased death rate . The current data indicate that P29474 deficiency is detrimental in bacterial meningitis . This effect seems to be related to an increased expression of ( certain ) cytokines / chemokines and adhesion molecules ; thus leading to increased meningeal inflammation and , subsequently , to aggravated intracranial complications .","Quality of life and the relevant factors in patients with chronic hepatitis B . BACKGROUND / AIMS : To assess HRQL in patients with chronic hepatitis B ( CHB ) and investigate the relevant factors . METHODOLOGY : A cross - sectional three - center study involving 407 inpatients with CHB was conducted . Subjects completed the epidemiological questionnaire and two validated questionnaires ( SF - 36 and QLICD - CH ) . Afterwards , the angiotensin - converting enzyme ( P12821 ) insertion / deletion ( I / D ) and dopamine receptor D4 ( P21917 ) gene polymorphisms were assessed in all patients . RESULTS : It was found that the scores of CHB patients in SF - 36 scale 8 domains were lower than those of the normal population ( all p < 0 . 001 ) . The anti - viral therapy could improve four - area - scores ( P20941 ( p = 0 . 004 ) , SOD ( p = 0 . 011 ) , SPD ( p = 0 . 032 ) , TOT ( p = 0 . 014 ) ) . Extraverted personality , social competence and ability to work were protective factors of HRQL , while severity of illness , better family economy and abnormal condition of liver function were risk factors . The scores in II genotype were higher than those in I / D + DD genotype of P12821 polymorphisms . The scores in short repeat sequences genotypes were higher than those in long repeat sequences genotype of P21917 polymorphisms . CONCLUSIONS : Patients with CHB had lower HRQL than normal population . Anti - viral treatments can improve their HRQL . Several health factors independently influence HRQL and P12821 and P21917 gene polymorphism is associated with HRQL of CHB patients .","[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK83___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .","5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .","DB04216 abrogates P05231 / P40763 signaling and inhibits glioblastoma cell line growth and migration . Evidence has suggested that P40763 functions as an oncogene in gliomagenesis . As a consequence , changes in the inflammatory microenvironment are thought to promote tumor development . Regardless of its origin , cancer - related inflammation has many tumor - promoting effects , such as the promotion of cell cycle progression , cell proliferation , cell migration and cell survival . Given that P05231 , a major cancer - related inflammatory cytokine , regulates P40763 activation and is upregulated in glioblastoma , we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by P05231 , and to determine the underlying mechanisms of action . In this study , we show that quercetin is a potent inhibitor of the P05231 - induced P40763 signaling pathway in T98G and U87 glioblastoma cells . Exposure to quercetin resulted in the reduction of P42704 , P23458 and P40763 activation by P05231 , as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by P05231 . Interestingly , quercetin also modulated the expression of two target genes regulated by P40763 , i . e . cyclin D1 and matrix metalloproteinase - 2 ( P08253 ) . Moreover , quercetin reduced the recruitment of P40763 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of P05231 . Overall , these results provide new insight into the role of quercetin as a blocker of the P40763 activation pathway stimulated by P05231 , with a potential role in the prevention and treatment of glioblastoma .","Strategy for a genetic assessment of antipsychotic and antidepressant - related proarrhythmia . Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic . In this field , accurate understanding of genetics , which per se is a non - controllable risk factor , may help clinicians to prevent life - threatening side effects . So far , a number of genes have been associated with arrhythmia : Q14524 , Q8IWT1 , CACNL1AC , Q12809 , P51787 , P15382 , Q01484 , Q5BKT4 , P63252 , Q9Y6J6 , Q92736 , Q9UK17 , Q9NZV8 , P12821 , O75052 , O14958 and Rad . These genes represent good candidates for the definition of a genetic pro - arrhythmic profile . A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed . Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics . A list of relevant rare mutations within the selected genes is presented , together with a complete list of Tag SNPs covering the whole genetic sequence . The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics . The selected variants , both mutations and polymorphisms , may help in defining a next - to - come genetic assessment to be performed before drug prescription in order to improve drug safety .","___MASK83___ attenuates matrix metalloproteinase - 2 and - 9 in monocrotaline - induced right ventricular hypertrophy in rats . Little is known about the influence of angiotensin converting enzyme ( P12821 ) inhibitors on matrix metalloproteinase ( MMP ) in right ventricular remodeling . We investigated the effect of captopril , an P12821 inhibitor , on P08253 and P14780 in monocrotaline - induced right ventricular hypertrophy . Six - week - old male Wistar rats were injected intraperitoneally with monocrotaline ( 60 mg / kg ) or saline . The rats were administrated captopril ( 30 mg / kg per day ) or a vehicle orally for 24 days from the day of monocrotaline injection . At day 25 , echocardiography was performed and hearts were excised . Expressions and activities of P08253 and P14780 were measured by Western blotting and by gelatin zymography , respectively . In monocrotaline - injected rats , right ventricular weight / tail length ratio increased significantly . Histological analysis revealed cardiomyocyte hypertrophy and fibrosis in right ventricular sections . Echocardiography showed right ventricular dysfunction compared with saline - injected rats . The right ventricular hypertrophy , fibrosis , and dysfunction were inhibited by captopril . However , captopril did not attenuate an increase in pulmonary artery pressure . P08253 and P14780 expressions and activities in right ventricles increased significantly in monocrotaline - injected rats and captopril inhibited them . These findings indicate that captopril attenuates the development of monocrotaline - induced right ventricular hypertrophy in association with inhibition of P08253 and P14780 in rats .","Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK56___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","P05231 in tear fluid after photorefractive keratectomy and its effects on keratocytes in culture . PURPOSE : To investigate the participation of interleukin - 6 ( P05231 ) after photorefractive keratectomy ( Q9H4B4 ) and its possible roles and sources in corneal wound healing . METHODS : P05231 , levels were measured in the tear fluids of patients before and after Q9H4B4 and in conditioned media of human corneal epithelial cells and keratocytes . Its effects on total collagen and collagen - type synthesis by keratocytes were studied with a 3H - proline incorporation assay and Northern blot analysis . Zymography was used to evaluate the metalloproteinase content in the conditioned medium of P05231 - stimulated keratocytes . RESULTS : P05231 is present in the tear fluid samples after photorefractive keratectomy , possibly synthesized by epithelial cells and keratocytes . CONCLUSIONS : P05231 stimulates collagen synthesis in general and collagen type I in particular . Furthermore , it reduces the production of P08253 , the latent form of the metalloproteinase , by cultured keratocytes . The results suggest that P05231 might be regarded as a mediator involved in corneal healing after excimer laser .","No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK75___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK75___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK75___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK75___ among adults with ADHD .","___MASK56___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .","[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .","Q9Y251 regulates retention and proliferation of primitive Sca - 1 +/ c - Kit +/ Lin - cells via modulation of the bone marrow microenvironment . Q9Y251 is involved in tumor growth and metastasis . Because of its unique cleavage of heparan sulfate , which binds cytokines , chemokines and proteases , we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis . We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells in the bone marrow ( BM ) of mice overexpressing heparanase ( hpa - Tg ) . This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment , manifested in increased P48061 turnover . Furthermore , heparanase overexpression in mice was accompanied by reduced protease activity of P14780 , elastase , and cathepsin K , which regulate stem and progenitor cell mobilization . Moreover , increased retention of the progenitor cells also resulted from up - regulated levels of stem cell factor ( P21583 ) in the BM , in particular in the stem cell - rich endosteum and endothelial regions . Increased P21583 - induced adhesion of primitive Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells to osteoblasts was also the result of elevation of the receptor c - Kit . Regulation of these phenomena is mediated by hyperphosphorylation of c - Myc in hematopoietic progenitors of hpa - Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro . Altogether , our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells .","Altered growth factor expression in the aging penis : the Brown - Norway rat model . The objective of the present study was to evaluate age - related changes in the protein and gene expression of modulators of erectile function ( nitric oxide [ NO ] and endothelin - 1 [ ET - 1 ] ) and growth factors such as transforming growth factor ( TGF - beta1 ) and vascular endothelial growth factor ( P15692 ) in the penile tissue of Brown - Norway ( BN ) rats . Young and old BN male rats were euthanized , and the penile tissue was processed for immunohistochemical and molecular analyses . Total RNA was extracted , and an Access reverse transcription - polymerase chain reaction ( RT - PCR ) system was used for messenger RNA ( mRNA ) expression analysis . Immunohistochemical studies showed a decreased expression of endothelial nitric oxide synthase ( P29474 ) protein and an increased staining for ET - 1 . Quantitative analysis of PCR products revealed decreased levels of P15692 mRNA expression in the old population of rats . The most significant decrease was detected between bands corresponding to splice forms 164 ( 21 % ) and 120 ( 18 % ) . The observed alterations in the gene expression of growth factors such as P15692 may contribute to the abnormal age - related morphological and physiological alterations in the erectile tissue .","DB00877 protects against myocardial ischemia - reperfusion injury through O60674 - P40763 signaling pathway . DB00877 ( Sirolimus ® ) is used to prevent rejection of transplanted organs and coronary restenosis . We reported that rapamycin induced cardioprotection against ischemia - reperfusion ( I / R ) injury through opening of mitochondrial K ( DB00171 ) channels . However , signaling mechanisms in rapamycin - induced cardioprotection are currently unknown . Considering that P40763 is protective in the heart , we investigated the potential role of this transcription factor in rapamycin - induced protection against ( I / R ) injury . Adult male ICR mice were treated with rapamycin ( 0 . 25mg / kg , i . p . ) or vehicle ( DB01093 ) with / without inhibitor of O60674 ( AG - 490 ) or P40763 ( stattic ) . One hour later , the hearts were subjected to I / R either in Langendorff mode or in situ ligation of left coronary artery . Additionally , primary murine cardiomyocytes were subjected to simulated ischemia - reoxygenation ( SI / RO ) injury in vitro . For in situ targeted knockdown of P40763 , lentiviral vector containing short hairpin RNA was injected into the left ventricle 3 weeks prior to initiating I / R injury . Infarct size , cardiac function , and cardiomyocyte necrosis and apoptosis were assessed . DB00877 reduced infarct size , improved cardiac function following I / R , and limited cardiomyocyte necrosis as well as apoptosis following SI / RO which were blocked by AG - 490 and stattic . In situ knock - down of P40763 attenuated rapamycin - induced protection against I / R injury . DB00877 triggered unique cardioprotective signaling including phosphorylation of P29323 , P40763 , P29474 and glycogen synthase kinase - 3ß in concert with increased prosurvival Bcl - 2 to Bax ratio . Our data suggest that O60674 - P40763 signaling plays an essential role in rapamycin - induced cardioprotection . We propose that rapamycin is a novel and clinically relevant pharmacological strategy to target P40763 activation for treatment of myocardial infarction .","Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK27___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .","___MASK37___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK37___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK37___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK37___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .","P00797 status does not predict the anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans . DB00519 Multicenter Study Group . The angiotensin - converting enzyme ( P12821 ) inhibitor trandolapril , a non - sulfhydryl prodrug which is hydrolysed into trandolaprilat , was studied in 322 hypertensives of African - American descent using a double - blind , randomised , placebo - controlled , parallel study design . Following 6 weeks of double - blind treatment with placebo or 0 . 25 to 16 mg / day trandolapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre - treatment plasma renin activity , and trandolaprilat concentration was performed . Two mg was the lowest effective trandolapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma trandolaprilat concentration . Pre - treatment plasma renin activity was not a reliable indicator of anti - hypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin - angiotensin - aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans .","An P12821 inhibitor reduces Th2 cytokines and TGF - beta1 and TGF - beta2 isoforms in murine lupus nephritis . BACKGROUND : P12821 ( P12821 ) inhibitors , such as captopril , are used to control hypertension . In patients and animals with primary nephropathies , these agents improve renal function more than that would be expected from their control of hypertension . Here , we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism ( s ) by which this agent exerts its renoprotective effects . METHODS : Lupus - prone , NZB / NZW F1 and MRL - lpr / lpr , mice were treated with captopril or with a control antihypertensive agent , verapamil . Mice were monitored for nephritis , and their sera and tissues analyzed for cytokine and transforming growth factor - beta ( TGF - beta ) expression . RESULTS : ___MASK83___ treatment delayed the onset of proteinuria when administered to prenephritic mice , whereas verapamil did not . ___MASK83___ treatment also retarded disease progression when given to lupus mice that had early disease , and even reversed severe proteinuria in at least some older animals with advanced disease . It reduced chronic renal lesions , but had no effect on autoantibody production . The improvement in renal disease correlated with reduced TGF - beta expression , particularly of the TGF - beta1 and TGF - beta2 isoforms , in the kidneys . Interestingly , in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines , interleukin ( IL ) - 4 and P22301 , suggesting a possible role of the immune system in captopril - mediated disease modulation . CONCLUSION : Since type 2 cytokines are known to promote lupus glomerulosclerosis , decreased P05112 and P22301 production in captopril - treated mice may be related to this agent ' s renoprotective effects . We argue here that P12821 inhibitors not only act as selective TGF - beta inhibitors , but also as selective immunomodulators , to improve lupus nephritis .","Des - γ - carboxy prothrombin ( P12821 ) as a potential autologous growth factor for the development of hepatocellular carcinoma . Des - γ - carboxy prothrombin ( P12821 ) is a prothrombin precursor produced in hepatocellular carcinoma ( HCC ) . Because of deficiency of vitamin K or γ - glutamyl carboxylase in HCC cells , the 10 glutamic acid ( DB00142 ) residues in prothrombin precursor did not completely carboxylate to γ - carboxylated glutamic acid ( Gla ) residues , leaving some DB00142 residues remained in N - terminal domain . These prothrombin precursors with DB00142 residues are called DCPs . P12821 displays insufficient coagulation activity . Since Liebman reported an elevated plasma P12821 in patients with HCC , P12821 has been used in the diagnosis of HCC . Recently , its biological malignant potential has been specified to describe P12821 as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells . P12821 was found to stimulate HCC growth through activation of the P12821 - DB00134 - P23458 - P40763 signaling pathway . P12821 might increase HCC invasion and metastasis through activation of matrix metalloproteinase ( MMPs ) and the P27361 / 2 MAPK signaling pathway . P12821 has also been found to play a crucial role in the formation of angiogenesis . P12821 could increase the angiogenic factors released from HCC and vascular endothelial cells . These effects of P12821 in angiogenesis might be related to activation of the P12821 - P35968 - P98160 - γ - MAPK signaling pathway . In this article , we summarized recent studies on P12821 in biological roles related to cancer progression and angiogenesis in HCC .","Acute erythropoietin cardioprotection is mediated by endothelial response . Increasing evidence indicates that high levels of serum erythropoietin ( Epo ) can lessen ischemia - reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect . To clarify the mechanisms underlying this cardioprotection , we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells ( ΔEpoR ) . Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase ( P29474 ) activity in vitro and in vivo , and enhanced nitric oxide ( NO ) production that was determined directly by real - time measurements of gaseous NO release . Epo stimulated phosphoinositide 3 - kinase ( PI3K ) / protein kinase B ( AKT ) and mitogen - activated protein kinase kinase ( MEK ) / extracellular signal regulated kinase ( P29323 ) signaling pathways , and inhibition of PI3K , but not MEK activity , blocked Epo - induced NO production . To verify the potential of this Epo effect in cardioprotection in vivo , ΔEpoR - mice with Epo response in heart restricted to endothelium were treated with Epo . These mice exhibited a similar increase in P29474 phosphorylation in coronary artery endothelium as that found in wild type ( WT ) mice . In addition , in both WT - and ΔEpoR - mice , exogenous Epo treatment prior to myocardial ischemia provided comparable protection . These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect . The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection .","Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice . BACKGROUND : Asthma is associated with airway hyperresponsiveness and enhanced T - cell number / activity on one hand and increased levels of exhaled nitric oxide ( NO ) with expression of inducible NO synthase ( P35228 ) on the other hand . These findings are in paradox , as NO also relaxes airway smooth muscle and has immunosuppressive properties . The exact role of the endothelial NOS ( P29474 ) isoform in asthma is still unknown . We hypothezised that a delicate regulation in the production of NO and its bioactive forms by P29474 might be the key to the pathogenesis of asthma . METHODS : The contribution of P29474 on the development of asthmatic features was examined . We used transgenic mice that overexpress P29474 and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin . RESULTS : P29474 overexpression resulted in both increased P29474 activity and NO production in the lungs . Isolated thoracic lymph nodes cells from P29474 overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines P01579 , P05113 and P22301 . No difference in serum IgE levels could be found . Further , there was a 50 % reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals . Finally , airway hyperresponsiveness to methacholine was abolished in P29474 overexpressing mice . CONCLUSION : These findings demonstrate that P29474 overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma . We suggest that a delicate balance in the production of bioactive forms of NO derived from P29474 might be essential in the pathophysiology of asthma .","Increased serum levels of neutrophil gelatinase - associated lipocalin in patients with essential thrombocythemia and polycythemia vera . Neutrophil gelatinaase - associated lipocalin ( P80188 ) is a glycoprotein bound with matrix metalloproteinase - 9 ( P14780 ) in human neutrophils , and elevated tissue P80188 expression has been documented in different infectious and inflammatory conditions . Recent evidence suggests that P80188 expression is induced in many types of human cancer . Moreover , P80188 is required for P11274 - P00519 - induced tumorigenesis . The aim of the present study was to measure serum levels of P80188 in patients with essential thrombocythemia ( ET ) and polycythemia vera ( PV ) . We also evaluated P80188 levels in patients with ET and PV with and without thrombotic events , to explore a possible correlation of P80188 with platelet and leukocyte activation , and in patients with sepsis . Serum P80188 levels in the study population were significantly higher than in healthy adults and in subjects with sepsis . A correlation between P80188 and the number of white cells and neutrophils was found in patients with PV and ET . P80188 serum levels were not different depending on the presence or not of the O60674 mutation , and a mutant allele dosage effect was not observed for P80188 levels . Patients with PV and ET with thrombosis did not have significantly higher levels of P80188 . We were unable to demonstrate a significant association between serum P80188 levels and CD11b or CD62 expression . In conclusion , our study reports evidence demonstrating that increased levels of P80188 appear to be a characteristic of patients with PV and ET .","Polymorphisms in the angiotensin - converting enzyme gene are associated with unipolar depression , P12821 activity and hypercortisolism . P12821 ( P12821 ) is assumed to influence the activity of the hypothalamic - pituitary - adrenocortical ( Q9Y251 ) system , which shows hyperactivity in the majority of patients with major depression . The P12821 gene , known to be associated with cardiovascular disorders , which in turn are accompanied with an increased susceptibility for depression , is therefore a promising candidate gene for affective disorders . We investigated the genetic association between 35 single - nucleotide polymorphisms ( SNPs ) and an insertion / deletion ( I / D ) - polymorphism in the P12821 gene and the susceptibility for unipolar major depression together with the genetic association with P12821 serum activity and functional parameters of the Q9Y251 system . Two independent case / control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated . A case / control sample was screened to detect genetic associations with unipolar major depression . In addition , a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression . In the screening sample , two SNPs within the P12821 gene were significantly associated with unipolar major depression . The association with unipolar major depression of one SNP ( rs4291 ) located in the promoter region of the P12821 gene was confirmed in our replication sample . The T - allele of this SNP was associated with depression and depressed T - allele carriers showed higher P12821 serum activity and Q9Y251 - axis hyperactivity . Variants of the P12821 gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression . We could show that SNP rs4291 influences P12821 activity and Q9Y251 - axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease .","Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK43___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .","Endothelial dysfunction in congestive heart failure : P12821 inhibition vs . angiotensin II antagonism . BACKGROUND : Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure ( CHF ) . The present study systematically investigated the effect of angiotensin II ( AT ( 1 ) ) - receptor blockade on vascular superoxide ( O ( 2 )(-) ) production and endothelial dysfunction . METHODS AND RESULTS : Vasodilator responses and O ( 2 )(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham - operated animals ( Sham ) . Rats were either treated with placebo ( P ) , with the AT ( 1 )- receptor antagonist Irbesartan ( 50 mg kg (- 1 ) day (- 1 ) ) or with the P12821 inhibitor DB00519 ( 0 . 3 mg kg (- 1 ) day (- 1 ) ) . In CHF - P , endothelium - dependent , acetylcholine - induced relaxation was significantly attenuated compared with Sham - P . Chronic treatment with DB00519 or Irbesartan significantly improved endothelium - dependent relaxation . Aortic O ( 2 )(-) formation was markedly increased in CHF , and was not significantly affected by DB00519 treatment , while it was reduced by Irbesartan . P29474 expression was reduced in CHF and normalised by both treatments . CONCLUSION : Endothelial vasomotor function in CHF rats was normalised by long - term treatment with an P12821 inhibitor or an AT ( 1 )- antagonist . Reduced aortic P29474 expression was normalised by both treatments , whereas aortic superoxide formation was only reduced by the AT ( 1 )- antagonist Irbesartan .","Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy . A number of candidate genes for lithium prophylactic efficacy have been proposed , some of them being also associated with a predisposition to bipolar illness . The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder , in relation to the putative role of these genes in the pathogenesis of this disorder . Some association with lithium prophylactic efficacy was found for the polymorphisms of P31645 , P21728 , P21964 , P23560 and P06241 genes , but not for 5HT2A , 5HT2C , P14416 , P35462 , P21917 , GSK - 3 , Q16620 , Q13224 and P14780 . Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed .","Synthetic triterpenoids , CDDO - Imidazolide and CDDO - Ethyl amide , induce chondrogenesis . Novel methods for inducing chondrogenesis are critical for cartilage tissue engineering and regeneration . Here we show that the synthetic oleanane triterpenoids , CDDO - Imidazolide ( CDDO - Im ) and CDDO - Ethyl amide ( CDDO - EA ) , at concentrations as low as 200 nM , induce chondrogenesis in organ cultures of newborn mouse calvaria . The cartilage phenotype was measured histologically with metachromatic toluidine blue staining for proteoglycans and by immunohistochemical staining for type II collagen . Furthermore , real - time polymerase chain reaction ( PCR ) analysis using mRNA from calvaria after 7 - day treatment with CDDO - Im and CDDO - EA showed up - regulation of the chondrocyte markers P48436 and type II collagen ( alpha1 ) . In addition , TGF - β ; BMPs 2 and 4 ; Smads 3 , 4 , 6 , and 7 ; and TIMPs - 1 and - 2 were increased . In contrast , P14780 was strongly down - regulated . Treatment of human bone marrow - derived DB05914 with CDDO - Im and CDDO - EA ( 100 nM ) induced expression of P48436 , collagen IIα1 , and aggrecan , as well as P12643 and phospho - Q99717 , confirming that the above triterpenoids induce chondrogenic differentiation . This is the first report of the use of these drugs for induction of chondrogenesis .","Transient estrogen exposure from birth affects uterine expression of developmental markers in neonatal gilts with lasting consequences in pregnant adults . Disruption of estrogen - sensitive , estrogen receptor ( ER ) - dependent events during porcine uterine development between birth ( postnatal day = P01160 0 ) and P01160 14 affects patterns of uterine morphoregulatory gene expression in the neonate with lasting consequences for reproductive success . Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate ( EV ) for 14 days from birth . Objectives here were to determine effects of EV exposure from birth through P01160 13 on neonatal uterine and adult endometrial markers of growth , patterning , and remodeling . Targets included the relaxin receptor ( Q9HBX9 ) , estrogen receptor - alpha ( P03372 ) and vascular endothelial growth factor ( P15692 ) , morphoregulatory markers P31260 and O00755 , and the matrix metalloproteinases ( MMP ) 2 and P14780 . Gilts were treated daily with EV ( 50 microg / kg body weight per day , i . m . ) or corn oil vehicle from birth through P01160 13 . Uteri were obtained from neonates on P01160 14 and from adults on pregnancy day 12 ( PxD 12 ) . In neonates , EV exposure from birth increased uterine Q9HBX9 gene expression , and both P03372 and P15692 proteins . At PxD 12 , endometrial Q9HBX9 mRNA remained elevated , while P03372 protein was reduced . Early EV treatment decreased neonatal uterine O00755 , but increased P31260 expression . O00755 expression was reduced in EV - treated adults . Transient EV exposure increased P14780 transcripts at P01160 14 , whereas both latent and active P14780 activity was increased due to early EV treatment in adults on PxD 12 . Results support the hypothesis that transient , estrogen - induced disruption of porcine uterine development from birth alters early programming events that lead to functional consequences in the adult ."],"string":"[\n \"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK48___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .\",\n \"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK8___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .\",\n \"Immunohistochemical studies of the epididymal duct in Egyptian water buffalo ( Bubalus bubalis ) . Using immunohistochemistry ( IHC ) , this study aimed to evaluate the regional distribution pattern of some biologically active proteins in the epididymis of Egyptian water buffalo and to determine the structural - functional relationships of the different epididymal structures . Wax - embedded sections from different regions of the epididymal duct from adult , clinically healthy , buffalo bulls were used . Primary antibodies against angiotensin converting enzyme ( P12821 ) , S - 100 , galactosyltransferase ( GalTase ) , alpha smooth muscle actin ( α - SMA ) , connexin 43 ( P17302 ) and vascular endothelial growth factor ( P15692 ) were used for immunohistochemical studies . The results showed that , in addition to the well - known principal and basal cells , the epididymal epithelium , similar to that of other species , possessed apical cells and intraepithelial leukocytes . IHC showed that , with the exception of P15692 which reacted negatively , all antibodies used displayed variable reactivity in the different epididymal structures . Apical cells expressed a strong reaction with P12821 along the entire length of the duct . The principal cells in the caput epididymis exhibited a distinct reactivity with S - 100 and GalTase . The peritubular muscular coat displayed a marked immunostaining for α - SMA and for P17302 . In conclusion these findings showed a regional - specific distribution pattern , distinct from that in bovine bulls . Some potential functional capacities , especially absorptive and secretory ones , are discussed in relation to the different epididymal regions .\",\n \"Inhibition of matrix metalloproteinase - 9 activity by trandolapril after middle cerebral artery occlusion in rats . We investigated whether an angiotensin - converting enzyme ( P12821 ) inhibitor could inhibit matrix metalloproteinase ( MMP ) activities in cerebral infarct lesions after middle cerebral artery occlusion ( MCAO ) in rats . After placebo or trandolapril ( 5 mg / kg per day ) was administered orally for 7 days , we permanently occluded the right middle cerebral artery . P12821 activity in extracts from the infarct side of placebo - treated rats was significantly higher than that in extracts from the non - infarct side from 5 days after MCAO , though they did not differ at 1 day . P12821 activities in extracts from both hemispheric segments in the trandolapril - treated group were significantly decreased compared with those in the placebo - treated group before MCAO , and this significant reduction persisted even at 7 days after MCAO . In the placebo - treated group , P14780 and P08253 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO , respectively . DB00519 treatment significantly reduced P14780 and P08253 activities to 68 . 5 % and 53 . 2 % , respectively . Seven days after MCAO , the ratios of infarct areas to the hemispheric sectional areas in placebo - and trandolapril - treated rats were 55 . 4 +/- 2 . 1 % and 30 . 9 +/- 2 . 9 % , respectively , and this difference was significant . Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril - treated rats . Cumulative survival in trandolapril - treated rats was significantly increased compared with that in placebo - treated rats . Thus , the inhibition of P14780 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia .\",\n \"Gene polymorphisms impact the risk of rejection with hemodynamic compromise : a multicenter study . BACKGROUND : Rejection with hemodynamic compromise ( P18577 ) is associated with high mortality in heart recipients . This study investigates the association between genetic polymorphisms and P18577 in pediatric heart recipients . METHODS : Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to P18577 by recipient race , age at transplantation , and genotype at 13 genetic polymorphisms ( P01375 - α A - 308G , P05231 G - 174C , P27352 - γ T + 874A , P22301 G - 1082A , C - 819T , and C - 592A ; FAS A - 670G , P48023 C - 843T , and P12821 I / D ; and P15692 A - 2578C , C - 1451T , C + 405G , and - 2549 I / D ) . RESULTS : P18577 occurred in 126 ( 23 . 7 % ) patients during the study period . Adjusting for age and race , P22301 G - 1082A , FAS A - 670G , and P12821 I / D genotypes were associated with P18577 . P22301 G - 1082A GG genotype was associated with decreased risk of P18577 with an adjusted hazard ratio ( HR ) of 0 . 49 ( 95 % confidence interval [ CI ] , 0 . 27 - 0 . 90 ; P = 0 . 020 ) . FAS A - 670G AA genotype was associated with increased risk of P18577 with an adjusted HR of 1 . 84 ( 95 % CI , 1 . 25 - 2 . 69 ; P = 0 . 002 ) . P12821 II genotype was associated with decreased risk of P18577 with an adjusted HR of 0 . 58 ( 95 % CI , 0 . 36 - 0 . 95 ; P = 0 . 031 ) . CONCLUSIONS : Recipients with a high anti - inflammatory and immune - regulatory genetic profile ( high interleukin - 10 ) were protected from P18577 . Conversely , recipients with a pro - apoptotic genetic profile ( high Fas ) or high angiotensin - 1 - converting enzyme producing genotype were at increased risk of P18577 . This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients .\",\n \"M ( 3 ) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation , hyperresponsiveness and remodeling in mice . M ( 3 ) muscarinic receptors are localized on inflammatory cells , airway smooth muscle , and submucosal glands , known to mediate bronchoconstriction , mucus secretion , and airway remodeling . It is hypothesized bencycloquidium bromide ( BCQB ) , a novel M ( 3 ) receptor antagonist , might have potential effects on airway hyperresponsiveness , inflammation and airway remodeling in a murine model of asthma . Mice sensitized and challenged with ovalbumin developed airway inflammation . Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts , and cytokine levels . Lung tissues were evaluated for cell infiltration , mucus hypersecretion , airway remodeling , and the expression of inflammatory biomarkers . Airway hyperresponsiveness was monitored by direct airway resistance analysis . Inhalation administration of BCQB significantly not only reduced ovalbumin - induced airway hyperresponsiveness comparing to methacholine , and prevented the ovalbumin - induced increase in total cell counts and eosinophil counts . Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin - induced mRNA expression of eotaxin , P05113 , P05112 and P14780 , and increased mRNA expression of IFN - γ and P01033 in a dose - dependent manner . Substantial IFN - γ / P05112 ( Th1 / Th2 ) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment . In addition , histological studies showed that BCQB dramatically inhibited ovalbumin - induced lung tissue eosinophil infiltration , airway mucus production and collagen deposition in lung tissues . Results reported in current paper suggest that M ( 3 ) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation , hyperresponsiveness and remodeling .\",\n \"___MASK8___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK8___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .\",\n \"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK54___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .\",\n \"Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .\",\n \"[ Adjustment effects of Herba epimedii , Fructus ligustrilucidi on NO / ET , Q9Y251 axis in asthmatic rats ] . OBJECTIVE : To study the neuro - endocrine adjustment effects of Herba Epimedii and Fructus Ligustrilucidi on the asthmatic rats . METHOD : Rat asthma model was duplicated by OVA ( ovalbumin ) through sensitizing and challenging . Fifty male rats were randomly divided into normal group , model group , adjustment group of Herba Epimedii and Fructus Ligustrilucidi , Peibenfang group and Asimei capsule group . Investigating levels of ET ( Endothelin ) , NO , P35228 ( inducible NOS ) , and P29474 ( constitutive NOS ) in blood serum and BALF ( bronchoalveolar lavage fluid ) , O00230 ( corticotrophin ) in serum , DB01285 ( adrenocorticotropin hormone ) in plasma , CHR ( corticotropin release hormone ) in hypothalamus , protein expression of GCR ( glucocorticoid receptor ) in lung tissue . RESULT : The adjustment of Herba Epimedii and Fructus Ligustrilucidi could inhibit ET and NO content in BALF ( all P < 0 . 05 ) , decrease the level of P35228 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , and increase the level of P29474 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , raise the concentration of serum O00230 ( P < 0 . 01 ) , enhance the protein expression of GCR in lung tissue ( P < 0 . 05 ) . CONCLUSION : The preventive and therapeutic effect of Herba Epimedii and Fructus Ligustrilucidi on asthma relates to their adjustment effect on ET / NO and Q9Y251 axis .\",\n \"Contribution of captopril thiol group to the prevention of spontaneous hypertension . We aimed to compare the effect of angiotensin converting enzyme ( P12821 ) inhibitors captopril ( containing thiol group ) and enalapril ( without thiol group ) on the development of spontaneous hypertension and to analyze mechanisms of their actions , particularly effects on oxidative stress and NO production . Six - week - old SHR were divided into three groups : control , group receiving captopril ( 50 mg / kg / day ) or enalapril ( 50 mg / kg / day ) for 6 weeks . At the end of experiment , systolic blood pressure ( SBP ) increased by 41 % in controls . Both captopril and enalapril prevented blood pressure increase , however , SBP in the captopril group ( 121 +/- 5 mmHg ) was significantly lower than that in the enalapril group ( 140 +/- 5 mmHg ) . Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group . ___MASK83___ and enalapril increased NO synthase activity in the heart and aorta to the similar level . Neither captopril nor enalapril was , however , able to increase the expression of P29474 . Both P12821 inhibitors increased the level of cGMP . However , cGMP level was significantly higher in the aorta of captopril group . We conclude that captopril , beside inhibition of P12821 , prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration .\",\n \"Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis . DB00435 ( NO ) plays a central role in the pathogenesis of bacterial meningitis . However , the role of NO produced by endothelial NO synthase ( P29474 ) in meningitis is still unclear . We investigated the influence of P29474 depletion on the inflammatory host response , intracranial complications , and outcome in experimental pneumococcal meningitis . Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected P29474 - deficient mice than in infected wild type mice . This effect could be attributed to an increased expression of P16109 , macrophage inflammatory protein - 2 , keratinocyte - derived cytokine , and interleukin ( IL ) - 1beta in the brain of infected P29474 - deficient mice . However , no differences in the cerebral expression of intercellular adhesion molecule - 1 , tumor necrosis factor - alpha , and P05231 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice . In addition to enhanced leukocyte infiltration into the P04141 , meningitis - associated intracranial complications including blood - brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected P29474 - deficient mice . The aggravation of intracranial complications was paralleled by a worsening of the disease , as evidenced by a more pronounced hypothermia , an enhanced weight reduction , and an increased death rate . The current data indicate that P29474 deficiency is detrimental in bacterial meningitis . This effect seems to be related to an increased expression of ( certain ) cytokines / chemokines and adhesion molecules ; thus leading to increased meningeal inflammation and , subsequently , to aggravated intracranial complications .\",\n \"Quality of life and the relevant factors in patients with chronic hepatitis B . BACKGROUND / AIMS : To assess HRQL in patients with chronic hepatitis B ( CHB ) and investigate the relevant factors . METHODOLOGY : A cross - sectional three - center study involving 407 inpatients with CHB was conducted . Subjects completed the epidemiological questionnaire and two validated questionnaires ( SF - 36 and QLICD - CH ) . Afterwards , the angiotensin - converting enzyme ( P12821 ) insertion / deletion ( I / D ) and dopamine receptor D4 ( P21917 ) gene polymorphisms were assessed in all patients . RESULTS : It was found that the scores of CHB patients in SF - 36 scale 8 domains were lower than those of the normal population ( all p < 0 . 001 ) . The anti - viral therapy could improve four - area - scores ( P20941 ( p = 0 . 004 ) , SOD ( p = 0 . 011 ) , SPD ( p = 0 . 032 ) , TOT ( p = 0 . 014 ) ) . Extraverted personality , social competence and ability to work were protective factors of HRQL , while severity of illness , better family economy and abnormal condition of liver function were risk factors . The scores in II genotype were higher than those in I / D + DD genotype of P12821 polymorphisms . The scores in short repeat sequences genotypes were higher than those in long repeat sequences genotype of P21917 polymorphisms . CONCLUSIONS : Patients with CHB had lower HRQL than normal population . Anti - viral treatments can improve their HRQL . Several health factors independently influence HRQL and P12821 and P21917 gene polymorphism is associated with HRQL of CHB patients .\",\n \"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK83___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .\",\n \"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .\",\n \"DB04216 abrogates P05231 / P40763 signaling and inhibits glioblastoma cell line growth and migration . Evidence has suggested that P40763 functions as an oncogene in gliomagenesis . As a consequence , changes in the inflammatory microenvironment are thought to promote tumor development . Regardless of its origin , cancer - related inflammation has many tumor - promoting effects , such as the promotion of cell cycle progression , cell proliferation , cell migration and cell survival . Given that P05231 , a major cancer - related inflammatory cytokine , regulates P40763 activation and is upregulated in glioblastoma , we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by P05231 , and to determine the underlying mechanisms of action . In this study , we show that quercetin is a potent inhibitor of the P05231 - induced P40763 signaling pathway in T98G and U87 glioblastoma cells . Exposure to quercetin resulted in the reduction of P42704 , P23458 and P40763 activation by P05231 , as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by P05231 . Interestingly , quercetin also modulated the expression of two target genes regulated by P40763 , i . e . cyclin D1 and matrix metalloproteinase - 2 ( P08253 ) . Moreover , quercetin reduced the recruitment of P40763 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of P05231 . Overall , these results provide new insight into the role of quercetin as a blocker of the P40763 activation pathway stimulated by P05231 , with a potential role in the prevention and treatment of glioblastoma .\",\n \"Strategy for a genetic assessment of antipsychotic and antidepressant - related proarrhythmia . Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic . In this field , accurate understanding of genetics , which per se is a non - controllable risk factor , may help clinicians to prevent life - threatening side effects . So far , a number of genes have been associated with arrhythmia : Q14524 , Q8IWT1 , CACNL1AC , Q12809 , P51787 , P15382 , Q01484 , Q5BKT4 , P63252 , Q9Y6J6 , Q92736 , Q9UK17 , Q9NZV8 , P12821 , O75052 , O14958 and Rad . These genes represent good candidates for the definition of a genetic pro - arrhythmic profile . A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed . Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics . A list of relevant rare mutations within the selected genes is presented , together with a complete list of Tag SNPs covering the whole genetic sequence . The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics . The selected variants , both mutations and polymorphisms , may help in defining a next - to - come genetic assessment to be performed before drug prescription in order to improve drug safety .\",\n \"___MASK83___ attenuates matrix metalloproteinase - 2 and - 9 in monocrotaline - induced right ventricular hypertrophy in rats . Little is known about the influence of angiotensin converting enzyme ( P12821 ) inhibitors on matrix metalloproteinase ( MMP ) in right ventricular remodeling . We investigated the effect of captopril , an P12821 inhibitor , on P08253 and P14780 in monocrotaline - induced right ventricular hypertrophy . Six - week - old male Wistar rats were injected intraperitoneally with monocrotaline ( 60 mg / kg ) or saline . The rats were administrated captopril ( 30 mg / kg per day ) or a vehicle orally for 24 days from the day of monocrotaline injection . At day 25 , echocardiography was performed and hearts were excised . Expressions and activities of P08253 and P14780 were measured by Western blotting and by gelatin zymography , respectively . In monocrotaline - injected rats , right ventricular weight / tail length ratio increased significantly . Histological analysis revealed cardiomyocyte hypertrophy and fibrosis in right ventricular sections . Echocardiography showed right ventricular dysfunction compared with saline - injected rats . The right ventricular hypertrophy , fibrosis , and dysfunction were inhibited by captopril . However , captopril did not attenuate an increase in pulmonary artery pressure . P08253 and P14780 expressions and activities in right ventricles increased significantly in monocrotaline - injected rats and captopril inhibited them . These findings indicate that captopril attenuates the development of monocrotaline - induced right ventricular hypertrophy in association with inhibition of P08253 and P14780 in rats .\",\n \"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK56___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"P05231 in tear fluid after photorefractive keratectomy and its effects on keratocytes in culture . PURPOSE : To investigate the participation of interleukin - 6 ( P05231 ) after photorefractive keratectomy ( Q9H4B4 ) and its possible roles and sources in corneal wound healing . METHODS : P05231 , levels were measured in the tear fluids of patients before and after Q9H4B4 and in conditioned media of human corneal epithelial cells and keratocytes . Its effects on total collagen and collagen - type synthesis by keratocytes were studied with a 3H - proline incorporation assay and Northern blot analysis . Zymography was used to evaluate the metalloproteinase content in the conditioned medium of P05231 - stimulated keratocytes . RESULTS : P05231 is present in the tear fluid samples after photorefractive keratectomy , possibly synthesized by epithelial cells and keratocytes . CONCLUSIONS : P05231 stimulates collagen synthesis in general and collagen type I in particular . Furthermore , it reduces the production of P08253 , the latent form of the metalloproteinase , by cultured keratocytes . The results suggest that P05231 might be regarded as a mediator involved in corneal healing after excimer laser .\",\n \"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK75___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK75___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK75___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK75___ among adults with ADHD .\",\n \"___MASK56___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .\",\n \"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .\",\n \"Q9Y251 regulates retention and proliferation of primitive Sca - 1 +/ c - Kit +/ Lin - cells via modulation of the bone marrow microenvironment . Q9Y251 is involved in tumor growth and metastasis . Because of its unique cleavage of heparan sulfate , which binds cytokines , chemokines and proteases , we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis . We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells in the bone marrow ( BM ) of mice overexpressing heparanase ( hpa - Tg ) . This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment , manifested in increased P48061 turnover . Furthermore , heparanase overexpression in mice was accompanied by reduced protease activity of P14780 , elastase , and cathepsin K , which regulate stem and progenitor cell mobilization . Moreover , increased retention of the progenitor cells also resulted from up - regulated levels of stem cell factor ( P21583 ) in the BM , in particular in the stem cell - rich endosteum and endothelial regions . Increased P21583 - induced adhesion of primitive Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells to osteoblasts was also the result of elevation of the receptor c - Kit . Regulation of these phenomena is mediated by hyperphosphorylation of c - Myc in hematopoietic progenitors of hpa - Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro . Altogether , our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells .\",\n \"Altered growth factor expression in the aging penis : the Brown - Norway rat model . The objective of the present study was to evaluate age - related changes in the protein and gene expression of modulators of erectile function ( nitric oxide [ NO ] and endothelin - 1 [ ET - 1 ] ) and growth factors such as transforming growth factor ( TGF - beta1 ) and vascular endothelial growth factor ( P15692 ) in the penile tissue of Brown - Norway ( BN ) rats . Young and old BN male rats were euthanized , and the penile tissue was processed for immunohistochemical and molecular analyses . Total RNA was extracted , and an Access reverse transcription - polymerase chain reaction ( RT - PCR ) system was used for messenger RNA ( mRNA ) expression analysis . Immunohistochemical studies showed a decreased expression of endothelial nitric oxide synthase ( P29474 ) protein and an increased staining for ET - 1 . Quantitative analysis of PCR products revealed decreased levels of P15692 mRNA expression in the old population of rats . The most significant decrease was detected between bands corresponding to splice forms 164 ( 21 % ) and 120 ( 18 % ) . The observed alterations in the gene expression of growth factors such as P15692 may contribute to the abnormal age - related morphological and physiological alterations in the erectile tissue .\",\n \"DB00877 protects against myocardial ischemia - reperfusion injury through O60674 - P40763 signaling pathway . DB00877 ( Sirolimus ® ) is used to prevent rejection of transplanted organs and coronary restenosis . We reported that rapamycin induced cardioprotection against ischemia - reperfusion ( I / R ) injury through opening of mitochondrial K ( DB00171 ) channels . However , signaling mechanisms in rapamycin - induced cardioprotection are currently unknown . Considering that P40763 is protective in the heart , we investigated the potential role of this transcription factor in rapamycin - induced protection against ( I / R ) injury . Adult male ICR mice were treated with rapamycin ( 0 . 25mg / kg , i . p . ) or vehicle ( DB01093 ) with / without inhibitor of O60674 ( AG - 490 ) or P40763 ( stattic ) . One hour later , the hearts were subjected to I / R either in Langendorff mode or in situ ligation of left coronary artery . Additionally , primary murine cardiomyocytes were subjected to simulated ischemia - reoxygenation ( SI / RO ) injury in vitro . For in situ targeted knockdown of P40763 , lentiviral vector containing short hairpin RNA was injected into the left ventricle 3 weeks prior to initiating I / R injury . Infarct size , cardiac function , and cardiomyocyte necrosis and apoptosis were assessed . DB00877 reduced infarct size , improved cardiac function following I / R , and limited cardiomyocyte necrosis as well as apoptosis following SI / RO which were blocked by AG - 490 and stattic . In situ knock - down of P40763 attenuated rapamycin - induced protection against I / R injury . DB00877 triggered unique cardioprotective signaling including phosphorylation of P29323 , P40763 , P29474 and glycogen synthase kinase - 3ß in concert with increased prosurvival Bcl - 2 to Bax ratio . Our data suggest that O60674 - P40763 signaling plays an essential role in rapamycin - induced cardioprotection . We propose that rapamycin is a novel and clinically relevant pharmacological strategy to target P40763 activation for treatment of myocardial infarction .\",\n \"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK27___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .\",\n \"___MASK37___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK37___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK37___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK37___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .\",\n \"P00797 status does not predict the anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans . DB00519 Multicenter Study Group . The angiotensin - converting enzyme ( P12821 ) inhibitor trandolapril , a non - sulfhydryl prodrug which is hydrolysed into trandolaprilat , was studied in 322 hypertensives of African - American descent using a double - blind , randomised , placebo - controlled , parallel study design . Following 6 weeks of double - blind treatment with placebo or 0 . 25 to 16 mg / day trandolapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre - treatment plasma renin activity , and trandolaprilat concentration was performed . Two mg was the lowest effective trandolapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma trandolaprilat concentration . Pre - treatment plasma renin activity was not a reliable indicator of anti - hypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin - angiotensin - aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans .\",\n \"An P12821 inhibitor reduces Th2 cytokines and TGF - beta1 and TGF - beta2 isoforms in murine lupus nephritis . BACKGROUND : P12821 ( P12821 ) inhibitors , such as captopril , are used to control hypertension . In patients and animals with primary nephropathies , these agents improve renal function more than that would be expected from their control of hypertension . Here , we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism ( s ) by which this agent exerts its renoprotective effects . METHODS : Lupus - prone , NZB / NZW F1 and MRL - lpr / lpr , mice were treated with captopril or with a control antihypertensive agent , verapamil . Mice were monitored for nephritis , and their sera and tissues analyzed for cytokine and transforming growth factor - beta ( TGF - beta ) expression . RESULTS : ___MASK83___ treatment delayed the onset of proteinuria when administered to prenephritic mice , whereas verapamil did not . ___MASK83___ treatment also retarded disease progression when given to lupus mice that had early disease , and even reversed severe proteinuria in at least some older animals with advanced disease . It reduced chronic renal lesions , but had no effect on autoantibody production . The improvement in renal disease correlated with reduced TGF - beta expression , particularly of the TGF - beta1 and TGF - beta2 isoforms , in the kidneys . Interestingly , in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines , interleukin ( IL ) - 4 and P22301 , suggesting a possible role of the immune system in captopril - mediated disease modulation . CONCLUSION : Since type 2 cytokines are known to promote lupus glomerulosclerosis , decreased P05112 and P22301 production in captopril - treated mice may be related to this agent ' s renoprotective effects . We argue here that P12821 inhibitors not only act as selective TGF - beta inhibitors , but also as selective immunomodulators , to improve lupus nephritis .\",\n \"Des - γ - carboxy prothrombin ( P12821 ) as a potential autologous growth factor for the development of hepatocellular carcinoma . Des - γ - carboxy prothrombin ( P12821 ) is a prothrombin precursor produced in hepatocellular carcinoma ( HCC ) . Because of deficiency of vitamin K or γ - glutamyl carboxylase in HCC cells , the 10 glutamic acid ( DB00142 ) residues in prothrombin precursor did not completely carboxylate to γ - carboxylated glutamic acid ( Gla ) residues , leaving some DB00142 residues remained in N - terminal domain . These prothrombin precursors with DB00142 residues are called DCPs . P12821 displays insufficient coagulation activity . Since Liebman reported an elevated plasma P12821 in patients with HCC , P12821 has been used in the diagnosis of HCC . Recently , its biological malignant potential has been specified to describe P12821 as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells . P12821 was found to stimulate HCC growth through activation of the P12821 - DB00134 - P23458 - P40763 signaling pathway . P12821 might increase HCC invasion and metastasis through activation of matrix metalloproteinase ( MMPs ) and the P27361 / 2 MAPK signaling pathway . P12821 has also been found to play a crucial role in the formation of angiogenesis . P12821 could increase the angiogenic factors released from HCC and vascular endothelial cells . These effects of P12821 in angiogenesis might be related to activation of the P12821 - P35968 - P98160 - γ - MAPK signaling pathway . In this article , we summarized recent studies on P12821 in biological roles related to cancer progression and angiogenesis in HCC .\",\n \"Acute erythropoietin cardioprotection is mediated by endothelial response . Increasing evidence indicates that high levels of serum erythropoietin ( Epo ) can lessen ischemia - reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect . To clarify the mechanisms underlying this cardioprotection , we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells ( ΔEpoR ) . Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase ( P29474 ) activity in vitro and in vivo , and enhanced nitric oxide ( NO ) production that was determined directly by real - time measurements of gaseous NO release . Epo stimulated phosphoinositide 3 - kinase ( PI3K ) / protein kinase B ( AKT ) and mitogen - activated protein kinase kinase ( MEK ) / extracellular signal regulated kinase ( P29323 ) signaling pathways , and inhibition of PI3K , but not MEK activity , blocked Epo - induced NO production . To verify the potential of this Epo effect in cardioprotection in vivo , ΔEpoR - mice with Epo response in heart restricted to endothelium were treated with Epo . These mice exhibited a similar increase in P29474 phosphorylation in coronary artery endothelium as that found in wild type ( WT ) mice . In addition , in both WT - and ΔEpoR - mice , exogenous Epo treatment prior to myocardial ischemia provided comparable protection . These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect . The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection .\",\n \"Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice . BACKGROUND : Asthma is associated with airway hyperresponsiveness and enhanced T - cell number / activity on one hand and increased levels of exhaled nitric oxide ( NO ) with expression of inducible NO synthase ( P35228 ) on the other hand . These findings are in paradox , as NO also relaxes airway smooth muscle and has immunosuppressive properties . The exact role of the endothelial NOS ( P29474 ) isoform in asthma is still unknown . We hypothezised that a delicate regulation in the production of NO and its bioactive forms by P29474 might be the key to the pathogenesis of asthma . METHODS : The contribution of P29474 on the development of asthmatic features was examined . We used transgenic mice that overexpress P29474 and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin . RESULTS : P29474 overexpression resulted in both increased P29474 activity and NO production in the lungs . Isolated thoracic lymph nodes cells from P29474 overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines P01579 , P05113 and P22301 . No difference in serum IgE levels could be found . Further , there was a 50 % reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals . Finally , airway hyperresponsiveness to methacholine was abolished in P29474 overexpressing mice . CONCLUSION : These findings demonstrate that P29474 overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma . We suggest that a delicate balance in the production of bioactive forms of NO derived from P29474 might be essential in the pathophysiology of asthma .\",\n \"Increased serum levels of neutrophil gelatinase - associated lipocalin in patients with essential thrombocythemia and polycythemia vera . Neutrophil gelatinaase - associated lipocalin ( P80188 ) is a glycoprotein bound with matrix metalloproteinase - 9 ( P14780 ) in human neutrophils , and elevated tissue P80188 expression has been documented in different infectious and inflammatory conditions . Recent evidence suggests that P80188 expression is induced in many types of human cancer . Moreover , P80188 is required for P11274 - P00519 - induced tumorigenesis . The aim of the present study was to measure serum levels of P80188 in patients with essential thrombocythemia ( ET ) and polycythemia vera ( PV ) . We also evaluated P80188 levels in patients with ET and PV with and without thrombotic events , to explore a possible correlation of P80188 with platelet and leukocyte activation , and in patients with sepsis . Serum P80188 levels in the study population were significantly higher than in healthy adults and in subjects with sepsis . A correlation between P80188 and the number of white cells and neutrophils was found in patients with PV and ET . P80188 serum levels were not different depending on the presence or not of the O60674 mutation , and a mutant allele dosage effect was not observed for P80188 levels . Patients with PV and ET with thrombosis did not have significantly higher levels of P80188 . We were unable to demonstrate a significant association between serum P80188 levels and CD11b or CD62 expression . In conclusion , our study reports evidence demonstrating that increased levels of P80188 appear to be a characteristic of patients with PV and ET .\",\n \"Polymorphisms in the angiotensin - converting enzyme gene are associated with unipolar depression , P12821 activity and hypercortisolism . P12821 ( P12821 ) is assumed to influence the activity of the hypothalamic - pituitary - adrenocortical ( Q9Y251 ) system , which shows hyperactivity in the majority of patients with major depression . The P12821 gene , known to be associated with cardiovascular disorders , which in turn are accompanied with an increased susceptibility for depression , is therefore a promising candidate gene for affective disorders . We investigated the genetic association between 35 single - nucleotide polymorphisms ( SNPs ) and an insertion / deletion ( I / D ) - polymorphism in the P12821 gene and the susceptibility for unipolar major depression together with the genetic association with P12821 serum activity and functional parameters of the Q9Y251 system . Two independent case / control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated . A case / control sample was screened to detect genetic associations with unipolar major depression . In addition , a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression . In the screening sample , two SNPs within the P12821 gene were significantly associated with unipolar major depression . The association with unipolar major depression of one SNP ( rs4291 ) located in the promoter region of the P12821 gene was confirmed in our replication sample . The T - allele of this SNP was associated with depression and depressed T - allele carriers showed higher P12821 serum activity and Q9Y251 - axis hyperactivity . Variants of the P12821 gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression . We could show that SNP rs4291 influences P12821 activity and Q9Y251 - axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease .\",\n \"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK43___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .\",\n \"Endothelial dysfunction in congestive heart failure : P12821 inhibition vs . angiotensin II antagonism . BACKGROUND : Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure ( CHF ) . The present study systematically investigated the effect of angiotensin II ( AT ( 1 ) ) - receptor blockade on vascular superoxide ( O ( 2 )(-) ) production and endothelial dysfunction . METHODS AND RESULTS : Vasodilator responses and O ( 2 )(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham - operated animals ( Sham ) . Rats were either treated with placebo ( P ) , with the AT ( 1 )- receptor antagonist Irbesartan ( 50 mg kg (- 1 ) day (- 1 ) ) or with the P12821 inhibitor DB00519 ( 0 . 3 mg kg (- 1 ) day (- 1 ) ) . In CHF - P , endothelium - dependent , acetylcholine - induced relaxation was significantly attenuated compared with Sham - P . Chronic treatment with DB00519 or Irbesartan significantly improved endothelium - dependent relaxation . Aortic O ( 2 )(-) formation was markedly increased in CHF , and was not significantly affected by DB00519 treatment , while it was reduced by Irbesartan . P29474 expression was reduced in CHF and normalised by both treatments . CONCLUSION : Endothelial vasomotor function in CHF rats was normalised by long - term treatment with an P12821 inhibitor or an AT ( 1 )- antagonist . Reduced aortic P29474 expression was normalised by both treatments , whereas aortic superoxide formation was only reduced by the AT ( 1 )- antagonist Irbesartan .\",\n \"Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy . A number of candidate genes for lithium prophylactic efficacy have been proposed , some of them being also associated with a predisposition to bipolar illness . The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder , in relation to the putative role of these genes in the pathogenesis of this disorder . Some association with lithium prophylactic efficacy was found for the polymorphisms of P31645 , P21728 , P21964 , P23560 and P06241 genes , but not for 5HT2A , 5HT2C , P14416 , P35462 , P21917 , GSK - 3 , Q16620 , Q13224 and P14780 . Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed .\",\n \"Synthetic triterpenoids , CDDO - Imidazolide and CDDO - Ethyl amide , induce chondrogenesis . Novel methods for inducing chondrogenesis are critical for cartilage tissue engineering and regeneration . Here we show that the synthetic oleanane triterpenoids , CDDO - Imidazolide ( CDDO - Im ) and CDDO - Ethyl amide ( CDDO - EA ) , at concentrations as low as 200 nM , induce chondrogenesis in organ cultures of newborn mouse calvaria . The cartilage phenotype was measured histologically with metachromatic toluidine blue staining for proteoglycans and by immunohistochemical staining for type II collagen . Furthermore , real - time polymerase chain reaction ( PCR ) analysis using mRNA from calvaria after 7 - day treatment with CDDO - Im and CDDO - EA showed up - regulation of the chondrocyte markers P48436 and type II collagen ( alpha1 ) . In addition , TGF - β ; BMPs 2 and 4 ; Smads 3 , 4 , 6 , and 7 ; and TIMPs - 1 and - 2 were increased . In contrast , P14780 was strongly down - regulated . Treatment of human bone marrow - derived DB05914 with CDDO - Im and CDDO - EA ( 100 nM ) induced expression of P48436 , collagen IIα1 , and aggrecan , as well as P12643 and phospho - Q99717 , confirming that the above triterpenoids induce chondrogenic differentiation . This is the first report of the use of these drugs for induction of chondrogenesis .\",\n \"Transient estrogen exposure from birth affects uterine expression of developmental markers in neonatal gilts with lasting consequences in pregnant adults . Disruption of estrogen - sensitive , estrogen receptor ( ER ) - dependent events during porcine uterine development between birth ( postnatal day = P01160 0 ) and P01160 14 affects patterns of uterine morphoregulatory gene expression in the neonate with lasting consequences for reproductive success . Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate ( EV ) for 14 days from birth . Objectives here were to determine effects of EV exposure from birth through P01160 13 on neonatal uterine and adult endometrial markers of growth , patterning , and remodeling . Targets included the relaxin receptor ( Q9HBX9 ) , estrogen receptor - alpha ( P03372 ) and vascular endothelial growth factor ( P15692 ) , morphoregulatory markers P31260 and O00755 , and the matrix metalloproteinases ( MMP ) 2 and P14780 . Gilts were treated daily with EV ( 50 microg / kg body weight per day , i . m . ) or corn oil vehicle from birth through P01160 13 . Uteri were obtained from neonates on P01160 14 and from adults on pregnancy day 12 ( PxD 12 ) . In neonates , EV exposure from birth increased uterine Q9HBX9 gene expression , and both P03372 and P15692 proteins . At PxD 12 , endometrial Q9HBX9 mRNA remained elevated , while P03372 protein was reduced . Early EV treatment decreased neonatal uterine O00755 , but increased P31260 expression . O00755 expression was reduced in EV - treated adults . Transient EV exposure increased P14780 transcripts at P01160 14 , whereas both latent and active P14780 activity was increased due to early EV treatment in adults on PxD 12 . Results support the hypothesis that transient , estrogen - induced disruption of porcine uterine development from birth alters early programming events that lead to functional consequences in the adult .\"\n]"},"candidates":{"kind":"list like","value":["___MASK27___","___MASK37___","___MASK43___","___MASK48___","___MASK54___","___MASK56___","___MASK75___","___MASK83___","___MASK8___"],"string":"[\n \"___MASK27___\",\n \"___MASK37___\",\n \"___MASK43___\",\n \"___MASK48___\",\n \"___MASK54___\",\n \"___MASK56___\",\n \"___MASK75___\",\n \"___MASK83___\",\n \"___MASK8___\"\n]"},"answer":{"kind":"string","value":"___MASK75___"},"id":{"kind":"string","value":"MH_train_374"}}},{"rowIdx":375,"cells":{"query":{"kind":"string","value":"interacts_with DB00862?"},"supports":{"kind":"list like","value":["Murine lupus susceptibility locus Sle1a controls regulatory T cell number and function through multiple mechanisms . The Sle1 locus is a key determinant of lupus susceptibility in the NZM2410 mouse model . Within Sle1 , we have previously shown that Sle1a expression enhances activation levels and effector functions of P01730 (+) T cells and reduces the size of the P01730 (+) CD25 (+) Foxp3 (+) regulatory T cell subset , leading to the production of autoreactive T cells that provide help to chromatin - specific B cells . In this study , we show that Sle1a P01730 (+) T cells express high levels of Q9Y6W8 , which is consistent with their increased ability to help autoreactive B cells . Furthermore , Sle1a P01730 (+) CD25 (+) T cells express low levels of Foxp3 . Mixed bone marrow chimeras demonstrated that these phenotypes require Sle1a to be expressed in the affected P01730 (+) T cells . Expression of other markers generally associated with regulatory T cells ( Tregs ) was similar regardless of Sle1a expression in Foxp3 (+) cells . This result , along with in vitro and in vivo suppression studies , suggests that Sle1a controls the number of Tregs rather than their function on a per cell basis . Both in vitro and in vivo suppression assays also showed that Sle1a expression induced effector T cells to be resistant to Treg suppression , as well as dendritic cells to overproduce P05231 , which inhibits Treg suppression . Overall , these results show that Sle1a controls both Treg number and function by multiple mechanisms , directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells .","Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .","Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .","High biochemical selectivity of tadalafil , sildenafil and vardenafil for human phosphodiesterase 5A1 ( O76074 ) over PDE11A4 suggests the absence of PDE11A4 cross - reaction in patients . The physiological role of phosphodiesterase ( PDE ) 11 is unknown and its biochemical characteristics are poorly understood . We have expressed human DB00117 - tagged PDE11A4 and purified the enzyme to apparent homogeneity . PDE11A4 displays K ( m ) values of 0 . 97 microM for cGMP and 2 . 4 microM for DB02527 , and maximal velocities were 4 - to 10 - fold higher for DB02527 than for cGMP . Given the homology between PDE11 and O76074 , we have compared the biochemical potencies of tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , vardenafil ( DB00862 , Bayer - GSK ) , and sildenafil ( Viagra , Pfizer Inc . ) for PDE11A4 and PDE5A1 . PDE5A1 / PDE11A4 selectivities are 40 - , 9300 - , and 1000 - fold for tadalafil , vardenafil , and sildenafil , respectively . This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients .","Hu23F2G , an antibody recognizing the leukocyte CD11 / P05107 integrin , reduces injury in a rabbit model of transient focal cerebral ischemia . Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion . Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell ' s intercellular adhesion molecule ( P05362 ) through the leukocyte integrin , CD11 / P05107 . We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11 / P05107 integrin in a rabbit model of transient focal ischemia . Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral , anterior cerebral , and internal carotid arteries using aneurysm clips for 2 h , followed by 6 h of reperfusion . Treatment with a maximally saturating dose ( 4 mg / kg ) of a humanized CD11 / P05107 monoclonal antibody ( Hu23F2G , Q9Y6W8 Corp . , Bothell , WA ) ( n = 8 ) or placebo ( n = 7 ) was administered 20 min after occlusion and given as a single intravenous bolus . Hemispheric ischemic neuronal damage ( IND ) as seen on hematoxylin - and eosin - stained sections was significantly reduced in Hu23F2G - treated animals by 57 % ( Hu23F2G : 15 +/- 6 . 9 % ; placebo : 35 +/- 5 % ; mean +/- SEM , P < 0 . 05 , t - test ) . Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains . Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration . ( No . of neutrophils / IND area : Hu23F2G 36 . 1 +/- 36 . 7 cm - 2 , placebo 460 . 6 +/- 101 . 8 cm - 2 , P = 0 . 001 . ) Antagonism of neutrophil migration at the level of the CD11 / P05107 integrin reduces ischemic injury in experimental stroke .","B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .","Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK39___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .","[ ___MASK8___ sodium ( Photofrin - II ) ] . ___MASK8___ sodium ( ___MASK8___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK8___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .","___MASK13___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .","Radiolabeled ligand binding to the catalytic or allosteric sites of O76074 and PDE11 . Cyclic nucleotide phosphodiesterases ( PDEs ) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes . Phosphodiesterase - 5 ( O76074 ) , which is highly specific for guanosine 3 '- 5 '- cyclic - monophosphate ( cGMP ) at both its catalytic site and its allosteric sites , has generated particular interest because it is potently and specifically inhibited by three drugs : sildenafil ( Viagra , Pfizer ) , tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , and vardenafil ( DB00862 , Bayer GSK ) . Previously , we have used [( 3 ) H ] cGMP to directly study the interaction of cGMP with the allosteric sites of O76074 , but because cGMP binds with relatively low affinity to the catalytic site , it has been difficult to devise a binding assay for this particular binding reaction . This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme . We now use a similar approach to study the characteristics of high - affinity [( 3 ) H ] inhibitor binding to the O76074 catalytic domain . For these studies , we have prepared [( 3 ) H ] sildenafil and [( 3 ) H ] tadalafil , two structurally different competitive inhibitors of O76074 . The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of O76074 . We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on O76074 . These techniques have also been successfully applied to the study of binding of radiolabeled O76074 inhibitors to PDE11 , suggesting that these methods are applicable to the study of other PDEs , and perhaps other enzyme families .","___MASK31___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK31___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .","DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .","A novel anti - human O75144 monoclonal antibody that enhances IgG production of B cells . O75144 , a newly identified member of the P33681 superfamily , plays a major role in immune responses . In this study , a functional anti - human O75144 monoclonal antibody ( MAb ) 3B3 was obtained and characterized by means of flow cytometry , Western blot , and competition assay . This MAb could specifically recognize a distinct epitope of the O75144 molecule . As a functional antibody , MAb 3B3 could inhibit the proliferation of T lymphocytes stimulated by O75144 - L929 transfectants . Furthermore , it could enhance IgG production of PWM - driven B cells . The results indicate that the Q9Y6W8 - O75144 signal is critically involved in specific humoral immunity .","[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK75___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .","Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK80___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .","P04035 inhibitors deplete circulating classical and non - classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 , CD16 , CD49d , CD64 , P33681 and CD195 ) . RESULTS : There were fewer circulating classical ( p = 0 . 0001 ) and non - classical ( p = 0 . 0013 ) monocytes in patients treated with a statin . CD64 expression was down - regulated ( p = 0 . 011 and p = 0 . 049 ) whereas CD49d expression was up - regulated ( p = 0 . 004 and p = 0 . 022 ) on classical and non - classical monocytes in this group . Patients receiving ___MASK39___ had fewer circulating classical monocytes ( p = 0 . 001 ) compared to patients administered DB00175 . Patients receiving DB00175 had fewer circulating non - classical monocytes ( p = 0 . 029 ) compared to patients administered ___MASK39___ . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .","P01730 + CD25 + regulatory T cells inhibit the maturation but not the initiation of an autoantibody response . To investigate the mechanism by which T regulatory ( Treg ) cells may control the early onset of autoimmunity , we have used an adoptive transfer model to track Treg , Th , and anti - chromatin B cell interactions in vivo . We show that anti - chromatin B cells secrete Abs by day 8 in vivo upon provision of undeviated , Th1 - or Th2 - type P01730 + T cell help , but this secretion is blocked by the coinjection of P01730 + CD25 + Treg cells . Although Treg cells do not interfere with the initial follicular entry or activation of Th or B cells at day 3 , Q9Y6W8 levels on Th cells are decreased . Furthermore , Treg cells must be administered during the initial phases of the Ab response to exert full suppression of autoantibody production . These studies indicate that CD25 + Treg cells act to inhibit the maturation , rather than the initiation , of autoantibody responses .","___MASK58___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .","Q9Y6W8 costimulation requires P60568 and can be prevented by P16410 engagement . We investigated the relationship between Q9Y6W8 , P10747 , P16410 , and P60568 to gain a better understanding of this family of costimulatory receptors in the immune response . Using magnetic beads coated with anti - CD3 and varying amounts of anti - Q9Y6W8 and anti - P16410 Abs , we show that P16410 ligation blocks Q9Y6W8 costimulation . In addition to inhibiting cellular proliferation , P16410 engagement prevented Q9Y6W8 - costimulated T cells from producing P05112 , P22301 , and P35225 . Both an indirect and direct mechanism of P16410 ' s actions were examined . First , P16410 engagement on resting cells was found to indirectly block Q9Y6W8 costimulation by interferring with the signals needed to induce Q9Y6W8 cell surface expression . Second , on preactivated cells that had high levels of Q9Y6W8 expression , P16410 ligation blocked the Q9Y6W8 - mediated induction of P05112 , P22301 , and P35225 , suggesting an interference with downstream signaling pathways . The addition of P60568 not only overcame both mechanisms , but also greatly augmented the level of cellular activation suggesting synergy between Q9Y6W8 and P60568 signaling . This cooperation between Q9Y6W8 and P60568 signaling was explored further by showing that the minimum level of P60568 produced by Q9Y6W8 costimulation was required for T cell proliferation . Finally , exogenous P60568 was required for sustained growth of Q9Y6W8 - costimulated T cells . These results indicate that stringent control of Q9Y6W8 costimulation is maintained initially by P16410 engagement and later by a requirement for exogenous P60568 .","Identification of Mycobacterium tuberculosis - specific Th1 , Th17 and Th22 cells using the expression of P29965 in tuberculous pleurisy . Important advances have been made in the immunodiagnosis of tuberculosis ( TB ) based on the detection of Mycobacterium tuberculosis ( MTB ) - specific T cells . However , the sensitivity and specificity of the immunological approach are relatively low because there are no specific markers for antigen - specific Th cells , and some of the Th cells that do not produce cytokines can be overlooked using this approach . In this study , we found that MTB - specific peptides of ESAT - 6 / P27918 - 10 can stimulate the expression of P29965 specifically in P01730 (+) T cells but not other cells from pleural fluid cells ( PFCs ) in patients with tuberculous pleurisy ( P20226 ) . P01730 (+) P29965 (+) but not P01730 (+) P29965 (-) T cells express IFN - γ , P60568 , P01375 - α , Q16552 or Q9GZX6 after stimulation with MTB - specific peptides . In addition , P01730 (+) P29965 (+) T cells were found to be mostly polyfunctional T cells that simultaneously produce IFN - γ , P60568 and P01375 - α and display an effector or effector memory phenotype ( CD45RA (-) CD45RO (+) P32248 (-) CD62L (-) Q9Y6W8 (-) ) . To determine the specificity of P01730 (+) P29965 (+) T cells , we incubated PFCs with ESTA - 6 / P27918 - 10 peptides and sorted live P01730 (+) P29965 (+) and P01730 (+) P29965 (-) T cells by flow cytometry . We further demonstrated that sorted P01730 (+) P29965 (+) , but not P01730 (+) P29965 (-) fractions , principally produced IFN - γ , P60568 , P01375 - α , Q16552 and Q9GZX6 following restimulation with ESTA - 6 / P27918 - 10 peptides . Taken together , our data indicate that the expression of P29965 on MTB - specific P01730 (+) T cells could be a good marker for the evaluation and isolation of MTB - specific Th cells and might also be useful in the diagnosis of TB .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","___MASK60___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK60___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .","Emerging oral drugs for erectile dysfunction . Erectile dysfunction ( ED ) is a common medical condition that affects the sexual life of millions of men worldwide . Many drugs are now available for the treatment of ED , with oral pharmacotherapy representing the first - line option for most patients . DB00203 citrate , an inhibitor of the enzyme phosphodiesterase type 5 ( O76074 ) , is the most widely prescribed oral agent and has a very satisfactory efficacy - safety profile in all patient categories . DB00820 ( DB00820 ; Eli Lilly & Co . , Q9Y6W8 ) and vardenafil ( DB00862 ; Bayer Pharmaceuticals , GlaxoSmithKline ) are new O76074 inhibitors that have recently been approved worldwide . Both have been associated with significant positive efficacy - safety profiles . DB00714 sublingual is a dopamine D1 and D2 receptor agonist , which has been approved for marketing in Europe . It is best selected for treating patients with mild - to - moderate ED , but it is seldom used in clinical practice due to its limited efficacy and side effects , particularly nausea . Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy . The efficacy of second - line treatment is high , but the attrition rate remains significant . For the purpose of this review , clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy , including O76074 inhibitors and sublingual apomorphine .","P06850 and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons . The stress - related neuropeptide DB05394 ( CRF ) and the serotonin system are both critically involved in the pathophysiology of mental disorders , including anxiety and depression . To understand the potential link between them , we investigated the impact of CRF on 5 - HT functions in pyramidal neurons of the prefrontal cortex ( P27918 ) , a brain region that is crucial for the control of emotion and cognition . One prominent function of serotonin in P27918 is to regulate GABAergic inhibitory transmission , as indicated by a 5 - HT - induced large , desensitizing ( approximately 4 min ) enhancement of the amplitude and frequency of spontaneous IPSCs ( sIPSCs ) . In P27918 slices exposed to CRF treatment , the regulation of sIPSCs by 5 - HT was significantly prolonged ( 8 - 10 min ) , and this effect of CRF was blocked by treatment with the competitive CRF receptor antagonist alpha - helical CRF9 - 41 and with the P34998 - specific antagonist astressin . Inhibiting phospholipase C or protein kinase C ( PKC ) abolished the prolongation by CRF of the effects of 5 - HT on sIPSCs . In P27918 slices prepared from animals previously exposed to acute stress ( forced swim or elevated platform ) , the regulation of sIPSCs by 5 - HT was significantly prolonged , mimicking the effect of CRF treatment . The stress - induced prolongation of the effects of 5 - HT on sIPSCs was diminished by alpha - helical CRF9 - 41 treatment , mimicked by direct activation of PKC , and reversed by short - term treatment with drugs that have anxiolytic efficacy . These results show that in response to stressful stimuli , CRF alters the serotonergic regulation of GABA transmission through a mechanism that is dependent on PKC . The interaction between CRF and 5 - HT may play an important role in psychiatric disorders , in which both are highly implicated .","Characterization of intratumoral follicular helper T cells in follicular lymphoma : role in the survival of malignant B cells . Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma ( FL ) has a key role in both lymphomagenesis and patient outcome . Malignant FL B cells are found admixed to specific stromal and immune cell subsets , in particular P01730 ( pos ) T cells displaying phenotypic features of follicular helper T cells ( T ( FH ) ) . The goal of our study was to functionally characterize intratumoral P01730 ( pos ) T cells . We showed that P32302 ( hi ) Q9Y6W8 ( hi ) P01730 ( pos ) T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features : ( i ) CD25 ( pos ) follicular regulatory T cells ( T ( FR ) ) , and ( ii ) CD25 ( neg ) T ( FH ) displaying a FL - B cell supportive activity without regulatory functions . Furthermore , despite their strong similarities with tonsil - derived T ( FH ) , purified FL - derived T ( FH ) displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis , in particular P01375 , P01374 , P05112 or P29965 . Interestingly , we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab - induced apoptosis . Altogether , our study demonstrates that tumor - infiltrating P01730 ( pos ) T cells are more heterogeneous than previously presumed , and underlines for the first time the crucial role of T ( FH ) in the complex set of cellular interactions within FL microenvironment ."],"string":"[\n \"Murine lupus susceptibility locus Sle1a controls regulatory T cell number and function through multiple mechanisms . The Sle1 locus is a key determinant of lupus susceptibility in the NZM2410 mouse model . Within Sle1 , we have previously shown that Sle1a expression enhances activation levels and effector functions of P01730 (+) T cells and reduces the size of the P01730 (+) CD25 (+) Foxp3 (+) regulatory T cell subset , leading to the production of autoreactive T cells that provide help to chromatin - specific B cells . In this study , we show that Sle1a P01730 (+) T cells express high levels of Q9Y6W8 , which is consistent with their increased ability to help autoreactive B cells . Furthermore , Sle1a P01730 (+) CD25 (+) T cells express low levels of Foxp3 . Mixed bone marrow chimeras demonstrated that these phenotypes require Sle1a to be expressed in the affected P01730 (+) T cells . Expression of other markers generally associated with regulatory T cells ( Tregs ) was similar regardless of Sle1a expression in Foxp3 (+) cells . This result , along with in vitro and in vivo suppression studies , suggests that Sle1a controls the number of Tregs rather than their function on a per cell basis . Both in vitro and in vivo suppression assays also showed that Sle1a expression induced effector T cells to be resistant to Treg suppression , as well as dendritic cells to overproduce P05231 , which inhibits Treg suppression . Overall , these results show that Sle1a controls both Treg number and function by multiple mechanisms , directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells .\",\n \"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .\",\n \"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .\",\n \"High biochemical selectivity of tadalafil , sildenafil and vardenafil for human phosphodiesterase 5A1 ( O76074 ) over PDE11A4 suggests the absence of PDE11A4 cross - reaction in patients . The physiological role of phosphodiesterase ( PDE ) 11 is unknown and its biochemical characteristics are poorly understood . We have expressed human DB00117 - tagged PDE11A4 and purified the enzyme to apparent homogeneity . PDE11A4 displays K ( m ) values of 0 . 97 microM for cGMP and 2 . 4 microM for DB02527 , and maximal velocities were 4 - to 10 - fold higher for DB02527 than for cGMP . Given the homology between PDE11 and O76074 , we have compared the biochemical potencies of tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , vardenafil ( DB00862 , Bayer - GSK ) , and sildenafil ( Viagra , Pfizer Inc . ) for PDE11A4 and PDE5A1 . PDE5A1 / PDE11A4 selectivities are 40 - , 9300 - , and 1000 - fold for tadalafil , vardenafil , and sildenafil , respectively . This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients .\",\n \"Hu23F2G , an antibody recognizing the leukocyte CD11 / P05107 integrin , reduces injury in a rabbit model of transient focal cerebral ischemia . Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion . Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell ' s intercellular adhesion molecule ( P05362 ) through the leukocyte integrin , CD11 / P05107 . We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11 / P05107 integrin in a rabbit model of transient focal ischemia . Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral , anterior cerebral , and internal carotid arteries using aneurysm clips for 2 h , followed by 6 h of reperfusion . Treatment with a maximally saturating dose ( 4 mg / kg ) of a humanized CD11 / P05107 monoclonal antibody ( Hu23F2G , Q9Y6W8 Corp . , Bothell , WA ) ( n = 8 ) or placebo ( n = 7 ) was administered 20 min after occlusion and given as a single intravenous bolus . Hemispheric ischemic neuronal damage ( IND ) as seen on hematoxylin - and eosin - stained sections was significantly reduced in Hu23F2G - treated animals by 57 % ( Hu23F2G : 15 +/- 6 . 9 % ; placebo : 35 +/- 5 % ; mean +/- SEM , P < 0 . 05 , t - test ) . Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains . Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration . ( No . of neutrophils / IND area : Hu23F2G 36 . 1 +/- 36 . 7 cm - 2 , placebo 460 . 6 +/- 101 . 8 cm - 2 , P = 0 . 001 . ) Antagonism of neutrophil migration at the level of the CD11 / P05107 integrin reduces ischemic injury in experimental stroke .\",\n \"B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .\",\n \"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK39___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .\",\n \"[ ___MASK8___ sodium ( Photofrin - II ) ] . ___MASK8___ sodium ( ___MASK8___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK8___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .\",\n \"___MASK13___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .\",\n \"Radiolabeled ligand binding to the catalytic or allosteric sites of O76074 and PDE11 . Cyclic nucleotide phosphodiesterases ( PDEs ) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes . Phosphodiesterase - 5 ( O76074 ) , which is highly specific for guanosine 3 '- 5 '- cyclic - monophosphate ( cGMP ) at both its catalytic site and its allosteric sites , has generated particular interest because it is potently and specifically inhibited by three drugs : sildenafil ( Viagra , Pfizer ) , tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , and vardenafil ( DB00862 , Bayer GSK ) . Previously , we have used [( 3 ) H ] cGMP to directly study the interaction of cGMP with the allosteric sites of O76074 , but because cGMP binds with relatively low affinity to the catalytic site , it has been difficult to devise a binding assay for this particular binding reaction . This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme . We now use a similar approach to study the characteristics of high - affinity [( 3 ) H ] inhibitor binding to the O76074 catalytic domain . For these studies , we have prepared [( 3 ) H ] sildenafil and [( 3 ) H ] tadalafil , two structurally different competitive inhibitors of O76074 . The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of O76074 . We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on O76074 . These techniques have also been successfully applied to the study of binding of radiolabeled O76074 inhibitors to PDE11 , suggesting that these methods are applicable to the study of other PDEs , and perhaps other enzyme families .\",\n \"___MASK31___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK31___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .\",\n \"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .\",\n \"A novel anti - human O75144 monoclonal antibody that enhances IgG production of B cells . O75144 , a newly identified member of the P33681 superfamily , plays a major role in immune responses . In this study , a functional anti - human O75144 monoclonal antibody ( MAb ) 3B3 was obtained and characterized by means of flow cytometry , Western blot , and competition assay . This MAb could specifically recognize a distinct epitope of the O75144 molecule . As a functional antibody , MAb 3B3 could inhibit the proliferation of T lymphocytes stimulated by O75144 - L929 transfectants . Furthermore , it could enhance IgG production of PWM - driven B cells . The results indicate that the Q9Y6W8 - O75144 signal is critically involved in specific humoral immunity .\",\n \"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK75___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .\",\n \"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK80___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .\",\n \"P04035 inhibitors deplete circulating classical and non - classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 , CD16 , CD49d , CD64 , P33681 and CD195 ) . RESULTS : There were fewer circulating classical ( p = 0 . 0001 ) and non - classical ( p = 0 . 0013 ) monocytes in patients treated with a statin . CD64 expression was down - regulated ( p = 0 . 011 and p = 0 . 049 ) whereas CD49d expression was up - regulated ( p = 0 . 004 and p = 0 . 022 ) on classical and non - classical monocytes in this group . Patients receiving ___MASK39___ had fewer circulating classical monocytes ( p = 0 . 001 ) compared to patients administered DB00175 . Patients receiving DB00175 had fewer circulating non - classical monocytes ( p = 0 . 029 ) compared to patients administered ___MASK39___ . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .\",\n \"P01730 + CD25 + regulatory T cells inhibit the maturation but not the initiation of an autoantibody response . To investigate the mechanism by which T regulatory ( Treg ) cells may control the early onset of autoimmunity , we have used an adoptive transfer model to track Treg , Th , and anti - chromatin B cell interactions in vivo . We show that anti - chromatin B cells secrete Abs by day 8 in vivo upon provision of undeviated , Th1 - or Th2 - type P01730 + T cell help , but this secretion is blocked by the coinjection of P01730 + CD25 + Treg cells . Although Treg cells do not interfere with the initial follicular entry or activation of Th or B cells at day 3 , Q9Y6W8 levels on Th cells are decreased . Furthermore , Treg cells must be administered during the initial phases of the Ab response to exert full suppression of autoantibody production . These studies indicate that CD25 + Treg cells act to inhibit the maturation , rather than the initiation , of autoantibody responses .\",\n \"___MASK58___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .\",\n \"Q9Y6W8 costimulation requires P60568 and can be prevented by P16410 engagement . We investigated the relationship between Q9Y6W8 , P10747 , P16410 , and P60568 to gain a better understanding of this family of costimulatory receptors in the immune response . Using magnetic beads coated with anti - CD3 and varying amounts of anti - Q9Y6W8 and anti - P16410 Abs , we show that P16410 ligation blocks Q9Y6W8 costimulation . In addition to inhibiting cellular proliferation , P16410 engagement prevented Q9Y6W8 - costimulated T cells from producing P05112 , P22301 , and P35225 . Both an indirect and direct mechanism of P16410 ' s actions were examined . First , P16410 engagement on resting cells was found to indirectly block Q9Y6W8 costimulation by interferring with the signals needed to induce Q9Y6W8 cell surface expression . Second , on preactivated cells that had high levels of Q9Y6W8 expression , P16410 ligation blocked the Q9Y6W8 - mediated induction of P05112 , P22301 , and P35225 , suggesting an interference with downstream signaling pathways . The addition of P60568 not only overcame both mechanisms , but also greatly augmented the level of cellular activation suggesting synergy between Q9Y6W8 and P60568 signaling . This cooperation between Q9Y6W8 and P60568 signaling was explored further by showing that the minimum level of P60568 produced by Q9Y6W8 costimulation was required for T cell proliferation . Finally , exogenous P60568 was required for sustained growth of Q9Y6W8 - costimulated T cells . These results indicate that stringent control of Q9Y6W8 costimulation is maintained initially by P16410 engagement and later by a requirement for exogenous P60568 .\",\n \"Identification of Mycobacterium tuberculosis - specific Th1 , Th17 and Th22 cells using the expression of P29965 in tuberculous pleurisy . Important advances have been made in the immunodiagnosis of tuberculosis ( TB ) based on the detection of Mycobacterium tuberculosis ( MTB ) - specific T cells . However , the sensitivity and specificity of the immunological approach are relatively low because there are no specific markers for antigen - specific Th cells , and some of the Th cells that do not produce cytokines can be overlooked using this approach . In this study , we found that MTB - specific peptides of ESAT - 6 / P27918 - 10 can stimulate the expression of P29965 specifically in P01730 (+) T cells but not other cells from pleural fluid cells ( PFCs ) in patients with tuberculous pleurisy ( P20226 ) . P01730 (+) P29965 (+) but not P01730 (+) P29965 (-) T cells express IFN - γ , P60568 , P01375 - α , Q16552 or Q9GZX6 after stimulation with MTB - specific peptides . In addition , P01730 (+) P29965 (+) T cells were found to be mostly polyfunctional T cells that simultaneously produce IFN - γ , P60568 and P01375 - α and display an effector or effector memory phenotype ( CD45RA (-) CD45RO (+) P32248 (-) CD62L (-) Q9Y6W8 (-) ) . To determine the specificity of P01730 (+) P29965 (+) T cells , we incubated PFCs with ESTA - 6 / P27918 - 10 peptides and sorted live P01730 (+) P29965 (+) and P01730 (+) P29965 (-) T cells by flow cytometry . We further demonstrated that sorted P01730 (+) P29965 (+) , but not P01730 (+) P29965 (-) fractions , principally produced IFN - γ , P60568 , P01375 - α , Q16552 and Q9GZX6 following restimulation with ESTA - 6 / P27918 - 10 peptides . Taken together , our data indicate that the expression of P29965 on MTB - specific P01730 (+) T cells could be a good marker for the evaluation and isolation of MTB - specific Th cells and might also be useful in the diagnosis of TB .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"___MASK60___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK60___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .\",\n \"Emerging oral drugs for erectile dysfunction . Erectile dysfunction ( ED ) is a common medical condition that affects the sexual life of millions of men worldwide . Many drugs are now available for the treatment of ED , with oral pharmacotherapy representing the first - line option for most patients . DB00203 citrate , an inhibitor of the enzyme phosphodiesterase type 5 ( O76074 ) , is the most widely prescribed oral agent and has a very satisfactory efficacy - safety profile in all patient categories . DB00820 ( DB00820 ; Eli Lilly & Co . , Q9Y6W8 ) and vardenafil ( DB00862 ; Bayer Pharmaceuticals , GlaxoSmithKline ) are new O76074 inhibitors that have recently been approved worldwide . Both have been associated with significant positive efficacy - safety profiles . DB00714 sublingual is a dopamine D1 and D2 receptor agonist , which has been approved for marketing in Europe . It is best selected for treating patients with mild - to - moderate ED , but it is seldom used in clinical practice due to its limited efficacy and side effects , particularly nausea . Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy . The efficacy of second - line treatment is high , but the attrition rate remains significant . For the purpose of this review , clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy , including O76074 inhibitors and sublingual apomorphine .\",\n \"P06850 and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons . The stress - related neuropeptide DB05394 ( CRF ) and the serotonin system are both critically involved in the pathophysiology of mental disorders , including anxiety and depression . To understand the potential link between them , we investigated the impact of CRF on 5 - HT functions in pyramidal neurons of the prefrontal cortex ( P27918 ) , a brain region that is crucial for the control of emotion and cognition . One prominent function of serotonin in P27918 is to regulate GABAergic inhibitory transmission , as indicated by a 5 - HT - induced large , desensitizing ( approximately 4 min ) enhancement of the amplitude and frequency of spontaneous IPSCs ( sIPSCs ) . In P27918 slices exposed to CRF treatment , the regulation of sIPSCs by 5 - HT was significantly prolonged ( 8 - 10 min ) , and this effect of CRF was blocked by treatment with the competitive CRF receptor antagonist alpha - helical CRF9 - 41 and with the P34998 - specific antagonist astressin . Inhibiting phospholipase C or protein kinase C ( PKC ) abolished the prolongation by CRF of the effects of 5 - HT on sIPSCs . In P27918 slices prepared from animals previously exposed to acute stress ( forced swim or elevated platform ) , the regulation of sIPSCs by 5 - HT was significantly prolonged , mimicking the effect of CRF treatment . The stress - induced prolongation of the effects of 5 - HT on sIPSCs was diminished by alpha - helical CRF9 - 41 treatment , mimicked by direct activation of PKC , and reversed by short - term treatment with drugs that have anxiolytic efficacy . These results show that in response to stressful stimuli , CRF alters the serotonergic regulation of GABA transmission through a mechanism that is dependent on PKC . The interaction between CRF and 5 - HT may play an important role in psychiatric disorders , in which both are highly implicated .\",\n \"Characterization of intratumoral follicular helper T cells in follicular lymphoma : role in the survival of malignant B cells . Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma ( FL ) has a key role in both lymphomagenesis and patient outcome . Malignant FL B cells are found admixed to specific stromal and immune cell subsets , in particular P01730 ( pos ) T cells displaying phenotypic features of follicular helper T cells ( T ( FH ) ) . The goal of our study was to functionally characterize intratumoral P01730 ( pos ) T cells . We showed that P32302 ( hi ) Q9Y6W8 ( hi ) P01730 ( pos ) T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features : ( i ) CD25 ( pos ) follicular regulatory T cells ( T ( FR ) ) , and ( ii ) CD25 ( neg ) T ( FH ) displaying a FL - B cell supportive activity without regulatory functions . Furthermore , despite their strong similarities with tonsil - derived T ( FH ) , purified FL - derived T ( FH ) displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis , in particular P01375 , P01374 , P05112 or P29965 . Interestingly , we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab - induced apoptosis . Altogether , our study demonstrates that tumor - infiltrating P01730 ( pos ) T cells are more heterogeneous than previously presumed , and underlines for the first time the crucial role of T ( FH ) in the complex set of cellular interactions within FL microenvironment .\"\n]"},"candidates":{"kind":"list like","value":["___MASK13___","___MASK31___","___MASK39___","___MASK58___","___MASK60___","___MASK75___","___MASK80___","___MASK8___"],"string":"[\n \"___MASK13___\",\n \"___MASK31___\",\n \"___MASK39___\",\n \"___MASK58___\",\n \"___MASK60___\",\n \"___MASK75___\",\n \"___MASK80___\",\n \"___MASK8___\"\n]"},"answer":{"kind":"string","value":"___MASK75___"},"id":{"kind":"string","value":"MH_train_375"}}},{"rowIdx":376,"cells":{"query":{"kind":"string","value":"interacts_with DB08870?"},"supports":{"kind":"list like","value":["DB00099 - induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy : safety , feasibility and evidence for an efficient in vivo purging . Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia ( CML ) . Further , the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation ( P09683 ) reduces the number of therapeutic options in a number of patients . To assess the possibility of stem cell mobilization ( DB00919 ) during imatinib therapy we performed granulocyte colony - stimulating factor ( filgrastim )- induced DB00919 and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients . Aphaeresis was successful in 13 patients ( 72 % ) ( > or = 2 . 0 x 10 ( 6 ) P28906 + cells / kg body weight ) and five ( 28 % ) harvests could be obtained , which were negative for P11274 / P00519 mRNA as assessed by nested - reverse transcription polymerase chain reaction ( RT - PCR ) . All harvests , except one , were negative after first round RT - PCR , implicating a low level of CML cell contamination . There was no significant change in peripheral P11274 / P00519 transcript load after DB00919 as assessed by quantitative real - time RT - PCR . Fifteen patients remained stable in complete cytogenetic remission ( CCR ) during a median observation period of 9 . 3 months . One patient achieved a molecular remission shortly after DB00919 . Another patient who exhibited rising P11274 / P00519 mRNA levels before DB00919 achieved CCR after autologous P09683 with the generated harvest . One patient with a Philadelphia chromosome - negative , P11274 / P00519 - positive CML showed a cytogenetic relapse 6 months after DB00919 . We conclude that filgrastim - induced P28906 + cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients . Additionally , we found evidence that this procedure could generate stem cell harvests that exhibit non - detectable levels of P11274 / P00519 mRNA .","Comparison of variations detection between whole - genome amplification methods used in single - cell resequencing . BACKGROUND : Single - cell resequencing ( SCRS ) provides many biomedical advances in variations detection at the single - cell level , but it currently relies on whole genome amplification ( WGA ) . Three methods are commonly used for WGA : multiple displacement amplification ( MDA ) , degenerate - oligonucleotide - primed PCR ( DOP - PCR ) and multiple annealing and looping - based amplification cycles ( MALBAC ) . However , a comprehensive comparison of variations detection performance between these WGA methods has not yet been performed . RESULTS : We systematically compared the advantages and disadvantages of different WGA methods , focusing particularly on variations detection . Low - coverage whole - genome sequencing revealed that DOP - PCR had the highest duplication ratio , but an even read distribution and the best reproducibility and accuracy for detection of copy - number variations ( CNVs ) . However , MDA had significantly higher genome recovery sensitivity ( ~ 84 % ) than DOP - PCR ( ~ 6 % ) and MALBAC ( ~ 52 % ) at high sequencing depth . MALBAC and MDA had comparable single - nucleotide variations detection efficiency , false - positive ratio , and allele drop - out ratio . We further demonstrated that SCRS data amplified by either MDA or MALBAC from a gastric cancer cell line could accurately detect gastric cancer CNVs with comparable sensitivity and specificity , including amplifications of 12p11 . 22 ( P01116 ) and 9p24 . 1 ( O60674 , Q9NZQ7 , and Q9BQ51 ) . CONCLUSIONS : Our findings provide a comprehensive comparison of variations detection performance using SCRS amplified by different WGA methods . It will guide researchers to determine which WGA method is best suited to individual experimental needs at single - cell level .","Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK27___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","JunB induced by constitutive P28908 - extracellular signal - regulated kinase 1 / 2 mitogen - activated protein kinase signaling activates the P28908 promoter in anaplastic large cell lymphoma and reed - sternberg cells of Hodgkin lymphoma . High expression of P28908 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . Possible interactions of P28908 and JunB were examined in this study . We found that the P28908 promoter in tumor cells of both nucleophosmin ( P06748 ) - anaplastic lymphoma kinase ( Q9UM73 ) - positive and P06748 - Q9UM73 - negative ALCL and HL is regulated by a constitutively active P28908 - extracellular signal - regulated kinase ( P29323 ) 1 / 2 mitogen - activated protein kinase ( MAPK ) . Phosphorylation of P27361 / 2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL . P28908 - P27361 / 2 MAPK signals induce JunB expression , which maintains high activity of the P28908 promoter . JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL . These results show a common mechanism of P28908 overexpression in ALCL and HL , although the outcome of P28908 signaling differs between P06748 - Q9UM73 - positive ALCL and P06748 - Q9UM73 - negative ALCL , cutaneous ALCL , and HL as we recently reported .","Microtubule - depolymerizing agents used in antibody - drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody - drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target - specificity and high therapeutic activity in patients with cancer . DB08870 represents a first - in - class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor - resident DCs to the tumor - draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen - specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin - based therapies , such as brentuximab vedotin , with immune - based therapies .","DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti - P28908 antibody - drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high - risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high - dose chemotherapy with autologous stem - cell support . There has been no standard therapy for relapsed / refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .","Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha - mediated ceramide de novo synthesis in colon cancer cells . PURPOSE : Cannabinoids have been recently proposed as a new family of potential antitumor agents . The present study was undertaken to investigate the expression of the two cannabinoid receptors , P21554 and CB2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation . EXPERIMENTAL DESIGN : Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD - 1 and HT29 colon cancer cell lines . The effects of the P21554 agonist arachinodyl - 2 '- chloroethylamide and the CB2 agonist N - cyclopentyl - 7 - methyl - 1 -( 2 - morpholin - 4 - ylethyl )- 1 , 8 - naphthyridin - 4 ( 1H )- on - 3 - carboxamide ( CB13 ) on tumor cell apoptosis and ceramide and tumor necrosis factor ( P01375 ) - alpha production were evaluated . The knockdown of P01375 mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 and , more efficiently , of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD - 1 and HT29 cells . Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis . The CB2 agonist CB13 also reduced the growth of DLD - 1 cells in a mouse model of colon cancer . The knockdown of P01375 mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 acts as a link between cannabinoid receptor activation and ceramide production .","Subclones with the t ( 9 ; 22 )/ P11274 - P00519 rearrangement occur in AML and seem to cooperate with distinct genetic alterations . In AML , cooperation of mutations suppressing differentiation ( ' class - II - mutations ' ) with ' class - I - mutations ' increasing cell proliferation is frequent . In rare cases of myeloid malignancies , the P11274 - P00519 fusion was reported to cooperate as class - I - mutation with class - II - mutations , but most cases had to be classified as blast phase of chronic myeloid leukaemia ( CML ) . We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions : 1 : 220 patients with inv ( 16 )/ Q13951 - P35749 ( 0 · 5 % ) , 2 : 272 AML cases with t ( 8 ; 21 )/ Q01196 - Q06455 ( 0 · 7 % ) , 1 : 1029 P06748 - mutated AML ( 0 · 1 % ) , and one patient with s - AML following P43034 with a 5q - deletion . Four patients had m - P11274 ( e1a2 ) P11274 - P00519 transcripts ; one case only had an M - P11274 ( b3a2 ) breakpoint . These cases allow some interesting conclusions : The P11274 - P00519 rearrangement apparently can cooperate with the P06748 mutation similar to other class - I - mutations . The identification of Philadelphia positive subclones in < 1 % of patients with Q03701 - leukaemias fits well with previous observations that most Q03701 - AML are accompanied by activating mutations in genes enhancing proliferation . Since we observed the occurrence of the Philadelphia positive subclones at diagnosis , at relapse , or throughout the disease , the time point of the emergence of Philadelphia subclones seems variable in AML . Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact .","P04141 - 1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow - derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS - induced P01375 and P05231 secretion in human monocyte - derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 / IFN - inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up - regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .","Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK30___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .","DB08870 : its role in the treatment of anaplastic large cell and Hodgkin ' s lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin ' s lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody - drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre - existing frontline chemotherapies and as a stand - alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1 - 2 adverse reactions such as neutropenia and there have been reports of grade 3 - 4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects .","[ Melanoma : from molecular studies to the treatment breakthrough ] . Melanoma holds a leading position in the mortality from skin tumors . Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients . Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and , consequently , to the development of novel targeted drugs . More than a half of melanomas contain amine acid substitutions in serine - threonine kinase P15056 . Clinical trials involving specific P15056 inhibitors -- vemurafenib and dabrafenib -- demonstrated high efficacy of these agents towards P15056 - mutated melanoma . MEK inhibitors may show activity against both P15056 -- and P01111 - driven tumors . Mucosal and acral melanomas frequently contain mutation in P10721 receptor and can be successfully treated by imatinib . There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules P16410 , P18621 and Q9NZQ7 . In some instances these drugs allow to obtain exceptionally prolonged responses . Whole genome sequencing led to the identification of new melanoma genes , e . g . Q12879 , Q9Y4A5 , Q70Z35 , P63000 , P49842 , O00743 , etc . Molecular testing , especially P15056 mutation analysis , has become a mandatory part of melanoma diagnosis . Nevertheless , despite the revolution in melanoma treatment , the prevention of excessive ultraviolet exposure , cancer awareness and early diagnosis remain the main tools for the management of this disease .","[ Establishment of hematological malignancy model in ex vivo cell culture ] . The aim of this study was to develop an ex vivo cell culture system for establishing the hematological malignancy model . Mouse bone marrow cells were transfected with GFP - expressed retroviral vectors encoding various leukemia / lymphoma - associated fusion proteins ( P41212 - P09619 , Rabaptin5 - P09619 , p210BCR - P00519 , Q01196 - Q06455 , P06748 - Q9UM73 ) . After transfection , the cells were cultured in IMDM containing 10 % FCS without growth factors , or with one of the following growth factor combinations : ( 1 ) murine c - kit ligand ( KL ) plus human flt3 ligand ( FL ) ; ( 2 ) P08700 , thrombopoietin , DB00099 , and hyper - P05231 ( 3 / T / G / Q9NP08 ) ; ( 3 ) KL / FL plus 3 / T / G / Q9NP08 . The flow cytometry was used to detect the ability of combinations of growth factors to complement the oncogene fusion protein to support self - renewal of the transfected cells . The results showed that the transfected cells could be amplified sustainably in the logarithmic growth way . The indicated combination of P21583 ( KL ) with flt - 3 ligand ( FL ) supported the self - renewal of the marrow cells transfected with vectors encoding P41212 - P09619 , Rabaptin5 - P09619 , Q01196 - Q06455 and P06748 - Q9UM73 , in addition to KL / FL , the self - renewal of Q92817 P11274 - P00519 transfected - marrow cells also required P08700 . The morphology of cells emerged from culture can be the predictor of the corresponding oncogene - associated malignancy . It is concluded that this study establishes a culture system ex vivo which provides a generalized method for studying hematological malignancies , and may facilitate the screening for therapeutic agents .","Sulphomucin colonic type intestinal metaplasia and carcinoma in the stomach . A histochemical study of 115 cases obtained by biopsy . One hundred fifteen gastroscopic biopsy specimens ( 54 cases of carcinoma and 61 of gastritis ) were used in this histochemical study . Intestinal metaplasia ( IM ) was classified into small intestinal type ( ST ) and colonic type ( CT ) . The former may be a reactive change only . The incidence of sulphomucin colonic type ( P09683 ) metaplasia was higher in gastric carcinomas than in benign lesions ( P less than 0 . 01 ) , and a relation between P09683 metaplasia and cancer was demonstrated by both histologic and histochemical procedures . This suggests that P09683 IM is correlated with certain precancerous lesions . There was no significant difference in the incidence of O - acetyl sialomucin colonic type ( O75051 ) metaplasia between benign and malignant diseases . Further study is needed to determine why slightly more than half of the P09683 IM was accompanied by O75051 IM .","Growth of Enterococcus mundtii O95980 in medium filtrate and purification of bacteriocin O95980 by cation - exchange chromatography . Bacteriocin O95980 ( bacST15 ) , produced by Enterococcus mundtii O95980 , inhibited the growth of a variety of bacteria , including exopolysaccharide ( EPS ) - producing strains isolated from biofilms in stainless steel pipes . Maximal production of bacST15 ( 51200 AU / ml ) was recorded after 20 h of growth in P59665 broth ( Biolab ) , which was maintained throughout fermentation . Only 12800 AU / ml bacST15 has been recorded in P59665 filtrate with components smaller than 8000 Da , suggesting that nutrients larger than 8000 Da are required for optimal bacST15 production . Cation - exchange chromatography yielded an active peptide , which is 3944 . 00 Da , according to electron - spray mass spectrometry and tricin - SDS PAGE . BacST15 is smaller than the 4287 Da reported for bacteriocins ATO6 and KS produced by E . mundtii . The iso - electric point of bacST15 is between 7 and 9 , and similar to that reported for pediocin P18621 .","AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK66___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .","___MASK36___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","Synovium infiltrating T cells induce excessive synovial cell function through P10747 / P33681 pathway in patients with rheumatoid arthritis . OBJECTIVE : To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis ( RA ) , we analyzed cellular interactions between synovial cells and infiltrating T cells via P10747 / P33681 - 1 and P33681 - 2 . METHODS : Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues . Expression of P10747 , P33681 - 1 , and P33681 - 2 of synovial cells was analyzed by immunohistochemical staining and immunofluorescence analysis . Interleukin 1beta ( IL - 1beta ) , P05231 , and matrix metalloprotease 3 ( P08254 ) secreted by synovial cells in the presence of infiltrating T cells were measured by ELISA . Nuclear transcription factor P10747 responsive complex was detected by a gel shift assay . RESULTS : Both P10747 + T cells and P33681 - 1 / P33681 - 2 + cells were found accumulating in the mononuclear cell infiltrate of RA synovial tissues and P33681 - 1 / P33681 - 2 + cells were mainly LeuM3 + synovial cells . P10747 responsive complex was detected in nuclear extracts of freshly isolated lymphocytes from RA synovial tissues , but not those from osteoarthritis synovial tissues or normal peripheral blood , suggesting in vivo activation of T cells by the P10747 / P33681 - 1 / P33681 - 2 interactions . The irradiated autologous synovium infiltrating T cells notably enhanced IL - 1beta , P05231 , and P08254 production by the synovial cells . The enhancement of proinflammatory cytokine and P08254 production by the synovial cells co - cultured with the T cells was abolished by the addition of P16410 - Ig , anti - P33681 - 1 , and anti - P33681 - 2 monoclonal antibodies . CONCLUSION : These results suggest that cellular interactions between synovium infiltrating T lymphocytes and synovial cells via P33681 / P10747 pathways are intimately associated with development and exacerbation of inflammation in RA synovial cells .","Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .","Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity . Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti - cancer , anti - diabetic , anti - atherosclerotic , anti - bacterial , and anti - inflammatory activities . However , the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet . In this study , we aimed to evaluate the anti - inflammatory mechanism of scutellarein ( P09683 ) , a flavonoid isolated from Erigeron breviscapus , Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil . For this purpose , a nitric oxide ( NO ) assay , polymerase chain reaction ( PCR ) , nuclear fractionation , immunoblot analysis , a kinase assay , and an overexpression strategy were employed . Scutellarein significantly inhibited NO production in a dose - dependent manner and reduced the mRNA expression levels of inducible NO synthase ( P35228 ) and tumor necrosis factor ( P01375 ) - α in lipopolysaccharide ( LPS ) - activated RAW264 . 7 cells . In addition , P09683 also dampened nuclear factor ( NF ) - κB - driven expression of a luciferase reporter gene upon transfection of a TIR - domain - containing adapter - inducing interferon - β ( Q8IUC6 ) construct into Human embryonic kidney 293 ( P29320 293 ) cells ; similarly , NF - κ B nuclear translocation was inhibited by P09683 . Moreover , the phosphorylation levels of various upstream signaling enzymes involved in NF - κB activation were decreased by P09683 treatment in LPS - treated RAW264 . 7 cells . Finally , P09683 strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src . Therefore , our data suggest that P09683 can block the inflammatory response by directly inhibiting Src kinase activity linked to NF - κB activation .","Design and application of a novel PNA probe for the detection at single cell level of JAK2V617F mutation in Myeloproliferative Neoplasms . BACKGROUND : Mutation ( s ) of the O60674 gene ( V617F ) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms ( Q9BQR3 ) patients and its detection is now a cornerstone in the diagnostic algorithm . METHODS : We developed a novel assay based on peptide nucleic acid ( PNA ) technology coupled to immuno - fluorescence microscopy ( PNA - Q5TCZ1 ) for the specific detection at a single cell level of O60674 - mutation thus improving both the diagnostic resolution and the study of clonal prevalence . RESULTS : Using this assay we found a percentage of mutated P28906 + cells ranging from 40 % to 100 % in Polycythemia Vera patients , from 15 % to 80 % in Essential Thrombocythemia and from 25 % to 100 % in Primary Myelofibrosis . This method allows to distinguish , with a high degree of specificity , at single cell level , between P28906 + progenitor stem cells harbouring the mutated or the wild type form of O60674 in P06748 patients . CONCLUSIONS : This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer .","P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK62___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK62___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK86___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .","Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non - transplanted cohort . Metachromatic leukodystrophy ( O15121 ) is a rare inborn error of metabolism leading to severe neurological symptoms and early death . Hematopoietic P09683 ( HSCT ) is considered a treatment option , but results are inconsistent and comparison with natural history is practically missing . We compare a girl with juvenile O15121 10 years after allogeneic HSCT not only with her untreated sister , but also with a large cohort of untreated patients . The girl received HSCT at the age of 5 years when first motor signs appeared . Over 10 years she was stable with respect to her clinical course and gained cognitive abilities . Magnetic resonance imaging ( Q9BWK5 ) showed clear regression of white matter changes and magnetic resonance spectroscopy ( P59665 ) demonstrated a reversal of the initial choline increase and N - acetyl - aspartate ( NAA ) decrease . Only axonal demyelinating neuropathy showed some progression . Her gross motor function and Q9BWK5 - scores were clearly better compared with her sister and the cohort of untreated patients . Difference to her sister became apparent only 4 years after HSCT . We conclude that HSCT , early in the course of disease , can lead to stabilization of juvenile O15121 with a course clearly different from the natural history . HSCT may prevent disease progression , if performed sufficient time before loss of walking , which typically initiates rapid deterioration .","Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK55___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .","Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .","Serum macrophage migration inhibitory factor ( MIF ) levels after allogeneic hematopoietic stem cell transplantation . P14174 ( MIF ) may play an important role in the pathogenesis of acute graft - versus - host disease ( aGVHD ) after allogeneic hematopoietic stem cell transplantation ( allo - HSCT ) , as MIF plays an important role to regulate the production of tumor necrosis factor - alpha ( P01375 ) , one of the inflammatory cytokines which induces and exacerbates aGVHD . We examined the association between serum MIF levels and aGVHD vs . chronic GVHD ( cGVHD ) in allo - P09683 patients in this study . We found a significant increase in the peak serum MIF ( 14 . 46 ng +/- 1 . 47 ng / ml ) at onset in patients that developed aGVHD ( n = 23 , P = 0 . 009 ) . We also found that mean serum MIF levels in patients who developed extensive type cGVHD within 6 months ( 12 . 58 +/- 2 . 18 ng / ml , n = 13 ) were significantly higher than MIF levels before allo - HSCT ( 7 . 86 +/- 1 . 17 ng / ml , n = 19 , P = 0 . 04 ) . Therefore , we speculated that serum MIF levels increase during the active phase of both aGVHD and cGVHD .","Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .","DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and / or refractory Hodgkin ' s lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR - HL ) have poor outcomes . DB08870 ( BV ) , an antibody - drug conjugate comprising an anti - P28908 antibody conjugated to the potent anti - microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo - P09683 ) in patients with RR - HL treated by BV in a named patient program in two French institutions . Twenty - four adult patients with histologically proven P28908 (+) RR - HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45 . 8 % ) , while five patients were in partial response ( 20 . 8 % ) , with an overall response rate of 66 . 6 % . Eight patients failed to respond to BV ( 33 . 3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto - P09683 ) , three patients received a tandem auto - P09683 / allo - P09683 , nine patients received allo - P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment - related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow - up of 20 months ( range 10 . 5 - 43 . 2 ) , none of them relapsed or died . BV followed by allo - P09683 represents an effective salvage regimen in patients with RR - HL .","Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via P40763 - dependent induction of P14902 . Hepatic stellate cells ( HSCs ) are critical for hepatic wound repair and tissue remodeling . They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver . The functional relationship between HSCs and the professional migratory APCs in the liver , that is , dendritic cells ( DCs ) , has not been evaluated . In this article , we report that murine liver DCs colocalize with HSCs in vivo under normal , steady - state conditions , and cluster with HSCs in vitro . In vitro , HSCs secrete high levels of DC chemoattractants , such as MΙP - 1α and P13500 , as well as cytokines that modulate DC activation , including P01375 - α , P05231 , and IL - 1β . Culture of HSCs with conventional liver myeloid ( m ) DCs resulted in increased P05231 and P22301 secretion compared with that of either cell population alone . Coculture also resulted in enhanced expression of costimulatory ( P33681 , P42081 ) and coinhibitory ( Q9NZQ7 ) molecules on mDCs . P19526 - induced mDC maturation required cell - cell contact and could be blocked , in part , by neutralizing MΙP - 1α or P13500 . P19526 - induced mDC maturation was dependent on activation of P40763 in mDCs and , in part , on P19526 - secreted P05231 . Despite upregulation of costimulatory molecules , mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation , which was independent of Q9NZQ7 , but dependent upon P19526 - induced P40763 activation and subsequent upregulation of P14902 . In conclusion , by promoting P14902 expression , HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity .","Functional validation of the anaplastic lymphoma kinase signature identifies P17676 and Q16548 as critical target genes . Anaplastic large cell lymphomas ( ALCLs ) represent a subset of lymphomas in which the anaplastic lymphoma kinase ( Q9UM73 ) gene is frequently fused to the nucleophosmin ( P06748 ) gene . We previously demonstrated that the constitutive phosphorylation of Q9UM73 chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that Q9UM73 activity is strictly required for the survival of Q9UM73 - positive ALCL cells . To elucidate the signaling pathways required for Q9UM73 - mediated transformation and tumor maintenance , we analyzed the transcriptomes of multiple Q9UM73 - positive ALCL cell lines , abrogating their Q9UM73 - mediated signaling by inducible Q9UM73 RNA interference ( RNAi ) or with potent and cell - permeable Q9UM73 inhibitors . Transcripts derived from the gene expression profiling ( GEP ) analysis uncovered a reproducible signature , which included a novel group of Q9UM73 - regulated genes . Functional RNAi screening on a set of these Q9UM73 transcriptional targets revealed that the transcription factor C / EBPbeta and the antiapoptotic protein Q16548 are absolutely necessary to induce cell transformation and / or to sustain the growth and survival of Q9UM73 - positive ALCL cells . Thus , we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions .","Advances in immunotherapy of chronic myeloid leukemia CML . Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene P11274 - P00519 . However , these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation . Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations . Compelling evidence indicates that more modern , antigen - specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective . Amongst these , particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia - associated antigens , since this approach allows to circumvent HLA - restriction of the leukemia - associated T cell epitopes that have been eventually identified . Combining these strategies with monoclonal antibodies , such as anti - P16410 or anti - P18621 , may help to obtain even stronger immune responses and better clinical results . This narrative review addresses this topic by focusing in particular on the cell - based immunotherapeutic strategies for CML and on the issue of the leukemia - associated antigens to be selected for targeting .","Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .","Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .","Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK55___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .","Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high - fat diet induced obese mice . Calorie restriction is the most effective way of expanding life - span and decreasing morbidity . It improves insulin sensitivity and delays the age - related loss of dopamine receptor D ( 2 ) ( P14416 ) expression in the brain . Conversely , high - fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild - type C57Bl6 male mice was restricted to 60 % of ad lib . intake while they were treated with the P14416 antagonist haloperidol or vehicle using s . c . implanted pellets . Mice with ad lib . access to food receiving vehicle treatment served as controls . All mice received high - fat food throughout the experiment . After 10 weeks , an i . p . glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie - restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . ___MASK73___ completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high - fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","Effects of C - phycocyanin and Spirulina on salicylate - induced tinnitus , expression of DB01221 receptor and inflammatory genes . Effects of C - phycocyanin ( C - PC ) , the active component of Spirulina platensis water extract on the expressions of N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , tumor necrosis factor - α ( P01375 - α ) , interleukin - 1β ( IL - 1β ) , and cyclooxygenase type 2 ( P35354 ) genes in the cochlea and inferior colliculus ( IC ) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate . The results showed that 4 - day salicylate treatment ( unlike 4 - day saline treatment ) caused a significant increase in Q13224 , P01375 - α , and IL - 1β mRNAs expression in the cochlea and IC . On the other hand , dietary supplementation with C - PC or Spirulina platensis water extract significantly reduced the salicylate - induced tinnitus and down - regulated the mRNAs expression of Q13224 , P01375 - α , IL - 1β mRNAs , and P35354 genes in the cochlea and IC of mice . The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes .","Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .","Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .","Altered expression of P11021 , P11142 and Q99497 in spinocerebellar ataxia type 17 identified by 2 - dimensional fluorescence difference in gel electrophoresis . BACKGROUND : Expansion of the CAG repeat of the TATA - box binding protein ( P20226 ) gene has been identified as the causative mutations in spinocerebellar ataxia 17 ( SCA17 ) . P20226 is ubiquitously expressed in both central nervous system and peripheral tissues . The underlying molecular changes of SCA17 are rarely explored . METHODS : To study the molecular mechanisms underlying SCA17 , we generated stably induced isogenic 293 cells expressing normal P20226 - Q ( 36 ) and expanded P20226 - Q ( 61 ) and analyzed the expressed proteins using two - dimensional difference in gel electrophoresis ( 2D - DIGE ) , followed by mass spectrometry and immunoblotting . RESULTS : Upon induction with doxycycline , the expanded P20226 - Q ( 61 ) formed aggregates with significant increase in the cell population at subG1 phase and cleaved caspase - 3 . Proteomics study identified a total of 16 proteins with expression changes greater than 1 . 5 fold . Among the 16 proteins , Q99497 , O76003 , P09651 , Q14691 , P06733 , P61978 and P06748 are increased , and P05154 , P11021 , P18206 , Q92945 , P11142 , P31943 , Q16891 , P55072 and P14866 are decreased in cells expressing P20226 - Q ( 61 ) compared with those expressing P20226 - Q ( 36 ) . The altered expression of P11021 , P11142 and Q99497 were further validated by 2D and Western immunoblot analyses . CONCLUSIONS : The results illustrate the utility of proteomics to identify alterations of proteins which underlie pathogenesis of SCA17 , and may serve as potential therapeutic targets .","Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .","Intracellular capture of P33681 in antigen - presenting cells reduces costimulatory activity . P16410 gene constructs were designed to express P16410 exclusively in the endoplasmic reticulum ( ER ) . Four different P16410 gene constructs were transfected into P29320 293 ( human embryonic kidney ) and A20 ( Balb / c mouse B lymphoma ) cells . All constructs contained an ER retention signal and coded for P16410 expression in the ER . One of the constructs , which contained the membrane part of P16410 , coded for an expression both on the cell surface and in the ER . Three of the expressed P16410 types ( including the ER - membrane - expressed form ) caused a reduced surface expression of P33681 in the A20 cells . Only constructs which allow dimerization of P16410 showed this effect . It is assumed that intracellular P16410 bound P33681 and inhibited therefore the transport of P33681 to the surface . The binding obviously caused also an enhanced degradation of the complexes because both proteins showed a low concentration in the transfected cell lines . P16410 - transfected and P33681 - reduced A20 cells showed a diminished costimulating activity upon T cells . This was demonstrated by a reduced proliferation of T cells from ovalbumin - immunized Balb / c mice , incubated with ovalbumin peptide - primed P16410 - transfected A20 cells .","Microenvironment of the murine mammary carcinoma 4T1 : endogenous P01579 affects tumor phenotype , growth , and metastasis . P01579 has a profound influence on growth and metastasis of solid tumors . This is true for the murine mammary carcinoma 4T1 which grows faster and metastasizes much more readily when transplanted into the mammary fatpads of P01579 (-/-) mice . We were interested in determining which infiltrating hematopoietic cells produce P01579 within the 4T1 tumor microenvironment . 4T1 tumors were infiltrated with progressively increasing numbers of F4 / 80 (+)/ CD11c (+) myeloid cells , many of which were also Gr - 1 (+) , and Gr - 1 (+)/ CD11b (+) granulocytes . Only small numbers of P01730 T cells , CD8 T cells , NK cells , and gammadelta T cells , the most likely P01579 - producing cells , were seen at any time point . Sensitive intracellular cytokine staining and flow cytometry revealed no tumor - infiltrating hematopoietic cells with detectable levels of intracellular P01579 , although P01579 mRNA transcripts were detected in tumor tissue . However , a progressive increase in the expression of three P01579 - inducible surface membrane proteins ( Q9NZQ7 , I - A ( d ) , and P05362 ) on growing 4T1 tumor cells indicated the presence of biologically active P01579 in the tumor microenvironment . Moreover , 4T1 tumor cells from in vitro culture expressed these surface molecules 48 h after intratumoral injection into mature tumors . These data suggest that very low amounts of endogenous P01579 elaborated by infiltrating hematopoietic cells within the microenvironment of a solid tumor can achieve biologically active concentrations and affect tumor phenotype , growth , and metastasis .","[ Cutaneous non - tuberculous mycobacterial infection following cord blood stem cell transplantation ] . We describe a 4 - year - old - girl with familial hemophagocytic lymphohistiocytosis ( FHL ) who developed disseminated cutaneous nontuberculous mycobacterial ( Q9P121 ) infection after unrelated cord blood stem cell transplantation ( uCBSCT ) . After transplantation , the patient developed steroid - refractory acute graft - versus - host disease , and was given methylprednisolone , cyclosporin and mycophenolate mofetil . Six months after uCBSCT , cutaneous lesions that looked like insect bites appeared and spread widely over the thighs . Q9P121 infection was diagnosed by skin biopsy although no organism could be identified . DB01017 ( MINO ) and sulfamethoxazole / trimethoprim ( ST ) were administered . However , the cutaneous disease followed a course of remissions and exacerbations . One month after the skin biopsy , mycobacterium chelonae was detected by bacteriological culture of abscess drainage . Ten months after uCBSCT , the cutaneous lesions quickly progressed and the inguinal lymph nodes became enlarged and painful . Then the antibiotics were switched from MINO and ST to amikacin and clarithromycin ( P62158 ) based on the results of mycobacterial susceptibility test . The cutaneous lesions gradually improved after continuous administration of P62158 . Cutaneous Q9P121 infection is rare , but it may occur in immunocompromised patients after P09683 .","Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK49___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK49___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .","Proteomic , cellular , and network analyses reveal new P51452 interactions with nucleolar proteins in HeLa cells . P51452 ( or Vaccinia virus phosphatase P28562 - related ; P51452 ) is a small dual - specificity phosphatase known to dephosphorylate c - Jun N - terminal kinases and extracellular signal - regulated kinases . In human cervical cancer cells , P51452 is overexpressed , localizes preferentially to the nucleus , and plays a key role in cellular proliferation and senescence triggering . Other P51452 functions are still unknown , as illustrated by recent and unpublished results from our group showing that this enzyme mediates DNA damage response or repair processes . In this study , we sought to identify new interactions between P51452 and proteins directly or indirectly involved in or correlated with its biological roles in HeLa cells exposed to gamma or UV radiation . By using Q86UG4 - DUSP as bait , we pulled down interacting proteins and identified them by LC - MS / MS . Of the 46 proteins obtained , six hits were extensively validated by immune techniques ; the proteins P06748 , HnRNP C1 / P06681 , and P19338 were the most promising targets found to directly interact with P51452 . We then analyzed the P51452 interactomes using physical protein - protein interaction networks using our hits as the seed list . The validated hits as well as unvalidated hits fluctuated on the P51452 interactomes of HeLa cells , independent of the time post radiation , which confirmed our proteomic and experimental data and clearly showed the proximity of P51452 to proteins involved in processes intimately related to DNA repair and senescence , such as P12956 and Tert , via interactions with nucleolar proteins , which were identified in this study , that regulate DNA / RNA structure and functions .","Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs : behavioural and biochemical evidence . Clinical evidence suggests that stimulation of the D ( 1 ) rather than P14416 is related to the development of dyskinesias in Parkinson ' s disease ( PD ) . We evaluated , in the 6 - hydroxydopamine rat model of PD , sensitization of contralateral turning ( P09683 ) behaviour and abnormal involuntary movements ( AIMs ) as behavioural parameters of dyskinetic response , and changes in zif - 268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D ( 2 )/ D ( 3 ) agonist ropinirole , defined as a mild dyskinetic drug in the clinic . Results were compared with previous findings on repeated L - dopa treatment . Ropinirole displayed a mild dyskinetic response characterized by P09683 only , which contrasted with the presence of P09683 in association with AIMs elicited by repeated L - dopa . Zif - 268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole , in contrast to hyper - expression of zif - 268 mRNA selectively induced by L - dopa in striatonigral neurons . Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats ; in contrast , a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole .","Kinetics of Th1 / Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo - P09683 : results of a prospective study . The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD ( cGVHD ) is still controversial . Earlier studies , which were either retrospective or analysed one or a few factors , did not show unequivocal results . We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo - P09683 to investigate their possible correlation with cGVHD . Levels of P05112 , P05231 , P22301 , P01579 , tumour necrosis factor - alpha ( P01375 ) and its soluble receptors were assessed by ELISA in 30 patients at different times after P09683 . Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines . A multivariate analysis was performed using principal component analysis and multi - factor Q9UNW9 ( analysis of variance ) . Eighteen patients developed cGVHD at a median time of 6 months ( range , 5 - 9 ) after P09683 . In multivariate analysis , we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after P09683 . These clusters changed their composition over time , but they constantly included natural killer ( NK ) and P16410 + T cells as negative predictors of cGVHD . P01375 prevailed among other cytokines before the onset of cGVHD . This prevalence could be related partly to the defect of immunoregulatory cells .","Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . ___MASK73___ was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .","___MASK73___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK73___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin ' s lymphoma . PURPOSE : DB08870 is an antibody - drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 - expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 - positive lymphomas . PATIENTS AND METHODS : In this multinational , open - label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin ' s lymphoma ( HL ) after autologous stem - cell transplantation ( auto - P09683 ) . Patients had histologically documented P28908 - positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1 . 8 mg / kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression - free survival time for all patients was 5 . 6 months , and the median duration of response for those in CR was 20 . 5 months . After a median observation time of more than 1 . 5 years , 31 patients were alive and free of documented progressive disease . The most common treatment - related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto - P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy .","3 , 4 - Dimethoxyphenyl bis - benzimidazole derivative , mitigates radiation - induced DNA damage . Radiation - induced DNA damage initiates a series of overlapping responses that include DNA damage recognition and repair , induction of cell cycle checkpoints , senescence and / or apoptosis . This study assessed the DNA damage response and whole genome expression profile in two mammalian cell lines ( P29320 and U87 ) in response to ( 5 -{ 4 - methylpiperazin - 1 - yl }- 2 -[ 2 '-( 3 , 4 - dimethoxyphenyl )- 5 '- benzimidazolyl ] benzimidazole ) P28067 and ionizing radiation . P28067 has been shown to act as a potent radiation protector , yielding significant levels of protection , i . e . , 20 . 9 % in P29320 cells and 21 . 2 % in U87 cells . Our findings revealed treatment with P28067 significantly reduced γ - P16104 , Q12888 and Rad51 foci formation after irradiation . Q96HU1 kinase , WNT signaling and p53 pathways were found to be activated in P28067 - treated cells . In addition , the DNA damage response genes , HSP70 , P10809 , Q06830 , Q9BXM0 , P27797 , P06748 , P0CG48 , and Q01105 showed differential regulation in P28067 , P28067 + radiation and radiation - treated cells . The data suggest that P28067 - influenced repertoire of repair proteins , which are an indispensable part of the cell , interplay with each other to reduce DNA damage and maintain the genomic integrity of the cell .","Induction of oral tolerance to oxidized low - density lipoprotein ameliorates atherosclerosis . BACKGROUND : Oxidation of low - density lipoprotein ( LDL ) and the subsequent processing of oxidized LDL ( oxLDL ) by macrophages results in activation of specific T cells , which contributes to the development of atherosclerosis . Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis . METHODS AND RESULTS : Tolerance to oxLDL and malondialdehyde - treated LDL ( MDA - LDL ) was induced in P01130 -/- mice fed a Western - type diet by oral administration of oxLDL or MDA - LDL before the induction of atherogenesis . Oral tolerance to oxLDL resulted in a significant attenuation of the initiation ( 30 % to 71 % ; P < 0 . 05 ) and progression ( 45 % ; P < 0 . 05 ) of atherogenesis . Tolerance to oxLDL induced a significant increase in P01730 + CD25 + Foxp3 + cells in spleen and mesenteric lymph nodes , and these cells specifically responded to oxLDL with increased transforming growth factor - beta production . Tolerance to oxLDL also increased the mRNA expression of Foxp3 , P16410 , and CD25 in the plaque . In contrast , tolerance to MDA - LDL did not affect atherogenesis . CONCLUSIONS : OxLDL - specific T cells , present in P01130 -/- mice and important contributors in the immune response leading to atherosclerotic plaque , can be counteracted by oxLDL - specific P01730 + CD25 + Foxp3 + regulatory T cells activated via oral tolerance induction to oxLDL . We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis .","Q9UM73 as a novel lymphoma - associated tumor antigen : identification of 2 HLA - A2 . 1 - restricted CD8 + T - cell epitopes . Oncogenic anaplastic lymphoma kinase ( Q9UM73 ) fusion proteins ( P06748 / Q9UM73 and associated variants ) are expressed in about 60 % of anaplastic large cell lymphomas ( ALCLs ) but are absent in normal tissues . In this study , we investigated whether Q9UM73 , which is expressed at high levels in lymphoma cells , could be a target for antigen - specific cell - mediated immunotherapy . A panel of Q9UM73 - derived peptides was tested for their binding affinity to HLA - A * 0201 molecules . Binding peptides were assessed for their capacity to elicit a specific immune response mediated by cytotoxic T lymphocytes ( CTLs ) both in vivo , in HLA - A * 0201 transgenic mice , and in vitro in the peripheral blood lymphocytes ( PBLs ) from healthy donors . Two HLA - A * 0201 - restricted CTL epitopes , p280 - 89 ( SLAMLDLLHV ) and p375 - 86 ( GVLLWEIFSL ) , both located in the Q9UM73 kinase domain were identified . The p280 - 89 - and p375 - 86 - induced peptide - specific CTL lines were able to specifically release interferon - gamma ( P01579 ) on stimulation with Q9UM73 peptide - pulsed autologous Epstein - Barr virus - transformed B cells ( LCLs ) or P24752 cells . Anti - Q9UM73 CTLs lysed HLA - matched ALCL and neuroblastoma cell lines endogenously expressing Q9UM73 proteins . CTL activity was inhibited by anti - HLA - A2 monoclonal antibody CR11 . 351 , consistent with a class I - restricted mechanism of cytotoxicity . These results show the existence of functional anti - Q9UM73 CTL precursors within the peripheral T - cell repertoire of healthy donors , clearly indicating Q9UM73 as a tumor antigen and Q9UM73 - derived peptides , p280 - 89 and p375 - 86 , as suitable epitopes for the development of vaccination strategies .","Association between high interleukin - 6 levels and adverse outcome after autologous haemopoietic stem cell transplantation . We studied interleukin - 6 ( P05231 ) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation ( P09683 ) ( either peripheral blood stem cell transplantation ( PBSCT ) or bone marrow transplantation ( BMT ) ) for neoplastic diseases to determine if there was a relationship between P05231 level and rate of haemopoietic recovery , length of stay in hospital , and survival . There was no apparent delay in post - transplant recovery associated with elevated P05231 levels . However , increased values of P05231 tended to be associated with an increased length of stay in hospital ( P = 0 . 083 ) . There was a highly significant adverse association between higher P05231 levels and survival following transplantation ( P = 0 . 0001 ) . This association remained significant ( P = 0 . 013 ) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT ( that is , excluding patients who had undergone PBSCT ) ( n = 13 ) . Knowledge of P05231 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic P09683 .","Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 ."],"string":"[\n \"DB00099 - induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy : safety , feasibility and evidence for an efficient in vivo purging . Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia ( CML ) . Further , the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation ( P09683 ) reduces the number of therapeutic options in a number of patients . To assess the possibility of stem cell mobilization ( DB00919 ) during imatinib therapy we performed granulocyte colony - stimulating factor ( filgrastim )- induced DB00919 and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients . Aphaeresis was successful in 13 patients ( 72 % ) ( > or = 2 . 0 x 10 ( 6 ) P28906 + cells / kg body weight ) and five ( 28 % ) harvests could be obtained , which were negative for P11274 / P00519 mRNA as assessed by nested - reverse transcription polymerase chain reaction ( RT - PCR ) . All harvests , except one , were negative after first round RT - PCR , implicating a low level of CML cell contamination . There was no significant change in peripheral P11274 / P00519 transcript load after DB00919 as assessed by quantitative real - time RT - PCR . Fifteen patients remained stable in complete cytogenetic remission ( CCR ) during a median observation period of 9 . 3 months . One patient achieved a molecular remission shortly after DB00919 . Another patient who exhibited rising P11274 / P00519 mRNA levels before DB00919 achieved CCR after autologous P09683 with the generated harvest . One patient with a Philadelphia chromosome - negative , P11274 / P00519 - positive CML showed a cytogenetic relapse 6 months after DB00919 . We conclude that filgrastim - induced P28906 + cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients . Additionally , we found evidence that this procedure could generate stem cell harvests that exhibit non - detectable levels of P11274 / P00519 mRNA .\",\n \"Comparison of variations detection between whole - genome amplification methods used in single - cell resequencing . BACKGROUND : Single - cell resequencing ( SCRS ) provides many biomedical advances in variations detection at the single - cell level , but it currently relies on whole genome amplification ( WGA ) . Three methods are commonly used for WGA : multiple displacement amplification ( MDA ) , degenerate - oligonucleotide - primed PCR ( DOP - PCR ) and multiple annealing and looping - based amplification cycles ( MALBAC ) . However , a comprehensive comparison of variations detection performance between these WGA methods has not yet been performed . RESULTS : We systematically compared the advantages and disadvantages of different WGA methods , focusing particularly on variations detection . Low - coverage whole - genome sequencing revealed that DOP - PCR had the highest duplication ratio , but an even read distribution and the best reproducibility and accuracy for detection of copy - number variations ( CNVs ) . However , MDA had significantly higher genome recovery sensitivity ( ~ 84 % ) than DOP - PCR ( ~ 6 % ) and MALBAC ( ~ 52 % ) at high sequencing depth . MALBAC and MDA had comparable single - nucleotide variations detection efficiency , false - positive ratio , and allele drop - out ratio . We further demonstrated that SCRS data amplified by either MDA or MALBAC from a gastric cancer cell line could accurately detect gastric cancer CNVs with comparable sensitivity and specificity , including amplifications of 12p11 . 22 ( P01116 ) and 9p24 . 1 ( O60674 , Q9NZQ7 , and Q9BQ51 ) . CONCLUSIONS : Our findings provide a comprehensive comparison of variations detection performance using SCRS amplified by different WGA methods . It will guide researchers to determine which WGA method is best suited to individual experimental needs at single - cell level .\",\n \"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK27___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"JunB induced by constitutive P28908 - extracellular signal - regulated kinase 1 / 2 mitogen - activated protein kinase signaling activates the P28908 promoter in anaplastic large cell lymphoma and reed - sternberg cells of Hodgkin lymphoma . High expression of P28908 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . Possible interactions of P28908 and JunB were examined in this study . We found that the P28908 promoter in tumor cells of both nucleophosmin ( P06748 ) - anaplastic lymphoma kinase ( Q9UM73 ) - positive and P06748 - Q9UM73 - negative ALCL and HL is regulated by a constitutively active P28908 - extracellular signal - regulated kinase ( P29323 ) 1 / 2 mitogen - activated protein kinase ( MAPK ) . Phosphorylation of P27361 / 2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL . P28908 - P27361 / 2 MAPK signals induce JunB expression , which maintains high activity of the P28908 promoter . JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL . These results show a common mechanism of P28908 overexpression in ALCL and HL , although the outcome of P28908 signaling differs between P06748 - Q9UM73 - positive ALCL and P06748 - Q9UM73 - negative ALCL , cutaneous ALCL , and HL as we recently reported .\",\n \"Microtubule - depolymerizing agents used in antibody - drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody - drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target - specificity and high therapeutic activity in patients with cancer . DB08870 represents a first - in - class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor - resident DCs to the tumor - draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen - specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin - based therapies , such as brentuximab vedotin , with immune - based therapies .\",\n \"DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti - P28908 antibody - drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high - risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high - dose chemotherapy with autologous stem - cell support . There has been no standard therapy for relapsed / refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .\",\n \"Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha - mediated ceramide de novo synthesis in colon cancer cells . PURPOSE : Cannabinoids have been recently proposed as a new family of potential antitumor agents . The present study was undertaken to investigate the expression of the two cannabinoid receptors , P21554 and CB2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation . EXPERIMENTAL DESIGN : Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD - 1 and HT29 colon cancer cell lines . The effects of the P21554 agonist arachinodyl - 2 '- chloroethylamide and the CB2 agonist N - cyclopentyl - 7 - methyl - 1 -( 2 - morpholin - 4 - ylethyl )- 1 , 8 - naphthyridin - 4 ( 1H )- on - 3 - carboxamide ( CB13 ) on tumor cell apoptosis and ceramide and tumor necrosis factor ( P01375 ) - alpha production were evaluated . The knockdown of P01375 mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 and , more efficiently , of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD - 1 and HT29 cells . Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis . The CB2 agonist CB13 also reduced the growth of DLD - 1 cells in a mouse model of colon cancer . The knockdown of P01375 mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 acts as a link between cannabinoid receptor activation and ceramide production .\",\n \"Subclones with the t ( 9 ; 22 )/ P11274 - P00519 rearrangement occur in AML and seem to cooperate with distinct genetic alterations . In AML , cooperation of mutations suppressing differentiation ( ' class - II - mutations ' ) with ' class - I - mutations ' increasing cell proliferation is frequent . In rare cases of myeloid malignancies , the P11274 - P00519 fusion was reported to cooperate as class - I - mutation with class - II - mutations , but most cases had to be classified as blast phase of chronic myeloid leukaemia ( CML ) . We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions : 1 : 220 patients with inv ( 16 )/ Q13951 - P35749 ( 0 · 5 % ) , 2 : 272 AML cases with t ( 8 ; 21 )/ Q01196 - Q06455 ( 0 · 7 % ) , 1 : 1029 P06748 - mutated AML ( 0 · 1 % ) , and one patient with s - AML following P43034 with a 5q - deletion . Four patients had m - P11274 ( e1a2 ) P11274 - P00519 transcripts ; one case only had an M - P11274 ( b3a2 ) breakpoint . These cases allow some interesting conclusions : The P11274 - P00519 rearrangement apparently can cooperate with the P06748 mutation similar to other class - I - mutations . The identification of Philadelphia positive subclones in < 1 % of patients with Q03701 - leukaemias fits well with previous observations that most Q03701 - AML are accompanied by activating mutations in genes enhancing proliferation . Since we observed the occurrence of the Philadelphia positive subclones at diagnosis , at relapse , or throughout the disease , the time point of the emergence of Philadelphia subclones seems variable in AML . Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact .\",\n \"P04141 - 1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow - derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS - induced P01375 and P05231 secretion in human monocyte - derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 / IFN - inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up - regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .\",\n \"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK30___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \\\" neurological dose \\\" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .\",\n \"DB08870 : its role in the treatment of anaplastic large cell and Hodgkin ' s lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin ' s lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody - drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre - existing frontline chemotherapies and as a stand - alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1 - 2 adverse reactions such as neutropenia and there have been reports of grade 3 - 4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects .\",\n \"[ Melanoma : from molecular studies to the treatment breakthrough ] . Melanoma holds a leading position in the mortality from skin tumors . Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients . Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and , consequently , to the development of novel targeted drugs . More than a half of melanomas contain amine acid substitutions in serine - threonine kinase P15056 . Clinical trials involving specific P15056 inhibitors -- vemurafenib and dabrafenib -- demonstrated high efficacy of these agents towards P15056 - mutated melanoma . MEK inhibitors may show activity against both P15056 -- and P01111 - driven tumors . Mucosal and acral melanomas frequently contain mutation in P10721 receptor and can be successfully treated by imatinib . There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules P16410 , P18621 and Q9NZQ7 . In some instances these drugs allow to obtain exceptionally prolonged responses . Whole genome sequencing led to the identification of new melanoma genes , e . g . Q12879 , Q9Y4A5 , Q70Z35 , P63000 , P49842 , O00743 , etc . Molecular testing , especially P15056 mutation analysis , has become a mandatory part of melanoma diagnosis . Nevertheless , despite the revolution in melanoma treatment , the prevention of excessive ultraviolet exposure , cancer awareness and early diagnosis remain the main tools for the management of this disease .\",\n \"[ Establishment of hematological malignancy model in ex vivo cell culture ] . The aim of this study was to develop an ex vivo cell culture system for establishing the hematological malignancy model . Mouse bone marrow cells were transfected with GFP - expressed retroviral vectors encoding various leukemia / lymphoma - associated fusion proteins ( P41212 - P09619 , Rabaptin5 - P09619 , p210BCR - P00519 , Q01196 - Q06455 , P06748 - Q9UM73 ) . After transfection , the cells were cultured in IMDM containing 10 % FCS without growth factors , or with one of the following growth factor combinations : ( 1 ) murine c - kit ligand ( KL ) plus human flt3 ligand ( FL ) ; ( 2 ) P08700 , thrombopoietin , DB00099 , and hyper - P05231 ( 3 / T / G / Q9NP08 ) ; ( 3 ) KL / FL plus 3 / T / G / Q9NP08 . The flow cytometry was used to detect the ability of combinations of growth factors to complement the oncogene fusion protein to support self - renewal of the transfected cells . The results showed that the transfected cells could be amplified sustainably in the logarithmic growth way . The indicated combination of P21583 ( KL ) with flt - 3 ligand ( FL ) supported the self - renewal of the marrow cells transfected with vectors encoding P41212 - P09619 , Rabaptin5 - P09619 , Q01196 - Q06455 and P06748 - Q9UM73 , in addition to KL / FL , the self - renewal of Q92817 P11274 - P00519 transfected - marrow cells also required P08700 . The morphology of cells emerged from culture can be the predictor of the corresponding oncogene - associated malignancy . It is concluded that this study establishes a culture system ex vivo which provides a generalized method for studying hematological malignancies , and may facilitate the screening for therapeutic agents .\",\n \"Sulphomucin colonic type intestinal metaplasia and carcinoma in the stomach . A histochemical study of 115 cases obtained by biopsy . One hundred fifteen gastroscopic biopsy specimens ( 54 cases of carcinoma and 61 of gastritis ) were used in this histochemical study . Intestinal metaplasia ( IM ) was classified into small intestinal type ( ST ) and colonic type ( CT ) . The former may be a reactive change only . The incidence of sulphomucin colonic type ( P09683 ) metaplasia was higher in gastric carcinomas than in benign lesions ( P less than 0 . 01 ) , and a relation between P09683 metaplasia and cancer was demonstrated by both histologic and histochemical procedures . This suggests that P09683 IM is correlated with certain precancerous lesions . There was no significant difference in the incidence of O - acetyl sialomucin colonic type ( O75051 ) metaplasia between benign and malignant diseases . Further study is needed to determine why slightly more than half of the P09683 IM was accompanied by O75051 IM .\",\n \"Growth of Enterococcus mundtii O95980 in medium filtrate and purification of bacteriocin O95980 by cation - exchange chromatography . Bacteriocin O95980 ( bacST15 ) , produced by Enterococcus mundtii O95980 , inhibited the growth of a variety of bacteria , including exopolysaccharide ( EPS ) - producing strains isolated from biofilms in stainless steel pipes . Maximal production of bacST15 ( 51200 AU / ml ) was recorded after 20 h of growth in P59665 broth ( Biolab ) , which was maintained throughout fermentation . Only 12800 AU / ml bacST15 has been recorded in P59665 filtrate with components smaller than 8000 Da , suggesting that nutrients larger than 8000 Da are required for optimal bacST15 production . Cation - exchange chromatography yielded an active peptide , which is 3944 . 00 Da , according to electron - spray mass spectrometry and tricin - SDS PAGE . BacST15 is smaller than the 4287 Da reported for bacteriocins ATO6 and KS produced by E . mundtii . The iso - electric point of bacST15 is between 7 and 9 , and similar to that reported for pediocin P18621 .\",\n \"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK66___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .\",\n \"___MASK36___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"Synovium infiltrating T cells induce excessive synovial cell function through P10747 / P33681 pathway in patients with rheumatoid arthritis . OBJECTIVE : To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis ( RA ) , we analyzed cellular interactions between synovial cells and infiltrating T cells via P10747 / P33681 - 1 and P33681 - 2 . METHODS : Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues . Expression of P10747 , P33681 - 1 , and P33681 - 2 of synovial cells was analyzed by immunohistochemical staining and immunofluorescence analysis . Interleukin 1beta ( IL - 1beta ) , P05231 , and matrix metalloprotease 3 ( P08254 ) secreted by synovial cells in the presence of infiltrating T cells were measured by ELISA . Nuclear transcription factor P10747 responsive complex was detected by a gel shift assay . RESULTS : Both P10747 + T cells and P33681 - 1 / P33681 - 2 + cells were found accumulating in the mononuclear cell infiltrate of RA synovial tissues and P33681 - 1 / P33681 - 2 + cells were mainly LeuM3 + synovial cells . P10747 responsive complex was detected in nuclear extracts of freshly isolated lymphocytes from RA synovial tissues , but not those from osteoarthritis synovial tissues or normal peripheral blood , suggesting in vivo activation of T cells by the P10747 / P33681 - 1 / P33681 - 2 interactions . The irradiated autologous synovium infiltrating T cells notably enhanced IL - 1beta , P05231 , and P08254 production by the synovial cells . The enhancement of proinflammatory cytokine and P08254 production by the synovial cells co - cultured with the T cells was abolished by the addition of P16410 - Ig , anti - P33681 - 1 , and anti - P33681 - 2 monoclonal antibodies . CONCLUSION : These results suggest that cellular interactions between synovium infiltrating T lymphocytes and synovial cells via P33681 / P10747 pathways are intimately associated with development and exacerbation of inflammation in RA synovial cells .\",\n \"Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .\",\n \"Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity . Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti - cancer , anti - diabetic , anti - atherosclerotic , anti - bacterial , and anti - inflammatory activities . However , the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet . In this study , we aimed to evaluate the anti - inflammatory mechanism of scutellarein ( P09683 ) , a flavonoid isolated from Erigeron breviscapus , Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil . For this purpose , a nitric oxide ( NO ) assay , polymerase chain reaction ( PCR ) , nuclear fractionation , immunoblot analysis , a kinase assay , and an overexpression strategy were employed . Scutellarein significantly inhibited NO production in a dose - dependent manner and reduced the mRNA expression levels of inducible NO synthase ( P35228 ) and tumor necrosis factor ( P01375 ) - α in lipopolysaccharide ( LPS ) - activated RAW264 . 7 cells . In addition , P09683 also dampened nuclear factor ( NF ) - κB - driven expression of a luciferase reporter gene upon transfection of a TIR - domain - containing adapter - inducing interferon - β ( Q8IUC6 ) construct into Human embryonic kidney 293 ( P29320 293 ) cells ; similarly , NF - κ B nuclear translocation was inhibited by P09683 . Moreover , the phosphorylation levels of various upstream signaling enzymes involved in NF - κB activation were decreased by P09683 treatment in LPS - treated RAW264 . 7 cells . Finally , P09683 strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src . Therefore , our data suggest that P09683 can block the inflammatory response by directly inhibiting Src kinase activity linked to NF - κB activation .\",\n \"Design and application of a novel PNA probe for the detection at single cell level of JAK2V617F mutation in Myeloproliferative Neoplasms . BACKGROUND : Mutation ( s ) of the O60674 gene ( V617F ) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms ( Q9BQR3 ) patients and its detection is now a cornerstone in the diagnostic algorithm . METHODS : We developed a novel assay based on peptide nucleic acid ( PNA ) technology coupled to immuno - fluorescence microscopy ( PNA - Q5TCZ1 ) for the specific detection at a single cell level of O60674 - mutation thus improving both the diagnostic resolution and the study of clonal prevalence . RESULTS : Using this assay we found a percentage of mutated P28906 + cells ranging from 40 % to 100 % in Polycythemia Vera patients , from 15 % to 80 % in Essential Thrombocythemia and from 25 % to 100 % in Primary Myelofibrosis . This method allows to distinguish , with a high degree of specificity , at single cell level , between P28906 + progenitor stem cells harbouring the mutated or the wild type form of O60674 in P06748 patients . CONCLUSIONS : This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer .\",\n \"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK62___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK62___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK86___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .\",\n \"Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non - transplanted cohort . Metachromatic leukodystrophy ( O15121 ) is a rare inborn error of metabolism leading to severe neurological symptoms and early death . Hematopoietic P09683 ( HSCT ) is considered a treatment option , but results are inconsistent and comparison with natural history is practically missing . We compare a girl with juvenile O15121 10 years after allogeneic HSCT not only with her untreated sister , but also with a large cohort of untreated patients . The girl received HSCT at the age of 5 years when first motor signs appeared . Over 10 years she was stable with respect to her clinical course and gained cognitive abilities . Magnetic resonance imaging ( Q9BWK5 ) showed clear regression of white matter changes and magnetic resonance spectroscopy ( P59665 ) demonstrated a reversal of the initial choline increase and N - acetyl - aspartate ( NAA ) decrease . Only axonal demyelinating neuropathy showed some progression . Her gross motor function and Q9BWK5 - scores were clearly better compared with her sister and the cohort of untreated patients . Difference to her sister became apparent only 4 years after HSCT . We conclude that HSCT , early in the course of disease , can lead to stabilization of juvenile O15121 with a course clearly different from the natural history . HSCT may prevent disease progression , if performed sufficient time before loss of walking , which typically initiates rapid deterioration .\",\n \"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK55___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .\",\n \"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .\",\n \"Serum macrophage migration inhibitory factor ( MIF ) levels after allogeneic hematopoietic stem cell transplantation . P14174 ( MIF ) may play an important role in the pathogenesis of acute graft - versus - host disease ( aGVHD ) after allogeneic hematopoietic stem cell transplantation ( allo - HSCT ) , as MIF plays an important role to regulate the production of tumor necrosis factor - alpha ( P01375 ) , one of the inflammatory cytokines which induces and exacerbates aGVHD . We examined the association between serum MIF levels and aGVHD vs . chronic GVHD ( cGVHD ) in allo - P09683 patients in this study . We found a significant increase in the peak serum MIF ( 14 . 46 ng +/- 1 . 47 ng / ml ) at onset in patients that developed aGVHD ( n = 23 , P = 0 . 009 ) . We also found that mean serum MIF levels in patients who developed extensive type cGVHD within 6 months ( 12 . 58 +/- 2 . 18 ng / ml , n = 13 ) were significantly higher than MIF levels before allo - HSCT ( 7 . 86 +/- 1 . 17 ng / ml , n = 19 , P = 0 . 04 ) . Therefore , we speculated that serum MIF levels increase during the active phase of both aGVHD and cGVHD .\",\n \"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .\",\n \"DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and / or refractory Hodgkin ' s lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR - HL ) have poor outcomes . DB08870 ( BV ) , an antibody - drug conjugate comprising an anti - P28908 antibody conjugated to the potent anti - microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo - P09683 ) in patients with RR - HL treated by BV in a named patient program in two French institutions . Twenty - four adult patients with histologically proven P28908 (+) RR - HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45 . 8 % ) , while five patients were in partial response ( 20 . 8 % ) , with an overall response rate of 66 . 6 % . Eight patients failed to respond to BV ( 33 . 3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto - P09683 ) , three patients received a tandem auto - P09683 / allo - P09683 , nine patients received allo - P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment - related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow - up of 20 months ( range 10 . 5 - 43 . 2 ) , none of them relapsed or died . BV followed by allo - P09683 represents an effective salvage regimen in patients with RR - HL .\",\n \"Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via P40763 - dependent induction of P14902 . Hepatic stellate cells ( HSCs ) are critical for hepatic wound repair and tissue remodeling . They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver . The functional relationship between HSCs and the professional migratory APCs in the liver , that is , dendritic cells ( DCs ) , has not been evaluated . In this article , we report that murine liver DCs colocalize with HSCs in vivo under normal , steady - state conditions , and cluster with HSCs in vitro . In vitro , HSCs secrete high levels of DC chemoattractants , such as MΙP - 1α and P13500 , as well as cytokines that modulate DC activation , including P01375 - α , P05231 , and IL - 1β . Culture of HSCs with conventional liver myeloid ( m ) DCs resulted in increased P05231 and P22301 secretion compared with that of either cell population alone . Coculture also resulted in enhanced expression of costimulatory ( P33681 , P42081 ) and coinhibitory ( Q9NZQ7 ) molecules on mDCs . P19526 - induced mDC maturation required cell - cell contact and could be blocked , in part , by neutralizing MΙP - 1α or P13500 . P19526 - induced mDC maturation was dependent on activation of P40763 in mDCs and , in part , on P19526 - secreted P05231 . Despite upregulation of costimulatory molecules , mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation , which was independent of Q9NZQ7 , but dependent upon P19526 - induced P40763 activation and subsequent upregulation of P14902 . In conclusion , by promoting P14902 expression , HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity .\",\n \"Functional validation of the anaplastic lymphoma kinase signature identifies P17676 and Q16548 as critical target genes . Anaplastic large cell lymphomas ( ALCLs ) represent a subset of lymphomas in which the anaplastic lymphoma kinase ( Q9UM73 ) gene is frequently fused to the nucleophosmin ( P06748 ) gene . We previously demonstrated that the constitutive phosphorylation of Q9UM73 chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that Q9UM73 activity is strictly required for the survival of Q9UM73 - positive ALCL cells . To elucidate the signaling pathways required for Q9UM73 - mediated transformation and tumor maintenance , we analyzed the transcriptomes of multiple Q9UM73 - positive ALCL cell lines , abrogating their Q9UM73 - mediated signaling by inducible Q9UM73 RNA interference ( RNAi ) or with potent and cell - permeable Q9UM73 inhibitors . Transcripts derived from the gene expression profiling ( GEP ) analysis uncovered a reproducible signature , which included a novel group of Q9UM73 - regulated genes . Functional RNAi screening on a set of these Q9UM73 transcriptional targets revealed that the transcription factor C / EBPbeta and the antiapoptotic protein Q16548 are absolutely necessary to induce cell transformation and / or to sustain the growth and survival of Q9UM73 - positive ALCL cells . Thus , we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions .\",\n \"Advances in immunotherapy of chronic myeloid leukemia CML . Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene P11274 - P00519 . However , these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation . Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations . Compelling evidence indicates that more modern , antigen - specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective . Amongst these , particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia - associated antigens , since this approach allows to circumvent HLA - restriction of the leukemia - associated T cell epitopes that have been eventually identified . Combining these strategies with monoclonal antibodies , such as anti - P16410 or anti - P18621 , may help to obtain even stronger immune responses and better clinical results . This narrative review addresses this topic by focusing in particular on the cell - based immunotherapeutic strategies for CML and on the issue of the leukemia - associated antigens to be selected for targeting .\",\n \"Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .\",\n \"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .\",\n \"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK55___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .\",\n \"Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high - fat diet induced obese mice . Calorie restriction is the most effective way of expanding life - span and decreasing morbidity . It improves insulin sensitivity and delays the age - related loss of dopamine receptor D ( 2 ) ( P14416 ) expression in the brain . Conversely , high - fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild - type C57Bl6 male mice was restricted to 60 % of ad lib . intake while they were treated with the P14416 antagonist haloperidol or vehicle using s . c . implanted pellets . Mice with ad lib . access to food receiving vehicle treatment served as controls . All mice received high - fat food throughout the experiment . After 10 weeks , an i . p . glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie - restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . ___MASK73___ completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high - fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"Effects of C - phycocyanin and Spirulina on salicylate - induced tinnitus , expression of DB01221 receptor and inflammatory genes . Effects of C - phycocyanin ( C - PC ) , the active component of Spirulina platensis water extract on the expressions of N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , tumor necrosis factor - α ( P01375 - α ) , interleukin - 1β ( IL - 1β ) , and cyclooxygenase type 2 ( P35354 ) genes in the cochlea and inferior colliculus ( IC ) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate . The results showed that 4 - day salicylate treatment ( unlike 4 - day saline treatment ) caused a significant increase in Q13224 , P01375 - α , and IL - 1β mRNAs expression in the cochlea and IC . On the other hand , dietary supplementation with C - PC or Spirulina platensis water extract significantly reduced the salicylate - induced tinnitus and down - regulated the mRNAs expression of Q13224 , P01375 - α , IL - 1β mRNAs , and P35354 genes in the cochlea and IC of mice . The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes .\",\n \"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .\",\n \"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .\",\n \"Altered expression of P11021 , P11142 and Q99497 in spinocerebellar ataxia type 17 identified by 2 - dimensional fluorescence difference in gel electrophoresis . BACKGROUND : Expansion of the CAG repeat of the TATA - box binding protein ( P20226 ) gene has been identified as the causative mutations in spinocerebellar ataxia 17 ( SCA17 ) . P20226 is ubiquitously expressed in both central nervous system and peripheral tissues . The underlying molecular changes of SCA17 are rarely explored . METHODS : To study the molecular mechanisms underlying SCA17 , we generated stably induced isogenic 293 cells expressing normal P20226 - Q ( 36 ) and expanded P20226 - Q ( 61 ) and analyzed the expressed proteins using two - dimensional difference in gel electrophoresis ( 2D - DIGE ) , followed by mass spectrometry and immunoblotting . RESULTS : Upon induction with doxycycline , the expanded P20226 - Q ( 61 ) formed aggregates with significant increase in the cell population at subG1 phase and cleaved caspase - 3 . Proteomics study identified a total of 16 proteins with expression changes greater than 1 . 5 fold . Among the 16 proteins , Q99497 , O76003 , P09651 , Q14691 , P06733 , P61978 and P06748 are increased , and P05154 , P11021 , P18206 , Q92945 , P11142 , P31943 , Q16891 , P55072 and P14866 are decreased in cells expressing P20226 - Q ( 61 ) compared with those expressing P20226 - Q ( 36 ) . The altered expression of P11021 , P11142 and Q99497 were further validated by 2D and Western immunoblot analyses . CONCLUSIONS : The results illustrate the utility of proteomics to identify alterations of proteins which underlie pathogenesis of SCA17 , and may serve as potential therapeutic targets .\",\n \"Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .\",\n \"Intracellular capture of P33681 in antigen - presenting cells reduces costimulatory activity . P16410 gene constructs were designed to express P16410 exclusively in the endoplasmic reticulum ( ER ) . Four different P16410 gene constructs were transfected into P29320 293 ( human embryonic kidney ) and A20 ( Balb / c mouse B lymphoma ) cells . All constructs contained an ER retention signal and coded for P16410 expression in the ER . One of the constructs , which contained the membrane part of P16410 , coded for an expression both on the cell surface and in the ER . Three of the expressed P16410 types ( including the ER - membrane - expressed form ) caused a reduced surface expression of P33681 in the A20 cells . Only constructs which allow dimerization of P16410 showed this effect . It is assumed that intracellular P16410 bound P33681 and inhibited therefore the transport of P33681 to the surface . The binding obviously caused also an enhanced degradation of the complexes because both proteins showed a low concentration in the transfected cell lines . P16410 - transfected and P33681 - reduced A20 cells showed a diminished costimulating activity upon T cells . This was demonstrated by a reduced proliferation of T cells from ovalbumin - immunized Balb / c mice , incubated with ovalbumin peptide - primed P16410 - transfected A20 cells .\",\n \"Microenvironment of the murine mammary carcinoma 4T1 : endogenous P01579 affects tumor phenotype , growth , and metastasis . P01579 has a profound influence on growth and metastasis of solid tumors . This is true for the murine mammary carcinoma 4T1 which grows faster and metastasizes much more readily when transplanted into the mammary fatpads of P01579 (-/-) mice . We were interested in determining which infiltrating hematopoietic cells produce P01579 within the 4T1 tumor microenvironment . 4T1 tumors were infiltrated with progressively increasing numbers of F4 / 80 (+)/ CD11c (+) myeloid cells , many of which were also Gr - 1 (+) , and Gr - 1 (+)/ CD11b (+) granulocytes . Only small numbers of P01730 T cells , CD8 T cells , NK cells , and gammadelta T cells , the most likely P01579 - producing cells , were seen at any time point . Sensitive intracellular cytokine staining and flow cytometry revealed no tumor - infiltrating hematopoietic cells with detectable levels of intracellular P01579 , although P01579 mRNA transcripts were detected in tumor tissue . However , a progressive increase in the expression of three P01579 - inducible surface membrane proteins ( Q9NZQ7 , I - A ( d ) , and P05362 ) on growing 4T1 tumor cells indicated the presence of biologically active P01579 in the tumor microenvironment . Moreover , 4T1 tumor cells from in vitro culture expressed these surface molecules 48 h after intratumoral injection into mature tumors . These data suggest that very low amounts of endogenous P01579 elaborated by infiltrating hematopoietic cells within the microenvironment of a solid tumor can achieve biologically active concentrations and affect tumor phenotype , growth , and metastasis .\",\n \"[ Cutaneous non - tuberculous mycobacterial infection following cord blood stem cell transplantation ] . We describe a 4 - year - old - girl with familial hemophagocytic lymphohistiocytosis ( FHL ) who developed disseminated cutaneous nontuberculous mycobacterial ( Q9P121 ) infection after unrelated cord blood stem cell transplantation ( uCBSCT ) . After transplantation , the patient developed steroid - refractory acute graft - versus - host disease , and was given methylprednisolone , cyclosporin and mycophenolate mofetil . Six months after uCBSCT , cutaneous lesions that looked like insect bites appeared and spread widely over the thighs . Q9P121 infection was diagnosed by skin biopsy although no organism could be identified . DB01017 ( MINO ) and sulfamethoxazole / trimethoprim ( ST ) were administered . However , the cutaneous disease followed a course of remissions and exacerbations . One month after the skin biopsy , mycobacterium chelonae was detected by bacteriological culture of abscess drainage . Ten months after uCBSCT , the cutaneous lesions quickly progressed and the inguinal lymph nodes became enlarged and painful . Then the antibiotics were switched from MINO and ST to amikacin and clarithromycin ( P62158 ) based on the results of mycobacterial susceptibility test . The cutaneous lesions gradually improved after continuous administration of P62158 . Cutaneous Q9P121 infection is rare , but it may occur in immunocompromised patients after P09683 .\",\n \"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK49___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK49___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .\",\n \"Proteomic , cellular , and network analyses reveal new P51452 interactions with nucleolar proteins in HeLa cells . P51452 ( or Vaccinia virus phosphatase P28562 - related ; P51452 ) is a small dual - specificity phosphatase known to dephosphorylate c - Jun N - terminal kinases and extracellular signal - regulated kinases . In human cervical cancer cells , P51452 is overexpressed , localizes preferentially to the nucleus , and plays a key role in cellular proliferation and senescence triggering . Other P51452 functions are still unknown , as illustrated by recent and unpublished results from our group showing that this enzyme mediates DNA damage response or repair processes . In this study , we sought to identify new interactions between P51452 and proteins directly or indirectly involved in or correlated with its biological roles in HeLa cells exposed to gamma or UV radiation . By using Q86UG4 - DUSP as bait , we pulled down interacting proteins and identified them by LC - MS / MS . Of the 46 proteins obtained , six hits were extensively validated by immune techniques ; the proteins P06748 , HnRNP C1 / P06681 , and P19338 were the most promising targets found to directly interact with P51452 . We then analyzed the P51452 interactomes using physical protein - protein interaction networks using our hits as the seed list . The validated hits as well as unvalidated hits fluctuated on the P51452 interactomes of HeLa cells , independent of the time post radiation , which confirmed our proteomic and experimental data and clearly showed the proximity of P51452 to proteins involved in processes intimately related to DNA repair and senescence , such as P12956 and Tert , via interactions with nucleolar proteins , which were identified in this study , that regulate DNA / RNA structure and functions .\",\n \"Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs : behavioural and biochemical evidence . Clinical evidence suggests that stimulation of the D ( 1 ) rather than P14416 is related to the development of dyskinesias in Parkinson ' s disease ( PD ) . We evaluated , in the 6 - hydroxydopamine rat model of PD , sensitization of contralateral turning ( P09683 ) behaviour and abnormal involuntary movements ( AIMs ) as behavioural parameters of dyskinetic response , and changes in zif - 268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D ( 2 )/ D ( 3 ) agonist ropinirole , defined as a mild dyskinetic drug in the clinic . Results were compared with previous findings on repeated L - dopa treatment . Ropinirole displayed a mild dyskinetic response characterized by P09683 only , which contrasted with the presence of P09683 in association with AIMs elicited by repeated L - dopa . Zif - 268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole , in contrast to hyper - expression of zif - 268 mRNA selectively induced by L - dopa in striatonigral neurons . Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats ; in contrast , a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole .\",\n \"Kinetics of Th1 / Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo - P09683 : results of a prospective study . The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD ( cGVHD ) is still controversial . Earlier studies , which were either retrospective or analysed one or a few factors , did not show unequivocal results . We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo - P09683 to investigate their possible correlation with cGVHD . Levels of P05112 , P05231 , P22301 , P01579 , tumour necrosis factor - alpha ( P01375 ) and its soluble receptors were assessed by ELISA in 30 patients at different times after P09683 . Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines . A multivariate analysis was performed using principal component analysis and multi - factor Q9UNW9 ( analysis of variance ) . Eighteen patients developed cGVHD at a median time of 6 months ( range , 5 - 9 ) after P09683 . In multivariate analysis , we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after P09683 . These clusters changed their composition over time , but they constantly included natural killer ( NK ) and P16410 + T cells as negative predictors of cGVHD . P01375 prevailed among other cytokines before the onset of cGVHD . This prevalence could be related partly to the defect of immunoregulatory cells .\",\n \"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . ___MASK73___ was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .\",\n \"___MASK73___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK73___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin ' s lymphoma . PURPOSE : DB08870 is an antibody - drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 - expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 - positive lymphomas . PATIENTS AND METHODS : In this multinational , open - label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin ' s lymphoma ( HL ) after autologous stem - cell transplantation ( auto - P09683 ) . Patients had histologically documented P28908 - positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1 . 8 mg / kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression - free survival time for all patients was 5 . 6 months , and the median duration of response for those in CR was 20 . 5 months . After a median observation time of more than 1 . 5 years , 31 patients were alive and free of documented progressive disease . The most common treatment - related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto - P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy .\",\n \"3 , 4 - Dimethoxyphenyl bis - benzimidazole derivative , mitigates radiation - induced DNA damage . Radiation - induced DNA damage initiates a series of overlapping responses that include DNA damage recognition and repair , induction of cell cycle checkpoints , senescence and / or apoptosis . This study assessed the DNA damage response and whole genome expression profile in two mammalian cell lines ( P29320 and U87 ) in response to ( 5 -{ 4 - methylpiperazin - 1 - yl }- 2 -[ 2 '-( 3 , 4 - dimethoxyphenyl )- 5 '- benzimidazolyl ] benzimidazole ) P28067 and ionizing radiation . P28067 has been shown to act as a potent radiation protector , yielding significant levels of protection , i . e . , 20 . 9 % in P29320 cells and 21 . 2 % in U87 cells . Our findings revealed treatment with P28067 significantly reduced γ - P16104 , Q12888 and Rad51 foci formation after irradiation . Q96HU1 kinase , WNT signaling and p53 pathways were found to be activated in P28067 - treated cells . In addition , the DNA damage response genes , HSP70 , P10809 , Q06830 , Q9BXM0 , P27797 , P06748 , P0CG48 , and Q01105 showed differential regulation in P28067 , P28067 + radiation and radiation - treated cells . The data suggest that P28067 - influenced repertoire of repair proteins , which are an indispensable part of the cell , interplay with each other to reduce DNA damage and maintain the genomic integrity of the cell .\",\n \"Induction of oral tolerance to oxidized low - density lipoprotein ameliorates atherosclerosis . BACKGROUND : Oxidation of low - density lipoprotein ( LDL ) and the subsequent processing of oxidized LDL ( oxLDL ) by macrophages results in activation of specific T cells , which contributes to the development of atherosclerosis . Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis . METHODS AND RESULTS : Tolerance to oxLDL and malondialdehyde - treated LDL ( MDA - LDL ) was induced in P01130 -/- mice fed a Western - type diet by oral administration of oxLDL or MDA - LDL before the induction of atherogenesis . Oral tolerance to oxLDL resulted in a significant attenuation of the initiation ( 30 % to 71 % ; P < 0 . 05 ) and progression ( 45 % ; P < 0 . 05 ) of atherogenesis . Tolerance to oxLDL induced a significant increase in P01730 + CD25 + Foxp3 + cells in spleen and mesenteric lymph nodes , and these cells specifically responded to oxLDL with increased transforming growth factor - beta production . Tolerance to oxLDL also increased the mRNA expression of Foxp3 , P16410 , and CD25 in the plaque . In contrast , tolerance to MDA - LDL did not affect atherogenesis . CONCLUSIONS : OxLDL - specific T cells , present in P01130 -/- mice and important contributors in the immune response leading to atherosclerotic plaque , can be counteracted by oxLDL - specific P01730 + CD25 + Foxp3 + regulatory T cells activated via oral tolerance induction to oxLDL . We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis .\",\n \"Q9UM73 as a novel lymphoma - associated tumor antigen : identification of 2 HLA - A2 . 1 - restricted CD8 + T - cell epitopes . Oncogenic anaplastic lymphoma kinase ( Q9UM73 ) fusion proteins ( P06748 / Q9UM73 and associated variants ) are expressed in about 60 % of anaplastic large cell lymphomas ( ALCLs ) but are absent in normal tissues . In this study , we investigated whether Q9UM73 , which is expressed at high levels in lymphoma cells , could be a target for antigen - specific cell - mediated immunotherapy . A panel of Q9UM73 - derived peptides was tested for their binding affinity to HLA - A * 0201 molecules . Binding peptides were assessed for their capacity to elicit a specific immune response mediated by cytotoxic T lymphocytes ( CTLs ) both in vivo , in HLA - A * 0201 transgenic mice , and in vitro in the peripheral blood lymphocytes ( PBLs ) from healthy donors . Two HLA - A * 0201 - restricted CTL epitopes , p280 - 89 ( SLAMLDLLHV ) and p375 - 86 ( GVLLWEIFSL ) , both located in the Q9UM73 kinase domain were identified . The p280 - 89 - and p375 - 86 - induced peptide - specific CTL lines were able to specifically release interferon - gamma ( P01579 ) on stimulation with Q9UM73 peptide - pulsed autologous Epstein - Barr virus - transformed B cells ( LCLs ) or P24752 cells . Anti - Q9UM73 CTLs lysed HLA - matched ALCL and neuroblastoma cell lines endogenously expressing Q9UM73 proteins . CTL activity was inhibited by anti - HLA - A2 monoclonal antibody CR11 . 351 , consistent with a class I - restricted mechanism of cytotoxicity . These results show the existence of functional anti - Q9UM73 CTL precursors within the peripheral T - cell repertoire of healthy donors , clearly indicating Q9UM73 as a tumor antigen and Q9UM73 - derived peptides , p280 - 89 and p375 - 86 , as suitable epitopes for the development of vaccination strategies .\",\n \"Association between high interleukin - 6 levels and adverse outcome after autologous haemopoietic stem cell transplantation . We studied interleukin - 6 ( P05231 ) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation ( P09683 ) ( either peripheral blood stem cell transplantation ( PBSCT ) or bone marrow transplantation ( BMT ) ) for neoplastic diseases to determine if there was a relationship between P05231 level and rate of haemopoietic recovery , length of stay in hospital , and survival . There was no apparent delay in post - transplant recovery associated with elevated P05231 levels . However , increased values of P05231 tended to be associated with an increased length of stay in hospital ( P = 0 . 083 ) . There was a highly significant adverse association between higher P05231 levels and survival following transplantation ( P = 0 . 0001 ) . This association remained significant ( P = 0 . 013 ) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT ( that is , excluding patients who had undergone PBSCT ) ( n = 13 ) . Knowledge of P05231 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic P09683 .\",\n \"Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK27___","___MASK30___","___MASK36___","___MASK49___","___MASK55___","___MASK62___","___MASK66___","___MASK73___","___MASK86___"],"string":"[\n \"___MASK27___\",\n \"___MASK30___\",\n \"___MASK36___\",\n \"___MASK49___\",\n \"___MASK55___\",\n \"___MASK62___\",\n \"___MASK66___\",\n \"___MASK73___\",\n \"___MASK86___\"\n]"},"answer":{"kind":"string","value":"___MASK49___"},"id":{"kind":"string","value":"MH_train_376"}}},{"rowIdx":377,"cells":{"query":{"kind":"string","value":"interacts_with DB01233?"},"supports":{"kind":"list like","value":["DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .","The relationship between gastric motility and nausea : gastric prokinetic agents as treatments . Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying . The mechanisms and treatments are unclear ( anti - emetic drugs are not fully effective against nausea ) . Can nausea be relieved by stimulating gastric emptying ? Physostigmine ( together with atropine ) has been shown experimentally to stimulate gastric motility , relieve nausea and restore normal gastric motility . Is this mimicked by gastric prokinetic drugs ? The answer is complicated by mixed pharmacology . DB01233 increases gastric motility by activating myenteric Q13639 receptors but also directly inhibits vomiting via D2 and 5 - Q9H205 receptor antagonism ; relationships between increased gastric motility and relief from nausea are therefore unclear . Similarly , the D2 receptor antagonist domperidone has direct anti - emetic activity . Nevertheless , more selective Q13639 and motilin receptor agonists ( erythromycin , directly stimulating gastric motility ) inhibit vomiting in animals ; low doses of erythromycin can also relieve symptoms in patients with gastroparesis . Ghrelin stimulates gastric motility and appetite mostly via vagus - dependent pathways , and inhibits vomiting in animals . To date , ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis . We conclude that nausea can be relieved by gastric prokinetic drugs , but more clinical studies are needed using drugs with selective activity . Other mechanisms ( e . g . ghrelin , vagal and central pathways , influencing a mechanistic continuum between appetite and nausea ) also require exploration . These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology , which focusses on mechanisms of nausea and vomiting .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist ___MASK57___ were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies .","17 DB00783 overcomes a P55008 block induced by P04035 inhibitors and fosters cell cycle progression without inducing P27361 and - 2 Q96HU1 kinases activation . P04035 inhibitors , such as ___MASK6___ and Simvastatin , cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media . Cells are induced to pause in P55008 and can readily resume growth upon removal of the enzymatic block . DB00286 , acting via their nuclear receptor , are mitogens for different normal and transformed cell types , where they foster cell cycle progression and cell division . In estrogen - responsive MCF - 7 human breast cancer cells , but not in non responsive cells , 17 beta - estradiol ( E2 ) induces cells arrested with ___MASK6___ or Simvastatin to proliferate in the presence of inhibitor , without restoring P04035 activity or affecting the protein prenylation pattern . Mitogenic stimulation of P55008 - arrested MCF - 7 cells with E2 includes primary transcriptional activation of c - fos , accompanied by transient binding in vivo of the estrogen receptor and / or other factors to the ERE and the estrogen - responsive DNA region of this proto - oncogene , as detected by dimethylsulphate genomic footprinting analysis . Mitogenic stimulation of growth - arrested MCF - 7 cells by E2 occurs , under these conditions , without evident activation of P27361 and - 2 kinases , and thus independently from the mitogen - responsive signal transduction pathways that converge on these enzymes .","Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP - PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .","Single - walled carbon nanotubes ( SWCNTs ) enhance DB00761 - , acetylcholine - , and serotonin - induced contractions and evoke oxidative stress on rabbit ileum . We examined the effects of intravenous administration of purified arc - discharge single - walled carbon nanotubes ( SWCNTs ) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases . The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals . SWCNTs increased the contractile responses induced by DB00761 , acetylcholine ( ACh ) , and serotonin ( 5 - HT ) in rabbit ileum . Verapamil , apamin , glibenclamide , quinine and charybdotoxin reduced the contractile responses induced by ACh and 5 - HT in ileum from rabbits treated with SWCNTs , indicating that voltage - dependent Ca2 + channels and small , intermediate , and large - conductance Ca ( 2 +)- activated , DB00171 - sensitive , and voltage - dependent K + channels are involved in these effects . Atropine and hexamethonium reduced the ACh response , indicating that muscarinic and nicotinic receptors are involved in this effect . DB00904 and GR 113808 reduced the 5 - HT response , indicating that serotonin 5 - Q9H205 and Q13639 receptors are involved in this effect . SWCNTs increased the malondialdehyde plus 4 - hydroxyalkenals and carbonyl levels in rabbit plasma and ileum , indicating that SWCNTs produce oxidative stress . SWCNTs did not produce relevant histological changes or modify the levels of the inflammatory mediators P35228 and P35354 in the ileum . In conclusion , this study demonstrates that the intravenous administration of SWCNTs can evoke oxidative stress and affect contractility in rabbit ileum . These effects could reduce the possibility of using the arc - discharge SWCNTs as cell markers or drug carriers to treat intestinal diseases .","DB01233 stimulates catecholamine - and granin - derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 ( Q13639 ) receptors . The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas . The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 ( 5 - HT ( 4 ) ) receptors in pheochromocytoma tissues . Tissue explants , obtained from 18 pheochromocytomas including the tumor removed from a 46 - year - old female patient who experienced life - threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas ( 9 benign and 8 malignant ) were studied . Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5 - HT ( 4 ) receptor ligands . In addition , total mRNAs were extracted from all the 18 tumors . Catecholamine - and granin - derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays . In addition , expression of 5 - HT ( 4 ) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase - PCR . RESULTS : DB01233 and the 5 - HT ( 4 ) receptor agonist cisapride were found to activate catecholamine - and granin - derived peptide secretions by cultured tumor cells . DB01233 - and cisapride - evoked catecholamine - and granin - derived peptide productions were inhibited by the 5 - HT ( 4 ) receptor antagonist GR 113808 . 5 - HT ( 4 ) receptor mRNAs were detected in the patient ' s tumor and the series of 17 additional pheochromocytomas . This study shows that pheochromocytomas express functional 5 - HT ( 4 ) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine - and granin - derived peptide secretion . All 5 - HT ( 4 ) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma .","Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK3___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .","Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK43___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .","Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .","Effects of cholinoceptor and 5 - hydroxytryptamine3 receptor antagonism on erythromycin - induced canine intestinal motility disruption and emesis . 1 . Erythromycin administration is associated with gastrointestinal problems , disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin ( 7 mg kg - 1 ) increased contractions of the proximal small intestine , and caused emesis in all fasted dogs and in 5 dogs after food . Atropine ( 50 mg kg - 1 min - 1 ) and hexamethonium ( 10 mg kg - 1 h - 1 ) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . DB01233 at a high dose ( 2 mg kg - 1 h - 1 ) reduced the incidence of emesis in the presence of increased intestinal motility , but a low dose ( 150 micrograms kg - 1 h - 1 ) was ineffective . 5 . A 5 - hydroxytryptamine3 ( 5 - Q9H205 ) receptor antagonist , MDL 72222 ( 1 mg kg - 1 ) , reduced emesis when given alone and combined with metoclopramide ( low dose ) . The Q13639 receptor agonist BRL24924 ( DB04917 , 1 mg kg - 1 ) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion , erythromycin - induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated , emesis occurs at least in part via a 5 - hydroxytryptaminergic mechanism , but does not involve the dopamine system .","Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization - activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f - channel isoforms expressed in the human atrium ( O60741 , 2 and 4 ) , Q9Y3Q4 mRNA levels measured by RT - PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 ) ; concurrently , miR - 1 expression was significantly reduced . In patch - clamped atrial myocytes , current - specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0 . 01 ) . β - Adrenergic and Q13639 receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 - mediated effect was significantly reduced ( P < 0 . 02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain - of - function of If , which may contribute to enhanced atrial ectopy .","Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK99___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .","The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK84___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .","Analysis of neurogenic contractions induced by ML - 1035 and other benzamides in the guinea - pig non - stimulated isolated ileum . 4 - Amino - 5 - chloro - substituted benzamides have been shown to increase gastric motility in - vivo and enhance field - stimulated and peristaltic contractions in - vitro . The present experiments examined the contractile response to a series of benzamides in the guinea - pig non - stimulated ileum . Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine ( % acetylcholine response = 12 +/- 2 , 19 +/- 3 , 26 +/- 2 , 51 +/- 3 , n = 13 , 8 , 17 , and 21 , with EC50 values of 0 . 85 , 1 . 8 , 5 . 7 , and 14 . 2 microM for cisapride , zacopride , metoclopramide , and ML - 1035 ( 4 - amino - 5 - chloro - 2 -(( 2 - methylsulphinyl )- ethoxy )- N - ( 2 -( diethylamino )- ethyl ) - benzamide hydrochloride ) , respectively ) . ML - 1035 contractions were completely blocked by atropine and tetrodotoxin , while ganglionic blockade with hexamethonium was ineffective . DB01233 has been reported to sensitize postjunctional muscarinic receptors , however , ML - 1035 did not enhance acetylcholine - induced contractions . Tropisetron ( ICS 205 - 930 , 1 microM ) , caused a parallel rightward shift in the concentration - response curve for both ML - 1035 and zacopride ( EC50 = 14 . 2 +/- 1 . 3 and 1 . 8 +/- 0 . 8 microM in the absence , and 26 +/- 2 . 7 and 6 . 9 +/- 2 . 3 microM in the presence of tropisetron for ML - 1035 and zacopride , respectively ) with apparent pKB values of 5 . 9 and 6 . 0 for the respective compounds . 5 - Hydroxytryptaminergic receptor desensitization by 2 - methyl - 5 - hydroxytryptamine ( 5 - Q9H205 ) and 5 - methoxytryptamine ( Q13639 ) , attenuated the response to ML - 1035 . ( ABSTRACT TRUNCATED AT 250 WORDS )","Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .","A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK91___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .","The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .","5 - hydroxytryptamine and its receptors in systemic vascular walls . 5 - hydroxytryptamine ( 5 - HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5 - HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5 - HT induces proliferation and migration via 5 - Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5 - Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase - 2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5 - HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5 - HT1 and / or 5 - HT2 receptors has been implicated in the angiogenic effect of 5 - HT . The extracellular signal - regulated kinase and endothelial NO synthase ( P29474 ) activation - dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5 - Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5 - Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5 - Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5 - Q13049 receptors . It is believed that increasing evidence on the role of 5 - HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5 - HT receptor - related drugs for treating cardiovascular diseases .","Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .","The additive effect of neurotransmitter genes in pathological gambling . As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling , known as pathological gambling . Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role . Polymorphisms at 31 different genes involved in dopamine , serotonin , norepinephrine , GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age , race , and sex - matched controls . Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable , and the 31 coded genes as the independent variables . Fifteen genes were included in the regression equation . The most significant were the P14416 , P21917 , Q01959 , P17752 , P18825 , NMDA1 , and P49768 genes . The r ( 2 ) or fraction of the variance was less than 0 . 02 for most genes . Dopamine , serotonin , and norepinephrine genes contributed approximately equally to the risk for pathological gambling . These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling . Multi - gene profiles in specific individuals may be of assistance in choosing the appropriate treatment .","A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36 , 320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 , P61073 , P80370 , P48380 , Q9H3S1 , Q8IUC6 and P19474 ) , nervous system ( Q96NK8 , O95897 , MAGI1 , Q9H3S1 and Q13639 ) and skin and hair properties ( P24530 , TRSP1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .","5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK2___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .","___MASK6___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .","Pharmacogenomics of antiplatelet drugs . ___MASK57___ , a platelet Q9H244 inhibitor , is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications . It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system , especially the P33261 enzyme . Candidate gene studies and genome - wide association studies have identified loss - of - function P33261 variants to be associated with a diminished pharmacologic response . Specifically , compared with noncarriers , carriers of at least one copy of a loss - of - function P33261 allele have ∼ 30 % lower levels of active clopidogrel metabolite and ∼ 25 % relatively less platelet inhibition with clopidogrel . Moreover , in patients treated with clopidogrel predominantly for percutaneous coronary intervention , carriers of 1 or 2 P33261 loss - of - function alleles are at increased risk for major adverse cardiovascular outcomes , with an ∼ 1 . 5 - fold increase in the risk of cardiovascular death , myocardial infarction , or stroke as well as an ∼ 3 - fold increase in risk for stent thrombosis . Tripling the dose of clopidogrel in carriers of a P33261 loss - of - function allele can achieve on - treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild - type individuals , but the impact on clinical outcomes remains unknown . Alternatively , 2 third - generation Q9H244 inhibitors are available : prasugrel and ticagrelor . These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by P33261 loss - of - function alleles .","p - Chloroamphetamine , a serotonin - releasing drug , elicited in rats a hyperglycemia mediated by the P08908 and P41595 / 2C receptors . The effects of a serotonin ( 5 - HT ) releasing drug , p - chloroamphetamine , on plasma glucose levels were investigated in rats . p - Chloroamphetamine elicited a significant hyperglycemia . The hyperglycemic effects of p - chloroamphetamine were completely prevented by the 5 - HT synthesis inhibitor , p - chlorophenylalanine . Prior adrenodemedullation abolished the hyperglycemia elicited by p - chloroamphetamine . p - Chloroamphetamine - induced hyperglycemia was prevented by methysergide , which blocks the 5 - HT1 and 5 - HT2 receptor , the P08908 / 1B / 2C receptor antagonist , (-)- propranolol , the selective P08908 receptor antagonist , 4 - ( 2 '- methoxyphenyl - 1 - [ 2 '- n - 2 \" pyridinyl ) - p - iodobenzamido ] - ethyl - pi perazine ( p - MPPI ) , the 5 - Q13049 / 2B / 2C receptor antagonists , ritanserin and 4 - isopropyl - 7 - methyl - 9 -( 2 - hydroxy - 1 - methyl - propoxycarbonyl )- 4 , 6A , 7 , 8 , 9 , 10 , 10A - octahydro - indolo [ 4 , 3 - FG ] quinolone maleate ( LY 53857 ) . However , the 5 - Q9H205 and Q13639 receptor antagonist , tropisetron , the Q13639 receptor antagonist , 2 - methoxy - 4 - amino - 5 - chloro - benzoic acid 2 -( diethylamino ) ethyl ester ( SDZ 205 - 557 ) , and the 5 - Q13049 receptor antagonist , ketanserin , did not affect the p - chloroamphetamine - induced hyperglycemia . These results suggest that p - chloroamphetamine - induced hyperglycemia is elicited by an enhanced 5 - HT release and facilitated adrenaline release . Moreover , our results indicate that p - chloroamphetamine - induced hyperglycemia is mediated by P08908 and P41595 / 2C receptors .","Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , ___MASK2___ , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .","Chronic Q13639 receptor activation decreases Aβ production and deposition in hAPP / P49768 mice . Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer ' s disease ( AD ) , because Aβ is postulated to play an important role in the pathogenesis of AD . Q13639 receptors are an interesting drug target in this regard , as their activation might stimulate α - secretase processing , which increases sAPPα and reduces Aβ , at least according to the central dogma in P05067 processing . Here we describe a novel high - affinity Q13639 receptor agonist SSP - 002392 that , in cultured human neuroblastoma cells , potently increases the levels of DB02527 and sAPPα at 100 - fold lower concentrations than the effective concentrations of prucalopride , a known selective Q13639 receptor agonist . Chronic administration of this compound in a hAPP / P49768 mouse model of Alzheimer ' s disease decreased soluble and insoluble Aβ in hippocampus , but the potential mechanisms underlying these observations seem to be complex . We found no evidence for direct α - secretase stimulation in the brain in vivo , but observed decreased P05067 and P56817 - 1 expression and elevated astroglia and microglia responses . Taken together these results provide support for a potential disease - modifying aspect when stimulating central Q13639 receptors ; however , the complexity of the phenomena warrants further research .","Fatal rhabdomyolysis in a patient with liver cirrhosis after switching from simvastatin to fluvastatin . P04035 inhibitors ( statins ) are widely used to treat hypercholesterolemia . Among the adverse effects associated with these drugs are statin - associated myopathies , ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis . ___MASK91___ - induced fatal rhabdomyolysis has not been previously reported . We describe here a patient with liver cirrhosis who experienced fluvastatin - induced fatal rhabdomyolysis . This patient had been treated with simvastatin ( 20 mg / day ) for coronary artery disease and was switched to fluvastatin ( 20 mg / day ) 10 days before admission . He was also taking aspirin , betaxolol , candesartan , lactulose , and entecavir . Rhabdomyolysis was complicated and continued to progress . He was treated with massive hydration , urine alkalization , intravenous furosemide , and continuous renal replacement therapy for acute renal failure , but eventually died due to rhabdomyolysis complicated by hepatic failure . In conclusion , fluvastatin should be used with caution in patients with liver cirrhosis , especially with other medications metabolized with P11712 .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","Effect of metoclopramide , ondansetron and granisetron on aldosterone secretion in man . The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 ( 5 - Q9H205 & 4 ) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i . v . in a randomised , cross - over sequence : ondansetron 8 mg , granisetron 3 mg , metoclopramide 20 mg , and saline 20 ml . DB01233 significantly increased the mean plasma aldosterone level to 196 % of basal level at 5 min . It rose to 234 % at 15 min and remained at more than 185 % of basal level for the duration of the experiment . The response to ondansetron and granisetron did not differ significantly from placebo . If dopamine antagonism is discounted , the results suggest that metoclopramide - induced aldosterone secretion results from its agonist activity at Q13639 receptors , although slow neuronal depolarization via an unidentified receptor remains a possibility . Antagonism at the 5 - Q9H205 receptor plays no role , as the selective antagonist , granisetron , did not elicit a significant response . It seems unlikely that the Q13639 receptor is the second , low affinity binding site of ondansetron , unless it had no agonist activity at this receptor .","LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .","DB01233 does not increase gastric muscle contractility in newborn rats . Feeding intolerance resulting from delayed gastric emptying is common in premature neonates . DB01233 ( MCP ) , the most frequently used prokinetic drug in neonates , enhances gastric muscle contractility through inhibition of dopamine receptors . Although its therapeutic benefit is established in adults , limited data are available to support its clinical use in infants . Hypothesizing that developmentally dependent differences are present , we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn , juvenile , and adult rats . The muscle strips were either contracted with electrical field stimulation ( O43281 ) to induce cholinergic nerve - mediated acetylcholine release or carbachol , a cholinergic agonist acting directly on the muscarinic receptor . Although in adult rats MCP increased O43281 - induced contraction by 294 ± 122 % of control ( P < 0 . 01 ) , no significant effect was observed in newborn fundic muscle . MCP had no effect on the magnitude of the carbachol - induced and / or bethanechol - induced gastric muscle contraction at any age . In response to dopamine , an 80 . 7 ± 5 . 3 % relaxation of adult fundic muscle was observed , compared with only a 8 . 4 ± 8 . 7 % response in newborn tissue ( P < 0 . 01 ) . P14416 expression was scant in neonates and significantly increased in adult gastric tissue ( P < 0 . 01 ) . In conclusion , the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression . To the extent that these novel data can be extrapolated to neonates , the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation .","Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the Q13639 receptor . OBJECTIVE : Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at Q13639 receptors . The 5 - Q9H205 antagonist tropisetron is thought to act as an antagonist at Q13639 receptors . In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the Q13639 receptor in aldosterone secretion . METHODS : Following a single - blind , random design , ten normal male volunteers received one of the following regimens on three occasions , with at least 2 - week intervals : metoclopramide 10 mg i . v . ; tropisetron 5 mg by slow i . v . i . , or ; tropisetron by slow i . v . i . , followed by 10 mg metoclopramide i . v . RESULTS : In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149 % of basal level and remained significantly elevated for the next 20 min . With tropisetron alone , there was a significant 37 . 8 % drop at 60 min and the aldosterone levels remained low for the duration of the experiment . DB01233 reversed the decline mediated by tropisetron significantly at 30 and 90 min . DB04630 levels after the latter regimen also did not differ significantly from baseline at any time period . CONCLUSION : These results would suggest the existence of a tonic stimulatory influence of 5 - HT via Q13639 receptors on aldosterone secretion , which could be augmented by metoclopramide and blocked by tropisetron . However , the effect of tropisetron per se should be interpreted with caution given the lack of a saline group .","Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK89___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK89___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .","Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK89___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .","Effects of enhancement and antagonism of 5 - hydroxytryptamine activity on the influence of metoclopramide on gastric emptying . This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying . Six subjects received the following pretreatments before metoclopramide and paracetamol : fluoxetine ( 5 - HT uptake inhibitor ) ; meterogoline ( 5 - HT1 antagonist ) ; pizotifen ( 5 - HT2 antagonist ) or methysergide ( 5 - HT1 and 5 - HT2 antagonist ) . One regimen consisted of metoclopramide ( 5 - Q9H205 antagonist and Q13639 agonist ) alone . Gastric emptying was measured by the mean cumulative fraction absorbed - time profiles of paracetamol . Methysergide / metoclopramide significantly delayed gastric emptying from 30 min onwards . DB01233 with either metergoline or pizotifen did not retard gastric emptying to the same extent , suggesting a greater influence with simultaneous 5 - HT1 and 5HT2 blockade . DB01233 / fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen . It was assumed that the influence of metoclopramide was not optimal at this stage , therefore possibly indicating domination of 5 - Q9H205 over Q13639 effects , resulting in gastric delay . It therefore seems as if all the 5 - HT receptors present in the gut have a role to play in the control of gastric emptying .","Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .","Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK99___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines ."],"string":"[\n \"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .\",\n \"The relationship between gastric motility and nausea : gastric prokinetic agents as treatments . Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying . The mechanisms and treatments are unclear ( anti - emetic drugs are not fully effective against nausea ) . Can nausea be relieved by stimulating gastric emptying ? Physostigmine ( together with atropine ) has been shown experimentally to stimulate gastric motility , relieve nausea and restore normal gastric motility . Is this mimicked by gastric prokinetic drugs ? The answer is complicated by mixed pharmacology . DB01233 increases gastric motility by activating myenteric Q13639 receptors but also directly inhibits vomiting via D2 and 5 - Q9H205 receptor antagonism ; relationships between increased gastric motility and relief from nausea are therefore unclear . Similarly , the D2 receptor antagonist domperidone has direct anti - emetic activity . Nevertheless , more selective Q13639 and motilin receptor agonists ( erythromycin , directly stimulating gastric motility ) inhibit vomiting in animals ; low doses of erythromycin can also relieve symptoms in patients with gastroparesis . Ghrelin stimulates gastric motility and appetite mostly via vagus - dependent pathways , and inhibits vomiting in animals . To date , ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis . We conclude that nausea can be relieved by gastric prokinetic drugs , but more clinical studies are needed using drugs with selective activity . Other mechanisms ( e . g . ghrelin , vagal and central pathways , influencing a mechanistic continuum between appetite and nausea ) also require exploration . These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology , which focusses on mechanisms of nausea and vomiting .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist ___MASK57___ were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies .\",\n \"17 DB00783 overcomes a P55008 block induced by P04035 inhibitors and fosters cell cycle progression without inducing P27361 and - 2 Q96HU1 kinases activation . P04035 inhibitors , such as ___MASK6___ and Simvastatin , cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media . Cells are induced to pause in P55008 and can readily resume growth upon removal of the enzymatic block . DB00286 , acting via their nuclear receptor , are mitogens for different normal and transformed cell types , where they foster cell cycle progression and cell division . In estrogen - responsive MCF - 7 human breast cancer cells , but not in non responsive cells , 17 beta - estradiol ( E2 ) induces cells arrested with ___MASK6___ or Simvastatin to proliferate in the presence of inhibitor , without restoring P04035 activity or affecting the protein prenylation pattern . Mitogenic stimulation of P55008 - arrested MCF - 7 cells with E2 includes primary transcriptional activation of c - fos , accompanied by transient binding in vivo of the estrogen receptor and / or other factors to the ERE and the estrogen - responsive DNA region of this proto - oncogene , as detected by dimethylsulphate genomic footprinting analysis . Mitogenic stimulation of growth - arrested MCF - 7 cells by E2 occurs , under these conditions , without evident activation of P27361 and - 2 kinases , and thus independently from the mitogen - responsive signal transduction pathways that converge on these enzymes .\",\n \"Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP - PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .\",\n \"Single - walled carbon nanotubes ( SWCNTs ) enhance DB00761 - , acetylcholine - , and serotonin - induced contractions and evoke oxidative stress on rabbit ileum . We examined the effects of intravenous administration of purified arc - discharge single - walled carbon nanotubes ( SWCNTs ) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases . The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals . SWCNTs increased the contractile responses induced by DB00761 , acetylcholine ( ACh ) , and serotonin ( 5 - HT ) in rabbit ileum . Verapamil , apamin , glibenclamide , quinine and charybdotoxin reduced the contractile responses induced by ACh and 5 - HT in ileum from rabbits treated with SWCNTs , indicating that voltage - dependent Ca2 + channels and small , intermediate , and large - conductance Ca ( 2 +)- activated , DB00171 - sensitive , and voltage - dependent K + channels are involved in these effects . Atropine and hexamethonium reduced the ACh response , indicating that muscarinic and nicotinic receptors are involved in this effect . DB00904 and GR 113808 reduced the 5 - HT response , indicating that serotonin 5 - Q9H205 and Q13639 receptors are involved in this effect . SWCNTs increased the malondialdehyde plus 4 - hydroxyalkenals and carbonyl levels in rabbit plasma and ileum , indicating that SWCNTs produce oxidative stress . SWCNTs did not produce relevant histological changes or modify the levels of the inflammatory mediators P35228 and P35354 in the ileum . In conclusion , this study demonstrates that the intravenous administration of SWCNTs can evoke oxidative stress and affect contractility in rabbit ileum . These effects could reduce the possibility of using the arc - discharge SWCNTs as cell markers or drug carriers to treat intestinal diseases .\",\n \"DB01233 stimulates catecholamine - and granin - derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 ( Q13639 ) receptors . The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas . The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 ( 5 - HT ( 4 ) ) receptors in pheochromocytoma tissues . Tissue explants , obtained from 18 pheochromocytomas including the tumor removed from a 46 - year - old female patient who experienced life - threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas ( 9 benign and 8 malignant ) were studied . Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5 - HT ( 4 ) receptor ligands . In addition , total mRNAs were extracted from all the 18 tumors . Catecholamine - and granin - derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays . In addition , expression of 5 - HT ( 4 ) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase - PCR . RESULTS : DB01233 and the 5 - HT ( 4 ) receptor agonist cisapride were found to activate catecholamine - and granin - derived peptide secretions by cultured tumor cells . DB01233 - and cisapride - evoked catecholamine - and granin - derived peptide productions were inhibited by the 5 - HT ( 4 ) receptor antagonist GR 113808 . 5 - HT ( 4 ) receptor mRNAs were detected in the patient ' s tumor and the series of 17 additional pheochromocytomas . This study shows that pheochromocytomas express functional 5 - HT ( 4 ) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine - and granin - derived peptide secretion . All 5 - HT ( 4 ) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma .\",\n \"Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK3___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .\",\n \"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK43___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .\",\n \"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .\",\n \"Effects of cholinoceptor and 5 - hydroxytryptamine3 receptor antagonism on erythromycin - induced canine intestinal motility disruption and emesis . 1 . Erythromycin administration is associated with gastrointestinal problems , disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin ( 7 mg kg - 1 ) increased contractions of the proximal small intestine , and caused emesis in all fasted dogs and in 5 dogs after food . Atropine ( 50 mg kg - 1 min - 1 ) and hexamethonium ( 10 mg kg - 1 h - 1 ) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . DB01233 at a high dose ( 2 mg kg - 1 h - 1 ) reduced the incidence of emesis in the presence of increased intestinal motility , but a low dose ( 150 micrograms kg - 1 h - 1 ) was ineffective . 5 . A 5 - hydroxytryptamine3 ( 5 - Q9H205 ) receptor antagonist , MDL 72222 ( 1 mg kg - 1 ) , reduced emesis when given alone and combined with metoclopramide ( low dose ) . The Q13639 receptor agonist BRL24924 ( DB04917 , 1 mg kg - 1 ) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion , erythromycin - induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated , emesis occurs at least in part via a 5 - hydroxytryptaminergic mechanism , but does not involve the dopamine system .\",\n \"Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization - activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f - channel isoforms expressed in the human atrium ( O60741 , 2 and 4 ) , Q9Y3Q4 mRNA levels measured by RT - PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 ) ; concurrently , miR - 1 expression was significantly reduced . In patch - clamped atrial myocytes , current - specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0 . 01 ) . β - Adrenergic and Q13639 receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 - mediated effect was significantly reduced ( P < 0 . 02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain - of - function of If , which may contribute to enhanced atrial ectopy .\",\n \"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK99___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .\",\n \"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK84___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .\",\n \"Analysis of neurogenic contractions induced by ML - 1035 and other benzamides in the guinea - pig non - stimulated isolated ileum . 4 - Amino - 5 - chloro - substituted benzamides have been shown to increase gastric motility in - vivo and enhance field - stimulated and peristaltic contractions in - vitro . The present experiments examined the contractile response to a series of benzamides in the guinea - pig non - stimulated ileum . Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine ( % acetylcholine response = 12 +/- 2 , 19 +/- 3 , 26 +/- 2 , 51 +/- 3 , n = 13 , 8 , 17 , and 21 , with EC50 values of 0 . 85 , 1 . 8 , 5 . 7 , and 14 . 2 microM for cisapride , zacopride , metoclopramide , and ML - 1035 ( 4 - amino - 5 - chloro - 2 -(( 2 - methylsulphinyl )- ethoxy )- N - ( 2 -( diethylamino )- ethyl ) - benzamide hydrochloride ) , respectively ) . ML - 1035 contractions were completely blocked by atropine and tetrodotoxin , while ganglionic blockade with hexamethonium was ineffective . DB01233 has been reported to sensitize postjunctional muscarinic receptors , however , ML - 1035 did not enhance acetylcholine - induced contractions . Tropisetron ( ICS 205 - 930 , 1 microM ) , caused a parallel rightward shift in the concentration - response curve for both ML - 1035 and zacopride ( EC50 = 14 . 2 +/- 1 . 3 and 1 . 8 +/- 0 . 8 microM in the absence , and 26 +/- 2 . 7 and 6 . 9 +/- 2 . 3 microM in the presence of tropisetron for ML - 1035 and zacopride , respectively ) with apparent pKB values of 5 . 9 and 6 . 0 for the respective compounds . 5 - Hydroxytryptaminergic receptor desensitization by 2 - methyl - 5 - hydroxytryptamine ( 5 - Q9H205 ) and 5 - methoxytryptamine ( Q13639 ) , attenuated the response to ML - 1035 . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \\\" dominant negative \\\" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .\",\n \"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK91___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .\",\n \"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .\",\n \"5 - hydroxytryptamine and its receptors in systemic vascular walls . 5 - hydroxytryptamine ( 5 - HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5 - HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5 - HT induces proliferation and migration via 5 - Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5 - Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase - 2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5 - HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5 - HT1 and / or 5 - HT2 receptors has been implicated in the angiogenic effect of 5 - HT . The extracellular signal - regulated kinase and endothelial NO synthase ( P29474 ) activation - dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5 - Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5 - Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5 - Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5 - Q13049 receptors . It is believed that increasing evidence on the role of 5 - HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5 - HT receptor - related drugs for treating cardiovascular diseases .\",\n \"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .\",\n \"The additive effect of neurotransmitter genes in pathological gambling . As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling , known as pathological gambling . Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role . Polymorphisms at 31 different genes involved in dopamine , serotonin , norepinephrine , GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age , race , and sex - matched controls . Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable , and the 31 coded genes as the independent variables . Fifteen genes were included in the regression equation . The most significant were the P14416 , P21917 , Q01959 , P17752 , P18825 , NMDA1 , and P49768 genes . The r ( 2 ) or fraction of the variance was less than 0 . 02 for most genes . Dopamine , serotonin , and norepinephrine genes contributed approximately equally to the risk for pathological gambling . These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling . Multi - gene profiles in specific individuals may be of assistance in choosing the appropriate treatment .\",\n \"A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36 , 320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 , P61073 , P80370 , P48380 , Q9H3S1 , Q8IUC6 and P19474 ) , nervous system ( Q96NK8 , O95897 , MAGI1 , Q9H3S1 and Q13639 ) and skin and hair properties ( P24530 , TRSP1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .\",\n \"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK2___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .\",\n \"___MASK6___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .\",\n \"Pharmacogenomics of antiplatelet drugs . ___MASK57___ , a platelet Q9H244 inhibitor , is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications . It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system , especially the P33261 enzyme . Candidate gene studies and genome - wide association studies have identified loss - of - function P33261 variants to be associated with a diminished pharmacologic response . Specifically , compared with noncarriers , carriers of at least one copy of a loss - of - function P33261 allele have ∼ 30 % lower levels of active clopidogrel metabolite and ∼ 25 % relatively less platelet inhibition with clopidogrel . Moreover , in patients treated with clopidogrel predominantly for percutaneous coronary intervention , carriers of 1 or 2 P33261 loss - of - function alleles are at increased risk for major adverse cardiovascular outcomes , with an ∼ 1 . 5 - fold increase in the risk of cardiovascular death , myocardial infarction , or stroke as well as an ∼ 3 - fold increase in risk for stent thrombosis . Tripling the dose of clopidogrel in carriers of a P33261 loss - of - function allele can achieve on - treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild - type individuals , but the impact on clinical outcomes remains unknown . Alternatively , 2 third - generation Q9H244 inhibitors are available : prasugrel and ticagrelor . These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by P33261 loss - of - function alleles .\",\n \"p - Chloroamphetamine , a serotonin - releasing drug , elicited in rats a hyperglycemia mediated by the P08908 and P41595 / 2C receptors . The effects of a serotonin ( 5 - HT ) releasing drug , p - chloroamphetamine , on plasma glucose levels were investigated in rats . p - Chloroamphetamine elicited a significant hyperglycemia . The hyperglycemic effects of p - chloroamphetamine were completely prevented by the 5 - HT synthesis inhibitor , p - chlorophenylalanine . Prior adrenodemedullation abolished the hyperglycemia elicited by p - chloroamphetamine . p - Chloroamphetamine - induced hyperglycemia was prevented by methysergide , which blocks the 5 - HT1 and 5 - HT2 receptor , the P08908 / 1B / 2C receptor antagonist , (-)- propranolol , the selective P08908 receptor antagonist , 4 - ( 2 '- methoxyphenyl - 1 - [ 2 '- n - 2 \\\" pyridinyl ) - p - iodobenzamido ] - ethyl - pi perazine ( p - MPPI ) , the 5 - Q13049 / 2B / 2C receptor antagonists , ritanserin and 4 - isopropyl - 7 - methyl - 9 -( 2 - hydroxy - 1 - methyl - propoxycarbonyl )- 4 , 6A , 7 , 8 , 9 , 10 , 10A - octahydro - indolo [ 4 , 3 - FG ] quinolone maleate ( LY 53857 ) . However , the 5 - Q9H205 and Q13639 receptor antagonist , tropisetron , the Q13639 receptor antagonist , 2 - methoxy - 4 - amino - 5 - chloro - benzoic acid 2 -( diethylamino ) ethyl ester ( SDZ 205 - 557 ) , and the 5 - Q13049 receptor antagonist , ketanserin , did not affect the p - chloroamphetamine - induced hyperglycemia . These results suggest that p - chloroamphetamine - induced hyperglycemia is elicited by an enhanced 5 - HT release and facilitated adrenaline release . Moreover , our results indicate that p - chloroamphetamine - induced hyperglycemia is mediated by P08908 and P41595 / 2C receptors .\",\n \"Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , ___MASK2___ , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .\",\n \"Chronic Q13639 receptor activation decreases Aβ production and deposition in hAPP / P49768 mice . Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer ' s disease ( AD ) , because Aβ is postulated to play an important role in the pathogenesis of AD . Q13639 receptors are an interesting drug target in this regard , as their activation might stimulate α - secretase processing , which increases sAPPα and reduces Aβ , at least according to the central dogma in P05067 processing . Here we describe a novel high - affinity Q13639 receptor agonist SSP - 002392 that , in cultured human neuroblastoma cells , potently increases the levels of DB02527 and sAPPα at 100 - fold lower concentrations than the effective concentrations of prucalopride , a known selective Q13639 receptor agonist . Chronic administration of this compound in a hAPP / P49768 mouse model of Alzheimer ' s disease decreased soluble and insoluble Aβ in hippocampus , but the potential mechanisms underlying these observations seem to be complex . We found no evidence for direct α - secretase stimulation in the brain in vivo , but observed decreased P05067 and P56817 - 1 expression and elevated astroglia and microglia responses . Taken together these results provide support for a potential disease - modifying aspect when stimulating central Q13639 receptors ; however , the complexity of the phenomena warrants further research .\",\n \"Fatal rhabdomyolysis in a patient with liver cirrhosis after switching from simvastatin to fluvastatin . P04035 inhibitors ( statins ) are widely used to treat hypercholesterolemia . Among the adverse effects associated with these drugs are statin - associated myopathies , ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis . ___MASK91___ - induced fatal rhabdomyolysis has not been previously reported . We describe here a patient with liver cirrhosis who experienced fluvastatin - induced fatal rhabdomyolysis . This patient had been treated with simvastatin ( 20 mg / day ) for coronary artery disease and was switched to fluvastatin ( 20 mg / day ) 10 days before admission . He was also taking aspirin , betaxolol , candesartan , lactulose , and entecavir . Rhabdomyolysis was complicated and continued to progress . He was treated with massive hydration , urine alkalization , intravenous furosemide , and continuous renal replacement therapy for acute renal failure , but eventually died due to rhabdomyolysis complicated by hepatic failure . In conclusion , fluvastatin should be used with caution in patients with liver cirrhosis , especially with other medications metabolized with P11712 .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"Effect of metoclopramide , ondansetron and granisetron on aldosterone secretion in man . The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 ( 5 - Q9H205 & 4 ) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i . v . in a randomised , cross - over sequence : ondansetron 8 mg , granisetron 3 mg , metoclopramide 20 mg , and saline 20 ml . DB01233 significantly increased the mean plasma aldosterone level to 196 % of basal level at 5 min . It rose to 234 % at 15 min and remained at more than 185 % of basal level for the duration of the experiment . The response to ondansetron and granisetron did not differ significantly from placebo . If dopamine antagonism is discounted , the results suggest that metoclopramide - induced aldosterone secretion results from its agonist activity at Q13639 receptors , although slow neuronal depolarization via an unidentified receptor remains a possibility . Antagonism at the 5 - Q9H205 receptor plays no role , as the selective antagonist , granisetron , did not elicit a significant response . It seems unlikely that the Q13639 receptor is the second , low affinity binding site of ondansetron , unless it had no agonist activity at this receptor .\",\n \"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .\",\n \"DB01233 does not increase gastric muscle contractility in newborn rats . Feeding intolerance resulting from delayed gastric emptying is common in premature neonates . DB01233 ( MCP ) , the most frequently used prokinetic drug in neonates , enhances gastric muscle contractility through inhibition of dopamine receptors . Although its therapeutic benefit is established in adults , limited data are available to support its clinical use in infants . Hypothesizing that developmentally dependent differences are present , we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn , juvenile , and adult rats . The muscle strips were either contracted with electrical field stimulation ( O43281 ) to induce cholinergic nerve - mediated acetylcholine release or carbachol , a cholinergic agonist acting directly on the muscarinic receptor . Although in adult rats MCP increased O43281 - induced contraction by 294 ± 122 % of control ( P < 0 . 01 ) , no significant effect was observed in newborn fundic muscle . MCP had no effect on the magnitude of the carbachol - induced and / or bethanechol - induced gastric muscle contraction at any age . In response to dopamine , an 80 . 7 ± 5 . 3 % relaxation of adult fundic muscle was observed , compared with only a 8 . 4 ± 8 . 7 % response in newborn tissue ( P < 0 . 01 ) . P14416 expression was scant in neonates and significantly increased in adult gastric tissue ( P < 0 . 01 ) . In conclusion , the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression . To the extent that these novel data can be extrapolated to neonates , the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation .\",\n \"Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the Q13639 receptor . OBJECTIVE : Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at Q13639 receptors . The 5 - Q9H205 antagonist tropisetron is thought to act as an antagonist at Q13639 receptors . In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the Q13639 receptor in aldosterone secretion . METHODS : Following a single - blind , random design , ten normal male volunteers received one of the following regimens on three occasions , with at least 2 - week intervals : metoclopramide 10 mg i . v . ; tropisetron 5 mg by slow i . v . i . , or ; tropisetron by slow i . v . i . , followed by 10 mg metoclopramide i . v . RESULTS : In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149 % of basal level and remained significantly elevated for the next 20 min . With tropisetron alone , there was a significant 37 . 8 % drop at 60 min and the aldosterone levels remained low for the duration of the experiment . DB01233 reversed the decline mediated by tropisetron significantly at 30 and 90 min . DB04630 levels after the latter regimen also did not differ significantly from baseline at any time period . CONCLUSION : These results would suggest the existence of a tonic stimulatory influence of 5 - HT via Q13639 receptors on aldosterone secretion , which could be augmented by metoclopramide and blocked by tropisetron . However , the effect of tropisetron per se should be interpreted with caution given the lack of a saline group .\",\n \"Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK89___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK89___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .\",\n \"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK89___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .\",\n \"Effects of enhancement and antagonism of 5 - hydroxytryptamine activity on the influence of metoclopramide on gastric emptying . This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying . Six subjects received the following pretreatments before metoclopramide and paracetamol : fluoxetine ( 5 - HT uptake inhibitor ) ; meterogoline ( 5 - HT1 antagonist ) ; pizotifen ( 5 - HT2 antagonist ) or methysergide ( 5 - HT1 and 5 - HT2 antagonist ) . One regimen consisted of metoclopramide ( 5 - Q9H205 antagonist and Q13639 agonist ) alone . Gastric emptying was measured by the mean cumulative fraction absorbed - time profiles of paracetamol . Methysergide / metoclopramide significantly delayed gastric emptying from 30 min onwards . DB01233 with either metergoline or pizotifen did not retard gastric emptying to the same extent , suggesting a greater influence with simultaneous 5 - HT1 and 5HT2 blockade . DB01233 / fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen . It was assumed that the influence of metoclopramide was not optimal at this stage , therefore possibly indicating domination of 5 - Q9H205 over Q13639 effects , resulting in gastric delay . It therefore seems as if all the 5 - HT receptors present in the gut have a role to play in the control of gastric emptying .\",\n \"Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .\",\n \"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK99___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .\"\n]"},"candidates":{"kind":"list like","value":["___MASK2___","___MASK3___","___MASK43___","___MASK57___","___MASK6___","___MASK84___","___MASK89___","___MASK91___","___MASK99___"],"string":"[\n \"___MASK2___\",\n \"___MASK3___\",\n \"___MASK43___\",\n \"___MASK57___\",\n \"___MASK6___\",\n \"___MASK84___\",\n \"___MASK89___\",\n \"___MASK91___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK99___"},"id":{"kind":"string","value":"MH_train_377"}}},{"rowIdx":378,"cells":{"query":{"kind":"string","value":"interacts_with DB00005?"},"supports":{"kind":"list like","value":["Effects of DB00005 and DB01017 in a rat model of spinal cord injury . Loss of function is usually considered the major consequence of spinal cord injury ( SCI ) . However , pain severely compromises the quality of life in nearly 70 % of SCI patients . The principal aim of this study was to assess the contribution of P01375 alpha ( P01375 ) to SCI pain . P01375 blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain , especially following SCI . Following T13 spinal cord hemisection , we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept , a fusion protein blocker of P01375 . Immediate treatment ( starting at the time of injury ) with etanercept resulted in markedly reduced mechanical allodynia 1 , 2 , 3 and 4 weeks after SCI . Delayed treatment had no effect . Immediate etanercept treatment also reduced spinal microglial activation assessed by OX - 42 immunostaining , a putative marker of activated microglia . To assess whether the effects of etanercept were mediated via decreased microglial activation , we examined the effects of the microglial inhibitor , minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment . DB01017 also significantly reduced microglial OX - 42 expression . Furthermore , minocycline decreased the expression of noxious - stimulation - induced c - Fos , suggesting an effect on evoked neuronal activity . This study demonstrates that P01375 plays an important role in the establishment of neuropathic pain following SCI , seemingly dependent on microglial activation . Pharmacological targeting of P01375 may offer therapeutic opportunities for treating SCI pain .","Potential role of pharmacogenetics in anti - P01375 treatment of rheumatoid arthritis and Crohn ' s disease . DB00005 , infliximab and adalimumab have shown clinical benefit in immune - mediated inflammatory diseases ; however , the outcome of treatment with these tumour - necrosis factor inhibitors remains insufficient in approximately 40 - 60 % and approximately 25 - 40 % of individuals with rheumatoid arthritis and Crohn ' s disease , respectively . Moreover , their use is accompanied by adverse events and unintentional immune suppression . Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression , and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn ' s disease . Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome . As we discuss here , replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice .","The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis . OBJECTIVE : The frequency of osteoclast precursors ( OCPF ) and the presence of bone marrow oedema ( BMO ) are potential response biomarkers in psoriatic arthritis ( PsA ) . Previous studies suggest a central role for tumour necrosis factor ( P01375 ) in the formation of osteoclast precursors . To better understand this association , the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis . METHODS : A total of 20 PsA patients with active erosive PsA were enrolled . DB00005 was administered twice weekly for 24 weeks . OCPF was measured and clinical assessments were performed at baseline , 2 , 12 and 24 weeks . Gadolinium enhanced MR images were obtained at baseline and 24 weeks . RESULTS : Significant improvements in joint score ( p < 0 . 001 ) , HAQ scores ( p < 0 . 001 ) and SF - 36 parameters were observed after 6 months of therapy with etanercept compared to baseline . The median OCPF decreased from 24 . 5 to 9 ( p = 0 . 04 ) and to 7 ( p = 0 . 006 ) after 3 months and 6 months of treatment , respectively . MR images were available for 13 patients . The BMO volume decreased in 47 and increased in 31 sites at 6 months . No correlation was noted between OCPF , BMO and clinical parameters . CONCLUSION : The rapid decline in OCPF and overall improvement in BMO after anti - TNFalpha therapy provides one mechanism to explain the anti - erosive effects of P01375 blockade in PsA . Persistence of BMO after etanercept treatment , despite a marked clinical response , was unexpected , and suggests ongoing subchondral inflammation or altered remodelling in PsA bone .","DB00065 but not etanercept induces apoptosis in lamina propria T - lymphocytes from patients with Crohn ' s disease . BACKGROUND & AIMS : Steroid - refractory Crohn ' s disease responds to therapy with the chimeric anti - tumor necrosis factor ( P01375 ) - alpha antibody infliximab . DB00005 , a recombinant P01375 receptor / immunoglobulin G fusion protein , is highly effective in rheumatoid arthritis but not in Crohn ' s disease . Because both infliximab and etanercept are P01375 - neutralizing drugs , we investigated the differences in P01375 - neutralizing capacity and human lymphocyte binding and apoptosis - inducing capacity of both molecules . METHODS : We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study P01375 neutralization by infliximab and etanercept . Lymphocyte binding and apoptosis - inducing capacity was investigated using fluorescence - activated cell sorter analysis , annexin V staining , and cleaved caspase - 3 immunoblotting using mixed lymphocyte reaction - stimulated peripheral blood lymphocytes ( PBL ) from healthy volunteers and lamina propria T cells from patients with Crohn ' s disease . RESULTS : Both infliximab and etanercept neutralized P01375 effectively . DB00065 bound to activated PBL and lamina propria T cells , whereas binding of etanercept was equal to a nonspecific control antibody . DB00065 but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody . DB00065 activated caspase 3 in a time - dependent manner , whereas etanercept did not . CONCLUSIONS : Although both infliximab and etanercept showed powerful P01375 neutralization , only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes . These data may provide a biological basis for the difference in efficacy of the 2 P01375 - neutralizing drugs .","P01375 - α blocker therapy and solid malignancy risk in ANCA - associated vasculitis . ANCA - associated vasculitides ( AAV ) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality . This group includes granulomatosis with polyangiitis ( Wegener ´ s , P02724 ) , microscopic polyangiitis ( DB00603 ) , and eosinophilic granulomatosis with polyangiitis ( Churg - Strauss , EGPA ) . The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs . These have broad mechanisms of action as well as important adverse effects . Efforts have been made to investigate novel agents with better - defined and narrower mechanisms of action , such as biologics , including P01375 - α blockers . DB00005 , a well - known P01375 - α blocker evaluated for P02724 in the Wegener ' s Granulomatosis DB00005 Trial ( WGET ) , was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period . A 5 - year follow - up after the WGET trial showed a sustained increase in incidence of solid malignancies , but this could no longer be solely attributed to etanercept exposure . These studies raised concerns about the use of the family of P01375 - α blockers in AAV . Here , we review the evidence about the association between therapeutic inhibition of tumor necrosis factor ( P01375 - α ) by etanercept and other P01375 - α blockers with the development of solid malignancies in P02724 and other AAV .","The attenuation of experimental lung metastasis by a bile acid acylated - heparin derivative . The inhibitory efficacies of new bile acid acylated - heparin derivative ( heparin - DOCA ) were evaluated on experimental lung metastasis . We evaluated the effect of heparin - DOCA on intercellular interactions including those between B16F10 and thrombin - activated platelets and P01375 - activated HUVECs , and between B16F10 and immobilized mouse P16109 . In addition , the inhibitory effects of heparin - DOCA on adhesion and invasion of B16F10 to Matrigel were studied . In an animal mouse study , the blood clot formation and the retention of red fluorescence protein ( RFP ) - B16F10 in lungs were assessed after heparin - DOCA and RFP - B16F10 intravenous administration . Furthermore , we investigated the anti - metastatic effect of heparin - DOCA against lung metastasis induced by B16F10 and SCC7 . ___MASK8___ - DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P - and P16581 - mediated interactions . Moreover , it reduced adhesion and invasion of B16F10 to Q13201 , thereby affecting the reduction of early retention of B16F10 in the lung . ___MASK8___ - DOCA attenuated lung colony formation on the surfaces and in interior of the lung , and attenuated metastasis by B16F10 and SCC7 . These results suggest that heparin - DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression .","Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK78___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .","Changes of urinary bladder contractility in high - fat diet - fed mice : the role of tumor necrosis factor - α . OBJECTIVES : To study the role of tumor necrosis factor - α in bladder dysfunction associated with obesity . METHODS : Male 8 - week - old C57BL / 6J mice were divided into three groups : ( i ) control mice ; ( ii ) vehicle - treated high - fat diet - fed mice ; and ( iii ) etanercept - treated high - fat diet - fed mice . High - fat diet feeding lasted for 12 weeks , vehicle or etanercept ( 0 . 8 mg / kg / day , a tumor necrosis factor - α antagonist ) treatment was given during the last 4 weeks . At the end of the treatment period , serum tumor necrosis factor - α , total cholesterol , triglyceride and blood glucose were measured . Bladder strip contractile responses to 1 μmol / L acetylcholine or 50 mmol / L DB00761 were studied in an organ bath . Bladder protein kinase Cζ , nuclear factor - κB and intercellular adhesion molecule - 1 expressions were analyzed using western blots . RESULTS : Serum levels of tumor necrosis factor - α total cholesterol , triglyceride and glucose were significantly elevated in high - fat diet - fed mice ; and the levels were not ameliorated by etanercept treatment . High - fat diet - fed mouse bladder showed reduced contractile responses to acetylcholine and DB00761 stimulation accompanied by high expression levels of phospho - protein kinase Cζ , nuclear nuclear factor - κB and intercellular adhesion molecule - 1 . DB00005 restored normal bladder contractile responses , as well as protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 expressions . CONCLUSIONS : A high - fat diet induces bodyweight gain , hyperlipidemia and hyperglycemia in mice . Elevated serum tumor necrosis factor - α level associated with increased protein kinase Cζ phosphorylation , nuclear factor - κB nuclear migration , intercellular adhesion molecule - 1 expression and impaired muscle contractility are shown in the high - fat diet - fed mouse bladder . P01375 - α antagonist treatment restores normal bladder contractility , and protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 levels .","___MASK47___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK47___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK47___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .","DB00005 maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects . OBJECTIVE : To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab , but presented side effects . METHODS : Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects . Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped . Disease Activity Score computed on 44 joints ( DAS - 44 ) , erythrocyte sedimentation rate ( P03372 ) 1st hour , Visual Analogue Scale ( VAS ) of pain , Health Assessment Questionnaire ( HAQ ) , and C reactive protein ( CRP ) were assessed every 8 weeks . RESULTS : 37 patients were analysed . Adverse events to infliximab were mostly infusion reactions . No statistically significant difference between infliximab , before withdrawal , and etanercept , after 24 weeks , was detected in terms of DAS - 44 ( 2 . 7 and 1 . 9 , respectively ) , HAQ ( 0 . 75 and 0 . 75 , respectively ) , P03372 ( 21 and 14 , respectively ) and CRP ( 0 . 5 and 0 . 3 , respectively ) . VAS pain decreased significantly after switching to etanercept treatment ( 40 and 24 , respectively ; p < 0 . 05 ) . CONCLUSIONS : Our study shows that etanercept maintains the clinical benefit achieved by infliximab , and suggests that a second tumour necrosis factor ( P01375 ) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events .","A non - innovator version of etanercept for treatment of arthritis . DB00005 is a soluble tumor necrosis factor ( P01375 ) receptor originally approved for treatment of moderate - to - severe rheumatoid arthritis , juvenile rheumatoid arthritis , and psoriatic arthritis . We have developed a non - innovator version of the recombinant protein etanercept , with the investigational name AVG01 ( trade name AVENT ™ ) , using a novel expression vector - based technology . Here we show , by extensive analytical characterization , that AVG01 is highly similar to the reference product Enbrel ® and demonstrates similar efficacy in pre - clinical studies .","P01375 blockade aggravates experimental chronic Chagas disease cardiomyopathy . Chronic Chagas disease cardiomyopathy ( CCC ) , caused by Trypanosoma cruzi , is an inflammatory dilated cardiomyopathy associated with increased circulating levels of P01375 . We investigate whether P01375 blockade with DB00005 during the chronic phase of T . cruzi infection could attenuate experimental CCC development . The effect of DB00005 was evaluated after 11 months of T . cruzi infection on survival , parasitism , left ventricular function , intensity of myocarditis , fibrosis , and left ventricular mRNA expression of cytokines and P01375 - induced genes . Left ventricular function was significantly reduced in treated animals as compared to infected untreated animals . Blood and cardiac parasitism as well as survival rate were not altered with DB00005 treatment . Inflammatory infiltrates were located predominantly in the subendocardic region in treated animals , whereas in untreated animals inflammation was scattered throughout the myocardium . Left ventricular mRNA P22301 expression was significantly higher , and P35228 , significantly lower in treated than in untreated animals . mRNA expression of P01375 , P01579 , TGF - beta , A20 and P01160 was similar in both groups . Our results suggest that P01375 / P01374 blockade with DB00005 enhances left ventricular dysfunction in T . cruzi - induced chronic cardiomyopathy and the absence of P01375 signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy .","Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK10___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK10___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK10___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK10___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK10___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK10___ increased the protein expression of hepatic P05181 and ___MASK10___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK10___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK10___ and RFP - induced hepatotoxicity .","Newly available treatments for psoriatic arthritis and their impact on skin psoriasis . Far from being a \" benign \" arthropathy , as it was initially characterized , psoriatic arthritis ( PsA ) affects approximately 0 . 2 % of the US population and can be associated with considerable joint damage , symptomatology , and quality of life impairment . PsA shares many characteristics with rheumatoid arthritis ( RA ) , and new , rationally designed drugs that are effective in RA also are proving active in PsA . Two such drugs , etanercept and infliximab , target tumor necrosis factor ( P01375 ) , a key component of the inflammatory response . This review discusses the rationale for and experience with the use of these agents in PsA . DB00005 is a dimeric fusion protein that binds specifically to P01375 , blocking its interaction with cell surface P01375 receptors . DB00065 is a chimeric ( murine / human ) monoclonal antibody that binds to P01375 and inhibits its binding to its receptor . A randomized placebo - controlled trial of etanercept in PsA found statistically significant benefits for this agent in measures of arthritic activity and psoriatic severity . There have been anecdotal reports of the efficacy of infliximab in PsA , but results from controlled clinical trials of this agent in PsA have not been reported . P01375 inhibitors represent new therapeutic options for patients with PsA . The potential advantages of treatment with etanercept and infliximab early in the disease course are discussed .","Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .","Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under DB00005 Therapy . The use of tumor necrosis factor - α ( P01375 - α ) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics . Squamous cell carcinoma is the second most common cancer of the skin , usually affecting sun - exposed areas of the body . We present here the case of a 75 - year - old woman with rheumatoid arthritis , who developed an intertoe squamous cell carcinoma ( SCC ) of the right foot . According to her history , she received etanercept and methotrexate for 5 years for rheumatoid arthritis . The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti - P01375 - α treatment . This is the first reported case of an interdigital SCC developed under the use of an anti - P01375 - α agent .","[ DB00005 and infections ] . The biological treatments for psoriasis , mainly the tumor necrosis factor - alpha inhibitors ( P01375 ) , have demonstrated their efficacy and safety beginning with the clinical trials up to their subsequent marketing . However , pharmacovigilance studies have detected a mild increase in infections . For the management of infectious risk in patients with psoriasis being treated with etanercept or other anti - P01375 medications , an evaluation should be made of the adequacy of its use in patients infected by HCV , HBV , HIV , with localized or generalized infections , with risk of sepsis ( carriers of intravenous catheter and indwelling urinary catheter ) or with underlying disorders that could predispose them to infections ( diabetes , hemodialysis ) . If a patient under treatment with etanercept presents an infection , if the infection is serious , treatment should be discontinued and if it is mild , the patient should be closely monitored and treatment interrupted if decided based on the evolution . Long experience on the use of etanercept in different diseases has made it possible to state that it has a good safety profile in regards to infections , if precautions are taken in regards to tuberculosis and the concomitance of other active infections during the treatment .","Does route of administration affect the outcome of P01375 antagonist therapy ? The tumor necrosis factor ( P01375 ) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis . Although infliximab , etanercept , and adalimumab are all members of this class , they differ in route of administration and dosing regimen . In the USA and in Europe , infliximab , in combination with oral methotrexate , is administered intravenously , initially at a dose of 3 mg / kg at weeks 0 , 2 , and 6 , then every 8 weeks thereafter . The US Food and Drug Administration ( FDA ) has further approved that the dosage can be increased to 10 mg / kg and the doses can be given as often as every 4 weeks to optimize patient outcome ( information based on the US package insert dated June 2002 ) . DB00005 and adalimumab are given subcutaneously and can be self - injected . The FDA - approved dose of etanercept is 25 mg twice weekly , and of adalimumab is 40 mg every 2 weeks with methotrexate , or 40 mg alone . Medication adherence , possibly the most important factor in maintaining the benefits of anti - P01375 therapy , is influenced by the interaction between the patient and his or her healthcare team , the patient ' s attitude toward the disease and medication regimen , and the choice of therapy .","Pilot study of etanercept in patients with relapsed cutaneous T - cell lymphomas . BACKGROUND : P01375 ( P01375 ) - alpha has been implicated in the pathogenesis of cutaneous T - cell lymphoma ( CTCL ) . OBJECTIVE : To assess the toxicity , safety , and efficacy of etanercept ( soluble P01375 receptor ) in patients with relapsed CTCL . METHODS : DB00005 was administered twice weekly at a dose of 25 mg subcutaneously . Patients with improvement after two months could be continued on treatment . RESULTS : Twelve out of the 13 patients enrolled on study were evaluable ( Stage I - IIA , 3 patients ; Stage IIB - IV disease , 9 patients ) . The median number of previous therapies was 7 ( range , 3 - 12 ) . DB00005 induced partial remission in one patient ( 8 % ) and minor response in one patient ( 8 % ) , both of whom had Stage IB disease . Most patients experienced no side effects . CONCLUSION : This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL . The effect of etanercept in a larger cohort of patients with early disease merits investigation .","Inhibitors of P78536 and P29466 as anti - inflammatory drugs . P01375 neutralising agents such as DB00065 ( Remicade ) , DB00005 ( Enbrel ) and the IL - 1 receptor antagonist DB00026 ( Kineret ) , are currently used clinically for the treatment of many inflammatory diseases such as Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , juvenile rheumatoid arthritis , psoriatic arthritis and psoriasis . These protein preparations are expensive to manufacture and administer , need to be injected and can cause allergic reactions . An alternative approach to lowering the levels of P01375 and IL - 1beta in inflammatory disease , is to inhibit the enzymes that generate these cytokines using cheaper small molecules . This paper is a broad overview of the progress that has been achieved so far , with respect to small molecule inhibitor design and pharmacological studies ( in animals and humans ) , for the metalloprotease Tumour Necrosis Factor - alpha Converting Enzyme ( P78536 ) and the cysteine protease P29466 ( Interleukin - 1beta Converting Enzyme , ICE ) . Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti - inflammatory agents in the future .","Sulindac metabolism and synergy with tumor necrosis factor - alpha in a drug - inflammation interaction model of idiosyncratic liver injury . Sulindac ( SLD ) is a nonsteroidal anti - inflammatory drug ( NSAID ) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs . In previous studies , cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide ( LPS ) led to liver injury , whereas neither SLD nor LPS alone caused liver damage . In studies presented here , further investigation of this animal model revealed that the concentration of tumor necrosis factor - alpha ( P01375 ) in plasma was significantly increased by LPS at 1 h , and SLD enhanced this response . DB00005 , a soluble P01375 receptor , reduced SLD / LPS - induced liver injury , suggesting a role for P01375 . SLD metabolites in plasma and liver were determined by LC / MS / MS . Cotreatment with LPS did not increase the concentrations of SLD or its metabolites , excluding the possibility that LPS contributed to liver injury through enhanced exposure to SLD or its metabolites . The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells ; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone . P01375 augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells . These results suggest that P01375 can enhance SLD sulfide - induced hepatotoxicity , thereby contributing to liver injury in SLD / LPS - cotreated rats .","DB00005 - induced anti - Jo - 1 - antibody - positive polymyositis in a patient with rheumatoid arthritis : a case report and review of the literature . Antitumor necrosis factor ( P01375 ) therapy has been associated with adverse immunologic events including systemic lupus erythematosus . However , the development of polymyositis ( PM ) / dermatomyositis ( DM ) associated with anti - P01375 therapy is extremely rare . We experienced a case of a 48 - year - old female with rheumatoid arthritis ( RA ) who had anti - Jo - 1 antibodies and interstitial lung disease but no previous history of PM / DM and who developed PM soon after the initiation of etanercept ( DB01613 ) therapy for RA . The patient recovered upon withdrawal from DB01613 and corticosteroid ( CS ) therapies . Only four reports of PM / DM associated with anti - P01375 therapy for RA could be found in the literature . The patients described in three of the four reports were positive for anti - Jo - 1 antibodies before the initiation of anti - P01375 therapy , and in all the cases , recovery occurred after the cessation of anti - P01375 - agent administration and CS therapy . These results suggest a relationship between the onset of PM / DM with anti - Jo - 1 antibody and anti - P01375 therapy for RA .","[ Juvenile psoriatic arthritis ] . A case of juvenile psoriatic arthritis in a 12 year - old boy was reported . The patient had a history of one and half a year of bilateral heel pain , followed by pain in the right knee and ankle and right hip joint . He developed psoriatic lesions affecting his nails and skin . He had increased erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) contents . Human leukocyte antigen ( HLA ) Q8TCY5 was detected but serum rheumatoid factor was not in the patient . A skin biopsy revealed psoriasis and ultrasonography demonstrated synovitis in right knee and ankle . Juvenile psoriatic arthritis was diagnosed based on his physical , laboratory and skin biopsy findings . A treatment with nonsteroidal anti - inflammatory drugs and sulfasalazine produced no effect . Leflunomide in conjunction with anti - P01375 biologic agents ( DB00005 ) was administered , followed by symptomatic improvement 2 weeks later .","Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .","[ Anti - P01375 treatment and spondyloarthropathies ] . Spondyloarthropathies are characterized by both axial and peripheral joint involvement , by the association with \" other diseases \" mainly Psoriasis , Crohn ' s and Anterior Uveitis and by the high prevalence of HLA B - 27 . While disease modifying drugs , such as DB00563 or Sulfasalazine , are only partially effective in controlling peripheral arthritis , the treatment of the axial part remained only symptomatic . The recently introduced anti - P01375 drugs DB00065 ( Remicade ) and DB00005 ( Enbrel ) for the treatment of Crohn ' s disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with highly promising results . The rationale and the early beneficial results of this new approach in spondyloarthropathies are reviewed .","DB00005 in psoriatic arthritis . Psoriatic arthritis ( PsA ) , an inflammatory arthritis associated with psoriasis , can lead to disability from progressive joint destruction and bony fusion . To date , conventional disease modifying antirheumatic drugs ( DMARDS ) have not convincingly lessened joint pain and inflammation in PsA and there is very little data on the limitation of radiographic progression with these agents . The biological agent etanercept ( Enbrel , Amgen , Inc , Thousand Oaks , California , USA ) is a soluble P01375 receptor fusion protein with proven efficacy in the treatment of rheumatoid arthritis ( RA ) . In a Phase II and Phase III trial , conducted in moderate - to - severe PsA , etanercept significantly reduced joint pain and swelling and lowered the erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) level . A significant decline in structural damage was observed as early as 6 months after starting the drug . DB00005 also improved quality of life measures ( Health Assesment Questionnaire [ HAQ ] and global assessment scores ) . Up to a third of patients experienced transient injection - site reactions . Rare cases of opportunistic infection , demyelinating disorders and aplastic anaemia have been reported , but a causal link has not been established . In summary , etanercept is a safe and effective agent for the treatment of PsA and represents a major advance in the therapy of this potentially crippling disease .","P01375 antagonist therapy and lymphoma development : twenty - six cases reported to the Food and Drug Administration . OBJECTIVE : DB00005 and infliximab are tumor necrosis factor ( P01375 ) antagonists that have been recently approved for the treatment of rheumatoid arthritis ( RA ) and Crohn ' s disease ( CD ) . This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents . METHODS : Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed . RESULTS : We identified 26 cases of lymphoproliferative disorders following treatment with etanercept ( 18 cases ) or infliximab ( 8 cases ) . The majority of cases ( 81 % ) were non - Hodgkin ' s lymphomas . The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short ( median 8 weeks ) . In 2 instances ( 1 infliximab , 1 etanercept ) , lymphoma regression was observed following discontinuation of anti - P01375 treatment , in the absence of specific cytotoxic therapy directed toward the lymphoma . CONCLUSION : Although data from a case series such as this can not establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease , the known predisposition of patients with RA and CD to lymphoma , the known excess of lymphoma in other immunosuppressed populations , and the known immunosuppressive effects of the anti - P01375 drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association .","Adverse reactions during biological drug therapy in psoriasis : clinical series and a review of the literature . AIM : Psoriasis is a chronic , inflammatory skin disorder , histologically characterized by epidermal hyperplasia , anomalous keratinocyte differentiation , angiogenesis , and by inflammatory cell infiltrate . Psoriasis has a significant impact on quality of life and is often associated with serious psychological effects . The use of biological agents is expanding worldwide as alternative treatment for chronic inflammatory diseases including psoriasis . The European Medicines Agency ( EMEA ) approved the use of DB00095 , DB00005 , DB00065 and DB00051 in the treatment of psoriasis on the basis of the positive findings obtained from well - designed clinical trials . The ongoing monitoring of tolerability and possible side - effects of these drugs has , however , recently lead to the EMEA suspending DB00095 on the grounds that the possible risks of its use outweighed the benefits . METHODS : Fifty - four patients treated with the two classes of biological drug ( DB00095 and anti - P01375 - α ) were studied . The choice of biological drug therapy was conditioned by the extent and seriousness of the disease and by the presence of concomitant pathologies . RESULTS : Nineteen patients presented adverse reactions , of which 9 necessitated interruption in treatment ( 6 DB00095 and 3 anti - P01375 - α ) . CONCLUSION : This work reports the adverse reactions to these biological therapies found in our patients along with a review of the literature concerning adverse reactions in psoriasis treatment . From our experience and basing ourselves on the literature reporting studies conducted in large centres , we feel that it is indispensable to continue monitoring any reactions during biological drug treatment . In this way , there is more likelihood of preventing , where possible , or better managing any reactions linked to the use of these drugs .","Rheumatoid arthritis in pregnancy : successful outcome with anti - P01375 agent ( DB00005 ) .","Use of etanercept in human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) patients . BACKGROUND : DB00005 ( Enbrel , Amgen , Thousand Oaks , CA ) , a soluble p75 tumor necrosis factor receptor : FC ( TNFR : FC ) fusion protein for plasma cytokines , specifically tumor necrosis factor - alpha ( P01375 ) , is used in the treatment of immune - mediated rheumatic diseases . To our knowledge , the use of etanercept in patients with human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) is relatively uncommon . OBJECTIVE : The main purpose of this short review is to examine the safety of etanercept in patients with HIV / AIDS . METHODS : A Medline search was conducted using the keywords etanercept and HIV and / or AIDS for any published articles between 1966 to the present ( September 2004 ) . RESULTS : A case report , one case series , and one clinical trial pertained to the use of etanercept in HIV patients . No reports were found on the use of etanercept in AIDS . In addition , two case reports were found documenting the use of infliximab in HIV patients . DISCUSSION : Preliminary reports indicate that the administration of etanercept does not appear to increase the morbidity or mortality rates in HIV . The inhibition of P01375 may actually improve the symptoms of HIV / AIDS - associated aphthous ulcers , cachexia , dementia , fatigue , and fever , as well as help manage concomitant rheumatic diseases and psoriasis . CONCLUSION : The use of etanercept shows promise for applications in disease management in patients with HIV / AIDS . Continued research efforts are necessary to establish the long - term safety and efficacy of etanercept and other biologic agents in this patient population .","P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK42___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .","P62158 interacts with angiotensin - converting enzyme - 2 ( Q9BYF1 ) and inhibits shedding of its ectodomain . P12821 - 2 ( Q9BYF1 ) is a regulatory protein of the renin - angiotensin system ( DB01367 ) and a receptor for the causative agent of severe - acute respiratory syndrome ( P49591 ) , the P49591 - coronavirus . We have previously shown that Q9BYF1 can be shed from the cell surface in response to phorbol esters by a process involving P01375 converting enzyme ( P78536 ; P78536 ) . In this study , we demonstrate that inhibitors of calmodulin also stimulate shedding of the Q9BYF1 ectodomain , a process at least partially mediated by a metalloproteinase . We also show that calmodulin associates with Q9BYF1 and that this interaction is decreased by calmodulin inhibitors .","The silent progression of metastatic malignancy during the treatment with soluble tumor necrosis factor receptor . DB00005 is singular among anti - tumor necrosis factor alpha ( P01375 ) agents , for being a soluble antibody to both P01375 and lymphtoxin - alpha . The long - term neutralization of two cachexins by etanercept would theoretically compromise early detection of malignancy . This case reports a patient who was treated by etanercept for 21 months due to ankylosing spondylitis . Metastatic malignancy of unknown origin developed , and silently led the patient to lethal hepatic rupture . With an example of a malignancy masking effect of soluble P01375 receptor , this article questions a need for vigilant attention to de novo carcinoma during the therapy , and calls for refined strategies in modulating autoimmune diseases .","Effects of etanercept , a tumour necrosis factor - alpha antagonist , in an experimental model of periodontitis in rats . BACKGROUND AND PURPOSE : DB00005 is a tumour necrosis factor antagonist with anti - inflammatory effects . The aim of our study was to evaluate , for the first time , the therapeutic efficacy of in vivo inhibition of P01375 in an experimental model of periodontitis . EXPERIMENTAL APPROACH : Periodontitis was induced in adult male Sprague - Dawley rats by placing a nylon thread ligature around the lower 1st molars . DB00005 was administered at a dose of 5 mg kg - 1 , s . c . , after placement of the ligature . KEY RESULTS : Periodontitis in rats resulted in an inflammatory process characterized by oedema , neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells , production of a range of inflammatory mediators , tissue damage , apoptosis and disease . Treatment of the rats with etanercept ( 5 mg kg - 1 , s . c . , after placement of the ligature ) significantly reduced the degree of ( 1 ) periodontitis inflammation and tissue injury ( histological score ) , ( 2 ) infiltration of neutrophils ( P05164 evaluation ) , ( 3 ) P35228 ( the expression of nitrotyrosine and cytokines ( eg P01375 ) ) and ( 4 ) apoptosis ( Bax and Bcl - 2 expression ) . CONCLUSIONS AND IMPLICATIONS : Taken together , our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury , events associated with periodontitis .","A case of tuberculous arthritis following the use of etanercept . DB00005 is a tumor necrosis factor ( P01375 ) inhibitor that has been used for the treatment of chronic inflammatory diseases including rheumatoid arthritis , ankylosing spondylitis and psoriatic arthritis . Because of its immunosuppressive activity , opportunistic infections have been noted in treated patients , most notably caused by Mycobacterium tuberculosis . Tuberculosis may present in an extrapulmonary or disseminated form . Since P01375 inhibitors have been used in Korea , a few cases of P01375 inhibitor associated tuberculosis have been described . However , tuberculous arthritis has not been previously reported . We describe a case of tuberculous arthritis in a 57 - year - old woman with rheumatoid arthritis who was treated with etanercept .","Clock gene modulation by P01375 depends on calcium and p38 Q96HU1 kinase signaling . A 24 - h treatment with the cytokine tumor necrosis factor - alpha ( P01375 ) suppresses transcription of E - box - driven clock genes ( D - site albumin promoter binding protein , Dbp ; Tyrotroph embryonic factor , Tef ; Q16534 , Hlf ; Period homolog to Drosophila 1 / 2 / 3 , Per1 , Per2 , and Per3 ) by yet unknown molecular mechanisms . The attenuation of clock genes has been suggested as a putative cause for the development of sickness behavior syndrome in infectious and autoimmune diseases . Here , the authors studied the effect of P01375 at early time points ( < 3 h ) on intracellular signaling events and clock gene expression in fibroblasts . Interaction of P01375 with P19438 ( Tnfrsf1a , CD120a , p55 ) , but not P20333 ( Tnfrsf1b , DB00005 , p75 ) , leads to fast downregulation of gene expression of Dbp and upregulation of negative regulators of the molecular clock , Per1 and Per2 , Q16526 ( Cry1 ) , and Differentiated embryo chondrocytes - 1 ( Dec1 ) . Since the decrease of Dbp is also observed in cells deficient for Per1 / Per2 , Cry1 / Cry2 , or Dec1 , these genes are unlikely to be responsible for inhibition of Dbp . The early effect of P01375 on the clock gene Per1 is dependent on p38 , mitogen - activated protein kinase ( MAPK ) , and / or calcium signaling , whereas the effect on Dbp is independent of p38 MAPK , but also involves calcium signaling . Both genes remain unaffected by the NF - kappaB and AP - 1 pathway . Taken collectively these data show p38 MAPK - and calcium - dependent P19438 - mediated transient increase of the negative regulator Per1 and an independent decrease of Dbp .","Central P01375 inhibition results in attenuated neurohumoral excitation in heart failure : a role for superoxide and nitric oxide . This study examined the effect of central tumor necrosis factor - alpha ( P01375 ) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus ( PVN ) and ventrolateral medulla ( VLM ) , key autonomic regulators , and their contribution to enhanced sympathetic drive in mice with congestive heart failure ( CHF ) . We also used a P01375 gene knockout ( KO ) mouse model to study the involvement of P01375 in body fluid homeostasis and sympathoexcitation in CHF . After implantation of intracerebroventricular ( ICV ) cannulae , myocardial infarction ( MI ) was induced in wild - type ( WT ) and KO mice by coronary artery ligation . Osmotic mini - pumps were implanted into one set of WT + MI / Sham mice for continuous ICV infusion of DB00005 ( DB01613 ) , a P01375 receptor fusion protein , or vehicle ( VEH ) . Gene expressions of neuronal nitric oxide synthase ( NOS ) and angiotensin receptor - type 2 were reduced , while those of inducible NOS , Nox2 homologs , superoxide , peroxynitrite and angiotensin receptor - type 1 were elevated in the brainstem and hypothalamus of MI + VEH . Plasma norepinephrine levels and the number of Fos - positive neurons were also increased in the PVN and VLM in MI + VEH . MI + DB01613 and KO + MI mice exhibited reduced oxidative stress , reduced sympathoexcitation and an improved cardiac function . These changes in WT + MI were associated with increased sodium and fluid retention . These results indicate that elevated P01375 in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide , contributing to fluid imbalance and sympathoexcitation in CHF .","[ Cytokines -- causes , players or bystanders in heart failure ] . BACKGROUND : Cytokines are important mediators of the immune system and are of pathophysiological relevance for different cardiac diseases . Currently , 18 cytokines carrying the name interleukin ( IL ) are known ; they can be subdivided into pro - and anti - inflammatory interleukins . CARDIAC CYTOKINES : They partly act in a negative inotropic manner and cause destruction of cardiomyocytes resulting in myocardial fibrosis . The proinflammatory cytokine tumor necrosis factor ( P01375 -) alpha induces cardiodepressive effects and causes apoptosis . P01375 , P05231 , soluble P01375 - receptor - 1 and - 2 are independent predictors of increased mortality of patients with heart failure . Experimental and clinical evidence has shown that plasma and tissue levels of P01375 were elevated to such extent as to explain at least some of the symptoms of heart failure due to the actions of this cytokine . CLINICAL TRIALS : Two multicenter studies ( RENAISSANCE , RECOVER ) , based on promising pilot studies , have disclosed no effect for the P01375 antagonists ( DB00005 ) on mortality and morbidity . It is not possible , however , to draw the conclusion from the data of these studies that P01375 plays no significant pathophysiological role in the etiology and progression of heart failure .","Inguinal Herniation of the Urinary Bladder Presenting as Recurrent Urinary Retention . Herniation of the urinary bladder into the inguinal canal is an uncommon finding , observed in 0 . 5 - 4 % of inguinal hernias ( Curry ( 2000 ) ) . It is usually associated with other conditions that increase intra - abdominal pressure such as bladder neck obstruction due to prostatic hypertrophy . Consequently , in men , it is usually associated with some degree of urinary retention . We present a 42 - year - old man in whom herniation of the urinary bladder was the cause of urinary retention , and not vice versa . The patient was on tumor necrosis factor alpha antagonist ( P01375 ) ( DB00005 ) for severe Ankylosing spondylitis . Initially , the urinary retention was thought to be a side effect of the medication , but after the drug was discontinued , urinary retention persisted . CT and Q9BWK5 demonstrated huge herniation of the urinary bladder into the inguinal canal . Immediately after the hernia was repaired , bladder function was restored . P01375 treatment was restarted , and no further urinary symptoms were observed in the next two years of follow - up . In this case , the primary illness and its treatment were distracting barriers to early diagnosis and treatment . In younger patients with a large hernia who develop unexpected urinary retention , herniation of the urinary bladder should be highly considered in the differential diagnosis .","Prospective open - label trial of etanercept as adjunctive therapy for kawasaki disease . OBJECTIVE : To determine the safety and pharmacokinetics of etanercept ( Amgen , Thousand Oaks , California ) a tumor necrosis factor - α receptor blocker , in children with acute Kawasaki disease ( KD ) . Standard therapy of acute KD includes intravenous immunoglobulin ( IVIG ) and high - dose aspirin , but a substantial number of patients are refractory and require additional treatment . P01375 - α levels are elevated in children with KD , suggesting a role for etanercept in treatment . STUDY DESIGN : We performed a prospective open - label trial of etanercept in patients with KD ( age range , 6 months - 5 years ; n = 17 ) meeting clinical criteria and with fever ≤ 10 days . All received IVIG and high - dose aspirin . They received etanercept immediately after IVIG infusion and then weekly two times . For the initial safety evaluation , the first 5 patients received 0 . 4 mg / kg / dose . Subsequent subjects received 0 . 8 mg / kg / dose . RESULTS : Fifteen patients completed the study . The pharmacokinetics were similar to that in older children in published series . No serious adverse events related to etanercept occurred . No patient demonstrated prolonged or recrudescent fever requiring re - treatment with IVIG . No patient showed an increase in coronary artery diameter or new coronary artery dilation / cardiac dysfunction . CONCLUSION : DB00005 appears to be safe and well tolerated in children with KD . The data support performance of a placebo - controlled trial .","DB00005 in psoriatic arthritis . In this update on etanercept ( DB01613 ) in psoriatic arthritis ( PsA ) we analyze this drug ' s mechanism of action , clinical efficacy / effectiveness , optimal dosage , disease - modifying antirheumatic drugs ( DMARD ) association , radiological progression , safety , switching aspects , and pharmacoeconomy . The efficacy / effectiveness of DB01613 in PsA has been demonstrated in randomized placebo - controlled trials as well as in observational studies representing routine clinical practice . At 1 and 2 years , DB01613 inhibited radiographic disease progression , assessed by the modified total Sharp score . DB01613 ( generally at a dosage of 50 mg / weekly ) can be used either in monotherapy or in combination with DMARD such as methotrexate . A systematic search of randomized , placebo - controlled trials of DB01613 to treat adults with plaque psoriasis or PsA suggests that the short - term risk / benefit ratio is favorable . Longterm studies , such as observational studies , confirmed this safety profile of DB01613 . A variable percentage of patients withdrew anti - tumor necrosis factor - α ( P01375 - α ) inhibitor treatment owing to inefficacy or poor tolerability . Observational studies showed that in the case of treatment failure with 1 agent , switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available P01375 - α blockers . The clinical effect of DB01613 is associated with favorable pharmacoeconomic considerations .","DB00005 : long - term clinical experience in rheumatoid arthritis and other arthritis . DB00005 is a dimeric fusion protein based on the p75 P01375 receptor . It binds to P01375 and blocks its biologic activity . In randomized , double - blind , placebo - controlled trials , etanercept has therapeutic activity in rheumatoid arthritis , psoriatic arthritis , polyarticular - course juvenile idiopathic arthritis and ankylosing spondylitis . DB00005 improves joint inflammation , physical function and slows / halts structural damage , especially when combined with methotrexate . A sustained response is observed in a substantial percentage of patients . Although some safety issues should be considered before starting etanercept treatment , in general terms , etanercept is a well tolerated drug with an acceptable safety profile . The use of any P01375 antagonist must be in agreement with the National Recommendations for Biologic Therapy , and in difficult clinical situations , a balance between risk / benefit needs to be obtained .","Clastogenic plasma factors in psoriasis -- comparison of phototherapy and anti - P01375 - α treatments . As previously described , Psoralen plus UVA ( PUVA ) therapy induces chromosome damage in psoriatic patients . This study evaluates whether these effects are transitory or persistent . In addition , we studied these effects after narrowband UVB ( nUVB ) and anti - tumor necrosis factor ( P01375 ) - α treatments . Among 40 responder patients , 10 received PUVA , 10 nUVB , 10 DB00065 and 10 DB00005 . Disease activity was determined with Psoriasis Area and Severity Index . Chromosomal breakage was evaluated by the clastogenic factor ( CF ) test . Potential clastogenic agents , malondialdehyde ( MDA ) and P01375 - α were measured . Before treatment , the plasma - adjusted clastogenic scores ( ACS ) of patients were increased . During treatment , a further increase in ACS was observed in both phototherapy groups . Chromosome damage persisted for PUVA patients at week 32 , while it diminished after nUVB to ACS values lower than before treatment . MDA and P01375 - α values were also increased at baseline . MDA decreased during treatment in all groups , but without reaching normal levels . Plasma P01375 - α remained unchanged in PUVA and nUVB but decreased in both anti - P01375 - α treatment groups . Psoriasis is accompanied by CF - induced chromosomal breakage that increases during PUVA and nUVB treatments . Plasma clastogenic activity persisted in the follow - up after PUVA , while after nUVB ACS returned to values even lower than baseline . Clastogenic activity during the induction phase with anti - P01375 - α remained unchanged .","___MASK80___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","Tumor - infiltrating macrophages induce apoptosis in activated CD8 (+) T cells by a mechanism requiring cell contact and mediated by both the cell - associated form of P01375 and nitric oxide . We have investigated the ability of different cells present in murine tumors to induce apoptosis of activated CD8 (+) T cells in vitro . Tumor cells do not induce apoptosis of T cells ; however , macrophages that infiltrate tumors are potent inducers of apoptosis . Tumor macrophages express cell surface - associated P01375 , P01375 type I ( CD120a ) and II ( DB00005 ) receptors , and , upon contact with T cells which induces release of P01579 from T cells , secrete nitric oxide . Killing of T cells in vitro is blocked by Abs to P01579 , P01375 , CD120a , or DB00005 , or N - methyl - L - arginine . In concert with that finding , tumor macrophages isolated from either P01375 type I or type II receptor -/- mice are not proapoptotic and do not produce nitric oxide upon contact with activated T cells . Control macrophages do not express P01375 receptors or release nitric oxide . Tumor cells or tumor - derived macrophages do not express P48023 , and blocking Abs to either Fas or P48023 have no effect on macrophage - mediated T cell killing . These results demonstrate that macrophages which infiltrate tumors are highly proapoptotic and may be responsible for elimination of activated antitumor T cells within the tumor bed .","Managing moderate - to - severe psoriasis in the elderly . Managing psoriasis in the elderly can be difficult for physicians , who must consider comorbidities , the resulting polypharmacy , and progressive functional impairment of several organs . Indeed , topical agents are the first - line treatment for limited disease . Phototherapy is recommended if topical drugs are not sufficient and the patient has multiple comorbidities and risk factors that make them a poor candidate for an oral or injectable systemic agent . The most important pharmacokinetic alteration in the elderly population is the decreased excretory capacity of the kidney ; thus , cyclosporine should be considered a last resort treatment , and the administered dose of methotrexate should be lowered according to the reduction in estimated creatinine clearance . Acitretin can be used in the absence of severe renal insufficiency , paying attention to lipid profile , treating eventual hyperlipidemia , and closely monitoring liver enzymes . Available data on biological drugs in the elderly are limited . Biologics are associated with a small but significant overall risk of infections . However , there is no convincing evidence that the relative risk of infection with anti - tumor necrosis factor ( P01375 ) - α therapy increases with age . Nevertheless , the package inserts for biologics recommend caution when administering these medications to the geriatric population , due to the high baseline risk of infection in such patients . DB00005 seems to be well tolerated , possibly because of its lower immunosuppressive characteristics compared with other biologics . However , studies with larger sample sizes are needed to confirm its safety .","DB00005 ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 that has been shown to provide rapid and sustained improvement in both of these diseases . Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time . To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate , and to examine the effect of etanercept on radiographic progression , a double blind , placebo controlled study was recently conducted , comparing etanercept with methotrexate ( median dose 20 mg per week ) . Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA , and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions . In patients with severe psoriatic arthritis ( PsA ) , a double blind , placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA . DB00005 has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases .","DB00005 in the treatment of active refractory Crohn ' s disease : a single - center pilot trial . OBJECTIVES : DB00005 , an injectable tumor necrosis factor ( P01375 ) receptor fusion protein , binds and inactivates human P01375 and is used in active rheumatoid arthritis . Blocking P01375 with monoclonal antibodies has also been beneficial in Crohn ' s disease . We attempted to determine the efficacy and safety of etanercept for induction of clinical , endoscopic , and histological improvement in patients with moderate to severe Crohn ' s disease despite standard treatment . METHODS : Ten patients with active Crohn ' s disease were treated with etanercept ( 25 mg s . c . ) twice per week for 12 wk . Background therapy was kept stable during the trial . Crohn ' s disease activity index ( CDAI ) , Inflammatory Bowel Disease Questionnaire , and P02741 levels were measured at weeks 0 , 2 , 4 , 8 , and 12 . Colonoscopies were performed before and after therapy in responders ; endoscopic biopsies were scored for inflammation . RESULTS : At week 2 after the start , a clinical response ( deltaCDAI > or = 70 ) was observed in 6 / 10 patients ( median = 305 [ 294 - 418 ] to 166 [ 107 - 392 ] ) , with reduction in serum P02741 levels ( median = 17 . 2 [ 6 . 8 - 67 . 2 ] to 9 . 1 [ 0 . 9 - 17 . 2 ] mg / dl ) . Colonoscopies showed a reduction in inflammatory lesions in the four patients who attained remission ( CDAI < 150 ) , whereas the inflammatory score of the biopsies did not decrease significantly . No moderate or severe adverse events were observed . CONCLUSIONS : DB00005 may be effective in Crohn ' s disease refractory to standard therapy .","DB00005 - induced Henoch - Schönlein purpura in a patient with ankylosing spondylitis . Ankylosing spondylitis ( AS ) is a chronic inflammatory disease that primarily affects the axial skeleton . Extra - articular manifestations are less common relative to other rheumatic diseases , and vasculitic complications typically involve the ascending aorta and aortic valve . The use of tumor necrosis factor inhibitors is efficacious in the treatment of patients with AS . Since their routine use , however , tumor necrosis factor inhibitors have been associated with the development of drug - induced complications including the induction of lupus and both cutaneous and systemic vasculitis . In this report , we describe a patient with severe longstanding AS , who developed Henoch - Schönlein purpura after commencing therapy with etanercept . P01375 inhibitor - induced Henoch - Schönlein purpura has been very rarely reported and has been mostly recognized in patients with rheumatoid arthritis .","Leukopenia and thrombocytopenia induced by etanercept : two case reports and literature review . P01375 - alpha ( P01375 ) is a proinflammatory cytokine , and its excess can lead to severe consequences . Those effects are known to be antagonized by P01375 inhibitors . DB00005 is a fusion protein that inhibits P01375 action . As P01375 regulation is related to cellular differentiation of various cellular types involved in immune response through expression of several other cytokines , it is possible that the use of its inhibitors may cause cytopenia . We report two cases of bicytopenia induced by etanercept . Both cases recovered after drug withdrawal . We discuss the need of introduction of routine laboratorial tests in patients using anti - P01375 therapy , in order to identify possible hematological changes .","P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .","Human tumor necrosis factor receptor p75 / 80 ( DB00005 ) gene structure and promoter characterization . P01375 receptor p75 ( P01375 - R p75 ) is a 75 - kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage . P01375 - R p75 belongs to the P01375 receptor superfamily characterized by cysteine - rich extracellular regions composed of three to six disulfide - linked domains . In the present report we have characterized , for the first time , the complete gene structure for human P01375 - R p75 , which spans approximately 43 kbp . The gene consists of 10 exons ( ranging from 34 base pairs to 2 . 5 kilobase pairs ) and nine introns ( 343 base pairs to 19 kilobase pairs ) . Consensus elements for transcription factors involved in T cell development and activation were noted in the 5 '- flanking region including T cell factor - 1 , Ikaros , AP - 1 , CK - 2 , interleukin - 6 receptor E ( IL - 6RE ) , ISRE , GAS , NF - kappaB , and Sp1 . The unusual ( GATA ) n and ( P10253 ) ( GGA ) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus . Characterization of the human P01375 - R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function , autoimmune disease , and nonrandom translocations in hematopoietic malignancies .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK90___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .","Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .","Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .","[ Anti - P01375 - α in the treatment of uveitis in the Besançon Hospital ] . BACKGROUND : Noninfectious chronic uveitis is a difficult - to - treat situation in which corticosteroids , immunosuppressive agents , and more recently , anti - tumor necrosis factor ( P01375 ) - α are used to prevent and / or reverse severe visual impairment . This single - center retrospective study was designed to assess the use ( indications , efficacy , and side effects ) of anti - P01375 - α agents in noninfectious uveitis . PATIENTS AND METHODS : Eight patients were analyzed : three children ( age , 7 - 15 years ) and five adults ( age , 27 - 44 years ) . Anti - P01375 - α agents were etanercept ( three patients ) , adalimumab ( four patients ) , and infliximab ( four patients ) . Diagnoses were Behçet ' s diseases ( n = 3 ) , sarcoidosis ( n = 1 ) , juvenile chronic arthritis ( n = 2 ) , spondyloarthropathy ( n = 2 ) , one of the latter two combined with Crohn disease . In all cases , anti - P01375 - α therapies were prescribed because uveitis and / or associated disease were not under control . RESULTS : DB00051 and infliximab were effective for all patients . One patient with infliximab needed to add corticosteroids and immunosuppressive agents because of relapse . DB00005 was stopped in all cases due to a lack of effectiveness or a change in indication . In all patients , anti - P01375 - α agents improved uveitis and the underlying systemic disease . In children , their use improved quality of life by corticosteroid weaning . Prescriptions did not comply with regulations for three children , because of age limits ( etanercept , one ; adalimumab , two ) . No adverse event was recorded . CONCLUSION : In this short case series , anti - P01375 - α agents were effective both on uveitis and the underlying systemic disease and were well tolerated in patients with noninfectious chronic uveitis .","DB00005 , a P01375 - α inhibitor , does not impede fracture healing .","Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK95___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .","Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK2___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK2___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions ."],"string":"[\n \"Effects of DB00005 and DB01017 in a rat model of spinal cord injury . Loss of function is usually considered the major consequence of spinal cord injury ( SCI ) . However , pain severely compromises the quality of life in nearly 70 % of SCI patients . The principal aim of this study was to assess the contribution of P01375 alpha ( P01375 ) to SCI pain . P01375 blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain , especially following SCI . Following T13 spinal cord hemisection , we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept , a fusion protein blocker of P01375 . Immediate treatment ( starting at the time of injury ) with etanercept resulted in markedly reduced mechanical allodynia 1 , 2 , 3 and 4 weeks after SCI . Delayed treatment had no effect . Immediate etanercept treatment also reduced spinal microglial activation assessed by OX - 42 immunostaining , a putative marker of activated microglia . To assess whether the effects of etanercept were mediated via decreased microglial activation , we examined the effects of the microglial inhibitor , minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment . DB01017 also significantly reduced microglial OX - 42 expression . Furthermore , minocycline decreased the expression of noxious - stimulation - induced c - Fos , suggesting an effect on evoked neuronal activity . This study demonstrates that P01375 plays an important role in the establishment of neuropathic pain following SCI , seemingly dependent on microglial activation . Pharmacological targeting of P01375 may offer therapeutic opportunities for treating SCI pain .\",\n \"Potential role of pharmacogenetics in anti - P01375 treatment of rheumatoid arthritis and Crohn ' s disease . DB00005 , infliximab and adalimumab have shown clinical benefit in immune - mediated inflammatory diseases ; however , the outcome of treatment with these tumour - necrosis factor inhibitors remains insufficient in approximately 40 - 60 % and approximately 25 - 40 % of individuals with rheumatoid arthritis and Crohn ' s disease , respectively . Moreover , their use is accompanied by adverse events and unintentional immune suppression . Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression , and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn ' s disease . Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome . As we discuss here , replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice .\",\n \"The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis . OBJECTIVE : The frequency of osteoclast precursors ( OCPF ) and the presence of bone marrow oedema ( BMO ) are potential response biomarkers in psoriatic arthritis ( PsA ) . Previous studies suggest a central role for tumour necrosis factor ( P01375 ) in the formation of osteoclast precursors . To better understand this association , the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis . METHODS : A total of 20 PsA patients with active erosive PsA were enrolled . DB00005 was administered twice weekly for 24 weeks . OCPF was measured and clinical assessments were performed at baseline , 2 , 12 and 24 weeks . Gadolinium enhanced MR images were obtained at baseline and 24 weeks . RESULTS : Significant improvements in joint score ( p < 0 . 001 ) , HAQ scores ( p < 0 . 001 ) and SF - 36 parameters were observed after 6 months of therapy with etanercept compared to baseline . The median OCPF decreased from 24 . 5 to 9 ( p = 0 . 04 ) and to 7 ( p = 0 . 006 ) after 3 months and 6 months of treatment , respectively . MR images were available for 13 patients . The BMO volume decreased in 47 and increased in 31 sites at 6 months . No correlation was noted between OCPF , BMO and clinical parameters . CONCLUSION : The rapid decline in OCPF and overall improvement in BMO after anti - TNFalpha therapy provides one mechanism to explain the anti - erosive effects of P01375 blockade in PsA . Persistence of BMO after etanercept treatment , despite a marked clinical response , was unexpected , and suggests ongoing subchondral inflammation or altered remodelling in PsA bone .\",\n \"DB00065 but not etanercept induces apoptosis in lamina propria T - lymphocytes from patients with Crohn ' s disease . BACKGROUND & AIMS : Steroid - refractory Crohn ' s disease responds to therapy with the chimeric anti - tumor necrosis factor ( P01375 ) - alpha antibody infliximab . DB00005 , a recombinant P01375 receptor / immunoglobulin G fusion protein , is highly effective in rheumatoid arthritis but not in Crohn ' s disease . Because both infliximab and etanercept are P01375 - neutralizing drugs , we investigated the differences in P01375 - neutralizing capacity and human lymphocyte binding and apoptosis - inducing capacity of both molecules . METHODS : We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study P01375 neutralization by infliximab and etanercept . Lymphocyte binding and apoptosis - inducing capacity was investigated using fluorescence - activated cell sorter analysis , annexin V staining , and cleaved caspase - 3 immunoblotting using mixed lymphocyte reaction - stimulated peripheral blood lymphocytes ( PBL ) from healthy volunteers and lamina propria T cells from patients with Crohn ' s disease . RESULTS : Both infliximab and etanercept neutralized P01375 effectively . DB00065 bound to activated PBL and lamina propria T cells , whereas binding of etanercept was equal to a nonspecific control antibody . DB00065 but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody . DB00065 activated caspase 3 in a time - dependent manner , whereas etanercept did not . CONCLUSIONS : Although both infliximab and etanercept showed powerful P01375 neutralization , only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes . These data may provide a biological basis for the difference in efficacy of the 2 P01375 - neutralizing drugs .\",\n \"P01375 - α blocker therapy and solid malignancy risk in ANCA - associated vasculitis . ANCA - associated vasculitides ( AAV ) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality . This group includes granulomatosis with polyangiitis ( Wegener ´ s , P02724 ) , microscopic polyangiitis ( DB00603 ) , and eosinophilic granulomatosis with polyangiitis ( Churg - Strauss , EGPA ) . The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs . These have broad mechanisms of action as well as important adverse effects . Efforts have been made to investigate novel agents with better - defined and narrower mechanisms of action , such as biologics , including P01375 - α blockers . DB00005 , a well - known P01375 - α blocker evaluated for P02724 in the Wegener ' s Granulomatosis DB00005 Trial ( WGET ) , was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period . A 5 - year follow - up after the WGET trial showed a sustained increase in incidence of solid malignancies , but this could no longer be solely attributed to etanercept exposure . These studies raised concerns about the use of the family of P01375 - α blockers in AAV . Here , we review the evidence about the association between therapeutic inhibition of tumor necrosis factor ( P01375 - α ) by etanercept and other P01375 - α blockers with the development of solid malignancies in P02724 and other AAV .\",\n \"The attenuation of experimental lung metastasis by a bile acid acylated - heparin derivative . The inhibitory efficacies of new bile acid acylated - heparin derivative ( heparin - DOCA ) were evaluated on experimental lung metastasis . We evaluated the effect of heparin - DOCA on intercellular interactions including those between B16F10 and thrombin - activated platelets and P01375 - activated HUVECs , and between B16F10 and immobilized mouse P16109 . In addition , the inhibitory effects of heparin - DOCA on adhesion and invasion of B16F10 to Matrigel were studied . In an animal mouse study , the blood clot formation and the retention of red fluorescence protein ( RFP ) - B16F10 in lungs were assessed after heparin - DOCA and RFP - B16F10 intravenous administration . Furthermore , we investigated the anti - metastatic effect of heparin - DOCA against lung metastasis induced by B16F10 and SCC7 . ___MASK8___ - DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P - and P16581 - mediated interactions . Moreover , it reduced adhesion and invasion of B16F10 to Q13201 , thereby affecting the reduction of early retention of B16F10 in the lung . ___MASK8___ - DOCA attenuated lung colony formation on the surfaces and in interior of the lung , and attenuated metastasis by B16F10 and SCC7 . These results suggest that heparin - DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression .\",\n \"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK78___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .\",\n \"Changes of urinary bladder contractility in high - fat diet - fed mice : the role of tumor necrosis factor - α . OBJECTIVES : To study the role of tumor necrosis factor - α in bladder dysfunction associated with obesity . METHODS : Male 8 - week - old C57BL / 6J mice were divided into three groups : ( i ) control mice ; ( ii ) vehicle - treated high - fat diet - fed mice ; and ( iii ) etanercept - treated high - fat diet - fed mice . High - fat diet feeding lasted for 12 weeks , vehicle or etanercept ( 0 . 8 mg / kg / day , a tumor necrosis factor - α antagonist ) treatment was given during the last 4 weeks . At the end of the treatment period , serum tumor necrosis factor - α , total cholesterol , triglyceride and blood glucose were measured . Bladder strip contractile responses to 1 μmol / L acetylcholine or 50 mmol / L DB00761 were studied in an organ bath . Bladder protein kinase Cζ , nuclear factor - κB and intercellular adhesion molecule - 1 expressions were analyzed using western blots . RESULTS : Serum levels of tumor necrosis factor - α total cholesterol , triglyceride and glucose were significantly elevated in high - fat diet - fed mice ; and the levels were not ameliorated by etanercept treatment . High - fat diet - fed mouse bladder showed reduced contractile responses to acetylcholine and DB00761 stimulation accompanied by high expression levels of phospho - protein kinase Cζ , nuclear nuclear factor - κB and intercellular adhesion molecule - 1 . DB00005 restored normal bladder contractile responses , as well as protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 expressions . CONCLUSIONS : A high - fat diet induces bodyweight gain , hyperlipidemia and hyperglycemia in mice . Elevated serum tumor necrosis factor - α level associated with increased protein kinase Cζ phosphorylation , nuclear factor - κB nuclear migration , intercellular adhesion molecule - 1 expression and impaired muscle contractility are shown in the high - fat diet - fed mouse bladder . P01375 - α antagonist treatment restores normal bladder contractility , and protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 levels .\",\n \"___MASK47___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK47___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK47___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .\",\n \"DB00005 maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects . OBJECTIVE : To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab , but presented side effects . METHODS : Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects . Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped . Disease Activity Score computed on 44 joints ( DAS - 44 ) , erythrocyte sedimentation rate ( P03372 ) 1st hour , Visual Analogue Scale ( VAS ) of pain , Health Assessment Questionnaire ( HAQ ) , and C reactive protein ( CRP ) were assessed every 8 weeks . RESULTS : 37 patients were analysed . Adverse events to infliximab were mostly infusion reactions . No statistically significant difference between infliximab , before withdrawal , and etanercept , after 24 weeks , was detected in terms of DAS - 44 ( 2 . 7 and 1 . 9 , respectively ) , HAQ ( 0 . 75 and 0 . 75 , respectively ) , P03372 ( 21 and 14 , respectively ) and CRP ( 0 . 5 and 0 . 3 , respectively ) . VAS pain decreased significantly after switching to etanercept treatment ( 40 and 24 , respectively ; p < 0 . 05 ) . CONCLUSIONS : Our study shows that etanercept maintains the clinical benefit achieved by infliximab , and suggests that a second tumour necrosis factor ( P01375 ) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events .\",\n \"A non - innovator version of etanercept for treatment of arthritis . DB00005 is a soluble tumor necrosis factor ( P01375 ) receptor originally approved for treatment of moderate - to - severe rheumatoid arthritis , juvenile rheumatoid arthritis , and psoriatic arthritis . We have developed a non - innovator version of the recombinant protein etanercept , with the investigational name AVG01 ( trade name AVENT ™ ) , using a novel expression vector - based technology . Here we show , by extensive analytical characterization , that AVG01 is highly similar to the reference product Enbrel ® and demonstrates similar efficacy in pre - clinical studies .\",\n \"P01375 blockade aggravates experimental chronic Chagas disease cardiomyopathy . Chronic Chagas disease cardiomyopathy ( CCC ) , caused by Trypanosoma cruzi , is an inflammatory dilated cardiomyopathy associated with increased circulating levels of P01375 . We investigate whether P01375 blockade with DB00005 during the chronic phase of T . cruzi infection could attenuate experimental CCC development . The effect of DB00005 was evaluated after 11 months of T . cruzi infection on survival , parasitism , left ventricular function , intensity of myocarditis , fibrosis , and left ventricular mRNA expression of cytokines and P01375 - induced genes . Left ventricular function was significantly reduced in treated animals as compared to infected untreated animals . Blood and cardiac parasitism as well as survival rate were not altered with DB00005 treatment . Inflammatory infiltrates were located predominantly in the subendocardic region in treated animals , whereas in untreated animals inflammation was scattered throughout the myocardium . Left ventricular mRNA P22301 expression was significantly higher , and P35228 , significantly lower in treated than in untreated animals . mRNA expression of P01375 , P01579 , TGF - beta , A20 and P01160 was similar in both groups . Our results suggest that P01375 / P01374 blockade with DB00005 enhances left ventricular dysfunction in T . cruzi - induced chronic cardiomyopathy and the absence of P01375 signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy .\",\n \"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK10___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK10___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK10___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK10___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK10___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK10___ increased the protein expression of hepatic P05181 and ___MASK10___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK10___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK10___ and RFP - induced hepatotoxicity .\",\n \"Newly available treatments for psoriatic arthritis and their impact on skin psoriasis . Far from being a \\\" benign \\\" arthropathy , as it was initially characterized , psoriatic arthritis ( PsA ) affects approximately 0 . 2 % of the US population and can be associated with considerable joint damage , symptomatology , and quality of life impairment . PsA shares many characteristics with rheumatoid arthritis ( RA ) , and new , rationally designed drugs that are effective in RA also are proving active in PsA . Two such drugs , etanercept and infliximab , target tumor necrosis factor ( P01375 ) , a key component of the inflammatory response . This review discusses the rationale for and experience with the use of these agents in PsA . DB00005 is a dimeric fusion protein that binds specifically to P01375 , blocking its interaction with cell surface P01375 receptors . DB00065 is a chimeric ( murine / human ) monoclonal antibody that binds to P01375 and inhibits its binding to its receptor . A randomized placebo - controlled trial of etanercept in PsA found statistically significant benefits for this agent in measures of arthritic activity and psoriatic severity . There have been anecdotal reports of the efficacy of infliximab in PsA , but results from controlled clinical trials of this agent in PsA have not been reported . P01375 inhibitors represent new therapeutic options for patients with PsA . The potential advantages of treatment with etanercept and infliximab early in the disease course are discussed .\",\n \"Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \\\" nongenomic \\\" pathway which , is clearly discernable from the classical , \\\" genomic \\\" action pathway of the P35869 by not requiring the participation of P27540 .\",\n \"Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under DB00005 Therapy . The use of tumor necrosis factor - α ( P01375 - α ) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics . Squamous cell carcinoma is the second most common cancer of the skin , usually affecting sun - exposed areas of the body . We present here the case of a 75 - year - old woman with rheumatoid arthritis , who developed an intertoe squamous cell carcinoma ( SCC ) of the right foot . According to her history , she received etanercept and methotrexate for 5 years for rheumatoid arthritis . The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti - P01375 - α treatment . This is the first reported case of an interdigital SCC developed under the use of an anti - P01375 - α agent .\",\n \"[ DB00005 and infections ] . The biological treatments for psoriasis , mainly the tumor necrosis factor - alpha inhibitors ( P01375 ) , have demonstrated their efficacy and safety beginning with the clinical trials up to their subsequent marketing . However , pharmacovigilance studies have detected a mild increase in infections . For the management of infectious risk in patients with psoriasis being treated with etanercept or other anti - P01375 medications , an evaluation should be made of the adequacy of its use in patients infected by HCV , HBV , HIV , with localized or generalized infections , with risk of sepsis ( carriers of intravenous catheter and indwelling urinary catheter ) or with underlying disorders that could predispose them to infections ( diabetes , hemodialysis ) . If a patient under treatment with etanercept presents an infection , if the infection is serious , treatment should be discontinued and if it is mild , the patient should be closely monitored and treatment interrupted if decided based on the evolution . Long experience on the use of etanercept in different diseases has made it possible to state that it has a good safety profile in regards to infections , if precautions are taken in regards to tuberculosis and the concomitance of other active infections during the treatment .\",\n \"Does route of administration affect the outcome of P01375 antagonist therapy ? The tumor necrosis factor ( P01375 ) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis . Although infliximab , etanercept , and adalimumab are all members of this class , they differ in route of administration and dosing regimen . In the USA and in Europe , infliximab , in combination with oral methotrexate , is administered intravenously , initially at a dose of 3 mg / kg at weeks 0 , 2 , and 6 , then every 8 weeks thereafter . The US Food and Drug Administration ( FDA ) has further approved that the dosage can be increased to 10 mg / kg and the doses can be given as often as every 4 weeks to optimize patient outcome ( information based on the US package insert dated June 2002 ) . DB00005 and adalimumab are given subcutaneously and can be self - injected . The FDA - approved dose of etanercept is 25 mg twice weekly , and of adalimumab is 40 mg every 2 weeks with methotrexate , or 40 mg alone . Medication adherence , possibly the most important factor in maintaining the benefits of anti - P01375 therapy , is influenced by the interaction between the patient and his or her healthcare team , the patient ' s attitude toward the disease and medication regimen , and the choice of therapy .\",\n \"Pilot study of etanercept in patients with relapsed cutaneous T - cell lymphomas . BACKGROUND : P01375 ( P01375 ) - alpha has been implicated in the pathogenesis of cutaneous T - cell lymphoma ( CTCL ) . OBJECTIVE : To assess the toxicity , safety , and efficacy of etanercept ( soluble P01375 receptor ) in patients with relapsed CTCL . METHODS : DB00005 was administered twice weekly at a dose of 25 mg subcutaneously . Patients with improvement after two months could be continued on treatment . RESULTS : Twelve out of the 13 patients enrolled on study were evaluable ( Stage I - IIA , 3 patients ; Stage IIB - IV disease , 9 patients ) . The median number of previous therapies was 7 ( range , 3 - 12 ) . DB00005 induced partial remission in one patient ( 8 % ) and minor response in one patient ( 8 % ) , both of whom had Stage IB disease . Most patients experienced no side effects . CONCLUSION : This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL . The effect of etanercept in a larger cohort of patients with early disease merits investigation .\",\n \"Inhibitors of P78536 and P29466 as anti - inflammatory drugs . P01375 neutralising agents such as DB00065 ( Remicade ) , DB00005 ( Enbrel ) and the IL - 1 receptor antagonist DB00026 ( Kineret ) , are currently used clinically for the treatment of many inflammatory diseases such as Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , juvenile rheumatoid arthritis , psoriatic arthritis and psoriasis . These protein preparations are expensive to manufacture and administer , need to be injected and can cause allergic reactions . An alternative approach to lowering the levels of P01375 and IL - 1beta in inflammatory disease , is to inhibit the enzymes that generate these cytokines using cheaper small molecules . This paper is a broad overview of the progress that has been achieved so far , with respect to small molecule inhibitor design and pharmacological studies ( in animals and humans ) , for the metalloprotease Tumour Necrosis Factor - alpha Converting Enzyme ( P78536 ) and the cysteine protease P29466 ( Interleukin - 1beta Converting Enzyme , ICE ) . Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti - inflammatory agents in the future .\",\n \"Sulindac metabolism and synergy with tumor necrosis factor - alpha in a drug - inflammation interaction model of idiosyncratic liver injury . Sulindac ( SLD ) is a nonsteroidal anti - inflammatory drug ( NSAID ) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs . In previous studies , cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide ( LPS ) led to liver injury , whereas neither SLD nor LPS alone caused liver damage . In studies presented here , further investigation of this animal model revealed that the concentration of tumor necrosis factor - alpha ( P01375 ) in plasma was significantly increased by LPS at 1 h , and SLD enhanced this response . DB00005 , a soluble P01375 receptor , reduced SLD / LPS - induced liver injury , suggesting a role for P01375 . SLD metabolites in plasma and liver were determined by LC / MS / MS . Cotreatment with LPS did not increase the concentrations of SLD or its metabolites , excluding the possibility that LPS contributed to liver injury through enhanced exposure to SLD or its metabolites . The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells ; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone . P01375 augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells . These results suggest that P01375 can enhance SLD sulfide - induced hepatotoxicity , thereby contributing to liver injury in SLD / LPS - cotreated rats .\",\n \"DB00005 - induced anti - Jo - 1 - antibody - positive polymyositis in a patient with rheumatoid arthritis : a case report and review of the literature . Antitumor necrosis factor ( P01375 ) therapy has been associated with adverse immunologic events including systemic lupus erythematosus . However , the development of polymyositis ( PM ) / dermatomyositis ( DM ) associated with anti - P01375 therapy is extremely rare . We experienced a case of a 48 - year - old female with rheumatoid arthritis ( RA ) who had anti - Jo - 1 antibodies and interstitial lung disease but no previous history of PM / DM and who developed PM soon after the initiation of etanercept ( DB01613 ) therapy for RA . The patient recovered upon withdrawal from DB01613 and corticosteroid ( CS ) therapies . Only four reports of PM / DM associated with anti - P01375 therapy for RA could be found in the literature . The patients described in three of the four reports were positive for anti - Jo - 1 antibodies before the initiation of anti - P01375 therapy , and in all the cases , recovery occurred after the cessation of anti - P01375 - agent administration and CS therapy . These results suggest a relationship between the onset of PM / DM with anti - Jo - 1 antibody and anti - P01375 therapy for RA .\",\n \"[ Juvenile psoriatic arthritis ] . A case of juvenile psoriatic arthritis in a 12 year - old boy was reported . The patient had a history of one and half a year of bilateral heel pain , followed by pain in the right knee and ankle and right hip joint . He developed psoriatic lesions affecting his nails and skin . He had increased erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) contents . Human leukocyte antigen ( HLA ) Q8TCY5 was detected but serum rheumatoid factor was not in the patient . A skin biopsy revealed psoriasis and ultrasonography demonstrated synovitis in right knee and ankle . Juvenile psoriatic arthritis was diagnosed based on his physical , laboratory and skin biopsy findings . A treatment with nonsteroidal anti - inflammatory drugs and sulfasalazine produced no effect . Leflunomide in conjunction with anti - P01375 biologic agents ( DB00005 ) was administered , followed by symptomatic improvement 2 weeks later .\",\n \"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .\",\n \"[ Anti - P01375 treatment and spondyloarthropathies ] . Spondyloarthropathies are characterized by both axial and peripheral joint involvement , by the association with \\\" other diseases \\\" mainly Psoriasis , Crohn ' s and Anterior Uveitis and by the high prevalence of HLA B - 27 . While disease modifying drugs , such as DB00563 or Sulfasalazine , are only partially effective in controlling peripheral arthritis , the treatment of the axial part remained only symptomatic . The recently introduced anti - P01375 drugs DB00065 ( Remicade ) and DB00005 ( Enbrel ) for the treatment of Crohn ' s disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with highly promising results . The rationale and the early beneficial results of this new approach in spondyloarthropathies are reviewed .\",\n \"DB00005 in psoriatic arthritis . Psoriatic arthritis ( PsA ) , an inflammatory arthritis associated with psoriasis , can lead to disability from progressive joint destruction and bony fusion . To date , conventional disease modifying antirheumatic drugs ( DMARDS ) have not convincingly lessened joint pain and inflammation in PsA and there is very little data on the limitation of radiographic progression with these agents . The biological agent etanercept ( Enbrel , Amgen , Inc , Thousand Oaks , California , USA ) is a soluble P01375 receptor fusion protein with proven efficacy in the treatment of rheumatoid arthritis ( RA ) . In a Phase II and Phase III trial , conducted in moderate - to - severe PsA , etanercept significantly reduced joint pain and swelling and lowered the erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) level . A significant decline in structural damage was observed as early as 6 months after starting the drug . DB00005 also improved quality of life measures ( Health Assesment Questionnaire [ HAQ ] and global assessment scores ) . Up to a third of patients experienced transient injection - site reactions . Rare cases of opportunistic infection , demyelinating disorders and aplastic anaemia have been reported , but a causal link has not been established . In summary , etanercept is a safe and effective agent for the treatment of PsA and represents a major advance in the therapy of this potentially crippling disease .\",\n \"P01375 antagonist therapy and lymphoma development : twenty - six cases reported to the Food and Drug Administration . OBJECTIVE : DB00005 and infliximab are tumor necrosis factor ( P01375 ) antagonists that have been recently approved for the treatment of rheumatoid arthritis ( RA ) and Crohn ' s disease ( CD ) . This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents . METHODS : Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed . RESULTS : We identified 26 cases of lymphoproliferative disorders following treatment with etanercept ( 18 cases ) or infliximab ( 8 cases ) . The majority of cases ( 81 % ) were non - Hodgkin ' s lymphomas . The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short ( median 8 weeks ) . In 2 instances ( 1 infliximab , 1 etanercept ) , lymphoma regression was observed following discontinuation of anti - P01375 treatment , in the absence of specific cytotoxic therapy directed toward the lymphoma . CONCLUSION : Although data from a case series such as this can not establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease , the known predisposition of patients with RA and CD to lymphoma , the known excess of lymphoma in other immunosuppressed populations , and the known immunosuppressive effects of the anti - P01375 drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association .\",\n \"Adverse reactions during biological drug therapy in psoriasis : clinical series and a review of the literature . AIM : Psoriasis is a chronic , inflammatory skin disorder , histologically characterized by epidermal hyperplasia , anomalous keratinocyte differentiation , angiogenesis , and by inflammatory cell infiltrate . Psoriasis has a significant impact on quality of life and is often associated with serious psychological effects . The use of biological agents is expanding worldwide as alternative treatment for chronic inflammatory diseases including psoriasis . The European Medicines Agency ( EMEA ) approved the use of DB00095 , DB00005 , DB00065 and DB00051 in the treatment of psoriasis on the basis of the positive findings obtained from well - designed clinical trials . The ongoing monitoring of tolerability and possible side - effects of these drugs has , however , recently lead to the EMEA suspending DB00095 on the grounds that the possible risks of its use outweighed the benefits . METHODS : Fifty - four patients treated with the two classes of biological drug ( DB00095 and anti - P01375 - α ) were studied . The choice of biological drug therapy was conditioned by the extent and seriousness of the disease and by the presence of concomitant pathologies . RESULTS : Nineteen patients presented adverse reactions , of which 9 necessitated interruption in treatment ( 6 DB00095 and 3 anti - P01375 - α ) . CONCLUSION : This work reports the adverse reactions to these biological therapies found in our patients along with a review of the literature concerning adverse reactions in psoriasis treatment . From our experience and basing ourselves on the literature reporting studies conducted in large centres , we feel that it is indispensable to continue monitoring any reactions during biological drug treatment . In this way , there is more likelihood of preventing , where possible , or better managing any reactions linked to the use of these drugs .\",\n \"Rheumatoid arthritis in pregnancy : successful outcome with anti - P01375 agent ( DB00005 ) .\",\n \"Use of etanercept in human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) patients . BACKGROUND : DB00005 ( Enbrel , Amgen , Thousand Oaks , CA ) , a soluble p75 tumor necrosis factor receptor : FC ( TNFR : FC ) fusion protein for plasma cytokines , specifically tumor necrosis factor - alpha ( P01375 ) , is used in the treatment of immune - mediated rheumatic diseases . To our knowledge , the use of etanercept in patients with human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) is relatively uncommon . OBJECTIVE : The main purpose of this short review is to examine the safety of etanercept in patients with HIV / AIDS . METHODS : A Medline search was conducted using the keywords etanercept and HIV and / or AIDS for any published articles between 1966 to the present ( September 2004 ) . RESULTS : A case report , one case series , and one clinical trial pertained to the use of etanercept in HIV patients . No reports were found on the use of etanercept in AIDS . In addition , two case reports were found documenting the use of infliximab in HIV patients . DISCUSSION : Preliminary reports indicate that the administration of etanercept does not appear to increase the morbidity or mortality rates in HIV . The inhibition of P01375 may actually improve the symptoms of HIV / AIDS - associated aphthous ulcers , cachexia , dementia , fatigue , and fever , as well as help manage concomitant rheumatic diseases and psoriasis . CONCLUSION : The use of etanercept shows promise for applications in disease management in patients with HIV / AIDS . Continued research efforts are necessary to establish the long - term safety and efficacy of etanercept and other biologic agents in this patient population .\",\n \"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK42___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .\",\n \"P62158 interacts with angiotensin - converting enzyme - 2 ( Q9BYF1 ) and inhibits shedding of its ectodomain . P12821 - 2 ( Q9BYF1 ) is a regulatory protein of the renin - angiotensin system ( DB01367 ) and a receptor for the causative agent of severe - acute respiratory syndrome ( P49591 ) , the P49591 - coronavirus . We have previously shown that Q9BYF1 can be shed from the cell surface in response to phorbol esters by a process involving P01375 converting enzyme ( P78536 ; P78536 ) . In this study , we demonstrate that inhibitors of calmodulin also stimulate shedding of the Q9BYF1 ectodomain , a process at least partially mediated by a metalloproteinase . We also show that calmodulin associates with Q9BYF1 and that this interaction is decreased by calmodulin inhibitors .\",\n \"The silent progression of metastatic malignancy during the treatment with soluble tumor necrosis factor receptor . DB00005 is singular among anti - tumor necrosis factor alpha ( P01375 ) agents , for being a soluble antibody to both P01375 and lymphtoxin - alpha . The long - term neutralization of two cachexins by etanercept would theoretically compromise early detection of malignancy . This case reports a patient who was treated by etanercept for 21 months due to ankylosing spondylitis . Metastatic malignancy of unknown origin developed , and silently led the patient to lethal hepatic rupture . With an example of a malignancy masking effect of soluble P01375 receptor , this article questions a need for vigilant attention to de novo carcinoma during the therapy , and calls for refined strategies in modulating autoimmune diseases .\",\n \"Effects of etanercept , a tumour necrosis factor - alpha antagonist , in an experimental model of periodontitis in rats . BACKGROUND AND PURPOSE : DB00005 is a tumour necrosis factor antagonist with anti - inflammatory effects . The aim of our study was to evaluate , for the first time , the therapeutic efficacy of in vivo inhibition of P01375 in an experimental model of periodontitis . EXPERIMENTAL APPROACH : Periodontitis was induced in adult male Sprague - Dawley rats by placing a nylon thread ligature around the lower 1st molars . DB00005 was administered at a dose of 5 mg kg - 1 , s . c . , after placement of the ligature . KEY RESULTS : Periodontitis in rats resulted in an inflammatory process characterized by oedema , neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells , production of a range of inflammatory mediators , tissue damage , apoptosis and disease . Treatment of the rats with etanercept ( 5 mg kg - 1 , s . c . , after placement of the ligature ) significantly reduced the degree of ( 1 ) periodontitis inflammation and tissue injury ( histological score ) , ( 2 ) infiltration of neutrophils ( P05164 evaluation ) , ( 3 ) P35228 ( the expression of nitrotyrosine and cytokines ( eg P01375 ) ) and ( 4 ) apoptosis ( Bax and Bcl - 2 expression ) . CONCLUSIONS AND IMPLICATIONS : Taken together , our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury , events associated with periodontitis .\",\n \"A case of tuberculous arthritis following the use of etanercept . DB00005 is a tumor necrosis factor ( P01375 ) inhibitor that has been used for the treatment of chronic inflammatory diseases including rheumatoid arthritis , ankylosing spondylitis and psoriatic arthritis . Because of its immunosuppressive activity , opportunistic infections have been noted in treated patients , most notably caused by Mycobacterium tuberculosis . Tuberculosis may present in an extrapulmonary or disseminated form . Since P01375 inhibitors have been used in Korea , a few cases of P01375 inhibitor associated tuberculosis have been described . However , tuberculous arthritis has not been previously reported . We describe a case of tuberculous arthritis in a 57 - year - old woman with rheumatoid arthritis who was treated with etanercept .\",\n \"Clock gene modulation by P01375 depends on calcium and p38 Q96HU1 kinase signaling . A 24 - h treatment with the cytokine tumor necrosis factor - alpha ( P01375 ) suppresses transcription of E - box - driven clock genes ( D - site albumin promoter binding protein , Dbp ; Tyrotroph embryonic factor , Tef ; Q16534 , Hlf ; Period homolog to Drosophila 1 / 2 / 3 , Per1 , Per2 , and Per3 ) by yet unknown molecular mechanisms . The attenuation of clock genes has been suggested as a putative cause for the development of sickness behavior syndrome in infectious and autoimmune diseases . Here , the authors studied the effect of P01375 at early time points ( < 3 h ) on intracellular signaling events and clock gene expression in fibroblasts . Interaction of P01375 with P19438 ( Tnfrsf1a , CD120a , p55 ) , but not P20333 ( Tnfrsf1b , DB00005 , p75 ) , leads to fast downregulation of gene expression of Dbp and upregulation of negative regulators of the molecular clock , Per1 and Per2 , Q16526 ( Cry1 ) , and Differentiated embryo chondrocytes - 1 ( Dec1 ) . Since the decrease of Dbp is also observed in cells deficient for Per1 / Per2 , Cry1 / Cry2 , or Dec1 , these genes are unlikely to be responsible for inhibition of Dbp . The early effect of P01375 on the clock gene Per1 is dependent on p38 , mitogen - activated protein kinase ( MAPK ) , and / or calcium signaling , whereas the effect on Dbp is independent of p38 MAPK , but also involves calcium signaling . Both genes remain unaffected by the NF - kappaB and AP - 1 pathway . Taken collectively these data show p38 MAPK - and calcium - dependent P19438 - mediated transient increase of the negative regulator Per1 and an independent decrease of Dbp .\",\n \"Central P01375 inhibition results in attenuated neurohumoral excitation in heart failure : a role for superoxide and nitric oxide . This study examined the effect of central tumor necrosis factor - alpha ( P01375 ) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus ( PVN ) and ventrolateral medulla ( VLM ) , key autonomic regulators , and their contribution to enhanced sympathetic drive in mice with congestive heart failure ( CHF ) . We also used a P01375 gene knockout ( KO ) mouse model to study the involvement of P01375 in body fluid homeostasis and sympathoexcitation in CHF . After implantation of intracerebroventricular ( ICV ) cannulae , myocardial infarction ( MI ) was induced in wild - type ( WT ) and KO mice by coronary artery ligation . Osmotic mini - pumps were implanted into one set of WT + MI / Sham mice for continuous ICV infusion of DB00005 ( DB01613 ) , a P01375 receptor fusion protein , or vehicle ( VEH ) . Gene expressions of neuronal nitric oxide synthase ( NOS ) and angiotensin receptor - type 2 were reduced , while those of inducible NOS , Nox2 homologs , superoxide , peroxynitrite and angiotensin receptor - type 1 were elevated in the brainstem and hypothalamus of MI + VEH . Plasma norepinephrine levels and the number of Fos - positive neurons were also increased in the PVN and VLM in MI + VEH . MI + DB01613 and KO + MI mice exhibited reduced oxidative stress , reduced sympathoexcitation and an improved cardiac function . These changes in WT + MI were associated with increased sodium and fluid retention . These results indicate that elevated P01375 in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide , contributing to fluid imbalance and sympathoexcitation in CHF .\",\n \"[ Cytokines -- causes , players or bystanders in heart failure ] . BACKGROUND : Cytokines are important mediators of the immune system and are of pathophysiological relevance for different cardiac diseases . Currently , 18 cytokines carrying the name interleukin ( IL ) are known ; they can be subdivided into pro - and anti - inflammatory interleukins . CARDIAC CYTOKINES : They partly act in a negative inotropic manner and cause destruction of cardiomyocytes resulting in myocardial fibrosis . The proinflammatory cytokine tumor necrosis factor ( P01375 -) alpha induces cardiodepressive effects and causes apoptosis . P01375 , P05231 , soluble P01375 - receptor - 1 and - 2 are independent predictors of increased mortality of patients with heart failure . Experimental and clinical evidence has shown that plasma and tissue levels of P01375 were elevated to such extent as to explain at least some of the symptoms of heart failure due to the actions of this cytokine . CLINICAL TRIALS : Two multicenter studies ( RENAISSANCE , RECOVER ) , based on promising pilot studies , have disclosed no effect for the P01375 antagonists ( DB00005 ) on mortality and morbidity . It is not possible , however , to draw the conclusion from the data of these studies that P01375 plays no significant pathophysiological role in the etiology and progression of heart failure .\",\n \"Inguinal Herniation of the Urinary Bladder Presenting as Recurrent Urinary Retention . Herniation of the urinary bladder into the inguinal canal is an uncommon finding , observed in 0 . 5 - 4 % of inguinal hernias ( Curry ( 2000 ) ) . It is usually associated with other conditions that increase intra - abdominal pressure such as bladder neck obstruction due to prostatic hypertrophy . Consequently , in men , it is usually associated with some degree of urinary retention . We present a 42 - year - old man in whom herniation of the urinary bladder was the cause of urinary retention , and not vice versa . The patient was on tumor necrosis factor alpha antagonist ( P01375 ) ( DB00005 ) for severe Ankylosing spondylitis . Initially , the urinary retention was thought to be a side effect of the medication , but after the drug was discontinued , urinary retention persisted . CT and Q9BWK5 demonstrated huge herniation of the urinary bladder into the inguinal canal . Immediately after the hernia was repaired , bladder function was restored . P01375 treatment was restarted , and no further urinary symptoms were observed in the next two years of follow - up . In this case , the primary illness and its treatment were distracting barriers to early diagnosis and treatment . In younger patients with a large hernia who develop unexpected urinary retention , herniation of the urinary bladder should be highly considered in the differential diagnosis .\",\n \"Prospective open - label trial of etanercept as adjunctive therapy for kawasaki disease . OBJECTIVE : To determine the safety and pharmacokinetics of etanercept ( Amgen , Thousand Oaks , California ) a tumor necrosis factor - α receptor blocker , in children with acute Kawasaki disease ( KD ) . Standard therapy of acute KD includes intravenous immunoglobulin ( IVIG ) and high - dose aspirin , but a substantial number of patients are refractory and require additional treatment . P01375 - α levels are elevated in children with KD , suggesting a role for etanercept in treatment . STUDY DESIGN : We performed a prospective open - label trial of etanercept in patients with KD ( age range , 6 months - 5 years ; n = 17 ) meeting clinical criteria and with fever ≤ 10 days . All received IVIG and high - dose aspirin . They received etanercept immediately after IVIG infusion and then weekly two times . For the initial safety evaluation , the first 5 patients received 0 . 4 mg / kg / dose . Subsequent subjects received 0 . 8 mg / kg / dose . RESULTS : Fifteen patients completed the study . The pharmacokinetics were similar to that in older children in published series . No serious adverse events related to etanercept occurred . No patient demonstrated prolonged or recrudescent fever requiring re - treatment with IVIG . No patient showed an increase in coronary artery diameter or new coronary artery dilation / cardiac dysfunction . CONCLUSION : DB00005 appears to be safe and well tolerated in children with KD . The data support performance of a placebo - controlled trial .\",\n \"DB00005 in psoriatic arthritis . In this update on etanercept ( DB01613 ) in psoriatic arthritis ( PsA ) we analyze this drug ' s mechanism of action , clinical efficacy / effectiveness , optimal dosage , disease - modifying antirheumatic drugs ( DMARD ) association , radiological progression , safety , switching aspects , and pharmacoeconomy . The efficacy / effectiveness of DB01613 in PsA has been demonstrated in randomized placebo - controlled trials as well as in observational studies representing routine clinical practice . At 1 and 2 years , DB01613 inhibited radiographic disease progression , assessed by the modified total Sharp score . DB01613 ( generally at a dosage of 50 mg / weekly ) can be used either in monotherapy or in combination with DMARD such as methotrexate . A systematic search of randomized , placebo - controlled trials of DB01613 to treat adults with plaque psoriasis or PsA suggests that the short - term risk / benefit ratio is favorable . Longterm studies , such as observational studies , confirmed this safety profile of DB01613 . A variable percentage of patients withdrew anti - tumor necrosis factor - α ( P01375 - α ) inhibitor treatment owing to inefficacy or poor tolerability . Observational studies showed that in the case of treatment failure with 1 agent , switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available P01375 - α blockers . The clinical effect of DB01613 is associated with favorable pharmacoeconomic considerations .\",\n \"DB00005 : long - term clinical experience in rheumatoid arthritis and other arthritis . DB00005 is a dimeric fusion protein based on the p75 P01375 receptor . It binds to P01375 and blocks its biologic activity . In randomized , double - blind , placebo - controlled trials , etanercept has therapeutic activity in rheumatoid arthritis , psoriatic arthritis , polyarticular - course juvenile idiopathic arthritis and ankylosing spondylitis . DB00005 improves joint inflammation , physical function and slows / halts structural damage , especially when combined with methotrexate . A sustained response is observed in a substantial percentage of patients . Although some safety issues should be considered before starting etanercept treatment , in general terms , etanercept is a well tolerated drug with an acceptable safety profile . The use of any P01375 antagonist must be in agreement with the National Recommendations for Biologic Therapy , and in difficult clinical situations , a balance between risk / benefit needs to be obtained .\",\n \"Clastogenic plasma factors in psoriasis -- comparison of phototherapy and anti - P01375 - α treatments . As previously described , Psoralen plus UVA ( PUVA ) therapy induces chromosome damage in psoriatic patients . This study evaluates whether these effects are transitory or persistent . In addition , we studied these effects after narrowband UVB ( nUVB ) and anti - tumor necrosis factor ( P01375 ) - α treatments . Among 40 responder patients , 10 received PUVA , 10 nUVB , 10 DB00065 and 10 DB00005 . Disease activity was determined with Psoriasis Area and Severity Index . Chromosomal breakage was evaluated by the clastogenic factor ( CF ) test . Potential clastogenic agents , malondialdehyde ( MDA ) and P01375 - α were measured . Before treatment , the plasma - adjusted clastogenic scores ( ACS ) of patients were increased . During treatment , a further increase in ACS was observed in both phototherapy groups . Chromosome damage persisted for PUVA patients at week 32 , while it diminished after nUVB to ACS values lower than before treatment . MDA and P01375 - α values were also increased at baseline . MDA decreased during treatment in all groups , but without reaching normal levels . Plasma P01375 - α remained unchanged in PUVA and nUVB but decreased in both anti - P01375 - α treatment groups . Psoriasis is accompanied by CF - induced chromosomal breakage that increases during PUVA and nUVB treatments . Plasma clastogenic activity persisted in the follow - up after PUVA , while after nUVB ACS returned to values even lower than baseline . Clastogenic activity during the induction phase with anti - P01375 - α remained unchanged .\",\n \"___MASK80___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"Tumor - infiltrating macrophages induce apoptosis in activated CD8 (+) T cells by a mechanism requiring cell contact and mediated by both the cell - associated form of P01375 and nitric oxide . We have investigated the ability of different cells present in murine tumors to induce apoptosis of activated CD8 (+) T cells in vitro . Tumor cells do not induce apoptosis of T cells ; however , macrophages that infiltrate tumors are potent inducers of apoptosis . Tumor macrophages express cell surface - associated P01375 , P01375 type I ( CD120a ) and II ( DB00005 ) receptors , and , upon contact with T cells which induces release of P01579 from T cells , secrete nitric oxide . Killing of T cells in vitro is blocked by Abs to P01579 , P01375 , CD120a , or DB00005 , or N - methyl - L - arginine . In concert with that finding , tumor macrophages isolated from either P01375 type I or type II receptor -/- mice are not proapoptotic and do not produce nitric oxide upon contact with activated T cells . Control macrophages do not express P01375 receptors or release nitric oxide . Tumor cells or tumor - derived macrophages do not express P48023 , and blocking Abs to either Fas or P48023 have no effect on macrophage - mediated T cell killing . These results demonstrate that macrophages which infiltrate tumors are highly proapoptotic and may be responsible for elimination of activated antitumor T cells within the tumor bed .\",\n \"Managing moderate - to - severe psoriasis in the elderly . Managing psoriasis in the elderly can be difficult for physicians , who must consider comorbidities , the resulting polypharmacy , and progressive functional impairment of several organs . Indeed , topical agents are the first - line treatment for limited disease . Phototherapy is recommended if topical drugs are not sufficient and the patient has multiple comorbidities and risk factors that make them a poor candidate for an oral or injectable systemic agent . The most important pharmacokinetic alteration in the elderly population is the decreased excretory capacity of the kidney ; thus , cyclosporine should be considered a last resort treatment , and the administered dose of methotrexate should be lowered according to the reduction in estimated creatinine clearance . Acitretin can be used in the absence of severe renal insufficiency , paying attention to lipid profile , treating eventual hyperlipidemia , and closely monitoring liver enzymes . Available data on biological drugs in the elderly are limited . Biologics are associated with a small but significant overall risk of infections . However , there is no convincing evidence that the relative risk of infection with anti - tumor necrosis factor ( P01375 ) - α therapy increases with age . Nevertheless , the package inserts for biologics recommend caution when administering these medications to the geriatric population , due to the high baseline risk of infection in such patients . DB00005 seems to be well tolerated , possibly because of its lower immunosuppressive characteristics compared with other biologics . However , studies with larger sample sizes are needed to confirm its safety .\",\n \"DB00005 ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 that has been shown to provide rapid and sustained improvement in both of these diseases . Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time . To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate , and to examine the effect of etanercept on radiographic progression , a double blind , placebo controlled study was recently conducted , comparing etanercept with methotrexate ( median dose 20 mg per week ) . Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA , and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions . In patients with severe psoriatic arthritis ( PsA ) , a double blind , placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA . DB00005 has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases .\",\n \"DB00005 in the treatment of active refractory Crohn ' s disease : a single - center pilot trial . OBJECTIVES : DB00005 , an injectable tumor necrosis factor ( P01375 ) receptor fusion protein , binds and inactivates human P01375 and is used in active rheumatoid arthritis . Blocking P01375 with monoclonal antibodies has also been beneficial in Crohn ' s disease . We attempted to determine the efficacy and safety of etanercept for induction of clinical , endoscopic , and histological improvement in patients with moderate to severe Crohn ' s disease despite standard treatment . METHODS : Ten patients with active Crohn ' s disease were treated with etanercept ( 25 mg s . c . ) twice per week for 12 wk . Background therapy was kept stable during the trial . Crohn ' s disease activity index ( CDAI ) , Inflammatory Bowel Disease Questionnaire , and P02741 levels were measured at weeks 0 , 2 , 4 , 8 , and 12 . Colonoscopies were performed before and after therapy in responders ; endoscopic biopsies were scored for inflammation . RESULTS : At week 2 after the start , a clinical response ( deltaCDAI > or = 70 ) was observed in 6 / 10 patients ( median = 305 [ 294 - 418 ] to 166 [ 107 - 392 ] ) , with reduction in serum P02741 levels ( median = 17 . 2 [ 6 . 8 - 67 . 2 ] to 9 . 1 [ 0 . 9 - 17 . 2 ] mg / dl ) . Colonoscopies showed a reduction in inflammatory lesions in the four patients who attained remission ( CDAI < 150 ) , whereas the inflammatory score of the biopsies did not decrease significantly . No moderate or severe adverse events were observed . CONCLUSIONS : DB00005 may be effective in Crohn ' s disease refractory to standard therapy .\",\n \"DB00005 - induced Henoch - Schönlein purpura in a patient with ankylosing spondylitis . Ankylosing spondylitis ( AS ) is a chronic inflammatory disease that primarily affects the axial skeleton . Extra - articular manifestations are less common relative to other rheumatic diseases , and vasculitic complications typically involve the ascending aorta and aortic valve . The use of tumor necrosis factor inhibitors is efficacious in the treatment of patients with AS . Since their routine use , however , tumor necrosis factor inhibitors have been associated with the development of drug - induced complications including the induction of lupus and both cutaneous and systemic vasculitis . In this report , we describe a patient with severe longstanding AS , who developed Henoch - Schönlein purpura after commencing therapy with etanercept . P01375 inhibitor - induced Henoch - Schönlein purpura has been very rarely reported and has been mostly recognized in patients with rheumatoid arthritis .\",\n \"Leukopenia and thrombocytopenia induced by etanercept : two case reports and literature review . P01375 - alpha ( P01375 ) is a proinflammatory cytokine , and its excess can lead to severe consequences . Those effects are known to be antagonized by P01375 inhibitors . DB00005 is a fusion protein that inhibits P01375 action . As P01375 regulation is related to cellular differentiation of various cellular types involved in immune response through expression of several other cytokines , it is possible that the use of its inhibitors may cause cytopenia . We report two cases of bicytopenia induced by etanercept . Both cases recovered after drug withdrawal . We discuss the need of introduction of routine laboratorial tests in patients using anti - P01375 therapy , in order to identify possible hematological changes .\",\n \"P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .\",\n \"Human tumor necrosis factor receptor p75 / 80 ( DB00005 ) gene structure and promoter characterization . P01375 receptor p75 ( P01375 - R p75 ) is a 75 - kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage . P01375 - R p75 belongs to the P01375 receptor superfamily characterized by cysteine - rich extracellular regions composed of three to six disulfide - linked domains . In the present report we have characterized , for the first time , the complete gene structure for human P01375 - R p75 , which spans approximately 43 kbp . The gene consists of 10 exons ( ranging from 34 base pairs to 2 . 5 kilobase pairs ) and nine introns ( 343 base pairs to 19 kilobase pairs ) . Consensus elements for transcription factors involved in T cell development and activation were noted in the 5 '- flanking region including T cell factor - 1 , Ikaros , AP - 1 , CK - 2 , interleukin - 6 receptor E ( IL - 6RE ) , ISRE , GAS , NF - kappaB , and Sp1 . The unusual ( GATA ) n and ( P10253 ) ( GGA ) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus . Characterization of the human P01375 - R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function , autoimmune disease , and nonrandom translocations in hematopoietic malignancies .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK90___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .\",\n \"Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .\",\n \"Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .\",\n \"[ Anti - P01375 - α in the treatment of uveitis in the Besançon Hospital ] . BACKGROUND : Noninfectious chronic uveitis is a difficult - to - treat situation in which corticosteroids , immunosuppressive agents , and more recently , anti - tumor necrosis factor ( P01375 ) - α are used to prevent and / or reverse severe visual impairment . This single - center retrospective study was designed to assess the use ( indications , efficacy , and side effects ) of anti - P01375 - α agents in noninfectious uveitis . PATIENTS AND METHODS : Eight patients were analyzed : three children ( age , 7 - 15 years ) and five adults ( age , 27 - 44 years ) . Anti - P01375 - α agents were etanercept ( three patients ) , adalimumab ( four patients ) , and infliximab ( four patients ) . Diagnoses were Behçet ' s diseases ( n = 3 ) , sarcoidosis ( n = 1 ) , juvenile chronic arthritis ( n = 2 ) , spondyloarthropathy ( n = 2 ) , one of the latter two combined with Crohn disease . In all cases , anti - P01375 - α therapies were prescribed because uveitis and / or associated disease were not under control . RESULTS : DB00051 and infliximab were effective for all patients . One patient with infliximab needed to add corticosteroids and immunosuppressive agents because of relapse . DB00005 was stopped in all cases due to a lack of effectiveness or a change in indication . In all patients , anti - P01375 - α agents improved uveitis and the underlying systemic disease . In children , their use improved quality of life by corticosteroid weaning . Prescriptions did not comply with regulations for three children , because of age limits ( etanercept , one ; adalimumab , two ) . No adverse event was recorded . CONCLUSION : In this short case series , anti - P01375 - α agents were effective both on uveitis and the underlying systemic disease and were well tolerated in patients with noninfectious chronic uveitis .\",\n \"DB00005 , a P01375 - α inhibitor , does not impede fracture healing .\",\n \"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK95___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .\",\n \"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK2___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK2___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK2___","___MASK42___","___MASK47___","___MASK78___","___MASK80___","___MASK8___","___MASK90___","___MASK95___"],"string":"[\n \"___MASK10___\",\n \"___MASK2___\",\n \"___MASK42___\",\n \"___MASK47___\",\n \"___MASK78___\",\n \"___MASK80___\",\n \"___MASK8___\",\n \"___MASK90___\",\n \"___MASK95___\"\n]"},"answer":{"kind":"string","value":"___MASK47___"},"id":{"kind":"string","value":"MH_train_378"}}},{"rowIdx":379,"cells":{"query":{"kind":"string","value":"interacts_with DB06441?"},"supports":{"kind":"list like","value":["P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .","Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .","Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .","Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK97___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .","DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .","Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .","Knockdown of receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) affects EMT - associated gene expression in human hepatoma cells . BACKGROUND : Receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) has been reported to be an important regulator of tumor proliferation , differentiation and wound repair . We investigated the effects of O43353 knockdown in human hepatoma cells on epithelial - to - mesenchymal transition ( EMT ) - associated gene expression . MATERIALS AND METHODS : HepG2 cells stably expressing O43353 - shRNA ( HepG2 - shRIPK2 ) were generated after puromycin selection . Total RNAs from HepG2 - shRIPK2 and from HepG2 - shcontrol cells were isolated and PCR - based arrays were performed to compare the 84 EMT - associated gene expressions . RESULTS : We observed that knockdown of O43353 down - regulated mRNA expression of jagged 1 ( P78504 ) ; plasminogen activator inhibitor - 1 ( P05121 ) ; regulator of G - protein signalling 2 , 24 kDa ( P41220 ) ; P12830 ( CDH1 ) ; fibroblast growth factor binding protein 1 ( Q14512 ) ; snail homolog 2 ( O43623 ) ; protein tyrosine phosphatase type IVA , member 1 ( Q93096 ) ; keratin 19 ( P08727 ) ; vimentin ( P08670 ) ; and survival of motor neuron protein - interacting protein 1 ( SIP1 ) . CONCLUSION : We found that knockdown of O43353 down - regulated nuclear factor kappa B ( NF - κB ) - dependent P05121 and P08670 gene expressions . O43353 might play an important role in hepatic cell migration . These findings could shed new light on carcinogenesis and on liver regeneration .","Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK65___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .","State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . ___MASK2___ is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .","[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK2___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .","DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .","___MASK42___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK42___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK42___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .","Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation . Angiogenic cytokines have been shown to influence vessel injury , and platelets represent a disposable circulating pool of angiogenic molecules . In the present study , objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation . We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg / day . We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor ( P15692 ) - A and its soluble receptor forms P17948 and P35968 , placenta growth factor , and stromal cell - derived factor - 1 . We also quantified soluble P16581 and P04275 to evaluate endothelial activation . Blood samples were drawn just before the first clopidogrel intake on day 1 , and after the last dosing ( day 7 ) . As expected , we observed a decrease in platelet reactivity in response to clopidogrel , confirmed by vasodilator - stimulated phosphoprotein phosphorylation assay . However , the 7 - day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation . These results show that circulating angiogenic factor level in healthy subjects is not driven by Q9H244 platelet receptor - induced activation and clopidogrel does not modify in a significant way the endothelial activation level .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .","Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .","New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . ___MASK2___ is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .","Variation in glucose homeostasis traits associated with Q99572 polymorphisms in mice and humans . CONTEXT : Extracellular nucleotide receptors are expressed in pancreatic B - cells . Purinergic signaling via these receptors may regulate pancreatic B - cell function . OBJECTIVE : We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction . DESIGN : In humans , we mined genome - wide meta - analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes . We performed additional testing in two genomic regions ( Q99571 / Q99572 and P47900 ) in a cohort from the Prevalence , Prediction , and Prevention of Diabetes in Botnia ( n = 3504 ) , which includes more refined measures of glucose homeostasis . In mice , we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background . RESULTS : Variants in five genes were associated with glycemic traits and in three genes with diabetes risk . In the Prevalence , Prediction , and Prevention of Diabetes in Botnia study , the minor allele in the missense functional variant rs1718119 ( A348T ) in Q99572 was associated with increased insulin sensitivity and secretion , consistent with its known effect on increased pore function . Both male and female P2x7 - C57 mice demonstrated impaired glucose tolerance compared with matched P2x7 - 129 mice . P01308 tolerance testing showed that P2x7 - C57 mice were also less responsive to insulin than P2x7 - 129 mice . CONCLUSIONS : We show association of the purinergic signaling pathway in general and hypofunctioning Q99572 variants in particular with impaired glucose homeostasis in both mice and humans .","Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK36___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .","Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .","The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK53___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK53___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .","( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .","Purinergic receptors involved in the immunomodulatory effects of DB00171 in human blood . We recently showed that the physiological compound DB00171 simultaneously inhibited P01375 and stimulated P22301 release in LPS - PHA stimulated blood . The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of DB00171 on P01375 and P22301 . Incubation of blood with DB00171 in the presence of selective P2 receptor antagonists showed that the stimulatory effect of DB00171 on P22301 release was completely annihilated by both 2 - MeSAMP ( a Q9H244 / 13 receptor antagonist ) and PSB - 0413 ( a Q9H244 receptor antagonist ) . On the other hand , the inhibitory effect of DB00171 on P01375 release was completely reversed by 5 '- P30566 ( a Q96G91 receptor antagonist ) as well as by H - 89 , an inhibitor of DB02527 - activated PKA . The concerted inhibition by DB00171 of P01375 release via Q96G91 activation and stimulation of P22301 release via Q9H244 activation implicates a novel approach towards immunomodulation by altering the balance among pro - and anti - inflammatory cytokines .","P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK2___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK2___ is in clinical development as an orally active agent .","New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK78___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .","P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK28___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .","The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .","Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . ___MASK2___ is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .","DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .","DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .","Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK19___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .","Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .","DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .","Autocrine regulation of γ - irradiation - induced DNA damage response via extracellular nucleotides - mediated activation of Q15077 and Q9H244 receptors . A key component of the response to DNA damage caused by ionizing radiation is DNA repair . Release of extracellular nucleotides , such as DB00171 , from cells plays a role in signaling via P2 receptors . We show here that release of DB00171 , followed by activation of P2Y receptors , is involved in the response to γ - irradiation - induced DNA damage . Formation of phosphorylated histone variant P16104 ( γ P16104 ) foci , which are induced in nuclei by DNA damage and contribute to accumulation of DNA - repair factors , was increased at 1 - 3h after γ - ray irradiation ( 2 . 0Gy ) of human lung cancer A549 cells . Focus formation was suppressed by pre - treatment with the ecto - nucleotidase apyrase . Pre - treatment with ecto - nucleotidase inhibitor ARL67156 or post - treatment with DB00171 or UTP facilitated induction of γ P16104 , indicating that extracellular nucleotides play a role in induction of γ P16104 foci . Next , we examined the effect of P2 receptor inhibitors on activation of ataxia telangiectasia mutated ( Q13315 ; a protein kinase ) and accumulation of Q12888 ( a DNA repair factor ) , both of which are important for DNA repair , at DNA damage sites . Q15077 receptor antagonist MRS2578 , Q9H244 receptor antagonist clopidogrel , and Q99572 receptor antagonists A438079 and oxATP significantly inhibited these processes . Release of DB00171 was detected within 2 . 5min after irradiation , but was blocked by A438079 . Activation of Q13315 and accumulation of Q12888 were decreased in Q15077 or Q9H244 receptor - knockdown cells . We conclude that autocrine / paracrine signaling through Q99572 - dependent DB00171 release and activation of Q15077 and Q9H244 receptors serves to amplify the cellular response to DNA damage caused by γ - irradiation ."],"string":"[\n \"P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .\",\n \"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .\",\n \"Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .\",\n \"Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK97___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\",\n \"DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .\",\n \"Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .\",\n \"Knockdown of receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) affects EMT - associated gene expression in human hepatoma cells . BACKGROUND : Receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) has been reported to be an important regulator of tumor proliferation , differentiation and wound repair . We investigated the effects of O43353 knockdown in human hepatoma cells on epithelial - to - mesenchymal transition ( EMT ) - associated gene expression . MATERIALS AND METHODS : HepG2 cells stably expressing O43353 - shRNA ( HepG2 - shRIPK2 ) were generated after puromycin selection . Total RNAs from HepG2 - shRIPK2 and from HepG2 - shcontrol cells were isolated and PCR - based arrays were performed to compare the 84 EMT - associated gene expressions . RESULTS : We observed that knockdown of O43353 down - regulated mRNA expression of jagged 1 ( P78504 ) ; plasminogen activator inhibitor - 1 ( P05121 ) ; regulator of G - protein signalling 2 , 24 kDa ( P41220 ) ; P12830 ( CDH1 ) ; fibroblast growth factor binding protein 1 ( Q14512 ) ; snail homolog 2 ( O43623 ) ; protein tyrosine phosphatase type IVA , member 1 ( Q93096 ) ; keratin 19 ( P08727 ) ; vimentin ( P08670 ) ; and survival of motor neuron protein - interacting protein 1 ( SIP1 ) . CONCLUSION : We found that knockdown of O43353 down - regulated nuclear factor kappa B ( NF - κB ) - dependent P05121 and P08670 gene expressions . O43353 might play an important role in hepatic cell migration . These findings could shed new light on carcinogenesis and on liver regeneration .\",\n \"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK65___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .\",\n \"State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . ___MASK2___ is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .\",\n \"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK2___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .\",\n \"DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .\",\n \"___MASK42___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK42___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK42___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .\",\n \"Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation . Angiogenic cytokines have been shown to influence vessel injury , and platelets represent a disposable circulating pool of angiogenic molecules . In the present study , objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation . We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg / day . We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor ( P15692 ) - A and its soluble receptor forms P17948 and P35968 , placenta growth factor , and stromal cell - derived factor - 1 . We also quantified soluble P16581 and P04275 to evaluate endothelial activation . Blood samples were drawn just before the first clopidogrel intake on day 1 , and after the last dosing ( day 7 ) . As expected , we observed a decrease in platelet reactivity in response to clopidogrel , confirmed by vasodilator - stimulated phosphoprotein phosphorylation assay . However , the 7 - day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation . These results show that circulating angiogenic factor level in healthy subjects is not driven by Q9H244 platelet receptor - induced activation and clopidogrel does not modify in a significant way the endothelial activation level .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .\",\n \"Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .\",\n \"New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . ___MASK2___ is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .\",\n \"Variation in glucose homeostasis traits associated with Q99572 polymorphisms in mice and humans . CONTEXT : Extracellular nucleotide receptors are expressed in pancreatic B - cells . Purinergic signaling via these receptors may regulate pancreatic B - cell function . OBJECTIVE : We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction . DESIGN : In humans , we mined genome - wide meta - analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes . We performed additional testing in two genomic regions ( Q99571 / Q99572 and P47900 ) in a cohort from the Prevalence , Prediction , and Prevention of Diabetes in Botnia ( n = 3504 ) , which includes more refined measures of glucose homeostasis . In mice , we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background . RESULTS : Variants in five genes were associated with glycemic traits and in three genes with diabetes risk . In the Prevalence , Prediction , and Prevention of Diabetes in Botnia study , the minor allele in the missense functional variant rs1718119 ( A348T ) in Q99572 was associated with increased insulin sensitivity and secretion , consistent with its known effect on increased pore function . Both male and female P2x7 - C57 mice demonstrated impaired glucose tolerance compared with matched P2x7 - 129 mice . P01308 tolerance testing showed that P2x7 - C57 mice were also less responsive to insulin than P2x7 - 129 mice . CONCLUSIONS : We show association of the purinergic signaling pathway in general and hypofunctioning Q99572 variants in particular with impaired glucose homeostasis in both mice and humans .\",\n \"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK36___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .\",\n \"Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .\",\n \"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK53___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK53___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .\",\n \"( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .\",\n \"Purinergic receptors involved in the immunomodulatory effects of DB00171 in human blood . We recently showed that the physiological compound DB00171 simultaneously inhibited P01375 and stimulated P22301 release in LPS - PHA stimulated blood . The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of DB00171 on P01375 and P22301 . Incubation of blood with DB00171 in the presence of selective P2 receptor antagonists showed that the stimulatory effect of DB00171 on P22301 release was completely annihilated by both 2 - MeSAMP ( a Q9H244 / 13 receptor antagonist ) and PSB - 0413 ( a Q9H244 receptor antagonist ) . On the other hand , the inhibitory effect of DB00171 on P01375 release was completely reversed by 5 '- P30566 ( a Q96G91 receptor antagonist ) as well as by H - 89 , an inhibitor of DB02527 - activated PKA . The concerted inhibition by DB00171 of P01375 release via Q96G91 activation and stimulation of P22301 release via Q9H244 activation implicates a novel approach towards immunomodulation by altering the balance among pro - and anti - inflammatory cytokines .\",\n \"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK2___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK2___ is in clinical development as an orally active agent .\",\n \"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK78___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .\",\n \"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK28___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .\",\n \"The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .\",\n \"Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . ___MASK2___ is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .\",\n \"DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .\",\n \"DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .\",\n \"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK19___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .\",\n \"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .\",\n \"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .\",\n \"Autocrine regulation of γ - irradiation - induced DNA damage response via extracellular nucleotides - mediated activation of Q15077 and Q9H244 receptors . A key component of the response to DNA damage caused by ionizing radiation is DNA repair . Release of extracellular nucleotides , such as DB00171 , from cells plays a role in signaling via P2 receptors . We show here that release of DB00171 , followed by activation of P2Y receptors , is involved in the response to γ - irradiation - induced DNA damage . Formation of phosphorylated histone variant P16104 ( γ P16104 ) foci , which are induced in nuclei by DNA damage and contribute to accumulation of DNA - repair factors , was increased at 1 - 3h after γ - ray irradiation ( 2 . 0Gy ) of human lung cancer A549 cells . Focus formation was suppressed by pre - treatment with the ecto - nucleotidase apyrase . Pre - treatment with ecto - nucleotidase inhibitor ARL67156 or post - treatment with DB00171 or UTP facilitated induction of γ P16104 , indicating that extracellular nucleotides play a role in induction of γ P16104 foci . Next , we examined the effect of P2 receptor inhibitors on activation of ataxia telangiectasia mutated ( Q13315 ; a protein kinase ) and accumulation of Q12888 ( a DNA repair factor ) , both of which are important for DNA repair , at DNA damage sites . Q15077 receptor antagonist MRS2578 , Q9H244 receptor antagonist clopidogrel , and Q99572 receptor antagonists A438079 and oxATP significantly inhibited these processes . Release of DB00171 was detected within 2 . 5min after irradiation , but was blocked by A438079 . Activation of Q13315 and accumulation of Q12888 were decreased in Q15077 or Q9H244 receptor - knockdown cells . We conclude that autocrine / paracrine signaling through Q99572 - dependent DB00171 release and activation of Q15077 and Q9H244 receptors serves to amplify the cellular response to DNA damage caused by γ - irradiation .\"\n]"},"candidates":{"kind":"list like","value":["___MASK19___","___MASK28___","___MASK2___","___MASK36___","___MASK42___","___MASK53___","___MASK65___","___MASK78___","___MASK97___"],"string":"[\n \"___MASK19___\",\n \"___MASK28___\",\n \"___MASK2___\",\n \"___MASK36___\",\n \"___MASK42___\",\n \"___MASK53___\",\n \"___MASK65___\",\n \"___MASK78___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK42___"},"id":{"kind":"string","value":"MH_train_379"}}},{"rowIdx":380,"cells":{"query":{"kind":"string","value":"interacts_with DB00277?"},"supports":{"kind":"list like","value":["Histone deacetylase - 2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase - 2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor - kappaB - activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant - activated phosphoinositide - 3 - kinase - delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid - resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers .","___MASK27___ binding to human and rat dopamine and 5 - HT receptors . ___MASK27___ ( ___MASK27___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK27___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK27___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK27___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .","Targeting the phosphatidylinositol 3 - kinase pathway in airway smooth muscle : rationale and promise . The phosphatidylinositol 3 - kinase ( PI3K ) signaling pathway plays a critical role in regulating cell growth , proliferation , survival , and motility . Structural alterations , e . g . airway remodeling , in asthma and chronic obstructive pulmonary disease ( P48444 ) are associated with increased airway smooth muscle ( P17405 ) cell growth and proliferation due to the frequent stimulation of P17405 by inflammatory mediators , contractile agonists , and growth factors . The critical role of the PI3K signaling pathway in regulating P17405 cell growth and proliferation is well established . However , recent discovery of the tumor suppressor proteins tuberous sclerosis complex 1 ( Q92574 ) and P49815 , also known as hamartin and tuberin , as downstream effectors of PI3K and upstream regulators of the mammalian target of rapamycin ( P42345 ) and S6 kinase 1 ( P23443 ) shed a new light on the PI3K signaling cascade in regulating cell growth and proliferation . The activity of Q92574 / P49815 is regulated by growth factors , nutrients , and energy ; thus , Q92574 / P49815 serves as a signaling module for protein translational regulation , cell cycle progression , and cell size , which are key events controlling cell growth and proliferation . This article highlights the potential contribution of the PI3K - Q92574 / P49815 - P42345 / P23443 pathway in smooth muscle remodeling . Pharmacologic manipulation of this signaling pathway could have a major impact on treatment of asthma and P48444 .","Decreased exercise - induced expression of nuclear factor - κB - regulated genes in muscle of patients with P48444 . BACKGROUND : Nuclear factor ( NF ) - κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with P48444 . Therefore , we investigated NF - κB activity and expression of NF - κB - regulated genes in muscle of patients with P48444 and control subjects before and after exercise . METHODS : Quadriceps specimens were obtained before , immediately after , and 2 h after a submaximal cycle ergometry test from seven patients with P48444 ( 50 . 6 ± 5 . 7 SEM Q99581 ( 1 ) of patients with P48444 ) and seven age - matched control subjects . NF - κB DNA - binding activity in muscle and peripheral blood mononuclear cells ( PBMCs ) was determined using electrophoretic mobility shift assay and enzyme - linked immunosorbent assay , respectively . mRNA expression and protein carbonylation were measured by real - time polymerase chain reaction and Western blot , respectively . RESULTS : In control subjects , P05231 , IκBα , tumor necrosis factor - α , IL - 1β , superoxide dismutase , thioredoxin , heme oxygenase 1 , and heat shock protein - 70 were upregulated in muscle after exercise , whereas in patients with P48444 only P05231 mRNA was increased . Exercise - induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with P48444 compared with control subjects . Basal muscle protein oxidation was higher in patients with P48444 than in control subjects , but attenuated in response to exercise . No exercise - induced changes in NF - κB DNA - binding activity in muscle and PBMCs of either group were detected . CONCLUSIONS : Skeletal muscle of patients with P48444 is characterized by an impaired response to exercise of NF - κB - regulated genes encoding inflammatory cytokines , antioxidants , stress proteins , and survival factors .","How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti - inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor - kappaB and activator protein - 1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase - 2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti - inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative / nitrative stress so that inflammation becomes resistant to the anti - inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti - inflammatory approaches to manage severe inflammatory diseases .","Phosphatidylinositol - 3 - OH kinase and nutrient - sensing P42345 pathways control T lymphocyte trafficking . Phosphatidylinositol - 3 - OH kinase ( PI ( 3 ) K ) and the nutrient sensor P42345 are evolutionarily conserved regulators of cell metabolism . Here we show that PI ( 3 ) K and P42345 determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes . The key lymph node - homing receptors CD62L ( P14151 ) and P32248 were highly expressed on naive T lymphocytes but were downregulated after immune activation . CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription . The O00329 subunit of PI ( 3 ) K controlled CD62L proteolysis through mitogen - activated protein kinases , whereas control of CD62L transcription by O00329 was mediated by P42345 through regulation of the transcription factor Q9Y5W3 . PI ( 3 ) K - P42345 nutrient - sensing pathways also determined expression of the chemokine receptor P32248 and regulated lymphocyte trafficking in vivo . Hence , lymphocytes use PI ( 3 ) K and P42345 to match metabolism and trafficking .","Critique on application of diaphragmatic time - tension index to spontaneously breathing humans . Bellemare and Grassino ( J . Appl . Physiol . 53 : 1196 - 1206 , 1982 ) have reported that the diphragmatic time - tension index ( TTdi ) ( i . e . , the product of mean transdiaphragmatic pressure / maximum transdiaphragmatic pressure and the inspiratory duty cycle ) can be used as a predictor of diaphragmatic fatigue in humans . However , the publications of these authors do not directly address the question of whether inspiratory flow or transdiaphragmatic pressure should be used to calculate the inspiratory duty cycle . To gather data on this point , we computed TTdi by both methods in spontaneously breathing normal adult males ( Q9BXJ7 ) and age - matched males with chronic obstructive pulmonary disease ( P48444 ) at rest and during treadmill exercise . During rest and exercise in both Q9BXJ7 and P48444 , the fraction of the breathing cycle over which diaphragmatic tension was maintained ( Tdi / TT ) exceeded the fraction of the breathing cycle over which inspiratory airflow was maintained ( TI / TT ) . Therefore , TTdi calculations using Tdi / TT were greater ( P less than 0 . 05 ) than TTdi computations using TI / TT . However , this difference in TTdi values was relatively small ( approximately 15 % ) .","Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK38___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .","___MASK72___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK72___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK72___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK72___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .","Genome - wide association study identifies five loci associated with lung function . Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease ( P48444 ) . We tested genome - wide association with forced expiratory volume in 1 s ( Q99581 ( 1 ) ) and the ratio of Q99581 ( 1 ) to forced vital capacity ( FVC ) in the SpiroMeta consortium ( n = 20 , 288 individuals of European ancestry ) . We conducted a meta - analysis of top signals with data from direct genotyping ( n < or = 32 , 184 additional individuals ) and in silico summary association data from the CHARGE Consortium ( n = 21 , 209 ) and the Health 2000 survey ( n < or = 883 ) . We confirmed the reported locus at 4q31 and identified associations with Q99581 ( 1 ) or Q99581 ( 1 )/ FVC and common variants at five additional loci : 2q35 in Q9HBL0 ( P = 1 . 11 x 10 (- 12 ) ) , 4q24 in Q8NEC7 ( 2 . 18 x 10 (- 23 ) ) , 5q33 in Q13639 ( P = 4 . 29 x 10 (- 9 ) ) , 6p21 in Q15109 ( P = 3 . 07 x 10 (- 15 ) ) and 15q23 in Q6ZMP0 ( P = 7 . 24 x 10 (- 15 ) ) . mRNA analyses showed expression of Q9HBL0 , Q8NEC7 , Q15109 , Q13639 and Q6ZMP0 in human lung tissue . These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK87___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK87___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK87___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK87___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK87___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK87___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK87___ .","Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .","Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post - translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase - 2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide - 3 - kinase - delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant - activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid - resistant inflammation .","P00747 activator inhibitor - 1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells . P00747 activator inhibitor - 1 ( P05121 ) plays a role in regulating levels of some cytokines and cell migration in addition to its classic role in inhibiting fibrinolysis . P05121 levels in induced - sputum of chronic obstructive pulmonary disease ( P48444 ) patients were elevated significantly and correlated negatively with pulmonary function . To study the role of P05121 in inflammatory process in P48444 , the authors transfected alveolar epithelial cells ( AECs ) with siRNA - targeted P05121 and stimulated the cells by cigarette smoke extraction ( CSE ) or lipopolysaccharides ( LPS ) . The expression of inflammatory factors , interleukin - 8 ( P10145 ) and leukotriene B4 ( LTB4 ) , and the monocyte migration were detected . The exposure to CSE or LPS induced the expression of P05121 , P10145 , and LTB4 in AECs and monocyte migration to AECs . However , they were attenuated after transfection with siRNA - targeted P05121 . In conclusion , P05121 stimulates inflammation induced by CSE or LPS in AECs through up - regulation of inflammatory factors and promoting inflammatory cell migration . P05121 may play a proinflammatory role in the pathogenesis of P48444 .","Molecular and behavioral effects mediated by Gs - coupled adenosine A2a , but not serotonin 5 - Ht4 or 5 - Ht6 receptors following antipsychotic administration . Typical antipsychotic agents are potent antagonists of Gi - coupled dopamine D2 receptors , but their mechanisms of action following this initial blockade remain poorly understood . We hypothesized that in striatal neurons , interruption of this inhibitory dopamine D2 input would unmask endogenous striatal Gs - coupled receptors . An increase in DB02527 levels generated by these unopposed receptors would then lead to the well - described behavioral and molecular effects of antipsychotic administration such as catalepsy and striatal c - fos and neurotensin gene transcription . We examined three striatal Gs - coupled receptor systems ( serotonin Q13639 , serotonin P50406 and adenosine A2a ) to assess their potential involvement in the mechanism of action of the typical antipsychotic haloperidol . Antagonists of each of these three receptor systems together with a 1 mg / kg dose of haloperidol were co - administered to Sprague - Dawley rats , and both the degree of catalepsy produced in the animals and the induction of striatal c - fos and neurotensin messenger RNAs were measured . Both the specific adenosine A2a antagonist 8 -( 3 - chlorostyryl )- caffeine and the general adenosine antagonist theophylline reduced haloperidol - dependent induction of striatal neurotensin and c - fos messenger RNA . Administration of these agents also greatly reduced the degree of catalepsy induced by haloperidol . Antagonists of the P50406 receptor failed to block the induction of striatal messenger RNAs , but the P50406 antagonist clozapine ( an important atypical antipsychotic agent in its own right ) was a potent inhibitor of catalepsy . Q13639 agents were unable to alter haloperidol ' s effects on striatal messenger RNA levels or catalepsy . We conclude that the striatal Gs - coupled adenosine A2a receptor is an important mediator of the molecular and behavioral sequelae following haloperidol administration .","Flavone as P09874 inhibitor : its effect on lipopolysaccharide induced gene - expression . The nuclear enzyme poly ( ADP - ribose ) polymerase - 1 ( P09874 ) which was initially known for its role in the repair of oxidative stress - induced DNA damage , has also been reported to play a mediating role in the inflammatory response . Studies with P09874 knockout models have shown that P09874 is a co - activator of Nuclear Factor - kappa B ( NF - kappaB ) , although this appears not to require its enzyme activity . In addition , drug - induced inhibition of the enzyme activity of P09874 was observed to reduce the production of pro - inflammatory mediators . In this study , the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of P09874 . Further evaluation of flavone in N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) - treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD (+) levels , as well as the formation of PAR - polymers was dose - dependently attenuated by flavone . In addition , flavone was found to reduce the lipopolysaccharide ( LPS ) - induced interleukin ( IL ) - 8 production in pulmonary epithelial cells , which was confirmed by transcription analysis . Furthermore , the transcription Inhibitor kappa B alpha ( of P25963 ) was significantly increased by flavone . The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases . P09874 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease ( P48444 ) and diabetes , by preservation of cellular NAD (+) levels and attenuating inflammatory conditions .","[ Moclobemide ( ___MASK82___ ) , the first P21397 - inhibitor : really something new ? ] .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK21___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines . Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer , the molecular mechanisms accounting for this are still unclear . Selective estrogen receptor modulators ( SERMs ) mimic estrogen action in certain tissues while opposing it in others . The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear . Here , we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha ( ERalpha ) . 17beta - Estradiol ( E2 ) induced the gene expression of c - Myc and DB01277 and increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 . ERalpha silencing abolished the E2 - stimulated c - Myc expression . E2 induced the recruitment of co - activators such as Q15788 , Q9Y6Q9 and CBP to the promoters of c - Myc and DB01277 , and Q15788 silencing abolished both the E2 - stimulated c - Myc expression and cell - cycle progression . In contrast , although raloxifene increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 , raloxifene had no effect on the gene expression of c - Myc or DB01277 . Raloxifene induced the recruitment of co - repressors such as Q92769 , O75376 and Q9Y618 to the promoter of DB01277 . Thus , the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ERalpha appear to be dependent on the recruitment of co - regulators .","Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK95___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK95___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .","Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease . Products of the prostaglandin H synthase ( PGHS ) metabolic pathway are thought to play a role in the pathogenesis of asthma . We determined the level of expression of the constitutive ( P23219 ) and inducible ( P35354 ) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma , patients with chronic obstructive pulmonary disease ( P48444 ) , and unaffected control subjects by immunocyto - and immunohistochemistry . Immunoreactivity for P35354 was significantly greater in the induced sputum of patients with asthma and patients with P48444 compared with unaffected control subjects . The level of P35354 was greater in asthma than in P48444 . Immunoreactivity for P23219 increased in cells in the induced sputum of patients with asthma and patients with P48444 compared with that of unaffected control subjects . Immunostained cells included macrophages , eosinophils , and neutrophils . Greater P35354 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects . In summary , we demonstrate an induction of P35354 in asthma , suggesting increased formation of prostanoids , which may contribute to the inflammatory process .","Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK35___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK35___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK35___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK73___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared ."],"string":"[\n \"Histone deacetylase - 2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase - 2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor - kappaB - activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant - activated phosphoinositide - 3 - kinase - delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid - resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers .\",\n \"___MASK27___ binding to human and rat dopamine and 5 - HT receptors . ___MASK27___ ( ___MASK27___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK27___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK27___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK27___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .\",\n \"Targeting the phosphatidylinositol 3 - kinase pathway in airway smooth muscle : rationale and promise . The phosphatidylinositol 3 - kinase ( PI3K ) signaling pathway plays a critical role in regulating cell growth , proliferation , survival , and motility . Structural alterations , e . g . airway remodeling , in asthma and chronic obstructive pulmonary disease ( P48444 ) are associated with increased airway smooth muscle ( P17405 ) cell growth and proliferation due to the frequent stimulation of P17405 by inflammatory mediators , contractile agonists , and growth factors . The critical role of the PI3K signaling pathway in regulating P17405 cell growth and proliferation is well established . However , recent discovery of the tumor suppressor proteins tuberous sclerosis complex 1 ( Q92574 ) and P49815 , also known as hamartin and tuberin , as downstream effectors of PI3K and upstream regulators of the mammalian target of rapamycin ( P42345 ) and S6 kinase 1 ( P23443 ) shed a new light on the PI3K signaling cascade in regulating cell growth and proliferation . The activity of Q92574 / P49815 is regulated by growth factors , nutrients , and energy ; thus , Q92574 / P49815 serves as a signaling module for protein translational regulation , cell cycle progression , and cell size , which are key events controlling cell growth and proliferation . This article highlights the potential contribution of the PI3K - Q92574 / P49815 - P42345 / P23443 pathway in smooth muscle remodeling . Pharmacologic manipulation of this signaling pathway could have a major impact on treatment of asthma and P48444 .\",\n \"Decreased exercise - induced expression of nuclear factor - κB - regulated genes in muscle of patients with P48444 . BACKGROUND : Nuclear factor ( NF ) - κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with P48444 . Therefore , we investigated NF - κB activity and expression of NF - κB - regulated genes in muscle of patients with P48444 and control subjects before and after exercise . METHODS : Quadriceps specimens were obtained before , immediately after , and 2 h after a submaximal cycle ergometry test from seven patients with P48444 ( 50 . 6 ± 5 . 7 SEM Q99581 ( 1 ) of patients with P48444 ) and seven age - matched control subjects . NF - κB DNA - binding activity in muscle and peripheral blood mononuclear cells ( PBMCs ) was determined using electrophoretic mobility shift assay and enzyme - linked immunosorbent assay , respectively . mRNA expression and protein carbonylation were measured by real - time polymerase chain reaction and Western blot , respectively . RESULTS : In control subjects , P05231 , IκBα , tumor necrosis factor - α , IL - 1β , superoxide dismutase , thioredoxin , heme oxygenase 1 , and heat shock protein - 70 were upregulated in muscle after exercise , whereas in patients with P48444 only P05231 mRNA was increased . Exercise - induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with P48444 compared with control subjects . Basal muscle protein oxidation was higher in patients with P48444 than in control subjects , but attenuated in response to exercise . No exercise - induced changes in NF - κB DNA - binding activity in muscle and PBMCs of either group were detected . CONCLUSIONS : Skeletal muscle of patients with P48444 is characterized by an impaired response to exercise of NF - κB - regulated genes encoding inflammatory cytokines , antioxidants , stress proteins , and survival factors .\",\n \"How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti - inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor - kappaB and activator protein - 1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase - 2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti - inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative / nitrative stress so that inflammation becomes resistant to the anti - inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti - inflammatory approaches to manage severe inflammatory diseases .\",\n \"Phosphatidylinositol - 3 - OH kinase and nutrient - sensing P42345 pathways control T lymphocyte trafficking . Phosphatidylinositol - 3 - OH kinase ( PI ( 3 ) K ) and the nutrient sensor P42345 are evolutionarily conserved regulators of cell metabolism . Here we show that PI ( 3 ) K and P42345 determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes . The key lymph node - homing receptors CD62L ( P14151 ) and P32248 were highly expressed on naive T lymphocytes but were downregulated after immune activation . CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription . The O00329 subunit of PI ( 3 ) K controlled CD62L proteolysis through mitogen - activated protein kinases , whereas control of CD62L transcription by O00329 was mediated by P42345 through regulation of the transcription factor Q9Y5W3 . PI ( 3 ) K - P42345 nutrient - sensing pathways also determined expression of the chemokine receptor P32248 and regulated lymphocyte trafficking in vivo . Hence , lymphocytes use PI ( 3 ) K and P42345 to match metabolism and trafficking .\",\n \"Critique on application of diaphragmatic time - tension index to spontaneously breathing humans . Bellemare and Grassino ( J . Appl . Physiol . 53 : 1196 - 1206 , 1982 ) have reported that the diphragmatic time - tension index ( TTdi ) ( i . e . , the product of mean transdiaphragmatic pressure / maximum transdiaphragmatic pressure and the inspiratory duty cycle ) can be used as a predictor of diaphragmatic fatigue in humans . However , the publications of these authors do not directly address the question of whether inspiratory flow or transdiaphragmatic pressure should be used to calculate the inspiratory duty cycle . To gather data on this point , we computed TTdi by both methods in spontaneously breathing normal adult males ( Q9BXJ7 ) and age - matched males with chronic obstructive pulmonary disease ( P48444 ) at rest and during treadmill exercise . During rest and exercise in both Q9BXJ7 and P48444 , the fraction of the breathing cycle over which diaphragmatic tension was maintained ( Tdi / TT ) exceeded the fraction of the breathing cycle over which inspiratory airflow was maintained ( TI / TT ) . Therefore , TTdi calculations using Tdi / TT were greater ( P less than 0 . 05 ) than TTdi computations using TI / TT . However , this difference in TTdi values was relatively small ( approximately 15 % ) .\",\n \"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK38___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .\",\n \"___MASK72___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK72___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK72___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK72___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .\",\n \"Genome - wide association study identifies five loci associated with lung function . Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease ( P48444 ) . We tested genome - wide association with forced expiratory volume in 1 s ( Q99581 ( 1 ) ) and the ratio of Q99581 ( 1 ) to forced vital capacity ( FVC ) in the SpiroMeta consortium ( n = 20 , 288 individuals of European ancestry ) . We conducted a meta - analysis of top signals with data from direct genotyping ( n < or = 32 , 184 additional individuals ) and in silico summary association data from the CHARGE Consortium ( n = 21 , 209 ) and the Health 2000 survey ( n < or = 883 ) . We confirmed the reported locus at 4q31 and identified associations with Q99581 ( 1 ) or Q99581 ( 1 )/ FVC and common variants at five additional loci : 2q35 in Q9HBL0 ( P = 1 . 11 x 10 (- 12 ) ) , 4q24 in Q8NEC7 ( 2 . 18 x 10 (- 23 ) ) , 5q33 in Q13639 ( P = 4 . 29 x 10 (- 9 ) ) , 6p21 in Q15109 ( P = 3 . 07 x 10 (- 15 ) ) and 15q23 in Q6ZMP0 ( P = 7 . 24 x 10 (- 15 ) ) . mRNA analyses showed expression of Q9HBL0 , Q8NEC7 , Q15109 , Q13639 and Q6ZMP0 in human lung tissue . These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK87___ and its - in terms of P36551 - inhibition - \\\" inactive \\\" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK87___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK87___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK87___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK87___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK87___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK87___ .\",\n \"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .\",\n \"Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post - translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase - 2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide - 3 - kinase - delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant - activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid - resistant inflammation .\",\n \"P00747 activator inhibitor - 1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells . P00747 activator inhibitor - 1 ( P05121 ) plays a role in regulating levels of some cytokines and cell migration in addition to its classic role in inhibiting fibrinolysis . P05121 levels in induced - sputum of chronic obstructive pulmonary disease ( P48444 ) patients were elevated significantly and correlated negatively with pulmonary function . To study the role of P05121 in inflammatory process in P48444 , the authors transfected alveolar epithelial cells ( AECs ) with siRNA - targeted P05121 and stimulated the cells by cigarette smoke extraction ( CSE ) or lipopolysaccharides ( LPS ) . The expression of inflammatory factors , interleukin - 8 ( P10145 ) and leukotriene B4 ( LTB4 ) , and the monocyte migration were detected . The exposure to CSE or LPS induced the expression of P05121 , P10145 , and LTB4 in AECs and monocyte migration to AECs . However , they were attenuated after transfection with siRNA - targeted P05121 . In conclusion , P05121 stimulates inflammation induced by CSE or LPS in AECs through up - regulation of inflammatory factors and promoting inflammatory cell migration . P05121 may play a proinflammatory role in the pathogenesis of P48444 .\",\n \"Molecular and behavioral effects mediated by Gs - coupled adenosine A2a , but not serotonin 5 - Ht4 or 5 - Ht6 receptors following antipsychotic administration . Typical antipsychotic agents are potent antagonists of Gi - coupled dopamine D2 receptors , but their mechanisms of action following this initial blockade remain poorly understood . We hypothesized that in striatal neurons , interruption of this inhibitory dopamine D2 input would unmask endogenous striatal Gs - coupled receptors . An increase in DB02527 levels generated by these unopposed receptors would then lead to the well - described behavioral and molecular effects of antipsychotic administration such as catalepsy and striatal c - fos and neurotensin gene transcription . We examined three striatal Gs - coupled receptor systems ( serotonin Q13639 , serotonin P50406 and adenosine A2a ) to assess their potential involvement in the mechanism of action of the typical antipsychotic haloperidol . Antagonists of each of these three receptor systems together with a 1 mg / kg dose of haloperidol were co - administered to Sprague - Dawley rats , and both the degree of catalepsy produced in the animals and the induction of striatal c - fos and neurotensin messenger RNAs were measured . Both the specific adenosine A2a antagonist 8 -( 3 - chlorostyryl )- caffeine and the general adenosine antagonist theophylline reduced haloperidol - dependent induction of striatal neurotensin and c - fos messenger RNA . Administration of these agents also greatly reduced the degree of catalepsy induced by haloperidol . Antagonists of the P50406 receptor failed to block the induction of striatal messenger RNAs , but the P50406 antagonist clozapine ( an important atypical antipsychotic agent in its own right ) was a potent inhibitor of catalepsy . Q13639 agents were unable to alter haloperidol ' s effects on striatal messenger RNA levels or catalepsy . We conclude that the striatal Gs - coupled adenosine A2a receptor is an important mediator of the molecular and behavioral sequelae following haloperidol administration .\",\n \"Flavone as P09874 inhibitor : its effect on lipopolysaccharide induced gene - expression . The nuclear enzyme poly ( ADP - ribose ) polymerase - 1 ( P09874 ) which was initially known for its role in the repair of oxidative stress - induced DNA damage , has also been reported to play a mediating role in the inflammatory response . Studies with P09874 knockout models have shown that P09874 is a co - activator of Nuclear Factor - kappa B ( NF - kappaB ) , although this appears not to require its enzyme activity . In addition , drug - induced inhibition of the enzyme activity of P09874 was observed to reduce the production of pro - inflammatory mediators . In this study , the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of P09874 . Further evaluation of flavone in N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) - treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD (+) levels , as well as the formation of PAR - polymers was dose - dependently attenuated by flavone . In addition , flavone was found to reduce the lipopolysaccharide ( LPS ) - induced interleukin ( IL ) - 8 production in pulmonary epithelial cells , which was confirmed by transcription analysis . Furthermore , the transcription Inhibitor kappa B alpha ( of P25963 ) was significantly increased by flavone . The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases . P09874 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease ( P48444 ) and diabetes , by preservation of cellular NAD (+) levels and attenuating inflammatory conditions .\",\n \"[ Moclobemide ( ___MASK82___ ) , the first P21397 - inhibitor : really something new ? ] .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK21___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines . Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer , the molecular mechanisms accounting for this are still unclear . Selective estrogen receptor modulators ( SERMs ) mimic estrogen action in certain tissues while opposing it in others . The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear . Here , we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha ( ERalpha ) . 17beta - Estradiol ( E2 ) induced the gene expression of c - Myc and DB01277 and increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 . ERalpha silencing abolished the E2 - stimulated c - Myc expression . E2 induced the recruitment of co - activators such as Q15788 , Q9Y6Q9 and CBP to the promoters of c - Myc and DB01277 , and Q15788 silencing abolished both the E2 - stimulated c - Myc expression and cell - cycle progression . In contrast , although raloxifene increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 , raloxifene had no effect on the gene expression of c - Myc or DB01277 . Raloxifene induced the recruitment of co - repressors such as Q92769 , O75376 and Q9Y618 to the promoter of DB01277 . Thus , the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ERalpha appear to be dependent on the recruitment of co - regulators .\",\n \"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK95___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK95___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .\",\n \"Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease . Products of the prostaglandin H synthase ( PGHS ) metabolic pathway are thought to play a role in the pathogenesis of asthma . We determined the level of expression of the constitutive ( P23219 ) and inducible ( P35354 ) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma , patients with chronic obstructive pulmonary disease ( P48444 ) , and unaffected control subjects by immunocyto - and immunohistochemistry . Immunoreactivity for P35354 was significantly greater in the induced sputum of patients with asthma and patients with P48444 compared with unaffected control subjects . The level of P35354 was greater in asthma than in P48444 . Immunoreactivity for P23219 increased in cells in the induced sputum of patients with asthma and patients with P48444 compared with that of unaffected control subjects . Immunostained cells included macrophages , eosinophils , and neutrophils . Greater P35354 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects . In summary , we demonstrate an induction of P35354 in asthma , suggesting increased formation of prostanoids , which may contribute to the inflammatory process .\",\n \"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK35___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK35___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK35___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK73___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .\"\n]"},"candidates":{"kind":"list like","value":["___MASK21___","___MASK27___","___MASK35___","___MASK38___","___MASK72___","___MASK73___","___MASK82___","___MASK87___","___MASK95___"],"string":"[\n \"___MASK21___\",\n \"___MASK27___\",\n \"___MASK35___\",\n \"___MASK38___\",\n \"___MASK72___\",\n \"___MASK73___\",\n \"___MASK82___\",\n \"___MASK87___\",\n \"___MASK95___\"\n]"},"answer":{"kind":"string","value":"___MASK95___"},"id":{"kind":"string","value":"MH_train_380"}}},{"rowIdx":381,"cells":{"query":{"kind":"string","value":"interacts_with DB00714?"},"supports":{"kind":"list like","value":["Pharmacological Q9BWK5 mapping of age - associated changes in basal ganglia circuitry of awake rhesus monkeys . While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson ' s disease ( PD ) are well studied , little is known about functional changes in the neural circuitry of this area during normal aging . Here we report the first survey of age - associated changes in the basal ganglia of behaviorally characterized , awake rhesus monkeys , using pharmacological Q9BWK5 to map responses to dopaminergic stimulation . DB00714 , a mixed D ( 1 )/ P14416 agonist , evoked little change in the substantia nigra ( SN ) of aged animals while significantly reducing activation in young adult monkeys . Compared to young animals , both apomorphine and DB01576 ( which increases synaptic dopamine levels ) significantly increased activation of the aged rhesus globus pallidus externa ( GPe ) . In addition , the aged animals showed decreased activity in the putamen in response to DB01576 administration . Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD , the apomorphine - evoked activation of their GPe corresponded with apomorphine - induced increases in neuronal activity seen in Parkinson ' s patients and animal models . Given the major role of the GPe in regulating motor behavior , the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age .","___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .","Intermediate phenotype analysis of patients , unaffected siblings , and healthy controls identifies Q05940 as a candidate gene for psychotic disorder and neurocognition . Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members , suggesting that genetic vulnerability to psychotic disorder impacts neurocognition . The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms ( SNPs ) are associated with ( 1 ) neurocognitive functioning across populations at different genetic risk for psychosis ( 2 ) and psychotic disorder . The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder . Follow - up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects . In the patients , 13 associations between SNPs and cognitive functioning were significant at P < . 05 , situated in P21728 , P35462 , Q01959 , P23560 , P09038 , Q05940 , Q13451 , and Q9UBC3 . Follow - up of these SNPs revealed a significant and directionally similar association for Q05940 ( alternatively Q05940 ) rs363227 in siblings ( B = - 0 . 13 , P = . 04 ) and a trend association in control subjects ( B = - 0 . 10 , P = . 12 ) . This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele ( linear OR = 1 . 51 , 95 % CI 1 . 10 - 2 . 07 , P = . 01 ) , which was reduced when covarying for cognitive performance ( OR = 1 . 29 , 95 % CI 0 . 92 - 1 . 81 , P = . 14 ) , suggesting mediation . Genetic variation in Q05940 may be linked to alterations in cognitive functioning underlying psychotic disorder , possibly through altered transport of monoamines into synaptic vesicles .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK47___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","Influence of P14416 and Q8NFD2 genotypes on apomorphine - induced growth hormone ( GH ) response in alcohol - dependent patients . BACKGROUND : D ( 2 ) receptor function can be assessed by growth hormone ( GH ) response to apomorphine . Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol - dependent subjects yielded inconsistent results . In this pilot study , we tested polymorphisms from the P14416 region for GH response to apomorphine challenge in more detail . METHODS : DB00714 challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence ; patients were genotyped for 11 polymorphisms including P14416 , Q8NFD2 , P13591 and Q9H892 . RESULTS : Associations ( p < 0 . 05 ) were found for Q8NFD2 ( rs11604671 , rs1800497 ) and P14416 ( rs6276 , rs1076560 ) , which are located on adjacent chromosomal positions . Consistent with PET studies suggesting a reduced D ( 2 ) receptor availability in patients carrying the Q8NFD2 rs1800497 T polymorphism ( formerly known as P14416 TaqI A1 ) we found a reduced GH response to apomorphine in those subjects . CONCLUSION : This has been the first study showing significant associations between apomorphine - induced GH response and SNPs in P14416 and Q8NFD2 in alcohol - dependent patients . In this respect , our preliminary results are in line with other reports which suggested that P14416 and Q8NFD2 polymorphisms influence D ( 2 ) receptor availability and signal transduction in the dopaminergic pathways . Small sample size in our study limits the generalizability of our results .","Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .","___MASK20___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK20___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK20___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK20___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK20___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .","P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .","Regulation of the natural killer cell response to interferon - alpha by biogenic amines . Monocytes , recovered from human peripheral blood by counter - current centrifugal elutriation ( CCE ) , suppressed baseline natural killer ( NK ) cell cytotoxicity ( NKCC ) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon - alpha ( IFN - alpha ) by a cell contact - dependent mechanism . Monocyte - induced suppression of resting and IFN - activated NK cells was abrogated by the biogenic amines histamine [ via H2 - type receptors ( P25021 ) ] and serotonin [ via P08908 - type receptors ( 5 - HT1AR ) ] . Our data are suggestive of a monocyte / NK cell interaction that is subject to regulation by biogenic amines .","DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .","Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .","D2 - dopamine receptor and alpha2 - adrenoreceptor - mediated analgesic response of quercetin . DB04216 , a bioflavonoid ( 100 - 300 mg / kg ) produced dose dependent increase in tail - flick latency , the analgesic effect being sensitive to reversal by naloxone ( 1 mg / kg ) . Prior treatment with haloperidol ( 1 mg / kg ) , D1 / D2 receptor antagonist haloperidol , sulpiride ( 50 mg / kg ) , a selective D2 receptor antagonist , yohimbine ( 5 mg / kg ) , a alpha2 - adrenoreceptor antagonist but not by P35240 23390 a , selective D1 receptor antagonist blocked this response . DB00714 ( 1 mg / kg ) a mixed D1 / D2 dopamine receptor agonist , and quinpirole ( 0 . 5 mg / kg ) , a selective D2 receptor agonist also produced antinociception , that was reversed by haloperidol ( 1 mg / kg ) , sulpiride ( 50 mg / kg ) , but not by yohimbine ( 5 mg / kg ) . The antinociceptive action of quercetin ( 200 mg / kg ) was potentiated by D2 agonist quinpirole ( 0 . 2 mg / kg ) . P21728 agonist SKF38393 ( 10 and 15 mg / kg ) failed to alter the antinociceptive effect of quercetin ( 200 mg / kg ) . DB04216 ( 200 mg / kg ) reversed reserpine ( 2 mg / kg - 4 hr ) induced hyperalgesia , which was reversed by sulpiride but not by yohimbine . Thus , a role of dopamine D2 and alpha2 - adrenoreceptors is postulated in the antinociceptive action of quercetin .","Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) - mediated osteoclast differentiation from monocyte / macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate - resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264 . 7 cells suppressed O14788 - induced osteoclastogenesis by inhibiting the expression of c - Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia - associated transcription factor ( O75030 ) independent of sumoylation . Down - regulation of Q9Y6X2 markedly enhances O14788 - mediated osteoclastogenesis in RAW264 . 7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down - regulates O14788 expression induced by interleukin - 6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down - regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL - 6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts .","Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder . In utero exposure of rodents to valproic acid ( DB00313 ) , a histone deacetylase ( HDAC ) inhibitor , has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder ( P51689 ) . We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of P51689 . We employed the social approach avoidance paradigm as a measure of social reciprocity , detection of biological motion that is crucial to social interactions , and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to DB00313 . We found no significant change in the expression of neural cell adhesion molecule polysialylation state ( P13591 PSA ) , a measure of construct validity , but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning . Finally , in all cases , we found chronic HDAC inhibition , with either pan - specific or Q13547 - 3 isoform - specific inhibitors , to significantly ameliorate deficits in both social cognition and its associated neuroplastic response . We conclude that in utero exposure to DB00313 provides a robust animal model for the social cognitive deficits of P51689 and a potential screen for the development of novel therapeutics for this condition .","Enhancement and inhibition of apomorphine - induced sensitization in rats exposed to immobilization stress : relationship with adaptation to stress . Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre - dispose to depression . Pre - clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress . The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine - induced sensitization . DB00714 was injected either before exposure or after the termination of immobilization , daily for 5 days , to monitor drug - induced behavioral sensitization and tolerance in immobilization stress - induced anorexia . We find that apomorphine - induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode . Conversely , apomorphine - induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode . It shows that apomorphine , if experienced during stress , produces greater sensitization and impairs stress tolerance . Conversely , sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode . It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and P08908 influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress . The results may help develop potential pharmacotherapies when substance abuse / dependence disorder and depression occur together .","DB00714 - induced aggressiveness and [ 3H ] citalopram binding after antidepressant treatment in rats . The effects of acute and repeated administration of antidepressive drugs on apomorphine - induced aggressive behavior and [ 3H ] citalopram binding were studied . In acute behavioral experiments with apomorphine pretreated ( 1 . 0 mg / kg , once daily ) animals , desipramine ( 10 mg / kg ) and clomipramine ( 10 mg / kg ) enhanced , buspirone ( 2 . 5 and 5 . 0 mg / kg ) completely blocked , but fluoxetine , amitriptyline , imipramine ( 10 mg / kg ) , and citalopram ( 10 and 20 mg / kg ) had no effect on the intensity of aggressive behavior . Repeated concomitant apomorphine ( 1 . 0 mg / kg ) and citalopram ( 10 mg / kg ) administration reduced the affinity ( Kd ) of the 5 - HT transporter binding sites in three brain regions . This finding was confirmed by an additional experiment as the effect of citalopram treatment . Repeated apomorphine ( 1 . 0 mg / kg ) or apomorphine ( 1 . 0 mg / kg ) plus desipramine ( 10 mg / kg ) treatment had no unidirectional effect on Kd , the maximal number of apparent binding sties ( Bmax ) was unchanged in all experiments . Our study indicates that the 5 - HT reuptake blockade has no major influence on the apomorphine - induced aggressive behavior , but the P08908 receptor subtype may be involved in the mediation of the aggressive behavior in this paradigm .","___MASK58___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK58___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .","P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .","P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .","Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl - containing histone deacetylase ( HDAC ) inhibitors 1 - 4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 ) and class II ( maize HD1 - A and human P56524 ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl - H3 and low acetyl - α - tubulin levels . Exceptions are compounds 3 f - i , 3 m - o , and 4 k , which showed higher tubulin acetylation than ___MASK16___ . In U937 cells , cell - cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1 - 4 . Five hydroxamates ( compounds 1 h - l ) effected a two - to greater than threefold greater percent apoptosis than ___MASK16___ , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest - scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .","Stimulatory effects of 5HT1A receptor agonists on luteinizing hormone - releasing hormone release from cultured fetal rat hypothalamic cells : interactions with progesterone . Previous works have suggested an interactive stimulatory effect of progesterone ( P ) and serotonin ( 5 - HT ) on luteinizing hormone release . The purpose of the present study was to determine whether 5 - HT via P08908 receptors interacts with P in the process of luteinizing hormone - releasing hormone ( P01148 ) release . Using fetal hypothalamic neurons in primary cell cultures the first goal of this study was to determine the effects of P08908 receptor agonists on P01148 secretion . 8 - Hydroxy - 2 ( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) or ipsapirone ( 10 (- 5 ) M ) significantly stimulated P01148 release . Pharmacological studies have allowed to rule out the possible involvement of alpha 2 - or beta - adrenoreceptors , or 5 - HT uptake sites , in the stimulatory effect of 8 - OH - DPAT on P01148 release , thus demonstrating the specific involvement of P08908 receptors in the stimulation of P01148 release . The second goal was to test the ability of P to stimulate P01148 release from fetal hypothalamic neurons . P ( 10 (- 6 ) M ) applied for 30 or 120 min significantly stimulated P01148 secretion . The maintenance of the stimulation of P01148 release by P after a cycloheximide treatment or by an impermeable analog of P , P - 3 - BSA , has suggested a nongenomic effect of P on P01148 release . The effects of a pretreatment of cells by P on 8 - OH - DPAT - induced P01148 release were tested . While 10 (- 7 ) M P alone did not stimulate P01148 release , this concentration of steroid potentiated the P01148 response to 10 (- 5 ) M 8 - OH - DPAT . These findings led to the conclusion that P acting at the level of the plasma membrane potentiates the stimulatory effect of P08908 receptor agonists on P01148 release .","P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .","Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK68___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","Neural cell adhesion molecule ( P13591 ) promotes the differentiation of hippocampal precursor cells to a neuronal lineage , especially to a glutamatergic neural cell type . Rat hippocampal precursor cells isolated from hippocampi of embryonic day 16 . 5 ( E16 . 5 ) rat embryos were found to proliferate in the presence of basic fibroblast growth factor . Addition of soluble neural cell adhesion molecule ( P13591 ) to these precursor cells reduced cell proliferation in a dose dependent manner and enhanced the induction of precursor cells ' differentiation to the neuronal lineage . Given these findings that P13591 induces the differentiation of hippocampal precursor cells , we investigated possible effects of P13591 on the expression of basic helix - loop - helix ( bHLH ) transcription factors during the differentiation . Soluble P13591 upregulated the transcription of bHLH transcription factors , neurogenin1 and Q13562 , but decreased Q5TA89 . Western blot analysis showed that P13591 increased the expression levels of CaMKII , p - MAPK , GluR1 and Q9UHB4 but decreased p - P40763 . These results support a role for P13591 in the inhibition of proliferation and the induction of neural differentiation of hippocampal neural precursor cells , and act as developmental regulators of the bHLH families , ultimately leading to the generation of glutamatergic neural cell types in the differentiation of hippocampal precursor cells .","Development of peptidomimetic ligands of Pro - DB00149 - DB00145 - NH ( 2 ) as allosteric modulators of the dopamine D ( 2 ) receptor . A variety of stable , small - molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro - DB00149 - DB00145 - NH ( 2 ) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro - bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β - turn . In addition , studies with peptidomimetics designed to mimic either a type VI β - turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH ( 2 ) pharmacophore in the same topological space as that seen in the type II β - turn . Extensive studies with the spiro - bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro - bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics .","___MASK92___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK92___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK92___ is a promising pharmacological tool in the treatment of renal edema .","Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .","Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .","P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .","___MASK70___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK70___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .","Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .","Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","Post - synaptic P08908 receptor involvement in yawning and penile erections induced by apomorphine , physostigmine and mCPP in rats . DB00714 and mCPP induced yawning associated with penile erections in rats , whereas physostigmine induced only yawns . DB00714 - induced yawning and penile erections were antagonized by low doses of raclopride , whereas physostigmine - induced yawning and mCPP - induced effects were only partly inhibited at high doses of raclopride . DB00747 as well as clozapine antagonized yawning and penile erections induced by apomorphine , mCPP and physostigmine . Similarly , the P08908 agonists 8 - OH - DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine , mCPP and physostigmine , and at similar doses induced lower lip retraction and hyperreactivity to handling . The beta / P08908 antagonist tertatolol reversed the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections and increased apomorphine - and physostigmine - induced yawn frequency but not penile erection frequency . Like tertatolol , propranolol increased apomorphine - and physostigmine - induced yawn frequency , whereas ICI 118551 increased only physostigmine - induced yawning . 8 - OH - DPAT - and S 14506 - induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol . Finally , p - chlorophenylalanine pretreatment produced about 95 % depletion in 5 - HT in hypothalamus , hippocampus , striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections . ( ABSTRACT TRUNCATED AT 250 WORDS )","Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .","___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .","Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK16___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .","Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .","Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells . Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment . We report that mesoderm commitment from human embryonic stem cells ( hESCs ) is initiated by epithelial - to - mesenchymal transition ( EMT ) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins , EpCAM / CD326 and P13591 / CD56 . Molecular and functional assays reveal that the earliest CD326 - CD56 + cells , generated from hESCs in the presence of activin A , P12644 , P15692 , and P09038 , represent a multipotent mesoderm - committed progenitor population . CD326 - CD56 + progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic , endothelial , mesenchymal ( bone , cartilage , fat , fibroblast ) , smooth muscle , and cardiomyocytes , while lacking the pluripotency of hESCs . CD326 - CD56 + cells are the precursors of previously reported , more lineage - restricted mesodermal progenitors . These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering .","Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .","Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK58___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .","Switching brain serotonin with oxytocin . Serotonin ( 5 - HT ) and oxytocin ( P01178 ) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism . We asked whether these chemical messengers interact in the regulation of emotion - based behavior by administering P01178 or placebo to 24 healthy subjects and mapping cerebral 5 - HT system by using 2 '- methoxyphenyl -( N - 2 '- pyridinyl )- p -[( 18 ) F ] fluoro - benzamidoethylpiperazine ( [( 18 ) F ] MPPF ) , an antagonist of P08908 receptors . P01178 increased [( 18 ) F ] MPPF nondisplaceable binding potential ( BPND ) in the dorsal raphe nucleus ( DRN ) , the core area of 5 - HT synthesis , and in the amygdala / hippocampal complex , insula , and orbitofrontal cortex . Importantly , the amygdala appears central in the regulation of 5 - HT by P01178 : [( 18 ) F ] MPPF BPND changes in the DRN correlated with changes in right amygdala , which were in turn correlated with changes in hippocampus , insula , subgenual , and orbitofrontal cortex , a circuit implicated in the control of stress , mood , and social behaviors . P01178 administration is known to inhibit amygdala activity and results in a decrease of anxiety , whereas high amygdala activity and 5 - HT dysregulation have been associated with increased anxiety . The present study reveals a previously unidentified form of interaction between these two systems in the human brain , i . e . , the role of P01178 in the inhibitory regulation of 5 - HT signaling , which could lead to novel therapeutic strategies for mental disorders .","Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","The human interleukin 18 gene Q14116 maps to 11q22 . 2 - q22 . 3 , closely linked to the P14416 gene locus and distinct from mapped IDDM loci .","Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high P23759 levels that sustain migration and invasiveness . Rhabdomyosarcoma is a muscle - derived malignant tumor mainly affecting children . The most frequent variant , embryonal rhabdomyosarcoma ( ERMS ) is characterized by overexpression of the transcription factor , P23759 which prevents ERMS cells from exiting the cell cycle and terminally differentiating . However , a role for P23759 in the invasive properties of ERMS cells has not been investigated in detail thus far . Here we show that ectopic expression of receptor for advanced glycation end - products ( RAGE ) in human ERMS cells results in the activation of a RAGE / myogenin axis which downregulates P23759 by transcriptional and post - translational mechanisms , as in normal myoblasts , and reduces metastasis formation . High P23759 sustains migration and invasiveness in ERMS cells by upregulating P29320 and P20827 and downregulating P13591 thus decreasing the neural cell adhesion molecule ( P13591 ) / polysialylated - P13591 ratio . Microarray gene expression analysis shows that compared with the RAGE (- ve ) TE671 / WT cells and similarly to primary human myoblasts , TE671 / RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion , and downregulation of cell migration related and major histocompatibility complex class I genes . Our data reveal a link between P23759 and metastasis occurrence in ERMSs , and support a role for the RAGE / myogenin axis in metastasis suppression . Thus , low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior .","[ Breast carcinoma with predominant neuroendocrine differentiation ] . Neuroendocrine differentiation can be identified in a subset of human breast carcinomas , either as scattered cells or as a predominant neuroendocrine component . We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells . Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma , a 67 - years - old woman presented with a metastastic neuroendocrine sternal mass . To establish a relationship between mammary carcinoma and bone metastasis , histological slides of both the breast tumor and axillary lymph nodes were reviewed , and an immunohistochemical study was performed . They showed that : a ) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin + , P13591 + , chromogranin - ( 80 % ) , associated with 2 other differentiated non endocrine components , one of metaplastic squamous carcinoma ( 10 % ) and the other of ductal carcinoma ( 10 % ) ; b ) 4 axillary lymph nodes were involved by the ductal component which contained few P13591 + but synaptophysin - cells ; c ) Estrogen and progesterone receptors and P04626 were negative in the breast tumor and the metastatic nodes . We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation , the outcome of each component and the prognostic relevance of such a diagnosis .","Design , synthesis and biological evaluation of pazopanib derivatives as antitumor agents . A novel series of pazopanib derivatives were designed , synthesized , and evaluated for their inhibitory activity against a series of kinases including P35968 , P00533 , P31749 , P37023 , and P00519 . The anti - angiogenic activities ex vivo of some compounds were also investigated . Compounds P2d and P2e demonstrated outstanding inhibitory activity against P35968 and P00519 and higher anti - angiogenic activity compared with ___MASK58___ , the reference standard . These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents .","A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .","Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK56___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .","In vitro analysis of the centripetal migration mechanisms of developing P01148 neurons . This study was designed to gain insight into the underlying mechanisms of the centripetal migration of developing P01148 neurons . The medial wall of the nasal pit ( Q8WYA6 ) of 12 . 5 - day - old rat embryos ( Q96BH3 . 5 ) was cultured singly or together with the Q96BH3 . 5 medial - basal wall of the forebrain vesicles ( mFV ) or with the Q14207 . 5 median eminence - arcuate complex ( ME - Arc ) . Further , the Q8WYA6 was cultured with the mFV and ME - Arc or with the mFV and nasal mesenchyme ( NM ) , which lay between the mFV and the Q8WYA6 , of Q96BH3 . 5 embryos ( triple culture ) . The Q8WYA6 gave rise first to fibers labeled with anti - neural cell adhesion molecules ( P13591 ) and then to P01148 neurons . In co - cultures , Q8WYA6 - and brain - derived P13591 fibers connected the Q8WYA6 and brain cultures , and frequently linked with each other to form knots at the periphery . P01148 neurons migrating along the Q8WYA6 - derived fibers directly or indirectly entered brain cultures . In the latter case , the cells strayed along the way from the Q8WYA6 - derived fibers to the brain - derived fibers at the knots and migrated retrogradely along the latter fibers to enter into the brain tissues ; this occurred most frequently into the Q14207 . 5 ME - Arc . In triple cultures , abundant P13591 fibers emerging from the Q8WYA6 were only found when the NM lay between the Q8WYA6 and mFV ; the fibers converged further to the mFV . These findings help elucidate the mechanisms underlying the centripetal P01148 cell migration from the Q8WYA6 to the hypothalamus .","Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .","Penile erection and yawning induced by P28335 receptor agonists in male rats : relationship with dopaminergic and oxytocinergic transmission . 1 -( 3 - Chlorophenyl ) piperazine ( m - CPP ) ( 0 . 1 - 4 mg / kg s . c . ) and N -( 3 - trifluoromethylphenyl )- piperazine ( TFMPP ) ( 0 . 5 - 4 mg / kg s . c . ) , P28335 receptor agonists , but not 8 - hydroxy - dipropylamino - tetralin ( 8 - OH - DPAT ) ( 0 . 1 and 0 . 2 mg / kg s . c . ) , a P08908 receptor agonist , induced penile erection and yawning with a U - inverted dose - response curve in male rats . The maximal effect was found with 0 . 5 mg / kg s . c . of m - CPP and with 1 mg / kg s . c . of TFMPP . The m - CPP ( 0 . 5 mg / kg s . c . ) and TFMPP ( 1 mg / kg s . c . ) responses were prevented by mianserin ( 0 . 2 mg / kg s . c . ) and by ritanserin ( 1 mg / kg s . c . ) given 15 min before m - CPP and TFMPP . In contrast , m - CPP - or TFMPP - induced penile erection and yawning were not antagonized by haloperidol ( 0 . 1 mg / kg s . c . ) or by [ d ( CH2 ) 5Tyr ( Me ) 2 , Orn8 ] vasotocin ( 5 micrograms i . c . v . ) . DB00714 - and oxytocin - induced penile erection , but not yawning , was also antagonized by mianserin and less effectively by ritanserin . The results suggest that P28335 receptor agonist - induced penile erection and yawning are not mediated by increased dopaminergic and / or oxytocinergic transmission , and raise the possibility that a neuronal dopamine - oxytocin - 5 - HT link is involved in the control of penile erection and not necessarily of yawning in male rats .","Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK70___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .","Clinical trials in thrombolytic therapy , Part 2 : The open - artery hypothesis and RAPID - 1 and RAPID - 2 . The open - artery hypothesis as supported by thrombolytic study results is discussed . The open - artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct - related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct - related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO - 1 ) trial suggested that early and complete patency is essential for short - term survival after AMI . Subsequent observations indicated that an open infarct - related artery at the time of hospital discharge is associated with improved long - term survival . In the ___MASK47___ Angiographic Phase II International Dose - Finding ( RAPID - 1 ) trial , complete patency was more frequent in patients who received a double - bolus regimen of reteplase than in patients who received standard - dose alteplase . Similar results were obtained in the ___MASK47___ versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID - 2 ) trial , which compared the same double - bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . ___MASK47___ seems more likely to produce normal blood flow soon after AMI than either standard - dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open - artery hypothesis .","Proteolysis of highly polysialylated P13591 by the tissue plasminogen activator - plasmin system in rats . P00750 ( tPA ) , a serine protease which converts the zymogen plasminogen to the active protease plasmin , is believed to regulate neurite extension and neural cell migration by modulating extracellular metabolism . The highly polysialylated form of the neural cell adhesion molecule ( P13591 - H ) is strongly expressed in the developing brain and is believed to play a role in organizing the neural network . In this report , we incubated neonatal rat brain homogenates with human tPA and rat plasminogen in order to determine whether P13591 - H would be degraded . P13591 - H was degraded by plasmin which was formed from rat plasminogen by human tPA . The degradation was inhibited by the addition of plasminogen activator inhibitor type 1 ( P05121 ) or aprotinin . These results suggest a possible contribution of the tPA - plasmin system to P13591 - H turnover in the developing brain .","Lack of allelic association of dopamine D1 and D2 ( TaqIA ) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism . Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA - polymorphisms of the dopamine D1 and D2 receptor ( P21728 , P14416 ) genes and is associated with poor treatment outcome . Therefore , 97 alcohol - dependent patients were assessed according to their sensitivity of central dopamine receptors ( apomorphine - induced secretion of growth hormone ) , clinical outcome during a 6 - month observation period , and genotypic constitution of the TaqIA restriction fragment length polymorphism ( RFLP ) at the P14416 locus and of the Bsp1286I RFLP at the P21728 locus . On the 1st day of detoxification , dopamine receptor hyposensitivity was found in treatment nonresponders , but not in responders . DB00714 - induced growth hormone release did not differ significantly in alcoholics with different genotypes of the P21728 and P14416 RFLPs . Neither did we find a significant allelic association with treatment response . Thus , we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome ."],"string":"[\n \"Pharmacological Q9BWK5 mapping of age - associated changes in basal ganglia circuitry of awake rhesus monkeys . While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson ' s disease ( PD ) are well studied , little is known about functional changes in the neural circuitry of this area during normal aging . Here we report the first survey of age - associated changes in the basal ganglia of behaviorally characterized , awake rhesus monkeys , using pharmacological Q9BWK5 to map responses to dopaminergic stimulation . DB00714 , a mixed D ( 1 )/ P14416 agonist , evoked little change in the substantia nigra ( SN ) of aged animals while significantly reducing activation in young adult monkeys . Compared to young animals , both apomorphine and DB01576 ( which increases synaptic dopamine levels ) significantly increased activation of the aged rhesus globus pallidus externa ( GPe ) . In addition , the aged animals showed decreased activity in the putamen in response to DB01576 administration . Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD , the apomorphine - evoked activation of their GPe corresponded with apomorphine - induced increases in neuronal activity seen in Parkinson ' s patients and animal models . Given the major role of the GPe in regulating motor behavior , the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age .\",\n \"___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .\",\n \"Intermediate phenotype analysis of patients , unaffected siblings , and healthy controls identifies Q05940 as a candidate gene for psychotic disorder and neurocognition . Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members , suggesting that genetic vulnerability to psychotic disorder impacts neurocognition . The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms ( SNPs ) are associated with ( 1 ) neurocognitive functioning across populations at different genetic risk for psychosis ( 2 ) and psychotic disorder . The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder . Follow - up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects . In the patients , 13 associations between SNPs and cognitive functioning were significant at P < . 05 , situated in P21728 , P35462 , Q01959 , P23560 , P09038 , Q05940 , Q13451 , and Q9UBC3 . Follow - up of these SNPs revealed a significant and directionally similar association for Q05940 ( alternatively Q05940 ) rs363227 in siblings ( B = - 0 . 13 , P = . 04 ) and a trend association in control subjects ( B = - 0 . 10 , P = . 12 ) . This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele ( linear OR = 1 . 51 , 95 % CI 1 . 10 - 2 . 07 , P = . 01 ) , which was reduced when covarying for cognitive performance ( OR = 1 . 29 , 95 % CI 0 . 92 - 1 . 81 , P = . 14 ) , suggesting mediation . Genetic variation in Q05940 may be linked to alterations in cognitive functioning underlying psychotic disorder , possibly through altered transport of monoamines into synaptic vesicles .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK47___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"Influence of P14416 and Q8NFD2 genotypes on apomorphine - induced growth hormone ( GH ) response in alcohol - dependent patients . BACKGROUND : D ( 2 ) receptor function can be assessed by growth hormone ( GH ) response to apomorphine . Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol - dependent subjects yielded inconsistent results . In this pilot study , we tested polymorphisms from the P14416 region for GH response to apomorphine challenge in more detail . METHODS : DB00714 challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence ; patients were genotyped for 11 polymorphisms including P14416 , Q8NFD2 , P13591 and Q9H892 . RESULTS : Associations ( p < 0 . 05 ) were found for Q8NFD2 ( rs11604671 , rs1800497 ) and P14416 ( rs6276 , rs1076560 ) , which are located on adjacent chromosomal positions . Consistent with PET studies suggesting a reduced D ( 2 ) receptor availability in patients carrying the Q8NFD2 rs1800497 T polymorphism ( formerly known as P14416 TaqI A1 ) we found a reduced GH response to apomorphine in those subjects . CONCLUSION : This has been the first study showing significant associations between apomorphine - induced GH response and SNPs in P14416 and Q8NFD2 in alcohol - dependent patients . In this respect , our preliminary results are in line with other reports which suggested that P14416 and Q8NFD2 polymorphisms influence D ( 2 ) receptor availability and signal transduction in the dopaminergic pathways . Small sample size in our study limits the generalizability of our results .\",\n \"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .\",\n \"___MASK20___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK20___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK20___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK20___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK20___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .\",\n \"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .\",\n \"Regulation of the natural killer cell response to interferon - alpha by biogenic amines . Monocytes , recovered from human peripheral blood by counter - current centrifugal elutriation ( CCE ) , suppressed baseline natural killer ( NK ) cell cytotoxicity ( NKCC ) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon - alpha ( IFN - alpha ) by a cell contact - dependent mechanism . Monocyte - induced suppression of resting and IFN - activated NK cells was abrogated by the biogenic amines histamine [ via H2 - type receptors ( P25021 ) ] and serotonin [ via P08908 - type receptors ( 5 - HT1AR ) ] . Our data are suggestive of a monocyte / NK cell interaction that is subject to regulation by biogenic amines .\",\n \"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .\",\n \"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .\",\n \"D2 - dopamine receptor and alpha2 - adrenoreceptor - mediated analgesic response of quercetin . DB04216 , a bioflavonoid ( 100 - 300 mg / kg ) produced dose dependent increase in tail - flick latency , the analgesic effect being sensitive to reversal by naloxone ( 1 mg / kg ) . Prior treatment with haloperidol ( 1 mg / kg ) , D1 / D2 receptor antagonist haloperidol , sulpiride ( 50 mg / kg ) , a selective D2 receptor antagonist , yohimbine ( 5 mg / kg ) , a alpha2 - adrenoreceptor antagonist but not by P35240 23390 a , selective D1 receptor antagonist blocked this response . DB00714 ( 1 mg / kg ) a mixed D1 / D2 dopamine receptor agonist , and quinpirole ( 0 . 5 mg / kg ) , a selective D2 receptor agonist also produced antinociception , that was reversed by haloperidol ( 1 mg / kg ) , sulpiride ( 50 mg / kg ) , but not by yohimbine ( 5 mg / kg ) . The antinociceptive action of quercetin ( 200 mg / kg ) was potentiated by D2 agonist quinpirole ( 0 . 2 mg / kg ) . P21728 agonist SKF38393 ( 10 and 15 mg / kg ) failed to alter the antinociceptive effect of quercetin ( 200 mg / kg ) . DB04216 ( 200 mg / kg ) reversed reserpine ( 2 mg / kg - 4 hr ) induced hyperalgesia , which was reversed by sulpiride but not by yohimbine . Thus , a role of dopamine D2 and alpha2 - adrenoreceptors is postulated in the antinociceptive action of quercetin .\",\n \"Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) - mediated osteoclast differentiation from monocyte / macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate - resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264 . 7 cells suppressed O14788 - induced osteoclastogenesis by inhibiting the expression of c - Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia - associated transcription factor ( O75030 ) independent of sumoylation . Down - regulation of Q9Y6X2 markedly enhances O14788 - mediated osteoclastogenesis in RAW264 . 7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down - regulates O14788 expression induced by interleukin - 6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down - regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL - 6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts .\",\n \"Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder . In utero exposure of rodents to valproic acid ( DB00313 ) , a histone deacetylase ( HDAC ) inhibitor , has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder ( P51689 ) . We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of P51689 . We employed the social approach avoidance paradigm as a measure of social reciprocity , detection of biological motion that is crucial to social interactions , and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to DB00313 . We found no significant change in the expression of neural cell adhesion molecule polysialylation state ( P13591 PSA ) , a measure of construct validity , but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning . Finally , in all cases , we found chronic HDAC inhibition , with either pan - specific or Q13547 - 3 isoform - specific inhibitors , to significantly ameliorate deficits in both social cognition and its associated neuroplastic response . We conclude that in utero exposure to DB00313 provides a robust animal model for the social cognitive deficits of P51689 and a potential screen for the development of novel therapeutics for this condition .\",\n \"Enhancement and inhibition of apomorphine - induced sensitization in rats exposed to immobilization stress : relationship with adaptation to stress . Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre - dispose to depression . Pre - clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress . The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine - induced sensitization . DB00714 was injected either before exposure or after the termination of immobilization , daily for 5 days , to monitor drug - induced behavioral sensitization and tolerance in immobilization stress - induced anorexia . We find that apomorphine - induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode . Conversely , apomorphine - induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode . It shows that apomorphine , if experienced during stress , produces greater sensitization and impairs stress tolerance . Conversely , sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode . It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and P08908 influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress . The results may help develop potential pharmacotherapies when substance abuse / dependence disorder and depression occur together .\",\n \"DB00714 - induced aggressiveness and [ 3H ] citalopram binding after antidepressant treatment in rats . The effects of acute and repeated administration of antidepressive drugs on apomorphine - induced aggressive behavior and [ 3H ] citalopram binding were studied . In acute behavioral experiments with apomorphine pretreated ( 1 . 0 mg / kg , once daily ) animals , desipramine ( 10 mg / kg ) and clomipramine ( 10 mg / kg ) enhanced , buspirone ( 2 . 5 and 5 . 0 mg / kg ) completely blocked , but fluoxetine , amitriptyline , imipramine ( 10 mg / kg ) , and citalopram ( 10 and 20 mg / kg ) had no effect on the intensity of aggressive behavior . Repeated concomitant apomorphine ( 1 . 0 mg / kg ) and citalopram ( 10 mg / kg ) administration reduced the affinity ( Kd ) of the 5 - HT transporter binding sites in three brain regions . This finding was confirmed by an additional experiment as the effect of citalopram treatment . Repeated apomorphine ( 1 . 0 mg / kg ) or apomorphine ( 1 . 0 mg / kg ) plus desipramine ( 10 mg / kg ) treatment had no unidirectional effect on Kd , the maximal number of apparent binding sties ( Bmax ) was unchanged in all experiments . Our study indicates that the 5 - HT reuptake blockade has no major influence on the apomorphine - induced aggressive behavior , but the P08908 receptor subtype may be involved in the mediation of the aggressive behavior in this paradigm .\",\n \"___MASK58___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK58___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .\",\n \"P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .\",\n \"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .\",\n \"Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl - containing histone deacetylase ( HDAC ) inhibitors 1 - 4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 ) and class II ( maize HD1 - A and human P56524 ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl - H3 and low acetyl - α - tubulin levels . Exceptions are compounds 3 f - i , 3 m - o , and 4 k , which showed higher tubulin acetylation than ___MASK16___ . In U937 cells , cell - cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1 - 4 . Five hydroxamates ( compounds 1 h - l ) effected a two - to greater than threefold greater percent apoptosis than ___MASK16___ , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest - scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .\",\n \"Stimulatory effects of 5HT1A receptor agonists on luteinizing hormone - releasing hormone release from cultured fetal rat hypothalamic cells : interactions with progesterone . Previous works have suggested an interactive stimulatory effect of progesterone ( P ) and serotonin ( 5 - HT ) on luteinizing hormone release . The purpose of the present study was to determine whether 5 - HT via P08908 receptors interacts with P in the process of luteinizing hormone - releasing hormone ( P01148 ) release . Using fetal hypothalamic neurons in primary cell cultures the first goal of this study was to determine the effects of P08908 receptor agonists on P01148 secretion . 8 - Hydroxy - 2 ( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) or ipsapirone ( 10 (- 5 ) M ) significantly stimulated P01148 release . Pharmacological studies have allowed to rule out the possible involvement of alpha 2 - or beta - adrenoreceptors , or 5 - HT uptake sites , in the stimulatory effect of 8 - OH - DPAT on P01148 release , thus demonstrating the specific involvement of P08908 receptors in the stimulation of P01148 release . The second goal was to test the ability of P to stimulate P01148 release from fetal hypothalamic neurons . P ( 10 (- 6 ) M ) applied for 30 or 120 min significantly stimulated P01148 secretion . The maintenance of the stimulation of P01148 release by P after a cycloheximide treatment or by an impermeable analog of P , P - 3 - BSA , has suggested a nongenomic effect of P on P01148 release . The effects of a pretreatment of cells by P on 8 - OH - DPAT - induced P01148 release were tested . While 10 (- 7 ) M P alone did not stimulate P01148 release , this concentration of steroid potentiated the P01148 response to 10 (- 5 ) M 8 - OH - DPAT . These findings led to the conclusion that P acting at the level of the plasma membrane potentiates the stimulatory effect of P08908 receptor agonists on P01148 release .\",\n \"P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .\",\n \"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK68___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"Neural cell adhesion molecule ( P13591 ) promotes the differentiation of hippocampal precursor cells to a neuronal lineage , especially to a glutamatergic neural cell type . Rat hippocampal precursor cells isolated from hippocampi of embryonic day 16 . 5 ( E16 . 5 ) rat embryos were found to proliferate in the presence of basic fibroblast growth factor . Addition of soluble neural cell adhesion molecule ( P13591 ) to these precursor cells reduced cell proliferation in a dose dependent manner and enhanced the induction of precursor cells ' differentiation to the neuronal lineage . Given these findings that P13591 induces the differentiation of hippocampal precursor cells , we investigated possible effects of P13591 on the expression of basic helix - loop - helix ( bHLH ) transcription factors during the differentiation . Soluble P13591 upregulated the transcription of bHLH transcription factors , neurogenin1 and Q13562 , but decreased Q5TA89 . Western blot analysis showed that P13591 increased the expression levels of CaMKII , p - MAPK , GluR1 and Q9UHB4 but decreased p - P40763 . These results support a role for P13591 in the inhibition of proliferation and the induction of neural differentiation of hippocampal neural precursor cells , and act as developmental regulators of the bHLH families , ultimately leading to the generation of glutamatergic neural cell types in the differentiation of hippocampal precursor cells .\",\n \"Development of peptidomimetic ligands of Pro - DB00149 - DB00145 - NH ( 2 ) as allosteric modulators of the dopamine D ( 2 ) receptor . A variety of stable , small - molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro - DB00149 - DB00145 - NH ( 2 ) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro - bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β - turn . In addition , studies with peptidomimetics designed to mimic either a type VI β - turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH ( 2 ) pharmacophore in the same topological space as that seen in the type II β - turn . Extensive studies with the spiro - bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro - bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics .\",\n \"___MASK92___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK92___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK92___ is a promising pharmacological tool in the treatment of renal edema .\",\n \"Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .\",\n \"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .\",\n \"P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .\",\n \"___MASK70___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK70___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .\",\n \"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .\",\n \"Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"Post - synaptic P08908 receptor involvement in yawning and penile erections induced by apomorphine , physostigmine and mCPP in rats . DB00714 and mCPP induced yawning associated with penile erections in rats , whereas physostigmine induced only yawns . DB00714 - induced yawning and penile erections were antagonized by low doses of raclopride , whereas physostigmine - induced yawning and mCPP - induced effects were only partly inhibited at high doses of raclopride . DB00747 as well as clozapine antagonized yawning and penile erections induced by apomorphine , mCPP and physostigmine . Similarly , the P08908 agonists 8 - OH - DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine , mCPP and physostigmine , and at similar doses induced lower lip retraction and hyperreactivity to handling . The beta / P08908 antagonist tertatolol reversed the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections and increased apomorphine - and physostigmine - induced yawn frequency but not penile erection frequency . Like tertatolol , propranolol increased apomorphine - and physostigmine - induced yawn frequency , whereas ICI 118551 increased only physostigmine - induced yawning . 8 - OH - DPAT - and S 14506 - induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol . Finally , p - chlorophenylalanine pretreatment produced about 95 % depletion in 5 - HT in hypothalamus , hippocampus , striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .\",\n \"___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .\",\n \"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK16___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .\",\n \"Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .\",\n \"Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells . Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment . We report that mesoderm commitment from human embryonic stem cells ( hESCs ) is initiated by epithelial - to - mesenchymal transition ( EMT ) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins , EpCAM / CD326 and P13591 / CD56 . Molecular and functional assays reveal that the earliest CD326 - CD56 + cells , generated from hESCs in the presence of activin A , P12644 , P15692 , and P09038 , represent a multipotent mesoderm - committed progenitor population . CD326 - CD56 + progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic , endothelial , mesenchymal ( bone , cartilage , fat , fibroblast ) , smooth muscle , and cardiomyocytes , while lacking the pluripotency of hESCs . CD326 - CD56 + cells are the precursors of previously reported , more lineage - restricted mesodermal progenitors . These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering .\",\n \"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .\",\n \"Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK58___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .\",\n \"Switching brain serotonin with oxytocin . Serotonin ( 5 - HT ) and oxytocin ( P01178 ) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism . We asked whether these chemical messengers interact in the regulation of emotion - based behavior by administering P01178 or placebo to 24 healthy subjects and mapping cerebral 5 - HT system by using 2 '- methoxyphenyl -( N - 2 '- pyridinyl )- p -[( 18 ) F ] fluoro - benzamidoethylpiperazine ( [( 18 ) F ] MPPF ) , an antagonist of P08908 receptors . P01178 increased [( 18 ) F ] MPPF nondisplaceable binding potential ( BPND ) in the dorsal raphe nucleus ( DRN ) , the core area of 5 - HT synthesis , and in the amygdala / hippocampal complex , insula , and orbitofrontal cortex . Importantly , the amygdala appears central in the regulation of 5 - HT by P01178 : [( 18 ) F ] MPPF BPND changes in the DRN correlated with changes in right amygdala , which were in turn correlated with changes in hippocampus , insula , subgenual , and orbitofrontal cortex , a circuit implicated in the control of stress , mood , and social behaviors . P01178 administration is known to inhibit amygdala activity and results in a decrease of anxiety , whereas high amygdala activity and 5 - HT dysregulation have been associated with increased anxiety . The present study reveals a previously unidentified form of interaction between these two systems in the human brain , i . e . , the role of P01178 in the inhibitory regulation of 5 - HT signaling , which could lead to novel therapeutic strategies for mental disorders .\",\n \"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"The human interleukin 18 gene Q14116 maps to 11q22 . 2 - q22 . 3 , closely linked to the P14416 gene locus and distinct from mapped IDDM loci .\",\n \"Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high P23759 levels that sustain migration and invasiveness . Rhabdomyosarcoma is a muscle - derived malignant tumor mainly affecting children . The most frequent variant , embryonal rhabdomyosarcoma ( ERMS ) is characterized by overexpression of the transcription factor , P23759 which prevents ERMS cells from exiting the cell cycle and terminally differentiating . However , a role for P23759 in the invasive properties of ERMS cells has not been investigated in detail thus far . Here we show that ectopic expression of receptor for advanced glycation end - products ( RAGE ) in human ERMS cells results in the activation of a RAGE / myogenin axis which downregulates P23759 by transcriptional and post - translational mechanisms , as in normal myoblasts , and reduces metastasis formation . High P23759 sustains migration and invasiveness in ERMS cells by upregulating P29320 and P20827 and downregulating P13591 thus decreasing the neural cell adhesion molecule ( P13591 ) / polysialylated - P13591 ratio . Microarray gene expression analysis shows that compared with the RAGE (- ve ) TE671 / WT cells and similarly to primary human myoblasts , TE671 / RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion , and downregulation of cell migration related and major histocompatibility complex class I genes . Our data reveal a link between P23759 and metastasis occurrence in ERMSs , and support a role for the RAGE / myogenin axis in metastasis suppression . Thus , low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior .\",\n \"[ Breast carcinoma with predominant neuroendocrine differentiation ] . Neuroendocrine differentiation can be identified in a subset of human breast carcinomas , either as scattered cells or as a predominant neuroendocrine component . We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells . Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma , a 67 - years - old woman presented with a metastastic neuroendocrine sternal mass . To establish a relationship between mammary carcinoma and bone metastasis , histological slides of both the breast tumor and axillary lymph nodes were reviewed , and an immunohistochemical study was performed . They showed that : a ) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin + , P13591 + , chromogranin - ( 80 % ) , associated with 2 other differentiated non endocrine components , one of metaplastic squamous carcinoma ( 10 % ) and the other of ductal carcinoma ( 10 % ) ; b ) 4 axillary lymph nodes were involved by the ductal component which contained few P13591 + but synaptophysin - cells ; c ) Estrogen and progesterone receptors and P04626 were negative in the breast tumor and the metastatic nodes . We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation , the outcome of each component and the prognostic relevance of such a diagnosis .\",\n \"Design , synthesis and biological evaluation of pazopanib derivatives as antitumor agents . A novel series of pazopanib derivatives were designed , synthesized , and evaluated for their inhibitory activity against a series of kinases including P35968 , P00533 , P31749 , P37023 , and P00519 . The anti - angiogenic activities ex vivo of some compounds were also investigated . Compounds P2d and P2e demonstrated outstanding inhibitory activity against P35968 and P00519 and higher anti - angiogenic activity compared with ___MASK58___ , the reference standard . These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents .\",\n \"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .\",\n \"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK56___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .\",\n \"In vitro analysis of the centripetal migration mechanisms of developing P01148 neurons . This study was designed to gain insight into the underlying mechanisms of the centripetal migration of developing P01148 neurons . The medial wall of the nasal pit ( Q8WYA6 ) of 12 . 5 - day - old rat embryos ( Q96BH3 . 5 ) was cultured singly or together with the Q96BH3 . 5 medial - basal wall of the forebrain vesicles ( mFV ) or with the Q14207 . 5 median eminence - arcuate complex ( ME - Arc ) . Further , the Q8WYA6 was cultured with the mFV and ME - Arc or with the mFV and nasal mesenchyme ( NM ) , which lay between the mFV and the Q8WYA6 , of Q96BH3 . 5 embryos ( triple culture ) . The Q8WYA6 gave rise first to fibers labeled with anti - neural cell adhesion molecules ( P13591 ) and then to P01148 neurons . In co - cultures , Q8WYA6 - and brain - derived P13591 fibers connected the Q8WYA6 and brain cultures , and frequently linked with each other to form knots at the periphery . P01148 neurons migrating along the Q8WYA6 - derived fibers directly or indirectly entered brain cultures . In the latter case , the cells strayed along the way from the Q8WYA6 - derived fibers to the brain - derived fibers at the knots and migrated retrogradely along the latter fibers to enter into the brain tissues ; this occurred most frequently into the Q14207 . 5 ME - Arc . In triple cultures , abundant P13591 fibers emerging from the Q8WYA6 were only found when the NM lay between the Q8WYA6 and mFV ; the fibers converged further to the mFV . These findings help elucidate the mechanisms underlying the centripetal P01148 cell migration from the Q8WYA6 to the hypothalamus .\",\n \"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .\",\n \"Penile erection and yawning induced by P28335 receptor agonists in male rats : relationship with dopaminergic and oxytocinergic transmission . 1 -( 3 - Chlorophenyl ) piperazine ( m - CPP ) ( 0 . 1 - 4 mg / kg s . c . ) and N -( 3 - trifluoromethylphenyl )- piperazine ( TFMPP ) ( 0 . 5 - 4 mg / kg s . c . ) , P28335 receptor agonists , but not 8 - hydroxy - dipropylamino - tetralin ( 8 - OH - DPAT ) ( 0 . 1 and 0 . 2 mg / kg s . c . ) , a P08908 receptor agonist , induced penile erection and yawning with a U - inverted dose - response curve in male rats . The maximal effect was found with 0 . 5 mg / kg s . c . of m - CPP and with 1 mg / kg s . c . of TFMPP . The m - CPP ( 0 . 5 mg / kg s . c . ) and TFMPP ( 1 mg / kg s . c . ) responses were prevented by mianserin ( 0 . 2 mg / kg s . c . ) and by ritanserin ( 1 mg / kg s . c . ) given 15 min before m - CPP and TFMPP . In contrast , m - CPP - or TFMPP - induced penile erection and yawning were not antagonized by haloperidol ( 0 . 1 mg / kg s . c . ) or by [ d ( CH2 ) 5Tyr ( Me ) 2 , Orn8 ] vasotocin ( 5 micrograms i . c . v . ) . DB00714 - and oxytocin - induced penile erection , but not yawning , was also antagonized by mianserin and less effectively by ritanserin . The results suggest that P28335 receptor agonist - induced penile erection and yawning are not mediated by increased dopaminergic and / or oxytocinergic transmission , and raise the possibility that a neuronal dopamine - oxytocin - 5 - HT link is involved in the control of penile erection and not necessarily of yawning in male rats .\",\n \"Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK70___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .\",\n \"Clinical trials in thrombolytic therapy , Part 2 : The open - artery hypothesis and RAPID - 1 and RAPID - 2 . The open - artery hypothesis as supported by thrombolytic study results is discussed . The open - artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct - related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct - related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO - 1 ) trial suggested that early and complete patency is essential for short - term survival after AMI . Subsequent observations indicated that an open infarct - related artery at the time of hospital discharge is associated with improved long - term survival . In the ___MASK47___ Angiographic Phase II International Dose - Finding ( RAPID - 1 ) trial , complete patency was more frequent in patients who received a double - bolus regimen of reteplase than in patients who received standard - dose alteplase . Similar results were obtained in the ___MASK47___ versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID - 2 ) trial , which compared the same double - bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . ___MASK47___ seems more likely to produce normal blood flow soon after AMI than either standard - dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open - artery hypothesis .\",\n \"Proteolysis of highly polysialylated P13591 by the tissue plasminogen activator - plasmin system in rats . P00750 ( tPA ) , a serine protease which converts the zymogen plasminogen to the active protease plasmin , is believed to regulate neurite extension and neural cell migration by modulating extracellular metabolism . The highly polysialylated form of the neural cell adhesion molecule ( P13591 - H ) is strongly expressed in the developing brain and is believed to play a role in organizing the neural network . In this report , we incubated neonatal rat brain homogenates with human tPA and rat plasminogen in order to determine whether P13591 - H would be degraded . P13591 - H was degraded by plasmin which was formed from rat plasminogen by human tPA . The degradation was inhibited by the addition of plasminogen activator inhibitor type 1 ( P05121 ) or aprotinin . These results suggest a possible contribution of the tPA - plasmin system to P13591 - H turnover in the developing brain .\",\n \"Lack of allelic association of dopamine D1 and D2 ( TaqIA ) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism . Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA - polymorphisms of the dopamine D1 and D2 receptor ( P21728 , P14416 ) genes and is associated with poor treatment outcome . Therefore , 97 alcohol - dependent patients were assessed according to their sensitivity of central dopamine receptors ( apomorphine - induced secretion of growth hormone ) , clinical outcome during a 6 - month observation period , and genotypic constitution of the TaqIA restriction fragment length polymorphism ( RFLP ) at the P14416 locus and of the Bsp1286I RFLP at the P21728 locus . On the 1st day of detoxification , dopamine receptor hyposensitivity was found in treatment nonresponders , but not in responders . DB00714 - induced growth hormone release did not differ significantly in alcoholics with different genotypes of the P21728 and P14416 RFLPs . Neither did we find a significant allelic association with treatment response . Thus , we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome .\"\n]"},"candidates":{"kind":"list like","value":["___MASK16___","___MASK20___","___MASK3___","___MASK47___","___MASK56___","___MASK58___","___MASK68___","___MASK70___","___MASK92___"],"string":"[\n \"___MASK16___\",\n \"___MASK20___\",\n \"___MASK3___\",\n \"___MASK47___\",\n \"___MASK56___\",\n \"___MASK58___\",\n \"___MASK68___\",\n \"___MASK70___\",\n \"___MASK92___\"\n]"},"answer":{"kind":"string","value":"___MASK56___"},"id":{"kind":"string","value":"MH_train_381"}}},{"rowIdx":382,"cells":{"query":{"kind":"string","value":"interacts_with DB09079?"},"supports":{"kind":"list like","value":["A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK21___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK21___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .","P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK50___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK50___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .","ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .","Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK6___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .","DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma ___MASK43___ , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","___MASK91___ response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . ___MASK91___ is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .","___MASK91___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK91___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .","P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .","Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti - tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( ___MASK11___ , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI - 571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) .","Skeletal receptors for steroid - family regulating glycoprotein hormones : A multilevel , integrated physiological control system . Pituitary glycoprotein hormone receptors , including Q01718 , P16473 , and P23945 , occur in bone . Their skeletal expression reflects that central endocrine control is evolutionarily recent . ___MASK43___ receptors , in osteoblasts or the adrenal cortex , drive P15692 synthesis . P15692 is essential to maintain vasculature . In bone , ___MASK43___ suppression by glucocorticoids can cause osteonecrosis . DB00024 receptors occur on osteoblasts and osteoclasts , in both cases reducing activity . Thus , DB00024 directly reduces skeletal turnover , consistent with evolutionary adaptation to stress . DB00094 receptors accelerate bone resorption , whereas estrogen promotes bone formation , the forces usually balancing . With ovarian failure , low estrogen with high DB00094 causes rapid bone loss . The skeletal DB00094 effect in the menopause seems paradoxical , but it is a logical adaptation in lactation , where prolonged DB00094 elevation also occurs . In addition to receptors , there is some synthesis of pituitary glycoproteins at distributed sites ; this is not well studied , but it may further modify the paradigm of central endocrine regulation .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK14___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .","___MASK97___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .","Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK71___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK71___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .","Regulatory roles of sex hormones in cutaneous biology and immunology . Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin . Pregnancy , menstruation and the menopause modulate the natural course of psoriasis , indicating a female hormone - induced regulation of skin inflammation . Estrogen in vitro down - regulates the production of the neutrophil , type 1 T cell and macrophage - attracting chemokines , P10145 , P02778 , P13501 , by keratinocytes , and suppresses IL - 12 production and antigen - presenting capacity while enhancing anti - inflammatory P22301 production by dendritic cells . These data indicate that estrogen may attenuate inflammation in psoriatic lesions . Estrogen , alone or together with progesterone , prevents or reverses skin atrophy , dryness and wrinkles associated with chronological or photo - aging . Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy . Estrogen also enhances collagen synthesis , and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts , thereby maintaining skin thickness . Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis . Progesterone increases sebum secretion . Estrogen accelerates cutaneous wound healing stimulating P01138 production in macrophages , GM - P04141 production in keratinocytes and P09038 and TGF - beta1 production in fibroblasts , leading to the enhancement of wound re - innervation , re - epithelialization and granulation tissue formation . In contrast , androgens prolong inflammation , reduce deposition of extracellular matrix in wounds , and reduce the rate of wound healing . Estrogen enhances P15692 production in macrophages , an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy . These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis , aging , chronic wounds or granuloma pyogenicum .","Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 ."],"string":"[\n \"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK21___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK21___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .\",\n \"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK50___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK50___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .\",\n \"ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .\",\n \"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK6___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .\",\n \"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma ___MASK43___ , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"___MASK91___ response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . ___MASK91___ is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .\",\n \"___MASK91___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK91___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .\",\n \"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .\",\n \"Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti - tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( ___MASK11___ , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI - 571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) .\",\n \"Skeletal receptors for steroid - family regulating glycoprotein hormones : A multilevel , integrated physiological control system . Pituitary glycoprotein hormone receptors , including Q01718 , P16473 , and P23945 , occur in bone . Their skeletal expression reflects that central endocrine control is evolutionarily recent . ___MASK43___ receptors , in osteoblasts or the adrenal cortex , drive P15692 synthesis . P15692 is essential to maintain vasculature . In bone , ___MASK43___ suppression by glucocorticoids can cause osteonecrosis . DB00024 receptors occur on osteoblasts and osteoclasts , in both cases reducing activity . Thus , DB00024 directly reduces skeletal turnover , consistent with evolutionary adaptation to stress . DB00094 receptors accelerate bone resorption , whereas estrogen promotes bone formation , the forces usually balancing . With ovarian failure , low estrogen with high DB00094 causes rapid bone loss . The skeletal DB00094 effect in the menopause seems paradoxical , but it is a logical adaptation in lactation , where prolonged DB00094 elevation also occurs . In addition to receptors , there is some synthesis of pituitary glycoproteins at distributed sites ; this is not well studied , but it may further modify the paradigm of central endocrine regulation .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK14___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .\",\n \"___MASK97___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .\",\n \"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK71___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK71___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .\",\n \"Regulatory roles of sex hormones in cutaneous biology and immunology . Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin . Pregnancy , menstruation and the menopause modulate the natural course of psoriasis , indicating a female hormone - induced regulation of skin inflammation . Estrogen in vitro down - regulates the production of the neutrophil , type 1 T cell and macrophage - attracting chemokines , P10145 , P02778 , P13501 , by keratinocytes , and suppresses IL - 12 production and antigen - presenting capacity while enhancing anti - inflammatory P22301 production by dendritic cells . These data indicate that estrogen may attenuate inflammation in psoriatic lesions . Estrogen , alone or together with progesterone , prevents or reverses skin atrophy , dryness and wrinkles associated with chronological or photo - aging . Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy . Estrogen also enhances collagen synthesis , and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts , thereby maintaining skin thickness . Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis . Progesterone increases sebum secretion . Estrogen accelerates cutaneous wound healing stimulating P01138 production in macrophages , GM - P04141 production in keratinocytes and P09038 and TGF - beta1 production in fibroblasts , leading to the enhancement of wound re - innervation , re - epithelialization and granulation tissue formation . In contrast , androgens prolong inflammation , reduce deposition of extracellular matrix in wounds , and reduce the rate of wound healing . Estrogen enhances P15692 production in macrophages , an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy . These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis , aging , chronic wounds or granuloma pyogenicum .\",\n \"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK11___","___MASK14___","___MASK21___","___MASK43___","___MASK50___","___MASK6___","___MASK71___","___MASK91___","___MASK97___"],"string":"[\n \"___MASK11___\",\n \"___MASK14___\",\n \"___MASK21___\",\n \"___MASK43___\",\n \"___MASK50___\",\n \"___MASK6___\",\n \"___MASK71___\",\n \"___MASK91___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK21___"},"id":{"kind":"string","value":"MH_train_382"}}},{"rowIdx":383,"cells":{"query":{"kind":"string","value":"interacts_with DB01277?"},"supports":{"kind":"list like","value":["P01308 - like growth factor - 1 activation of extracellular signal - related kinase - 1 and - 2 in growth hormone - secreting cells . Intracellular pathways mediating feedback regulation by insulin - like growth factor - 1 ( DB01277 ) of pituitary GH gene expression remain incompletely understood . Extracellular signal - related kinases ( ERKs ) , a family of serine / threonine kinases , are activated by tyrosine kinase - associated growth factor receptors . To further define the DB01277 postreceptor events occurring in GH - secreting cells , we investigated the activity of ERKs in response to DB01277 in GC cells following stable transfection with either wild type human DB01277 receptor cDNA ( WT cells ) or a mutant cDNA encoding a truncated , kinase - defective DB01277 receptor with a dominant negative effect on endogenous receptor function ( 952STOP cells ) . Zymography of immunoprecipitated ERKs in myelin basic protein ( MBP ) - containing polyacrylamide gels demonstrated dose - dependent induction of P27361 and - 2 activity by DB01277 in GC cells with maximal activity occurring at 6 min . DB01277 - induced P29323 activity in WT - transfected cells was up to 80 - fold basal and 4 - fold that observed in GC cells . 952STOP cells expressing the tyrosine kinase - deficient receptor were refractory to DB01277 action , demonstrating minimal P29323 induction . In contrast , 12 - O - tetradecanoylphorbol 13 - acetate stimulated P29323 activity to the same degree in all three cell types regardless of their P08069 status . DB02587 ( 50 microM ) , isobutylmethylxanthine ( 0 . 5 mM ) , and forskolin / isobutylmethylxanthine in combination attenuated DB01277 - induced P29323 activity in WT cells by 54 , 55 , and 75 % respectively . The rapid , dose - dependent , and DB01277 receptor - dependent activation of ERKs and the attenuation of this effect by DB02527 suggest an interrelated role for both molecules in DB01277 signal transduction in GH - secreting cells .","Hypermethylation of P30279 May Reflect a Smoking - Induced Precancerous Change in the Lung . It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event , specific to overt cancer tissue . Using MethyLight assays , we analyzed 316 lung tissue samples from 151 cancer - free subjects ( 121 ever - smokers and 30 never - smokers ) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers . Only P25054 ( 39 % ) , P30279 ( 21 % ) , CDH1 ( 7 % ) , and P10826 ( 4 % ) were hypermethylated in > 2 % of these cancer - free subjects . P30279 was hypermethylated more frequently in ever - smokers ( 26 % ) than in never - smokers ( 3 % ) . P30279 hypermethylation was also associated with increased age and upper lobe sample location . P25054 was frequently hypermethylated in both ever - smokers ( 41 % ) and never - smokers ( 30 % ) . Q8NE79 , P55290 , CDKN2A ( p16 ) , P42772 , P53355 , P17936 , Q9BY67 , Q8NCM2 , Q96L42 , P16455 , Q14982 , P29122 , Q9NS23 , RUNX , and Q9ULZ3 were rarely hypermethylated ( < 2 % ) in all subjects . Hypermethylation of P30279 may reflect a smoking - induced precancerous change in the lung .","Growth factors and glucose homeostasis in diabetic rats : effects of exercise training . To investigate the alterations of glucose homeostasis and variables of the insulin - like growth factor - 1 ( DB01277 ) growth system in sedentary and trained diabetic ( TD ) rats , Wistar rats were divided into sedentary control ( SC ) , trained control ( TC ) , sedentary diabetic ( SD ) , and TD groups . Diabetes was induced by Alloxan ( 35 mg kg (- 1 ) b . w . ) . Training program consisted of swimming 5 days week (- 1 ) , 1 h day (- 1 ) , during 8 weeks . Rats were sacrificed and blood was collected for determinations of serum glucose , insulin , growth hormone ( GH ) , DB01277 , and IGF binding protein - 3 ( P17936 ) . Muscle and liver were removed to evaluate glycogen content . Cerebellum was extracted to determinate DB01277 content . Diabetes decreased serum GH , DB01277 , P17936 , liver glycogen , and cerebellum DB01277 peptide content in baseline condition . Physical training recovered liver glycogen and increased serum and cerebellum DB01277 peptide in diabetic rats . Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum DB01277 concentrations .","Serum measurements of testosterone , insulin - like growth factor 1 , and insulin - like growth factor binding protein - 3 in the diagnosis of prostate cancer among Korean men . AIM : To investigate the relationships of serum testosterone , insulin - like growth factor ( IGF ) - 1 and IGF - binding protein ( IGFBP ) - 3 levels with prostate cancer risk and also with known prognostic parameters of prostate cancer in Korean men who received radical retropubic prostatectomy ( O75783 ) for clinically - localized prostate cancer . METHODS : Serum levels of total testosterone , free testosterone , DB01277 and P17936 were determined in 592 patients who subsequently received prostate biopsy . Results were compared between patients who eventually received O75783 for prostate cancer ( n = 159 ) and those who were not diagnosed with prostate cancer from biopsy ( control group , n = 433 ) . Among the prostate cancer only patients , serum hormonal levels obtained were analyzed in relation to serum prostate specific antigen ( PSA ) , pathological T stage and pathological Gleason score . RESULTS : Prostate cancer patients and the control group demonstrated no significant differences regarding serum levels of total testosterone , free testosterone , DB01277 and P17936 across the different age groups . Among the cancer only patients , no significant associations were observed for serum levels of total testosterone , free testosterone , DB01277 and P17936 levels with pathological T stage , pathological Gleason score and preoperative PSA . CONCLUSION : Our data indicate that simple quantifications of serum testosterone and DB01277 along with P17936 levels might not provide useful clinical information in the diagnosis of clinically localized prostate cancer in Korean men . Also , our results suggest that serum levels of testosterone , DB01277 and P17936 might not be significantly associated with known prognostic factors of clinically localized prostate cancer in Korean men .","Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK59___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .","P17936 is a poor parameter for assessment of clinical activity in acromegaly . OBJECTIVE : Elevated serum P05019 and IGF binding protein - 3 ( P17936 ) levels have been found in patients with active acromegaly . We have studied the relative diagnostic merits of measurements of P17936 compared with P05019 as a parameter of disease activity in these patients . DESIGN / PATIENTS : Thirty untreated patients with acromegaly were compared with 30 healthy adults . MEASUREMENTS : Twenty - four - hour sampling for serum GH in patients with acromegaly , serum P05019 and P17936 . RESULTS : Mean P05019 levels were 22 . 0 nmol / l ( range 6 . 5 - 38 . 4 ) in the healthy adults and 118 . 7 nmol / l ( range 67 . 7 - 206 . 0 ) in patients with acromegaly . Mean P17936 levels were 3 . 5 mg / l ( range 2 . 1 - 4 . 8 ) in controls and 5 . 4 mg / l ( range 4 . 2 - 6 . 6 ) in patients with acromegaly . Mean P05019 / P17936 ratios were 6 . 5 nmol / mg ( range 1 . 9 - 14 . 5 ) in the healthy adults and 22 . 0 nmol / mg ( range 14 . 3 - 32 . 7 ) in patients with acromegaly . There was a considerable overlap for P17936 levels but not for P05019 levels , between normals and acromegalics . The P05019 / P17936 ratio also showed overlap between normals and acromegalics . There was a significant correlation between the mean 24 - hour GH and P17936 levels ( P = 0 . 036 ) and between the P05019 and P17936 levels ( P < 0 . 002 ) in acromegaly . In patients with acromegaly , the P17936 levels showed a decrement , but the P05019 / P17936 ratio did not change significantly with age . CONCLUSIONS : P18065 has no additional discriminatory value over DB01277 measurements for the assessment of clinical activity in acromegaly . In acromegaly , P17936 decreases with increasing age . In acromegaly , P17936 levels significantly correlate with mean 24 - hour GH levels and P05019 levels .","Analysis of mRNA transcripts for insulin - like growth factor receptors and binding proteins in bovine embryos derived from somatic cell nuclear transfer . The low efficiency of animal production using somatic cell nuclear transfer procedures is considered to be the result of an incomplete reprogramming of donor cell nucleus , which leads to abnormal expression of developmentally important genes . The objective of this study was to determine the abundance of gene transcripts of insulin - like growth factor ( IGF ) - related genes in cloned bovine embryos reconstructed with somatic cells . Single embryos derived from nuclear transfer reconstructed with somatic cells ( NT - SC ) or embryo blastomeres ( NTEM ) , in vitro fertilization ( IVF ) , in vivo production ( Vivo ) , and parthenogenetic treatment ( PA ) were analyzed . The relative abundance of mRNA was examined by real - time PCR . Transcripts of the DB01277 receptor ( r ) and IGF binding protein ( BP ) - 2 were detected in all embryos , regardless of origin . IGF - IIr and P17936 transcripts signals in NT - SC embryos were detected with significantly lower frequencies of 25 and 50 % , respectively . Although IGF - Ir and IGFIIr transcript levels were not significantly different in NT - SC , NT - EM , IVF , Vivo , and PA embryos , the relative abundance in individual embryos indicated large variation in NT - SC . P18065 and P17936 levels were high in the Vivo embryos compared with NT - SC , NT - EM , IVF , or PA embryos . These results suggest differences in levels of transcripts of IGF - related genes in the bovine embryos produced by NT compared with IVF , Vivo , and PA .","Diagnostic utility of serum GH , DB01277 and P17936 in patients of acromegaly with uncontrolled diabetes : a pilot study . PURPOSE : Diagnosis of acromegaly in presence of uncontrolled diabetes mellitus is not well validated . METHOD : The study included 10 patients of active acromegaly with uncontrolled blood glucose , 10 patients of type 2 diabetes mellitus with poor glycemic control and 10 healthy subjects . The growth hormone level following oral glucose tolerance test and insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor - binding protein - 3 ( P17936 ) were done at baseline in all the 3 groups and it was repeated after short term glycemic control in type 2 diabetics and acromegalics with diabetics RESULTS : In the acromegalic group the basal GH value was very high ( 36 . 5 + 1 . 6 ) ng / ml and it was non - suppressible ( 32 . 5 + 1 . 43 ) ng / ml after OGTT . The mean DB01277 and P17936 values were also high at baseline ( 208 . 38 + 38 . 51 ) ng / ml , and 7322 + 370 ng / ml respectively . In the non - acromegalic diabetic patients , the basal growth hormone value was marginally elevated ( 2 . 3 + 0 . 02 ) ng / ml . However , it was suppressible to 0 . 2 + 0 . 04 ng / ml after oral glucose load . In them the DB01277 and P17936 values were not elevated and comparable to that of healthy controls . CONCLUSIONS : Basal serum GH and P17936 levels are not influenced by degree of glycemic control however serum DB01277 levels should be interpreted with caution in patients of acromegaly with diabetes . Oral glucose load test has discriminating ability to diagnose acromegaly even with poorly controlled diabetes .","[ Chronic renal failure and growth hormone : effects on GH - IGF axis and leptin ] . AIM : To analyze the changes in DB01277 , P17936 , leptin and insulin after replacement doses of recombinant human growth hormone ( rhGH ) in short prepubertal children with chronic renal failure ( CRF ) . PATIENTS AND METHODS : Eleven children ( 3F : 8M ) , with mean age of 9 . 6 years , were treated with rhGH ( 0 . 23 mg / Kg weekly for 12 months ) . Serum leptin , insulin , glucose , DB01277 and P17936 were measured before , 6 and 12 months after beginning rhGH treatment . RESULTS : The serum levels of leptin , insulin and glucose did not vary during the treatment ; normal leptin and glucose levels and high insulin were observed . There was a significant increment of DB01277 and P17936 during the use of rhGH . CONCLUSIONS : The replacement doses of rhGH during 12 months in a selected group of CRF children determined an increment in DB01277 and P17936 , associated to normal serum leptin and insulin resistance .","Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK82___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .","P05019 enhances cortisol secretion from guinea - pig adrenal gland : in vivo and in vitro study . P01308 - like growth factor ( IGF ) - I is a ubiquitously synthesized peptide that , along with P01344 , acts via the IGF - R type I receptor . P05019 and its receptor are expressed in the adrenal gland of humans and bovines , the secretion of which they seem to stimulate . As in humans and cows , the main glucocorticoid hormone secreted by guinea - pig adrenals is cortisol , and hence we have studied the adrenocortical effects of P05019 in this species . In vivo experiments showed that prolonged P05019 administration raised the plasma concentration of cortisol in both normal and dexamethasone / captopril - treated guinea pigs , thereby ruling out the possibility that P05019 may act by activating the hypothalamic - pituitary - adrenal axis and the renin - angiotensin system . In vitro experiments demonstrated that P05019 enhanced basal , but not maximally agonist [ DB01285 and angiotensin - II ( Ang - II ) ] - stimulated , cortisol secretion from freshly dispersed guinea - pig inner adrenocortical cells . The P05019 immuno - neutralization suppressed the P05019 secretagogue effect , without altering the cortisol response to both DB01285 and Ang - II . P05019 raised cyclic - AMP and inositol triphosphate release from dispersed guinea - pig cells , and the effect was reversed by the adenylate cyclase inhibitor SQ - 22536 and the phospholipase - C ( P98160 ) inhibitor U - 73122 . SQ - 22536 , U - 73122 , the protein kinase ( PK ) A inhibitor H - 89 and the PKC inhibitor calphostin - C decreased by approximately 50 % the cortisol response of dispersed cells to P05019 , and the combined exposure to SQ - 22536 and U - 73122 abolished it . We conclude that P05019 stimulates glucocorticoid secretion from guinea - pig adrenocortical cells , acting via selective receptors coupled to both the adenylate cyclase / PKA - and P98160 / PKC - dependent signaling cascades .","Short - term isotretinoin treatment decreases insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 levels : does isotretinoin affect growth hormone physiology ? BACKGROUND : DB00982 is an effective treatment for acne vulgaris . However , it has numerous side - effects . It was previously reported that serum growth hormone ( GH ) levels decreased with isotretinoin treatment . OBJECTIVES : To analyse whether isotretinoin has any effects on insulin - like growth factor - 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and GH levels . METHODS : Forty - seven patients aged 21 . 5 +/- 5 . 1 years ( mean +/- SD ) with acne vulgaris were included in this study . DB00982 therapy was initiated at a dose of 0 . 5 - 0 . 75 mg kg (- 1 ) daily and then adjusted to 0 . 88 mg kg (- 1 ) daily as maintenance dosage after 1 month . Screening for biochemical and hormonal parameters was performed just before initiation and after 3 months of isotretinoin treatment . RESULTS : DB01277 and P17936 levels decreased significantly after treatment ( P < 0 . 01 ) , while GH levels did not change . Post - treatment , significant increases were seen in aspartate aminotransferase , total cholesterol , low - density lipoprotein cholesterol , triglycerides and low - density lipoprotein cholesterol / high - density lipoprotein cholesterol ratio ( P < 0 . 0001 ) while high - density lipoprotein cholesterol levels were significantly decreased ( P < 0 . 0001 ) . CONCLUSIONS : DB00982 therapy may have an effect on GH physiology , and further studies are needed to understand this association .","Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .","The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK32___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK32___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK32___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK32___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .","Phase 2 trial of cixutumumab in children , adolescents , and young adults with refractory solid tumors : a report from the Children ' s Oncology Group . PURPOSE : This phase 2 study was designed to assess the efficacy of single agent cixutumumab ( DB05759 ) and gain further information about associated toxicities and pharmacodynamics in children , adolescents , and young adults with recurrent or refractory solid tumors . PATIENTS AND METHODS : Patients with relapsed or refractory solid tumors were treated with 9 mg / kg of cixutumumab as a 1 - hour IV infusion once weekly . Strata included : osteosarcoma , Ewing sarcoma , rhabdomyosarcoma , neuroblastoma ( evaluable disease ) , neuroblastoma ( measurable disease ) , Wilms tumor , adrenocortical carcinoma , synovial sarcoma , hepatoblastoma , and retinoblastoma . Correlative studies in consenting patients included an assessment of c - peptide , P17936 , DB01277 , IGF - 2 , hGH , and insulin in consenting patients . RESULTS : One hundred sixteen patients with 114 eligible having a median age of 12 years ( range , 2 - 30 ) were enrolled . Five patients achieved a partial response : 4 / 20 with neuroblastoma ( evaluable only ) and 1 / 20 with rhabdomyosarcoma . Fourteen patients had stable disease for a median of 10 cycles . Hematologic and non - hematologic toxicities were generally mild and infrequent . Serum DB01277 and P17936 increased in response to therapy with cixutumumab . CONCLUSION : Cixutumumab is well tolerated in children with refractory solid tumors . Limited objective single - agent activity of cixutumumab was observed ; however , prolonged stable disease was observed in 15 % of patients . Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway .","Association of IGF1 and P17936 polymorphisms with colorectal polyps and colorectal cancer risk . PURPOSE : DB01277 ( IGF1 ) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis . The bioavailability of IGF1 is regulated by the insulin - like growth factor binding protein 3 ( P17936 ) . The purpose of this study was to examine the association of genetic variants in IGF1 ( rs6214 , rs6220 , and rs35767 ) and P17936 ( rs2854744 and rs2854746 ) with risk of colorectal polyps and colorectal cancer . METHODS : In this ongoing colorectal cancer study of Austria ( CORSA ) , a total of 3 , 360 Caucasian participants , consisting of 178 colorectal cancer patients , 328 patients with high risk polyps , 1 , 059 patients with low risk colorectal polyps , and 1 , 795 colonoscopy - negative controls , were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna . Multiple logistic regression was applied to compare individuals of the control group against three different risk groups , namely , colorectal cancer group , high risk polyp group , and low risk polyp group . RESULTS : Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk ( OR = 1 . 79 , 95 % CI 1 . 04 - 1 . 90 ) compared to the colonoscopy - negative controls ; this was also found when combining colorectal cancer cases and high risk polyp group ( OR = 1 . 39 , 95 % CI 1 . 01 - 1 . 90 ) . CONCLUSION : Our results suggest that the SNP rs6214 of IGF1 could have an impact on developing colorectal cancer and colorectal polyps with villous elements .","Efficacy of ganitumab ( Q99217 479 ) , alone and in combination with rapamycin , in Ewing ' s and osteogenic sarcoma models . Ewing ' s and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents . Recent data suggest that sarcomas may depend on the insulin - like growth factor type 1 ( DB01277 ) receptor ( P08069 ) and / or the insulin receptor ( P06213 ) to drive tumor growth , survival , and resistance to mammalian target of rapamycin complex 1 ( mTORC1 ) inhibitors . We evaluated the therapeutic value of ganitumab ( Q99217 479 ; C ( 6472 ) H ( 10028 ) N ( 1728 ) O ( 2020 ) S ( 42 ) ) , an anti - P08069 , fully human monoclonal antibody , alone and in combination with rapamycin ( mTORC1 inhibitor ) in Ewing ' s ( SK - ES - 1 and A673 ) and osteogenic ( SJSA - 1 ) sarcoma models . P08069 was activated by DB01277 but not by insulin in each sarcoma model . P06213 was also activated by DB01277 in the SJSA - 1 and SK - ES - 1 models , but not in the A673 model where insulin was the preferred P06213 ligand . Ganitumab significantly inhibited the growth of SJSA - 1 and SK - ES - 1 xenografts ; inhibition was associated with decreased P08069 and Akt phosphorylation , reduced total P08069 and bromodeoxyuridine detection , and increased caspase - 3 expression . Ganitumab inhibited rapamycin - induced P08069 , Akt , and glycogen synthase kinase - 3β hyperphosphorylation in each sarcoma model . However , ganitumab in combination with rapamycin also resulted in a marked increase in P06213 expression and activity in the SJSA - 1 and A673 models . The in vivo efficacy of ganitumab in the two ganitumab - sensitive models ( SJSA - 1 and SK - ES - 1 ) was significantly enhanced in combination with rapamycin . Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that P06213 signaling is an important mechanism of resistance to P08069 blockade .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK68___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )","Inflammatory responses of the substantia nigra after acute hypoxia in neonatal rats . The neocortex and the striatum are the brain regions most known to be particularly vulnerable to acute insults like hypoxia or ischemia . In this work , we assess the possibility of cellular damage to the substantia nigra ( SN ) after hypoxia - reoxygenation in the new born rat . The aim of the present paper was to evaluate the expression of growth factor P05019 , and growth factor binding proteins P17936 and P24593 genes and induction of NOS family members ( P29475 , P29474 and P35228 ) and P01375 genes together with glia activation , in the SN at 5 and 48 h after severe hypoxia in the 7 day - old rat , a model for the term human fetus . At early time , while IGFs remain unchanged , we found a transient increase in P29474 and P29475 . Two days after the injury , P29475 expression remained high , P35228 and P01375 increased and also P14136 protein expression was observed together with a profusion of reactive astrocytes distributed throughout the SN . This study on the acute effects of hypoxia on the developing brain provides additional insights into the vulnerability of the SN , a brain region involved in neurodegenerative pathologies .","P42345 complex 2 in adipose tissue negatively controls whole - body growth . P42345 ( P42345 ) , a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors , is found in 2 structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . mTORC2 , which consists of rictor , Q9BPZ7 , Q9BVC4 , and P42345 , is activated by insulin / IGF1 and phosphorylates DB00133 - 473 in the hydrophobic motif of Akt / P31749 . Though the role of P42345 in single cells is relatively well characterized , the role of P42345 signaling in specific tissues and how this may contribute to overall body growth is poorly understood . To examine the role of mTORC2 in an individual tissue , we generated adipose - specific rictor knockout mice ( rictor ( ad -/-) ) . Rictor ( ad -/-) mice are increased in body size due to an increase in size of nonadipose organs , including heart , kidney , spleen , and bone . Furthermore , rictor ( ad -/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic , but glucose tolerant , and display elevated levels of insulin - like growth factor 1 ( IGF1 ) and IGF1 binding protein 3 ( P17936 ) . These effects are observed in mice on either a high - fat or a normal diet , but are generally more pronounced in mice on a high - fat diet . Our findings suggest that adipose tissue , in particular mTORC2 in adipose tissue , plays an unexpectedly central role in controlling whole - body growth .","Ramadan fasting and the GH / DB01277 axis of trained men during submaximal exercise . AIMS : The aim of this study was to explore possible changes in body composition , blood glucose regulation , plasma growth hormone ( GH ) , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) , and insulin concentrations of trained athletes in response to the intermittent fasting and dehydration of Ramadan observance . METHODS : Nine trained male rugby players ( age 19 +/- 2 years , height 1 . 78 +/- 0 . 74 m ) were tested 3 times : before Ramadan ( C ) , at the end of the first week ( Q96GN5 ) , and during the fourth week ( R2 ) . They performed a progressive cycle ergometer test at each visit . The work rate was increased in 6 - min stages corresponding to 20 , 30 , 40 , 50 and 60 % of W max . Substrate oxidation was evaluated by indirect calorimetry . On each occasion , substrate and plasma hormone concentrations were measured at rest and at the end of the exercise . RESULTS : Ramadan fasting induced a significant decrease in body mass and body fat ( R2 vs . C , p < 0 . 001 ) . Plasma concentrations of glucose , insulin , GH , DB01277 and P17936 did not change significantly between C and R2 , either at rest or following exercise . CONCLUSION : Ramadan fasting induces positive changes in body composition without disturbing glucose regulation or activity of the GH / DB01277 system .","Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK85___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK85___ .","Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV - 1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin - positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 - related Drosophila models has further strengthened the hypothesis that both Q13148 \" loss - of - function \" and \" gain - of - function \" mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies .","Effect of individualized exercise training combined with diet restriction on inflammatory markers and DB01277 / P17936 in obese children . AIMS : The present study was designed to examine the possible changes in body composition , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) and inflammatory markers of obese children in response to a 2 - month program of exercise training combined with dietary restriction . METHODS : Twenty - eight obese children ( age 13 . 2 +/- 0 . 7 years , body mass index 30 . 9 +/- 1 . 3 ) were randomly assigned to a diet / training group or a control group and were tested two times : once before and once at the end of the experimental period . They performed a progressive cycle ergometer test at each visit . Substrate oxidation was evaluated by indirect calorimetry . Training was individualized at the point when fat oxidation was maximal ( Lipox ( max ) ) . RESULTS : Diet / training induced a significant decrease in body weight and body fat ( after vs . before , p < 0 . 01 ) . Plasma concentrations of DB01277 , P17936 and inflammatory markers were significantly decreased after the completion of the program . The diet / training program resulted in an increase in VO ( 2max ) ACSM ( 24 . 6 +/- 2 . 5 to 33 . 1 +/- 3 . 1 ml / min / kg , p < 0 . 001 ) at the end of the intervention period . CONCLUSION : These data suggest that in the presence of weight loss , exercise training improves inflammatory markers and DB01277 and P17936 levels in obese children .","Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .","Tyrosine phosphorylation of insulin receptor substrate - 1 ( P35568 ) by oxidant stress in cerebellar granule neurons : modulation by N - methyl - D - aspartate through calcineurin activity . P06213 - substrate - 1 ( P35568 ) is a docking protein for several tyrosine kinase receptors . Upon tyrosine phosphorylation , P35568 binds to signaling molecules that express Src homology 2 ( SH - 2 ) binding domains , including phosphatidylinositol 3 - kinase ( PI 3 - kinase ) , phosphotyrosine phosphatase Q06124 ( Syp ) , Nck , Crk and Grb - 2 . Hydrogen peroxide ( H ( 2 ) O ( 2 ) ) induces tyrosine phosphorylation of key signaling mediators presumably by inhibition of tyrosine phosphatases . In many cell types , the activation of extracellular signal - related kinases ( e . g . MAPK ) and other protein kinases by H ( 2 ) O ( 2 ) leads to transcriptional activation . In the current study , we examined the effect of H ( 2 ) O ( 2 ) on P35568 tyrosine phosphorylation in primary cultured rat cerebellar granule neurons . H ( 2 ) O ( 2 ) stimulated the rapid tyrosine phosphorylation of P35568 and Q8NFH3 / Q8TCB0 Q96HU1 kinase , and induced its association with PI 3 - kinase . H ( 2 ) O ( 2 )- induced P35568 phosphorylation was rapidly reversible ( 5 min ) whereas MAPK phosphorylation persisted for up to 1 h . DB01221 reversed H ( 2 ) O ( 2 )- mediated tyrosine phosphorylation of P35568 and its association with PI 3 - kinase . The dephosphorylation of P35568 by DB01221 was calcium - dependent and was inhibited by the calcineurin inhibitor cyclosporine . P62158 - dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine - phosphorylated P35568 as substrates . These data highlight the role of multiple phosphatases in the regulation of P35568 tyrosine phosphorylation and identify a novel functional property of calcineurin .","Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .","[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK45___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .","Matrix metalloproteinase 19 regulates insulin - like growth factor - mediated proliferation , migration , and adhesion in human keratinocytes through proteolysis of insulin - like growth factor binding protein - 3 . Unlike most other matrix metalloproteinases ( MMPs ) Q99542 is expressed in undifferentiated basal keratinocytes of healthy human skin . The human keratinocyte cell line HaCaT , which like basal keratinocytes constitutively expresses Q99542 , down - regulated the expression of Q99542 at high calcium concentrations . DB01373 - regulation occurred through P12830 mediated cell - cell contacts because neutralizing anti - P12830 antibodies restored Q99542 expression in high calcium . Overexpression of Q99542 in HaCaT cells ( HaCaT - WT ) increased cellular proliferation , as well as migration and adhesion on type I collagen . This was due to proteolysis of the insulin - like growth factor ( IGF ) binding protein - 3 by Q99542 , which augmented signaling through the P08069 , as evidenced by its increased autophosphorylation . Conversely , these effects were not observed in cells transfected with P08253 or a catalytically inactive Q99542 mutant . As further proof that increased IGF - signaling promoted adhesion and migration in HaCaT - WT cells , we reproduced these effects by treating parental HaCaT with P05019 . We observed dephosphorylation of the focal adhesion kinase in HaCaT - WT as well as P05019 - treated HaCaT cells , suggesting that inactivating focal adhesion kinase is a mechanism by which P05019 enhances adhesion . Furthermore , P05019 - triggered motility on type I collagen was mediated by MMP activity , which , however , was distinct from Q99542 . Considering the coexpression of P17936 and Q99542 in the skin , we conclude that Q99542 is a likely candidate to be the major P17936 degrading MMP in the quiescent epidermis . This activity might have widespread consequences for the behavior of epidermal keratinocytes .","Growth hormone reserve in adult beta thalassemia patients . Reduced serum insulin - like growth factor - 1 ( DB01277 ) and hypogonadotrophic hypogonadism are common features of adult beta - thalassemia , and warrant evaluation of the growth hormone ( GH ) - DB01277 axis . The aim of this study was to determine GH reserve in beta - thalassemia patients ( 9 females , 7 males , 15 major , 1 intermedia ) , age 29 . 3 +/- 6 . 9 years , BMI 21 . 3 +/- 1 . 9 kg / m2 , and in 20 age , sex and BMI - matched healthy controls , using the GH - releasing hormone ( P01286 ) - arginine test . The associations between peak GH response and hormonal and biochemical indices were evaluated . Using BMI - related cut - off limits for peak GH response in the P01286 - arginine test , 4 / 16 beta - thalassemia patients had peak GH lower than 11 . 5 microg / l , the cut - off limit suggested for lean subjects , and were diagnosed as GH deficient ( GHD ) . Using 9 microg / l as the cut - off limit 2 / 16 patients were GHD . Reduced serum DB01277 and P17936 were present in 69 % and 19 % of the patients , respectively . Peak GH did not correlate with serum DB01277 , DB00024 , and fT4 levels or gonadal status . Neither peak GH nor DB01277 correlated with serum ferritin . Our findings suggest that GHD is present in up to a quarter of adult beta - thalassemia patients . The clinical benefits of GH therapy need to be determined . GHD alone does not account for the high prevalence of reduced DB01277 in adult beta - thalassemia .","Effects of alternate - day or daily prednisone treatment on GH and cortisol levels in growth - retarded children after renal transplantation . Growth retardation after renal transplantation ( RTx ) is generally attributed to prednisone ( PDN ) administration , although the exact mechanism is poorly understood . In a group of 19 growth - retarded patients after RTx , we studied the effect of alternate - day ( group AD , n = 12 ) and daily ( group D , n = 7 ) PDN treatment on the spontaneous plasma growth hormone ( GH ) and cortisol profiles , for 48 h in group AD and for 24 h in group D . The maximal plasma GH response to arginine provocation ( ATT ) and plasma levels of insulin - like growth factor - 1 ( DB01277 ) , IGF - 2 and serum IGF - binding proteins ( IGFBP ) were also determined . For both groups the PDN doses were recalculated as daily doses for comparison . The median PDN dose in both groups was similar , 0 . 15 mg / kg / day , with a range of 0 . 10 - 0 . 25 mg / kg / day . Glomerular filtration rate ( Q92565 ) was above 20 ml / min / 1 . 73 m2 in all patients . We hypothesized that alternate - day PDN therapy and even more so daily PDN therapy would have a deleterious effect on GH and cortisol secretion and would result in lower GH - dependent growth factors as compared to control data of healthy children . Our findings revealed that growth - retarded renal allograft patients , receiving either alternate - day or daily PDN therapy , have significantly lower mean plasma GH levels than controls , but normal diurnal rhythm of GH and cortisol secretion as well as normal immunoreactive DB01277 and - 2 levels . Mean serum P08833 levels were normal , but mean serum P17936 levels were significantly increased , while a significant negative correlation was found between the Q92565 and serum P17936 levels . ( ABSTRACT TRUNCATED AT 250 WORDS )","Evaluation of the synergistic effect of insulin resistance and insulin - like growth factors on the risk of breast carcinoma . BACKGROUND : The purpose of the current study was to investigate the association between insulin resistance ( which was measured using fasting blood C - peptide ) and its joint association with insulin - like growth factors ( DB01277 , IGF - 2 , and IGF binding protein - 3 [ P17936 ] ) on the risk of breast carcinoma . METHODS : Included in the current study were 400 case - control pairs from the Shanghai Breast Cancer Study . Pretreatment biospecimens and interview data were collected from all breast carcinoma cases and their individually matched controls . RESULTS : Breast carcinoma risk was found to be statistically significantly increased when higher blood levels of C - peptide and IGFs were noted in a dose - response manner . There was a statistically significant twofold to threefold increased risk of breast carcinoma for women in the highest quartile of C - peptide , DB01277 , or P17936 compared with women in the lowest quartiles . Women with high levels of both C - peptide and DB01277 or P17936 also were found to have a substantially higher risk of breast carcinoma than those women with a high level of only one of these molecules . The adjusted odds ratios ( ORs ) were 3 . 79 ( 95 % confidence interval [ 95 % CI ] , 2 . 03 - 7 . 08 ) for those with a higher level of both C - peptide and DB01277 and 4 . 03 ( 95 % CI , 2 . 06 - 7 . 86 ) for those with a higher level of both C - peptide and P17936 . CONCLUSIONS : The results of the current study suggest that insulin resistance and IGFs may synergistically increase the risk of breast carcinoma .","Syngeneic living - donor liver transplantation for hemangioendothelioma : a clinical model for studying liver regeneration . A 22 - year - old Caucasian patient underwent living - donor liver transplantation ( LDLT ) for hepatic hemangioendothelioma in a healthy liver . The organ donor was his monozygotic twin brother . Surgery was uneventful in both donor and recipient , who received the same postoperative treatment ( i . e . no immunosuppression for the recipient ) . Although both donor and recipient achieved a full liver function recovery , the volume of the recipient ' s graft increased much more than the donor ' s residual liver in the first postoperative month ( 1 . 6 - fold vs . 1 . 2 - fold ) . This different growth rate correlated with growth hormone ( GH ) / insulin growth factor ( IGF ) axis dynamics : the donor had significantly lower insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor 2 ( IGF - 2 ) and insulin - like growth factor binding protein 3 ( P17936 ) values than the recipient on postoperative days ( POD ) 3 - 30 , although they had similar GH values . Other potential regenerative factors , e . g . tumor necrosis alpha , interleukin 6 ( P05231 ) , insulin and C peptide did not correlate with liver regeneration rate . The particular endocrine picture of the graft may be explained by a modified GH - hepatocyte interaction due to cold ischemia during preservation resulting in a higher IGF production . Whether this is a potential molecular tool by means of which transplanted partial livers promote their regeneration remains to be seen in a larger number of patients .","Q12778 content is reduced in cystic fibrosis and increases with P05019 treatment . Cystic fibrosis - related diabetes is to date the most frequent complication in cystic fibrosis ( CF ) . The mechanisms underlying this condition are not well understood , and a possible role of insulin resistance is debated . We investigated insulin signal transduction in CF . Total insulin receptor , P35568 , p85 PI3K , and AKT contents were substantially normal in CF cells ( CFBE41o - ) , whereas winged helix forkhead ( FOX ) O1 contents were reduced both in baseline conditions and after insulin stimulation . In addition , CF cells showed increased P27361 / 2 , and reduced β2 arrestin contents . No significant change in O14508 was observed . By using a P13569 inhibitor and siRNA , changes in Q12778 were related to P13569 loss of function . In a CF - affected mouse model , Q12778 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild - type . DB01277 ( P05019 ) increased Q12778 content in vitro and in vivo in muscle and adipose tissue . In conclusion ; we present the first description of reduced Q12778 content in CF , which is compatible with reduced gluconeogenesis and increased adipogenesis , both features of insulin insensitivity . P05019 treatment was effective in increasing Q12778 , thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis - related diabetes .","Phase II open label , multi - center clinical trial of modulation of intermediate endpoint biomarkers by 1α - hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin . BACKGROUND : Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention . Major risk factors for this disease have been associated with low serum levels of vitamin D . Here , we evaluate the biologic activity of a less calcemic vitamin D analog 1α - hydroxyvitamin D2 [ 1α - OH - D2 ] ( Bone Care International , Inc . ) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia ( HG P63167 ) . METHODS : Patients with clinically organ - confined prostate cancer and HG P63167 were randomized to 1α - OH - D2 versus placebo for 28 days prior to radical prostatectomy . Intermediate endpoint biomarkers included serum vitamin D metabolites , TGFß 1 / 2 , free / total PSA , DB01277 , P17936 , P09038 , and P15692 . Tissue endpoints included histology , MIB - 1 and TUNEL staining , microvessel density and factor VIII staining , androgen receptor and PSA , vitamin D receptor expression and nuclear morphometry . RESULTS : The 1α - OH - D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days . While serum vitamin D metabolite levels only slightly increased , evidence of biologic activity was observed with significant reductions in serum PTH levels . TGF - ß2 was the only biomarker significantly altered by vitamin D supplementation . Whether reduced TGF - ß2 levels in our study is an early indicator of response to vitamin D remains unclear . CONCLUSIONS : While further investigation of vitamin D may be warranted based on preclinical studies , results of the present trial do not appear to justify evaluation of 1α - OH - D2 in larger clinical prostate cancer prevention studies .","Effects of insulin - like growth factor ( IGF ) binding protein - 3 ( P17936 ) on endometrial cancer ( HHUA ) cell apoptosis and P01133 stimulated cell proliferation in vitro . OBJECTIVE : P17936 has been demonstrated to stimulate or inhibit cell proliferation independently of its ability to bind IGF and a specific P17936 receptor has been proposed . P01133 has been implicated in the cancer development and carcinogenesis . Only limited data are available on the crosstalk between P17936 signaling and P01133 induced cell survival and signal transduction . The current studies were undertaken to characterize P17936 binding to endometrial cancer cells ( HHUA ) and determine its biological effects , as well as whether P17936 exposure alters the cell proliferation stimulated by P01133 . METHODS : Cell proliferation and apoptosis were analyzed by ELISA using specific antibodies . The interaction between HHUA cell and P17936 was analyzed using a biosensor . The phosphorylation abundance of specific proteins and their phosphorylation in response to P01133 and P17936 was analyzed by immunoprecipitation followed by immunoblotting . RESULTS : Biosensor analysis showed that P17936 could bind to HHUA cell surface . P17936 inhibited BrdU uptake , potentiated ssDNA production and induced p53 in HHUA cells . Although P01133 stimulated HHUA cell proliferation and Akt phosphorylation , P17936 inhibited cell proliferation and Akt phosphorylation that had been stimulated by P01133 . However , P01133 receptor phosphorylation and expression were not reduced by P17936 . Since HHUA cells lack IGF receptors and do not show biological response to IGF these results suggest that P17936 can bind to HHUA cells , inhibit cell proliferation and induce apoptosis independently of its ability to bind to IGFs possibly by binding to an P17936 receptor . CONCLUSIONS : Taken together these findings demonstrate that P17936 binds to HHUA cell surface , and inhibits cell division induced by P01133 , possibly by modulating the P01133 - mediated signal transduction system .","Effects of the route of oestrogen administration on DB01277 and P17936 in healthy postmenopausal women : results from a randomized placebo - controlled study . OBJECTIVE : Oestrogens can modulate the action or secretion of GH . Previous studies in postmenopausal women have shown a differential effect between transdermal 17beta - oestradiol and oral ethynyl - oestradiol on GH and DB01277 concentrations . This secondary analysis , based on a large randomized trial , aimed to estimate the effect of the route of administration of 17beta - oestradiol in combined hormone replacement therapy with progesterone on DB01277 and P17936 levels . DESIGN : DB01277 and P17936 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17beta - oestradiol orally combined with a daily intake of 100 mg progesterone ( group 1 ; n = 63 ) , or 50 microg of 17beta - oestradiol transdermally combined with a daily intake of 100 mg progesterone ( group 2 ; n = 68 ) , or triple dummy placebo ( group 3 ; n = 65 ) over a 6 - month period . IGF1 and P17936 levels were available for 133 women . RESULTS : Oral oestrogen significantly decreased DB01277 levels compared to placebo ( P = 0 . 04 ) and transdermal oestrogen ( P = 0 . 004 ) , whereas transdermal oestrogen had no effect on DB01277 levels compared to placebo ( P = 0 . 56 ) . As regards P17936 , no significant difference was detected between the three groups . CONCLUSIONS : Our data indicate that the route of oestrogen administration can influence DB01277 levels . DB01277 concentrations decreased significantly with oral oestrogen , whereas no significant change was observed with transdermal oestrogen at 6 months . The clinical relevance of these differential effects remains to be determined , particularly with regard to the risk for cardiovascular diseases .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","P15692 and serum withdrawal induced changes in the transcript profile in human endometrial endothelial cells . The changes in transcript profile induced by vascular endothelial growth factor ( P15692 ) and serum withdrawal in primary human endometrial endothelial cells ( ECs ) were investigated using microarrays , gene ontology and pathway analysis . P15692 altered the levels of transcripts involved in angiogenesis , cell survival , and apoptosis , including up - and downregulation of P31749 , Q92934 , MIF , and P17936 and O15123 , respectively . Serum deprivation induced downregulation of cell - cycle - related transcripts such as mitosis regulators Q12834 and SPC25 . Of the transcripts regulated by both P15692 and partial serum deprivation , remarkably 88 of 89 showed reciprocal regulation ( p < 1 x 10 (- 49 ) ) . These are predominantly cell - fate - associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts . Our results show that in addition to the known role of P15692 as an EC growth and survival promoter , it also regulates apoptosis - related messenger RNAs ( mRNAs ) , many of which were reciprocally regulated following serum withdrawal .","[ Pattern of abnormal skeletal development in girls with idiopathic precocious puberty and therapeutic effect of Chinese herbs for nourishing yin and purging fire ] . OBJECTIVE : To explore the pattern of abnormal skeletal development in girls with idiopathic precocious puberty ( IPP ) and the therapeutic effect of Chinese herbs for nourishing yin and purging fire ( CH ) . METHODS : Measurement of bone age , bone mineral content ( BMC ) and bone density ( BD ) were performed and levels of serum gla - protein ( BGP ) , insulin - like growth factor 1 ( DB01277 ) and insulin - like growth factor binding protein 3 ( P17936 ) were determined in girls with IPP at various stages of pubertal development . Data were compared with those collected from matched girls , and the correlativity between various parameters and the extent of the disease were analyzed to explore the pattern . Thirty - eight girls out of them were treated with CH and the therapeutic effect was observed . RESULTS : The bone age of the IPP girls was ahead of time obviously ( P < 0 . 05 ) , levels of BMC , BD and serum BGP , DB01277 were significantly higher than the levels in the healthy girls of matched age ( P < 0 . 05 ) . And the degree of these changes were markedly positive correlated with the severity of disease ( P < 0 . 05 ) . After being remitted with CH treatment , the advanced bone age was apparently alleviated , and above - mentioned abnormal criteria were lowered significantly ( P < 0 . 05 ) . CONCLUSION : The skeletal development of the girls with IPP was accelerated and the skeletal maturity were ahead of time , the more serious the condition of disease , the more obvious the acceleration and the advanced bone age . CH could decelerate skeletal development and delay the skeletal maturity of IPP patients .","Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .","Relationship of plasma adiponectin with sex hormone and insulin - like growth factor levels . OBJECTIVE : Recent studies have suggested that a relationship between adiponectin and sex hormone , prolactin , and insulin - like growth factor levels could be important for breast cancer risk and insulin sensitivity . Therefore , we assessed the relationship of adiponectin with plasma concentrations of estrone ; estradiol ; estrone sulfate ; testosterone ; androstenedione ; dehydroepiandrosterone ( DB01708 ) ; DB05804 ( DHEAS ) ; sex hormone binding globulin ( P04278 ) ; prolactin ; insulin - like growth factor ( DB01277 ) ; its binding protein , IGF binding protein 3 ( P17936 ) ; c - peptide ; and IGF binding protein 1 ( P08833 ) among 360 postmenopausal women not taking postmenopausal hormones from the Nurses ' Health Study . RESEARCH METHODS AND PROCEDURES : Multivariate models were adjusted for physical activity , alcohol consumption , age at blood draw , age at first birth / parity , fasting status , and time of day of blood draw ; a separate model was additionally adjusted for BMI at blood draw . RESULTS : DB00286 were inversely associated with adiponectin levels ; however , except for free estradiol , these associations were substantially attenuated after adjustment for BMI . Free estradiol levels were 27 % lower among women in the top vs . bottom quartile of adiponectin levels . No consistent associations were observed for the androgens , prolactin , DB01277 , and P17936 . However , P04278 , c - peptide , and P08833 were strongly and independently associated with adiponectin levels ( r = 0 . 29 , - 0 . 30 , 0 . 24 , respectively ) . CONCLUSION : With the exceptions of P04278 , c - peptide , and P08833 , the studied analytes were modestly associated with adiponectin and the associations were , in large part , mediated by body fat .","Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .","Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK16___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .","The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve .","DB01277 , its binding protein 3 , and sex hormones in girls during puberty . The aim of the study was to estimate relationships between serum concentration of insulin - like growth factor 1 ( DB01277 ) , its binding protein ( P17936 ) , estradiol and testosterone in girls during puberty , taking into consideration gonadotropins level and nutritional status . Eighty - six girls aged 9 . 8 - 14 . 7 were examined . The girls were divided into three groups according to the pubertal stage . Body height , weight and thicknesses of skin folds were measured . Biochemical parameters were assessed using RIA method . It has been found that all investigated parameters are growing with pubertal development . There are significant positive correlations between DB01277 and testosterone , DB01277 and estradiol serum concentrations as well as between DB01277 serum concentration , BMI and sum of skin folds thicknesses . It has been also proved that there are positive correlations between P17936 and estradiol serum concentration as well as between P17936 and age , body height and body weight in girls during puberty .","Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .","Monitoring the activation state of the insulin - like growth factor - 1 receptor and its interaction with protein tyrosine phosphatase 1B using bioluminescence resonance energy transfer . We have developed two bioluminescence resonance energy transfer ( BRET ) - based approaches to monitor 1 ) ligand - induced conformational changes within partially purified insulin - like growth factor - 1 ( DB01277 ) receptors ( P08069 ) and 2 ) P08069 interaction with a substrate - trapping mutant of protein tyrosine phosphatase 1B ( P18031 - D181A ) in living cells . In the first assay , human P08069 fused to Renilla reniformis luciferase ( Rluc ) or yellow fluorescent protein ( YFP ) were cotransfected in human embryonic kidney ( P29320 ) - 293 cells . The chimeric receptors were then partially purified by wheat germ lectin chromatography , and BRET measurements were performed in vitro . In the second assay , BRET measurements were performed on living P29320 - 293 cells cotransfected with P08069 - Rluc and YFP - P18031 - D181A . Ligand - induced conformational changes within the P08069 and interaction of the P08069 with P18031 could be detected as an energy transfer between Rluc and YFP . Dose - response experiments with DB01277 , IGF - 2 , and insulin demonstrated that the effects of these ligands on BRET correlate well with their known pharmacological properties toward the P08069 . Inhibition of P08069 autophosphorylation by the tyrphostin AG1024 ( 3 - bromo - 5 - t - butyl - 4 - hydroxy - benzylidenemalonitrile ) resulted in the inhibition of IGF1 - induced BRET signal between the P08069 and P18031 . In addition , an anti - P08069 antibody known to inhibit the biological effects of DB01277 inhibited ligand - induced BRET signal within the P08069 , as well as between P08069 and P18031 . This inhibition of BRET signal paralleled the inhibition of the ligand - induced autophosphorylation of the P08069 by this antibody . In conclusion , these BRET - based assays permit 1 ) the rapid evaluation of the effects of agonists or inhibitory molecules on P08069 activation and 2 ) the analysis of the regulation of P08069 - P18031 interaction in living cells .","P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .","[ Research advances on Q9UKQ2 expression and Q9UKQ2 - mediated tumor metastasis ] . A disintegrin - metalloproteinase 28 ( Q9UKQ2 ) is one of important members of ADAM family , that is involved in various biological events including cell adhesion , proteolysis , growth and metastasis of solid tumors and hematological malignancies . Studies have shown that Q9UKQ2 is highly expressed in several human tumors , such as lung , breast and bladder cancers , and chronic lymphocytic leukemia , and its tissue expression levels correlate with cancer metastasis . Q9UKQ2 - mediated cancer cell metastasis may be related with the cleavage of von Willebrand ' s factor ( P04275 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and connective tissue growth factor ( P29279 ) , as well as the promoting Q14242 / P16109 - mediated cell adhesion . This review summarizes the basic and translational aspects of Q9UKQ2 biology that might stimulate the interest in Q9UKQ2 research and discovery of novel Q9UKQ2 targets , providing potential novel therapies for metastatic cancers .","Efficacy and safety of mecasermin rinfabate . There has been interest in using recombinant human ( rh ) insulin - like growth factor ( IGF ) - I ( rhIGF - I ) to treat short stature , either alone or in combination with its binding protein ( insulin - like growth factor binding protein [ IGFBP ] - 3 ) . P05019 has been shown to increase growth velocity in children with IGF deficiency , either as a result of growth hormone insensitivity syndrome ( GHIS ) or IGF gene deletion . However , there have been adverse events , particularly hypoglycaemia , reported with administration of unbound rhIGF - I . In addition , the serum half - life of unbound rhIGF - I is shorter when administered to patients with GHIS , who have low serum concentrations of its binding proteins P17936 and acid - labile subunit ( P35858 ) , than when administered to normal volunteers or to the patient with an P05019 gene deletion ( who had normal levels of P17936 ) . iPlex ( mecasermin rinfabate ) , an equimolar mixture of P05019 and its binding protein P17936 , was developed to prolong the half - life and to counteract acute adverse events ( particularly hypoglycaemia ) associated with administration of P05019 . Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders , it does appear that mecasermin rinfabate has a longer half - life in patients with GHIS than unbound P05019 , and fewer reports of adverse events ( including hypoglycaemia ) when administered to patients with diabetes .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","Endocrine manifestations of chromosome 22q11 . 2 microdeletion syndrome . BACKGROUND : Endocrine abnormalities , including hypocalcemia , thyroid dysfunction , and short stature , are associated with chromosome 22q11 . 2 microdeletion syndrome . This study was undertaken to examine the frequencies and clinical features of endocrine abnormalities in patients with 22q11 . 2 microdeletion syndrome . METHODS : We analyzed 61 patients with 22q11 . 2 microdeletion syndrome diagnosed based on the verification of microdeletion by fluorescent in situ hybridization ( Q5TCZ1 ) using a probe of the DiGeorge syndrome critical region ( P54198 ) at 22q11 . 2 and a control probe , ARSA at 22q13 . Serum total calcium , phosphorus , and intact parathyroid hormone ( PTH ) levels were measured , thyroid function test was performed , and serum DB01277 and P17936 levels were also estimated . Height and weight of patients were compared with individual chronological ages . RESULTS : Hypocalcemia was found in 20 patients ( 32 . 8 % ) , and overt hypoparathyroidism in 8 ( 13 . 1 % ) . Two patients ( 3 . 3 % ) showed autoimmune thyroid diseases , 1 each with Graves ' disease and Hashimoto thyroiditis . Ten patients ( 16 . 4 % ) were below the third percentile in height , but the serum DB01277 level was normal in 9 out of these 10 patients . CONCLUSION : Our findings show that patients with chromosome 22q11 . 2 microdeletion syndrome present with variable endocrine manifestations and variable clinical phenotypes . In addition to Q5TCZ1 analysis , careful endocrine evaluations are required in patients with this microdeletion syndrome , particularly for those with hypoparathyroidism or thyroid dysfunction .","Anabolic effects of insulin - like growth factor in combination with insulin - like growth factor binding protein - 3 in severely burned adults . BACKGROUND : The purpose of this study was to determine the anabolic effects of recombinant human insulin - like growth factor - I ( rhIGF - 1 ) complexed with its principal binding protein DB01277 binding protein - 3 ( P17936 ) in severely burned adults . METHODS : Ten burned adults were studied consecutively after receiving saline ( pretreatment ) , then rhIGF - 1 / P17936 ( treatment ) for 5 days . Doses were 1 , 2 , and 4 mg / kg per day . DB09341 , electrolytes , hormones , and leg muscle protein metabolism were determined . Nine other studies were performed on similarly injured adults at comparable times to the treatment studies to control for time effects . RESULTS : Serum DB01277 and P17936 levels increased with all doses , but no incremental increases were found . Leg protein balance improved with rhIGF - 1 / P17936 , which was associated with an increase in muscle protein fractional synthetic rate . These effects were independent of time . All patients were euglycemic without electrolyte imbalances . CONCLUSION : Net protein synthesis in the isolated leg of severely burned adults improved with rhIGF - 1 / P17936 without development of glucose abnormalities .","DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .","Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5 - HT ligands . The brominated cyclodipeptides barettin ( cyclo [( 6 - bromo - 8 - entryptophan ) arginine ] ) and 8 , 9 - dihydrobarettin ( cyclo [( 6 - bromotryptophan ) arginine ] ) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose - dependent manner in concentrations ranging from 0 . 5 to 25 microM . To further establish the molecular target and mode of action of these compounds , we investigated their affinity to human serotonin receptors . The tryptophan residue in the barettins resembles that of endogenous serotonin [ 5 - hydroxytryptamine ] . A selection of human serotonin receptors , including representatives from all subfamilies ( 1 - 7 ) , were transfected into P29320 - 293 cells . Barettin selectively interacted with the serotonin receptors 5 - Q13049 , P28335 , and Q13639 at concentrations close to that of endogenous serotonin , with the corresponding Ki values being 1 . 93 , 0 . 34 , and 1 . 91 microM , respectively . 8 , 9 - Dihydrobarettin interacted exclusively with the P28335 receptor with a Ki value of 4 . 63 microM ; it failed to show affinity to 5 - Q13049 and Q13639 , indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins .","Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .","P01286 antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro . We investigated the effect of a P01286 antagonist , Q16674 - 602on the metastatic cascade in vitro of three human cancers , DBTRG - 05 glioblastoma , MDA - MB - 468 estrogen - independent breast , and ES - 2 clear cell ovarian cancer . P01286 receptors and their main splice variant , SV1 were detected on all three cell lines . After treatment with Q16674 - 602 , the cell viability decreased significantly , significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased . The attachment of cancer cells to fibronectin and matrigel was severely hindered . Wound - healing experiments demonstrated a reduced cellular motility in all three cell lines . The upregulation of caveolin - 1 and P12830 , and thepowerful downregulation of NF - kappaB and beta - catenin was detected . Our study suggests that the clinical application of highly potent P01286 antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well .","Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK59___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain ."],"string":"[\n \"P01308 - like growth factor - 1 activation of extracellular signal - related kinase - 1 and - 2 in growth hormone - secreting cells . Intracellular pathways mediating feedback regulation by insulin - like growth factor - 1 ( DB01277 ) of pituitary GH gene expression remain incompletely understood . Extracellular signal - related kinases ( ERKs ) , a family of serine / threonine kinases , are activated by tyrosine kinase - associated growth factor receptors . To further define the DB01277 postreceptor events occurring in GH - secreting cells , we investigated the activity of ERKs in response to DB01277 in GC cells following stable transfection with either wild type human DB01277 receptor cDNA ( WT cells ) or a mutant cDNA encoding a truncated , kinase - defective DB01277 receptor with a dominant negative effect on endogenous receptor function ( 952STOP cells ) . Zymography of immunoprecipitated ERKs in myelin basic protein ( MBP ) - containing polyacrylamide gels demonstrated dose - dependent induction of P27361 and - 2 activity by DB01277 in GC cells with maximal activity occurring at 6 min . DB01277 - induced P29323 activity in WT - transfected cells was up to 80 - fold basal and 4 - fold that observed in GC cells . 952STOP cells expressing the tyrosine kinase - deficient receptor were refractory to DB01277 action , demonstrating minimal P29323 induction . In contrast , 12 - O - tetradecanoylphorbol 13 - acetate stimulated P29323 activity to the same degree in all three cell types regardless of their P08069 status . DB02587 ( 50 microM ) , isobutylmethylxanthine ( 0 . 5 mM ) , and forskolin / isobutylmethylxanthine in combination attenuated DB01277 - induced P29323 activity in WT cells by 54 , 55 , and 75 % respectively . The rapid , dose - dependent , and DB01277 receptor - dependent activation of ERKs and the attenuation of this effect by DB02527 suggest an interrelated role for both molecules in DB01277 signal transduction in GH - secreting cells .\",\n \"Hypermethylation of P30279 May Reflect a Smoking - Induced Precancerous Change in the Lung . It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event , specific to overt cancer tissue . Using MethyLight assays , we analyzed 316 lung tissue samples from 151 cancer - free subjects ( 121 ever - smokers and 30 never - smokers ) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers . Only P25054 ( 39 % ) , P30279 ( 21 % ) , CDH1 ( 7 % ) , and P10826 ( 4 % ) were hypermethylated in > 2 % of these cancer - free subjects . P30279 was hypermethylated more frequently in ever - smokers ( 26 % ) than in never - smokers ( 3 % ) . P30279 hypermethylation was also associated with increased age and upper lobe sample location . P25054 was frequently hypermethylated in both ever - smokers ( 41 % ) and never - smokers ( 30 % ) . Q8NE79 , P55290 , CDKN2A ( p16 ) , P42772 , P53355 , P17936 , Q9BY67 , Q8NCM2 , Q96L42 , P16455 , Q14982 , P29122 , Q9NS23 , RUNX , and Q9ULZ3 were rarely hypermethylated ( < 2 % ) in all subjects . Hypermethylation of P30279 may reflect a smoking - induced precancerous change in the lung .\",\n \"Growth factors and glucose homeostasis in diabetic rats : effects of exercise training . To investigate the alterations of glucose homeostasis and variables of the insulin - like growth factor - 1 ( DB01277 ) growth system in sedentary and trained diabetic ( TD ) rats , Wistar rats were divided into sedentary control ( SC ) , trained control ( TC ) , sedentary diabetic ( SD ) , and TD groups . Diabetes was induced by Alloxan ( 35 mg kg (- 1 ) b . w . ) . Training program consisted of swimming 5 days week (- 1 ) , 1 h day (- 1 ) , during 8 weeks . Rats were sacrificed and blood was collected for determinations of serum glucose , insulin , growth hormone ( GH ) , DB01277 , and IGF binding protein - 3 ( P17936 ) . Muscle and liver were removed to evaluate glycogen content . Cerebellum was extracted to determinate DB01277 content . Diabetes decreased serum GH , DB01277 , P17936 , liver glycogen , and cerebellum DB01277 peptide content in baseline condition . Physical training recovered liver glycogen and increased serum and cerebellum DB01277 peptide in diabetic rats . Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum DB01277 concentrations .\",\n \"Serum measurements of testosterone , insulin - like growth factor 1 , and insulin - like growth factor binding protein - 3 in the diagnosis of prostate cancer among Korean men . AIM : To investigate the relationships of serum testosterone , insulin - like growth factor ( IGF ) - 1 and IGF - binding protein ( IGFBP ) - 3 levels with prostate cancer risk and also with known prognostic parameters of prostate cancer in Korean men who received radical retropubic prostatectomy ( O75783 ) for clinically - localized prostate cancer . METHODS : Serum levels of total testosterone , free testosterone , DB01277 and P17936 were determined in 592 patients who subsequently received prostate biopsy . Results were compared between patients who eventually received O75783 for prostate cancer ( n = 159 ) and those who were not diagnosed with prostate cancer from biopsy ( control group , n = 433 ) . Among the prostate cancer only patients , serum hormonal levels obtained were analyzed in relation to serum prostate specific antigen ( PSA ) , pathological T stage and pathological Gleason score . RESULTS : Prostate cancer patients and the control group demonstrated no significant differences regarding serum levels of total testosterone , free testosterone , DB01277 and P17936 across the different age groups . Among the cancer only patients , no significant associations were observed for serum levels of total testosterone , free testosterone , DB01277 and P17936 levels with pathological T stage , pathological Gleason score and preoperative PSA . CONCLUSION : Our data indicate that simple quantifications of serum testosterone and DB01277 along with P17936 levels might not provide useful clinical information in the diagnosis of clinically localized prostate cancer in Korean men . Also , our results suggest that serum levels of testosterone , DB01277 and P17936 might not be significantly associated with known prognostic factors of clinically localized prostate cancer in Korean men .\",\n \"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK59___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .\",\n \"P17936 is a poor parameter for assessment of clinical activity in acromegaly . OBJECTIVE : Elevated serum P05019 and IGF binding protein - 3 ( P17936 ) levels have been found in patients with active acromegaly . We have studied the relative diagnostic merits of measurements of P17936 compared with P05019 as a parameter of disease activity in these patients . DESIGN / PATIENTS : Thirty untreated patients with acromegaly were compared with 30 healthy adults . MEASUREMENTS : Twenty - four - hour sampling for serum GH in patients with acromegaly , serum P05019 and P17936 . RESULTS : Mean P05019 levels were 22 . 0 nmol / l ( range 6 . 5 - 38 . 4 ) in the healthy adults and 118 . 7 nmol / l ( range 67 . 7 - 206 . 0 ) in patients with acromegaly . Mean P17936 levels were 3 . 5 mg / l ( range 2 . 1 - 4 . 8 ) in controls and 5 . 4 mg / l ( range 4 . 2 - 6 . 6 ) in patients with acromegaly . Mean P05019 / P17936 ratios were 6 . 5 nmol / mg ( range 1 . 9 - 14 . 5 ) in the healthy adults and 22 . 0 nmol / mg ( range 14 . 3 - 32 . 7 ) in patients with acromegaly . There was a considerable overlap for P17936 levels but not for P05019 levels , between normals and acromegalics . The P05019 / P17936 ratio also showed overlap between normals and acromegalics . There was a significant correlation between the mean 24 - hour GH and P17936 levels ( P = 0 . 036 ) and between the P05019 and P17936 levels ( P < 0 . 002 ) in acromegaly . In patients with acromegaly , the P17936 levels showed a decrement , but the P05019 / P17936 ratio did not change significantly with age . CONCLUSIONS : P18065 has no additional discriminatory value over DB01277 measurements for the assessment of clinical activity in acromegaly . In acromegaly , P17936 decreases with increasing age . In acromegaly , P17936 levels significantly correlate with mean 24 - hour GH levels and P05019 levels .\",\n \"Analysis of mRNA transcripts for insulin - like growth factor receptors and binding proteins in bovine embryos derived from somatic cell nuclear transfer . The low efficiency of animal production using somatic cell nuclear transfer procedures is considered to be the result of an incomplete reprogramming of donor cell nucleus , which leads to abnormal expression of developmentally important genes . The objective of this study was to determine the abundance of gene transcripts of insulin - like growth factor ( IGF ) - related genes in cloned bovine embryos reconstructed with somatic cells . Single embryos derived from nuclear transfer reconstructed with somatic cells ( NT - SC ) or embryo blastomeres ( NTEM ) , in vitro fertilization ( IVF ) , in vivo production ( Vivo ) , and parthenogenetic treatment ( PA ) were analyzed . The relative abundance of mRNA was examined by real - time PCR . Transcripts of the DB01277 receptor ( r ) and IGF binding protein ( BP ) - 2 were detected in all embryos , regardless of origin . IGF - IIr and P17936 transcripts signals in NT - SC embryos were detected with significantly lower frequencies of 25 and 50 % , respectively . Although IGF - Ir and IGFIIr transcript levels were not significantly different in NT - SC , NT - EM , IVF , Vivo , and PA embryos , the relative abundance in individual embryos indicated large variation in NT - SC . P18065 and P17936 levels were high in the Vivo embryos compared with NT - SC , NT - EM , IVF , or PA embryos . These results suggest differences in levels of transcripts of IGF - related genes in the bovine embryos produced by NT compared with IVF , Vivo , and PA .\",\n \"Diagnostic utility of serum GH , DB01277 and P17936 in patients of acromegaly with uncontrolled diabetes : a pilot study . PURPOSE : Diagnosis of acromegaly in presence of uncontrolled diabetes mellitus is not well validated . METHOD : The study included 10 patients of active acromegaly with uncontrolled blood glucose , 10 patients of type 2 diabetes mellitus with poor glycemic control and 10 healthy subjects . The growth hormone level following oral glucose tolerance test and insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor - binding protein - 3 ( P17936 ) were done at baseline in all the 3 groups and it was repeated after short term glycemic control in type 2 diabetics and acromegalics with diabetics RESULTS : In the acromegalic group the basal GH value was very high ( 36 . 5 + 1 . 6 ) ng / ml and it was non - suppressible ( 32 . 5 + 1 . 43 ) ng / ml after OGTT . The mean DB01277 and P17936 values were also high at baseline ( 208 . 38 + 38 . 51 ) ng / ml , and 7322 + 370 ng / ml respectively . In the non - acromegalic diabetic patients , the basal growth hormone value was marginally elevated ( 2 . 3 + 0 . 02 ) ng / ml . However , it was suppressible to 0 . 2 + 0 . 04 ng / ml after oral glucose load . In them the DB01277 and P17936 values were not elevated and comparable to that of healthy controls . CONCLUSIONS : Basal serum GH and P17936 levels are not influenced by degree of glycemic control however serum DB01277 levels should be interpreted with caution in patients of acromegaly with diabetes . Oral glucose load test has discriminating ability to diagnose acromegaly even with poorly controlled diabetes .\",\n \"[ Chronic renal failure and growth hormone : effects on GH - IGF axis and leptin ] . AIM : To analyze the changes in DB01277 , P17936 , leptin and insulin after replacement doses of recombinant human growth hormone ( rhGH ) in short prepubertal children with chronic renal failure ( CRF ) . PATIENTS AND METHODS : Eleven children ( 3F : 8M ) , with mean age of 9 . 6 years , were treated with rhGH ( 0 . 23 mg / Kg weekly for 12 months ) . Serum leptin , insulin , glucose , DB01277 and P17936 were measured before , 6 and 12 months after beginning rhGH treatment . RESULTS : The serum levels of leptin , insulin and glucose did not vary during the treatment ; normal leptin and glucose levels and high insulin were observed . There was a significant increment of DB01277 and P17936 during the use of rhGH . CONCLUSIONS : The replacement doses of rhGH during 12 months in a selected group of CRF children determined an increment in DB01277 and P17936 , associated to normal serum leptin and insulin resistance .\",\n \"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK82___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .\",\n \"P05019 enhances cortisol secretion from guinea - pig adrenal gland : in vivo and in vitro study . P01308 - like growth factor ( IGF ) - I is a ubiquitously synthesized peptide that , along with P01344 , acts via the IGF - R type I receptor . P05019 and its receptor are expressed in the adrenal gland of humans and bovines , the secretion of which they seem to stimulate . As in humans and cows , the main glucocorticoid hormone secreted by guinea - pig adrenals is cortisol , and hence we have studied the adrenocortical effects of P05019 in this species . In vivo experiments showed that prolonged P05019 administration raised the plasma concentration of cortisol in both normal and dexamethasone / captopril - treated guinea pigs , thereby ruling out the possibility that P05019 may act by activating the hypothalamic - pituitary - adrenal axis and the renin - angiotensin system . In vitro experiments demonstrated that P05019 enhanced basal , but not maximally agonist [ DB01285 and angiotensin - II ( Ang - II ) ] - stimulated , cortisol secretion from freshly dispersed guinea - pig inner adrenocortical cells . The P05019 immuno - neutralization suppressed the P05019 secretagogue effect , without altering the cortisol response to both DB01285 and Ang - II . P05019 raised cyclic - AMP and inositol triphosphate release from dispersed guinea - pig cells , and the effect was reversed by the adenylate cyclase inhibitor SQ - 22536 and the phospholipase - C ( P98160 ) inhibitor U - 73122 . SQ - 22536 , U - 73122 , the protein kinase ( PK ) A inhibitor H - 89 and the PKC inhibitor calphostin - C decreased by approximately 50 % the cortisol response of dispersed cells to P05019 , and the combined exposure to SQ - 22536 and U - 73122 abolished it . We conclude that P05019 stimulates glucocorticoid secretion from guinea - pig adrenocortical cells , acting via selective receptors coupled to both the adenylate cyclase / PKA - and P98160 / PKC - dependent signaling cascades .\",\n \"Short - term isotretinoin treatment decreases insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 levels : does isotretinoin affect growth hormone physiology ? BACKGROUND : DB00982 is an effective treatment for acne vulgaris . However , it has numerous side - effects . It was previously reported that serum growth hormone ( GH ) levels decreased with isotretinoin treatment . OBJECTIVES : To analyse whether isotretinoin has any effects on insulin - like growth factor - 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and GH levels . METHODS : Forty - seven patients aged 21 . 5 +/- 5 . 1 years ( mean +/- SD ) with acne vulgaris were included in this study . DB00982 therapy was initiated at a dose of 0 . 5 - 0 . 75 mg kg (- 1 ) daily and then adjusted to 0 . 88 mg kg (- 1 ) daily as maintenance dosage after 1 month . Screening for biochemical and hormonal parameters was performed just before initiation and after 3 months of isotretinoin treatment . RESULTS : DB01277 and P17936 levels decreased significantly after treatment ( P < 0 . 01 ) , while GH levels did not change . Post - treatment , significant increases were seen in aspartate aminotransferase , total cholesterol , low - density lipoprotein cholesterol , triglycerides and low - density lipoprotein cholesterol / high - density lipoprotein cholesterol ratio ( P < 0 . 0001 ) while high - density lipoprotein cholesterol levels were significantly decreased ( P < 0 . 0001 ) . CONCLUSIONS : DB00982 therapy may have an effect on GH physiology , and further studies are needed to understand this association .\",\n \"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \\\" correctors \\\" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \\\" potentiators \\\" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .\",\n \"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK32___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK32___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK32___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK32___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .\",\n \"Phase 2 trial of cixutumumab in children , adolescents , and young adults with refractory solid tumors : a report from the Children ' s Oncology Group . PURPOSE : This phase 2 study was designed to assess the efficacy of single agent cixutumumab ( DB05759 ) and gain further information about associated toxicities and pharmacodynamics in children , adolescents , and young adults with recurrent or refractory solid tumors . PATIENTS AND METHODS : Patients with relapsed or refractory solid tumors were treated with 9 mg / kg of cixutumumab as a 1 - hour IV infusion once weekly . Strata included : osteosarcoma , Ewing sarcoma , rhabdomyosarcoma , neuroblastoma ( evaluable disease ) , neuroblastoma ( measurable disease ) , Wilms tumor , adrenocortical carcinoma , synovial sarcoma , hepatoblastoma , and retinoblastoma . Correlative studies in consenting patients included an assessment of c - peptide , P17936 , DB01277 , IGF - 2 , hGH , and insulin in consenting patients . RESULTS : One hundred sixteen patients with 114 eligible having a median age of 12 years ( range , 2 - 30 ) were enrolled . Five patients achieved a partial response : 4 / 20 with neuroblastoma ( evaluable only ) and 1 / 20 with rhabdomyosarcoma . Fourteen patients had stable disease for a median of 10 cycles . Hematologic and non - hematologic toxicities were generally mild and infrequent . Serum DB01277 and P17936 increased in response to therapy with cixutumumab . CONCLUSION : Cixutumumab is well tolerated in children with refractory solid tumors . Limited objective single - agent activity of cixutumumab was observed ; however , prolonged stable disease was observed in 15 % of patients . Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway .\",\n \"Association of IGF1 and P17936 polymorphisms with colorectal polyps and colorectal cancer risk . PURPOSE : DB01277 ( IGF1 ) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis . The bioavailability of IGF1 is regulated by the insulin - like growth factor binding protein 3 ( P17936 ) . The purpose of this study was to examine the association of genetic variants in IGF1 ( rs6214 , rs6220 , and rs35767 ) and P17936 ( rs2854744 and rs2854746 ) with risk of colorectal polyps and colorectal cancer . METHODS : In this ongoing colorectal cancer study of Austria ( CORSA ) , a total of 3 , 360 Caucasian participants , consisting of 178 colorectal cancer patients , 328 patients with high risk polyps , 1 , 059 patients with low risk colorectal polyps , and 1 , 795 colonoscopy - negative controls , were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna . Multiple logistic regression was applied to compare individuals of the control group against three different risk groups , namely , colorectal cancer group , high risk polyp group , and low risk polyp group . RESULTS : Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk ( OR = 1 . 79 , 95 % CI 1 . 04 - 1 . 90 ) compared to the colonoscopy - negative controls ; this was also found when combining colorectal cancer cases and high risk polyp group ( OR = 1 . 39 , 95 % CI 1 . 01 - 1 . 90 ) . CONCLUSION : Our results suggest that the SNP rs6214 of IGF1 could have an impact on developing colorectal cancer and colorectal polyps with villous elements .\",\n \"Efficacy of ganitumab ( Q99217 479 ) , alone and in combination with rapamycin , in Ewing ' s and osteogenic sarcoma models . Ewing ' s and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents . Recent data suggest that sarcomas may depend on the insulin - like growth factor type 1 ( DB01277 ) receptor ( P08069 ) and / or the insulin receptor ( P06213 ) to drive tumor growth , survival , and resistance to mammalian target of rapamycin complex 1 ( mTORC1 ) inhibitors . We evaluated the therapeutic value of ganitumab ( Q99217 479 ; C ( 6472 ) H ( 10028 ) N ( 1728 ) O ( 2020 ) S ( 42 ) ) , an anti - P08069 , fully human monoclonal antibody , alone and in combination with rapamycin ( mTORC1 inhibitor ) in Ewing ' s ( SK - ES - 1 and A673 ) and osteogenic ( SJSA - 1 ) sarcoma models . P08069 was activated by DB01277 but not by insulin in each sarcoma model . P06213 was also activated by DB01277 in the SJSA - 1 and SK - ES - 1 models , but not in the A673 model where insulin was the preferred P06213 ligand . Ganitumab significantly inhibited the growth of SJSA - 1 and SK - ES - 1 xenografts ; inhibition was associated with decreased P08069 and Akt phosphorylation , reduced total P08069 and bromodeoxyuridine detection , and increased caspase - 3 expression . Ganitumab inhibited rapamycin - induced P08069 , Akt , and glycogen synthase kinase - 3β hyperphosphorylation in each sarcoma model . However , ganitumab in combination with rapamycin also resulted in a marked increase in P06213 expression and activity in the SJSA - 1 and A673 models . The in vivo efficacy of ganitumab in the two ganitumab - sensitive models ( SJSA - 1 and SK - ES - 1 ) was significantly enhanced in combination with rapamycin . Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that P06213 signaling is an important mechanism of resistance to P08069 blockade .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK68___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Inflammatory responses of the substantia nigra after acute hypoxia in neonatal rats . The neocortex and the striatum are the brain regions most known to be particularly vulnerable to acute insults like hypoxia or ischemia . In this work , we assess the possibility of cellular damage to the substantia nigra ( SN ) after hypoxia - reoxygenation in the new born rat . The aim of the present paper was to evaluate the expression of growth factor P05019 , and growth factor binding proteins P17936 and P24593 genes and induction of NOS family members ( P29475 , P29474 and P35228 ) and P01375 genes together with glia activation , in the SN at 5 and 48 h after severe hypoxia in the 7 day - old rat , a model for the term human fetus . At early time , while IGFs remain unchanged , we found a transient increase in P29474 and P29475 . Two days after the injury , P29475 expression remained high , P35228 and P01375 increased and also P14136 protein expression was observed together with a profusion of reactive astrocytes distributed throughout the SN . This study on the acute effects of hypoxia on the developing brain provides additional insights into the vulnerability of the SN , a brain region involved in neurodegenerative pathologies .\",\n \"P42345 complex 2 in adipose tissue negatively controls whole - body growth . P42345 ( P42345 ) , a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors , is found in 2 structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . mTORC2 , which consists of rictor , Q9BPZ7 , Q9BVC4 , and P42345 , is activated by insulin / IGF1 and phosphorylates DB00133 - 473 in the hydrophobic motif of Akt / P31749 . Though the role of P42345 in single cells is relatively well characterized , the role of P42345 signaling in specific tissues and how this may contribute to overall body growth is poorly understood . To examine the role of mTORC2 in an individual tissue , we generated adipose - specific rictor knockout mice ( rictor ( ad -/-) ) . Rictor ( ad -/-) mice are increased in body size due to an increase in size of nonadipose organs , including heart , kidney , spleen , and bone . Furthermore , rictor ( ad -/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic , but glucose tolerant , and display elevated levels of insulin - like growth factor 1 ( IGF1 ) and IGF1 binding protein 3 ( P17936 ) . These effects are observed in mice on either a high - fat or a normal diet , but are generally more pronounced in mice on a high - fat diet . Our findings suggest that adipose tissue , in particular mTORC2 in adipose tissue , plays an unexpectedly central role in controlling whole - body growth .\",\n \"Ramadan fasting and the GH / DB01277 axis of trained men during submaximal exercise . AIMS : The aim of this study was to explore possible changes in body composition , blood glucose regulation , plasma growth hormone ( GH ) , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) , and insulin concentrations of trained athletes in response to the intermittent fasting and dehydration of Ramadan observance . METHODS : Nine trained male rugby players ( age 19 +/- 2 years , height 1 . 78 +/- 0 . 74 m ) were tested 3 times : before Ramadan ( C ) , at the end of the first week ( Q96GN5 ) , and during the fourth week ( R2 ) . They performed a progressive cycle ergometer test at each visit . The work rate was increased in 6 - min stages corresponding to 20 , 30 , 40 , 50 and 60 % of W max . Substrate oxidation was evaluated by indirect calorimetry . On each occasion , substrate and plasma hormone concentrations were measured at rest and at the end of the exercise . RESULTS : Ramadan fasting induced a significant decrease in body mass and body fat ( R2 vs . C , p < 0 . 001 ) . Plasma concentrations of glucose , insulin , GH , DB01277 and P17936 did not change significantly between C and R2 , either at rest or following exercise . CONCLUSION : Ramadan fasting induces positive changes in body composition without disturbing glucose regulation or activity of the GH / DB01277 system .\",\n \"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK85___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK85___ .\",\n \"Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV - 1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin - positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 - related Drosophila models has further strengthened the hypothesis that both Q13148 \\\" loss - of - function \\\" and \\\" gain - of - function \\\" mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies .\",\n \"Effect of individualized exercise training combined with diet restriction on inflammatory markers and DB01277 / P17936 in obese children . AIMS : The present study was designed to examine the possible changes in body composition , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) and inflammatory markers of obese children in response to a 2 - month program of exercise training combined with dietary restriction . METHODS : Twenty - eight obese children ( age 13 . 2 +/- 0 . 7 years , body mass index 30 . 9 +/- 1 . 3 ) were randomly assigned to a diet / training group or a control group and were tested two times : once before and once at the end of the experimental period . They performed a progressive cycle ergometer test at each visit . Substrate oxidation was evaluated by indirect calorimetry . Training was individualized at the point when fat oxidation was maximal ( Lipox ( max ) ) . RESULTS : Diet / training induced a significant decrease in body weight and body fat ( after vs . before , p < 0 . 01 ) . Plasma concentrations of DB01277 , P17936 and inflammatory markers were significantly decreased after the completion of the program . The diet / training program resulted in an increase in VO ( 2max ) ACSM ( 24 . 6 +/- 2 . 5 to 33 . 1 +/- 3 . 1 ml / min / kg , p < 0 . 001 ) at the end of the intervention period . CONCLUSION : These data suggest that in the presence of weight loss , exercise training improves inflammatory markers and DB01277 and P17936 levels in obese children .\",\n \"Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .\",\n \"Tyrosine phosphorylation of insulin receptor substrate - 1 ( P35568 ) by oxidant stress in cerebellar granule neurons : modulation by N - methyl - D - aspartate through calcineurin activity . P06213 - substrate - 1 ( P35568 ) is a docking protein for several tyrosine kinase receptors . Upon tyrosine phosphorylation , P35568 binds to signaling molecules that express Src homology 2 ( SH - 2 ) binding domains , including phosphatidylinositol 3 - kinase ( PI 3 - kinase ) , phosphotyrosine phosphatase Q06124 ( Syp ) , Nck , Crk and Grb - 2 . Hydrogen peroxide ( H ( 2 ) O ( 2 ) ) induces tyrosine phosphorylation of key signaling mediators presumably by inhibition of tyrosine phosphatases . In many cell types , the activation of extracellular signal - related kinases ( e . g . MAPK ) and other protein kinases by H ( 2 ) O ( 2 ) leads to transcriptional activation . In the current study , we examined the effect of H ( 2 ) O ( 2 ) on P35568 tyrosine phosphorylation in primary cultured rat cerebellar granule neurons . H ( 2 ) O ( 2 ) stimulated the rapid tyrosine phosphorylation of P35568 and Q8NFH3 / Q8TCB0 Q96HU1 kinase , and induced its association with PI 3 - kinase . H ( 2 ) O ( 2 )- induced P35568 phosphorylation was rapidly reversible ( 5 min ) whereas MAPK phosphorylation persisted for up to 1 h . DB01221 reversed H ( 2 ) O ( 2 )- mediated tyrosine phosphorylation of P35568 and its association with PI 3 - kinase . The dephosphorylation of P35568 by DB01221 was calcium - dependent and was inhibited by the calcineurin inhibitor cyclosporine . P62158 - dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine - phosphorylated P35568 as substrates . These data highlight the role of multiple phosphatases in the regulation of P35568 tyrosine phosphorylation and identify a novel functional property of calcineurin .\",\n \"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .\",\n \"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK45___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .\",\n \"Matrix metalloproteinase 19 regulates insulin - like growth factor - mediated proliferation , migration , and adhesion in human keratinocytes through proteolysis of insulin - like growth factor binding protein - 3 . Unlike most other matrix metalloproteinases ( MMPs ) Q99542 is expressed in undifferentiated basal keratinocytes of healthy human skin . The human keratinocyte cell line HaCaT , which like basal keratinocytes constitutively expresses Q99542 , down - regulated the expression of Q99542 at high calcium concentrations . DB01373 - regulation occurred through P12830 mediated cell - cell contacts because neutralizing anti - P12830 antibodies restored Q99542 expression in high calcium . Overexpression of Q99542 in HaCaT cells ( HaCaT - WT ) increased cellular proliferation , as well as migration and adhesion on type I collagen . This was due to proteolysis of the insulin - like growth factor ( IGF ) binding protein - 3 by Q99542 , which augmented signaling through the P08069 , as evidenced by its increased autophosphorylation . Conversely , these effects were not observed in cells transfected with P08253 or a catalytically inactive Q99542 mutant . As further proof that increased IGF - signaling promoted adhesion and migration in HaCaT - WT cells , we reproduced these effects by treating parental HaCaT with P05019 . We observed dephosphorylation of the focal adhesion kinase in HaCaT - WT as well as P05019 - treated HaCaT cells , suggesting that inactivating focal adhesion kinase is a mechanism by which P05019 enhances adhesion . Furthermore , P05019 - triggered motility on type I collagen was mediated by MMP activity , which , however , was distinct from Q99542 . Considering the coexpression of P17936 and Q99542 in the skin , we conclude that Q99542 is a likely candidate to be the major P17936 degrading MMP in the quiescent epidermis . This activity might have widespread consequences for the behavior of epidermal keratinocytes .\",\n \"Growth hormone reserve in adult beta thalassemia patients . Reduced serum insulin - like growth factor - 1 ( DB01277 ) and hypogonadotrophic hypogonadism are common features of adult beta - thalassemia , and warrant evaluation of the growth hormone ( GH ) - DB01277 axis . The aim of this study was to determine GH reserve in beta - thalassemia patients ( 9 females , 7 males , 15 major , 1 intermedia ) , age 29 . 3 +/- 6 . 9 years , BMI 21 . 3 +/- 1 . 9 kg / m2 , and in 20 age , sex and BMI - matched healthy controls , using the GH - releasing hormone ( P01286 ) - arginine test . The associations between peak GH response and hormonal and biochemical indices were evaluated . Using BMI - related cut - off limits for peak GH response in the P01286 - arginine test , 4 / 16 beta - thalassemia patients had peak GH lower than 11 . 5 microg / l , the cut - off limit suggested for lean subjects , and were diagnosed as GH deficient ( GHD ) . Using 9 microg / l as the cut - off limit 2 / 16 patients were GHD . Reduced serum DB01277 and P17936 were present in 69 % and 19 % of the patients , respectively . Peak GH did not correlate with serum DB01277 , DB00024 , and fT4 levels or gonadal status . Neither peak GH nor DB01277 correlated with serum ferritin . Our findings suggest that GHD is present in up to a quarter of adult beta - thalassemia patients . The clinical benefits of GH therapy need to be determined . GHD alone does not account for the high prevalence of reduced DB01277 in adult beta - thalassemia .\",\n \"Effects of alternate - day or daily prednisone treatment on GH and cortisol levels in growth - retarded children after renal transplantation . Growth retardation after renal transplantation ( RTx ) is generally attributed to prednisone ( PDN ) administration , although the exact mechanism is poorly understood . In a group of 19 growth - retarded patients after RTx , we studied the effect of alternate - day ( group AD , n = 12 ) and daily ( group D , n = 7 ) PDN treatment on the spontaneous plasma growth hormone ( GH ) and cortisol profiles , for 48 h in group AD and for 24 h in group D . The maximal plasma GH response to arginine provocation ( ATT ) and plasma levels of insulin - like growth factor - 1 ( DB01277 ) , IGF - 2 and serum IGF - binding proteins ( IGFBP ) were also determined . For both groups the PDN doses were recalculated as daily doses for comparison . The median PDN dose in both groups was similar , 0 . 15 mg / kg / day , with a range of 0 . 10 - 0 . 25 mg / kg / day . Glomerular filtration rate ( Q92565 ) was above 20 ml / min / 1 . 73 m2 in all patients . We hypothesized that alternate - day PDN therapy and even more so daily PDN therapy would have a deleterious effect on GH and cortisol secretion and would result in lower GH - dependent growth factors as compared to control data of healthy children . Our findings revealed that growth - retarded renal allograft patients , receiving either alternate - day or daily PDN therapy , have significantly lower mean plasma GH levels than controls , but normal diurnal rhythm of GH and cortisol secretion as well as normal immunoreactive DB01277 and - 2 levels . Mean serum P08833 levels were normal , but mean serum P17936 levels were significantly increased , while a significant negative correlation was found between the Q92565 and serum P17936 levels . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Evaluation of the synergistic effect of insulin resistance and insulin - like growth factors on the risk of breast carcinoma . BACKGROUND : The purpose of the current study was to investigate the association between insulin resistance ( which was measured using fasting blood C - peptide ) and its joint association with insulin - like growth factors ( DB01277 , IGF - 2 , and IGF binding protein - 3 [ P17936 ] ) on the risk of breast carcinoma . METHODS : Included in the current study were 400 case - control pairs from the Shanghai Breast Cancer Study . Pretreatment biospecimens and interview data were collected from all breast carcinoma cases and their individually matched controls . RESULTS : Breast carcinoma risk was found to be statistically significantly increased when higher blood levels of C - peptide and IGFs were noted in a dose - response manner . There was a statistically significant twofold to threefold increased risk of breast carcinoma for women in the highest quartile of C - peptide , DB01277 , or P17936 compared with women in the lowest quartiles . Women with high levels of both C - peptide and DB01277 or P17936 also were found to have a substantially higher risk of breast carcinoma than those women with a high level of only one of these molecules . The adjusted odds ratios ( ORs ) were 3 . 79 ( 95 % confidence interval [ 95 % CI ] , 2 . 03 - 7 . 08 ) for those with a higher level of both C - peptide and DB01277 and 4 . 03 ( 95 % CI , 2 . 06 - 7 . 86 ) for those with a higher level of both C - peptide and P17936 . CONCLUSIONS : The results of the current study suggest that insulin resistance and IGFs may synergistically increase the risk of breast carcinoma .\",\n \"Syngeneic living - donor liver transplantation for hemangioendothelioma : a clinical model for studying liver regeneration . A 22 - year - old Caucasian patient underwent living - donor liver transplantation ( LDLT ) for hepatic hemangioendothelioma in a healthy liver . The organ donor was his monozygotic twin brother . Surgery was uneventful in both donor and recipient , who received the same postoperative treatment ( i . e . no immunosuppression for the recipient ) . Although both donor and recipient achieved a full liver function recovery , the volume of the recipient ' s graft increased much more than the donor ' s residual liver in the first postoperative month ( 1 . 6 - fold vs . 1 . 2 - fold ) . This different growth rate correlated with growth hormone ( GH ) / insulin growth factor ( IGF ) axis dynamics : the donor had significantly lower insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor 2 ( IGF - 2 ) and insulin - like growth factor binding protein 3 ( P17936 ) values than the recipient on postoperative days ( POD ) 3 - 30 , although they had similar GH values . Other potential regenerative factors , e . g . tumor necrosis alpha , interleukin 6 ( P05231 ) , insulin and C peptide did not correlate with liver regeneration rate . The particular endocrine picture of the graft may be explained by a modified GH - hepatocyte interaction due to cold ischemia during preservation resulting in a higher IGF production . Whether this is a potential molecular tool by means of which transplanted partial livers promote their regeneration remains to be seen in a larger number of patients .\",\n \"Q12778 content is reduced in cystic fibrosis and increases with P05019 treatment . Cystic fibrosis - related diabetes is to date the most frequent complication in cystic fibrosis ( CF ) . The mechanisms underlying this condition are not well understood , and a possible role of insulin resistance is debated . We investigated insulin signal transduction in CF . Total insulin receptor , P35568 , p85 PI3K , and AKT contents were substantially normal in CF cells ( CFBE41o - ) , whereas winged helix forkhead ( FOX ) O1 contents were reduced both in baseline conditions and after insulin stimulation . In addition , CF cells showed increased P27361 / 2 , and reduced β2 arrestin contents . No significant change in O14508 was observed . By using a P13569 inhibitor and siRNA , changes in Q12778 were related to P13569 loss of function . In a CF - affected mouse model , Q12778 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild - type . DB01277 ( P05019 ) increased Q12778 content in vitro and in vivo in muscle and adipose tissue . In conclusion ; we present the first description of reduced Q12778 content in CF , which is compatible with reduced gluconeogenesis and increased adipogenesis , both features of insulin insensitivity . P05019 treatment was effective in increasing Q12778 , thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis - related diabetes .\",\n \"Phase II open label , multi - center clinical trial of modulation of intermediate endpoint biomarkers by 1α - hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin . BACKGROUND : Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention . Major risk factors for this disease have been associated with low serum levels of vitamin D . Here , we evaluate the biologic activity of a less calcemic vitamin D analog 1α - hydroxyvitamin D2 [ 1α - OH - D2 ] ( Bone Care International , Inc . ) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia ( HG P63167 ) . METHODS : Patients with clinically organ - confined prostate cancer and HG P63167 were randomized to 1α - OH - D2 versus placebo for 28 days prior to radical prostatectomy . Intermediate endpoint biomarkers included serum vitamin D metabolites , TGFß 1 / 2 , free / total PSA , DB01277 , P17936 , P09038 , and P15692 . Tissue endpoints included histology , MIB - 1 and TUNEL staining , microvessel density and factor VIII staining , androgen receptor and PSA , vitamin D receptor expression and nuclear morphometry . RESULTS : The 1α - OH - D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days . While serum vitamin D metabolite levels only slightly increased , evidence of biologic activity was observed with significant reductions in serum PTH levels . TGF - ß2 was the only biomarker significantly altered by vitamin D supplementation . Whether reduced TGF - ß2 levels in our study is an early indicator of response to vitamin D remains unclear . CONCLUSIONS : While further investigation of vitamin D may be warranted based on preclinical studies , results of the present trial do not appear to justify evaluation of 1α - OH - D2 in larger clinical prostate cancer prevention studies .\",\n \"Effects of insulin - like growth factor ( IGF ) binding protein - 3 ( P17936 ) on endometrial cancer ( HHUA ) cell apoptosis and P01133 stimulated cell proliferation in vitro . OBJECTIVE : P17936 has been demonstrated to stimulate or inhibit cell proliferation independently of its ability to bind IGF and a specific P17936 receptor has been proposed . P01133 has been implicated in the cancer development and carcinogenesis . Only limited data are available on the crosstalk between P17936 signaling and P01133 induced cell survival and signal transduction . The current studies were undertaken to characterize P17936 binding to endometrial cancer cells ( HHUA ) and determine its biological effects , as well as whether P17936 exposure alters the cell proliferation stimulated by P01133 . METHODS : Cell proliferation and apoptosis were analyzed by ELISA using specific antibodies . The interaction between HHUA cell and P17936 was analyzed using a biosensor . The phosphorylation abundance of specific proteins and their phosphorylation in response to P01133 and P17936 was analyzed by immunoprecipitation followed by immunoblotting . RESULTS : Biosensor analysis showed that P17936 could bind to HHUA cell surface . P17936 inhibited BrdU uptake , potentiated ssDNA production and induced p53 in HHUA cells . Although P01133 stimulated HHUA cell proliferation and Akt phosphorylation , P17936 inhibited cell proliferation and Akt phosphorylation that had been stimulated by P01133 . However , P01133 receptor phosphorylation and expression were not reduced by P17936 . Since HHUA cells lack IGF receptors and do not show biological response to IGF these results suggest that P17936 can bind to HHUA cells , inhibit cell proliferation and induce apoptosis independently of its ability to bind to IGFs possibly by binding to an P17936 receptor . CONCLUSIONS : Taken together these findings demonstrate that P17936 binds to HHUA cell surface , and inhibits cell division induced by P01133 , possibly by modulating the P01133 - mediated signal transduction system .\",\n \"Effects of the route of oestrogen administration on DB01277 and P17936 in healthy postmenopausal women : results from a randomized placebo - controlled study . OBJECTIVE : Oestrogens can modulate the action or secretion of GH . Previous studies in postmenopausal women have shown a differential effect between transdermal 17beta - oestradiol and oral ethynyl - oestradiol on GH and DB01277 concentrations . This secondary analysis , based on a large randomized trial , aimed to estimate the effect of the route of administration of 17beta - oestradiol in combined hormone replacement therapy with progesterone on DB01277 and P17936 levels . DESIGN : DB01277 and P17936 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17beta - oestradiol orally combined with a daily intake of 100 mg progesterone ( group 1 ; n = 63 ) , or 50 microg of 17beta - oestradiol transdermally combined with a daily intake of 100 mg progesterone ( group 2 ; n = 68 ) , or triple dummy placebo ( group 3 ; n = 65 ) over a 6 - month period . IGF1 and P17936 levels were available for 133 women . RESULTS : Oral oestrogen significantly decreased DB01277 levels compared to placebo ( P = 0 . 04 ) and transdermal oestrogen ( P = 0 . 004 ) , whereas transdermal oestrogen had no effect on DB01277 levels compared to placebo ( P = 0 . 56 ) . As regards P17936 , no significant difference was detected between the three groups . CONCLUSIONS : Our data indicate that the route of oestrogen administration can influence DB01277 levels . DB01277 concentrations decreased significantly with oral oestrogen , whereas no significant change was observed with transdermal oestrogen at 6 months . The clinical relevance of these differential effects remains to be determined , particularly with regard to the risk for cardiovascular diseases .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"P15692 and serum withdrawal induced changes in the transcript profile in human endometrial endothelial cells . The changes in transcript profile induced by vascular endothelial growth factor ( P15692 ) and serum withdrawal in primary human endometrial endothelial cells ( ECs ) were investigated using microarrays , gene ontology and pathway analysis . P15692 altered the levels of transcripts involved in angiogenesis , cell survival , and apoptosis , including up - and downregulation of P31749 , Q92934 , MIF , and P17936 and O15123 , respectively . Serum deprivation induced downregulation of cell - cycle - related transcripts such as mitosis regulators Q12834 and SPC25 . Of the transcripts regulated by both P15692 and partial serum deprivation , remarkably 88 of 89 showed reciprocal regulation ( p < 1 x 10 (- 49 ) ) . These are predominantly cell - fate - associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts . Our results show that in addition to the known role of P15692 as an EC growth and survival promoter , it also regulates apoptosis - related messenger RNAs ( mRNAs ) , many of which were reciprocally regulated following serum withdrawal .\",\n \"[ Pattern of abnormal skeletal development in girls with idiopathic precocious puberty and therapeutic effect of Chinese herbs for nourishing yin and purging fire ] . OBJECTIVE : To explore the pattern of abnormal skeletal development in girls with idiopathic precocious puberty ( IPP ) and the therapeutic effect of Chinese herbs for nourishing yin and purging fire ( CH ) . METHODS : Measurement of bone age , bone mineral content ( BMC ) and bone density ( BD ) were performed and levels of serum gla - protein ( BGP ) , insulin - like growth factor 1 ( DB01277 ) and insulin - like growth factor binding protein 3 ( P17936 ) were determined in girls with IPP at various stages of pubertal development . Data were compared with those collected from matched girls , and the correlativity between various parameters and the extent of the disease were analyzed to explore the pattern . Thirty - eight girls out of them were treated with CH and the therapeutic effect was observed . RESULTS : The bone age of the IPP girls was ahead of time obviously ( P < 0 . 05 ) , levels of BMC , BD and serum BGP , DB01277 were significantly higher than the levels in the healthy girls of matched age ( P < 0 . 05 ) . And the degree of these changes were markedly positive correlated with the severity of disease ( P < 0 . 05 ) . After being remitted with CH treatment , the advanced bone age was apparently alleviated , and above - mentioned abnormal criteria were lowered significantly ( P < 0 . 05 ) . CONCLUSION : The skeletal development of the girls with IPP was accelerated and the skeletal maturity were ahead of time , the more serious the condition of disease , the more obvious the acceleration and the advanced bone age . CH could decelerate skeletal development and delay the skeletal maturity of IPP patients .\",\n \"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \\\" inducible \\\" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \\\" constitutive \\\" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .\",\n \"Relationship of plasma adiponectin with sex hormone and insulin - like growth factor levels . OBJECTIVE : Recent studies have suggested that a relationship between adiponectin and sex hormone , prolactin , and insulin - like growth factor levels could be important for breast cancer risk and insulin sensitivity . Therefore , we assessed the relationship of adiponectin with plasma concentrations of estrone ; estradiol ; estrone sulfate ; testosterone ; androstenedione ; dehydroepiandrosterone ( DB01708 ) ; DB05804 ( DHEAS ) ; sex hormone binding globulin ( P04278 ) ; prolactin ; insulin - like growth factor ( DB01277 ) ; its binding protein , IGF binding protein 3 ( P17936 ) ; c - peptide ; and IGF binding protein 1 ( P08833 ) among 360 postmenopausal women not taking postmenopausal hormones from the Nurses ' Health Study . RESEARCH METHODS AND PROCEDURES : Multivariate models were adjusted for physical activity , alcohol consumption , age at blood draw , age at first birth / parity , fasting status , and time of day of blood draw ; a separate model was additionally adjusted for BMI at blood draw . RESULTS : DB00286 were inversely associated with adiponectin levels ; however , except for free estradiol , these associations were substantially attenuated after adjustment for BMI . Free estradiol levels were 27 % lower among women in the top vs . bottom quartile of adiponectin levels . No consistent associations were observed for the androgens , prolactin , DB01277 , and P17936 . However , P04278 , c - peptide , and P08833 were strongly and independently associated with adiponectin levels ( r = 0 . 29 , - 0 . 30 , 0 . 24 , respectively ) . CONCLUSION : With the exceptions of P04278 , c - peptide , and P08833 , the studied analytes were modestly associated with adiponectin and the associations were , in large part , mediated by body fat .\",\n \"Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .\",\n \"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK16___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .\",\n \"The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve .\",\n \"DB01277 , its binding protein 3 , and sex hormones in girls during puberty . The aim of the study was to estimate relationships between serum concentration of insulin - like growth factor 1 ( DB01277 ) , its binding protein ( P17936 ) , estradiol and testosterone in girls during puberty , taking into consideration gonadotropins level and nutritional status . Eighty - six girls aged 9 . 8 - 14 . 7 were examined . The girls were divided into three groups according to the pubertal stage . Body height , weight and thicknesses of skin folds were measured . Biochemical parameters were assessed using RIA method . It has been found that all investigated parameters are growing with pubertal development . There are significant positive correlations between DB01277 and testosterone , DB01277 and estradiol serum concentrations as well as between DB01277 serum concentration , BMI and sum of skin folds thicknesses . It has been also proved that there are positive correlations between P17936 and estradiol serum concentration as well as between P17936 and age , body height and body weight in girls during puberty .\",\n \"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .\",\n \"Monitoring the activation state of the insulin - like growth factor - 1 receptor and its interaction with protein tyrosine phosphatase 1B using bioluminescence resonance energy transfer . We have developed two bioluminescence resonance energy transfer ( BRET ) - based approaches to monitor 1 ) ligand - induced conformational changes within partially purified insulin - like growth factor - 1 ( DB01277 ) receptors ( P08069 ) and 2 ) P08069 interaction with a substrate - trapping mutant of protein tyrosine phosphatase 1B ( P18031 - D181A ) in living cells . In the first assay , human P08069 fused to Renilla reniformis luciferase ( Rluc ) or yellow fluorescent protein ( YFP ) were cotransfected in human embryonic kidney ( P29320 ) - 293 cells . The chimeric receptors were then partially purified by wheat germ lectin chromatography , and BRET measurements were performed in vitro . In the second assay , BRET measurements were performed on living P29320 - 293 cells cotransfected with P08069 - Rluc and YFP - P18031 - D181A . Ligand - induced conformational changes within the P08069 and interaction of the P08069 with P18031 could be detected as an energy transfer between Rluc and YFP . Dose - response experiments with DB01277 , IGF - 2 , and insulin demonstrated that the effects of these ligands on BRET correlate well with their known pharmacological properties toward the P08069 . Inhibition of P08069 autophosphorylation by the tyrphostin AG1024 ( 3 - bromo - 5 - t - butyl - 4 - hydroxy - benzylidenemalonitrile ) resulted in the inhibition of IGF1 - induced BRET signal between the P08069 and P18031 . In addition , an anti - P08069 antibody known to inhibit the biological effects of DB01277 inhibited ligand - induced BRET signal within the P08069 , as well as between P08069 and P18031 . This inhibition of BRET signal paralleled the inhibition of the ligand - induced autophosphorylation of the P08069 by this antibody . In conclusion , these BRET - based assays permit 1 ) the rapid evaluation of the effects of agonists or inhibitory molecules on P08069 activation and 2 ) the analysis of the regulation of P08069 - P18031 interaction in living cells .\",\n \"P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .\",\n \"[ Research advances on Q9UKQ2 expression and Q9UKQ2 - mediated tumor metastasis ] . A disintegrin - metalloproteinase 28 ( Q9UKQ2 ) is one of important members of ADAM family , that is involved in various biological events including cell adhesion , proteolysis , growth and metastasis of solid tumors and hematological malignancies . Studies have shown that Q9UKQ2 is highly expressed in several human tumors , such as lung , breast and bladder cancers , and chronic lymphocytic leukemia , and its tissue expression levels correlate with cancer metastasis . Q9UKQ2 - mediated cancer cell metastasis may be related with the cleavage of von Willebrand ' s factor ( P04275 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and connective tissue growth factor ( P29279 ) , as well as the promoting Q14242 / P16109 - mediated cell adhesion . This review summarizes the basic and translational aspects of Q9UKQ2 biology that might stimulate the interest in Q9UKQ2 research and discovery of novel Q9UKQ2 targets , providing potential novel therapies for metastatic cancers .\",\n \"Efficacy and safety of mecasermin rinfabate . There has been interest in using recombinant human ( rh ) insulin - like growth factor ( IGF ) - I ( rhIGF - I ) to treat short stature , either alone or in combination with its binding protein ( insulin - like growth factor binding protein [ IGFBP ] - 3 ) . P05019 has been shown to increase growth velocity in children with IGF deficiency , either as a result of growth hormone insensitivity syndrome ( GHIS ) or IGF gene deletion . However , there have been adverse events , particularly hypoglycaemia , reported with administration of unbound rhIGF - I . In addition , the serum half - life of unbound rhIGF - I is shorter when administered to patients with GHIS , who have low serum concentrations of its binding proteins P17936 and acid - labile subunit ( P35858 ) , than when administered to normal volunteers or to the patient with an P05019 gene deletion ( who had normal levels of P17936 ) . iPlex ( mecasermin rinfabate ) , an equimolar mixture of P05019 and its binding protein P17936 , was developed to prolong the half - life and to counteract acute adverse events ( particularly hypoglycaemia ) associated with administration of P05019 . Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders , it does appear that mecasermin rinfabate has a longer half - life in patients with GHIS than unbound P05019 , and fewer reports of adverse events ( including hypoglycaemia ) when administered to patients with diabetes .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"Endocrine manifestations of chromosome 22q11 . 2 microdeletion syndrome . BACKGROUND : Endocrine abnormalities , including hypocalcemia , thyroid dysfunction , and short stature , are associated with chromosome 22q11 . 2 microdeletion syndrome . This study was undertaken to examine the frequencies and clinical features of endocrine abnormalities in patients with 22q11 . 2 microdeletion syndrome . METHODS : We analyzed 61 patients with 22q11 . 2 microdeletion syndrome diagnosed based on the verification of microdeletion by fluorescent in situ hybridization ( Q5TCZ1 ) using a probe of the DiGeorge syndrome critical region ( P54198 ) at 22q11 . 2 and a control probe , ARSA at 22q13 . Serum total calcium , phosphorus , and intact parathyroid hormone ( PTH ) levels were measured , thyroid function test was performed , and serum DB01277 and P17936 levels were also estimated . Height and weight of patients were compared with individual chronological ages . RESULTS : Hypocalcemia was found in 20 patients ( 32 . 8 % ) , and overt hypoparathyroidism in 8 ( 13 . 1 % ) . Two patients ( 3 . 3 % ) showed autoimmune thyroid diseases , 1 each with Graves ' disease and Hashimoto thyroiditis . Ten patients ( 16 . 4 % ) were below the third percentile in height , but the serum DB01277 level was normal in 9 out of these 10 patients . CONCLUSION : Our findings show that patients with chromosome 22q11 . 2 microdeletion syndrome present with variable endocrine manifestations and variable clinical phenotypes . In addition to Q5TCZ1 analysis , careful endocrine evaluations are required in patients with this microdeletion syndrome , particularly for those with hypoparathyroidism or thyroid dysfunction .\",\n \"Anabolic effects of insulin - like growth factor in combination with insulin - like growth factor binding protein - 3 in severely burned adults . BACKGROUND : The purpose of this study was to determine the anabolic effects of recombinant human insulin - like growth factor - I ( rhIGF - 1 ) complexed with its principal binding protein DB01277 binding protein - 3 ( P17936 ) in severely burned adults . METHODS : Ten burned adults were studied consecutively after receiving saline ( pretreatment ) , then rhIGF - 1 / P17936 ( treatment ) for 5 days . Doses were 1 , 2 , and 4 mg / kg per day . DB09341 , electrolytes , hormones , and leg muscle protein metabolism were determined . Nine other studies were performed on similarly injured adults at comparable times to the treatment studies to control for time effects . RESULTS : Serum DB01277 and P17936 levels increased with all doses , but no incremental increases were found . Leg protein balance improved with rhIGF - 1 / P17936 , which was associated with an increase in muscle protein fractional synthetic rate . These effects were independent of time . All patients were euglycemic without electrolyte imbalances . CONCLUSION : Net protein synthesis in the isolated leg of severely burned adults improved with rhIGF - 1 / P17936 without development of glucose abnormalities .\",\n \"DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .\",\n \"Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5 - HT ligands . The brominated cyclodipeptides barettin ( cyclo [( 6 - bromo - 8 - entryptophan ) arginine ] ) and 8 , 9 - dihydrobarettin ( cyclo [( 6 - bromotryptophan ) arginine ] ) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose - dependent manner in concentrations ranging from 0 . 5 to 25 microM . To further establish the molecular target and mode of action of these compounds , we investigated their affinity to human serotonin receptors . The tryptophan residue in the barettins resembles that of endogenous serotonin [ 5 - hydroxytryptamine ] . A selection of human serotonin receptors , including representatives from all subfamilies ( 1 - 7 ) , were transfected into P29320 - 293 cells . Barettin selectively interacted with the serotonin receptors 5 - Q13049 , P28335 , and Q13639 at concentrations close to that of endogenous serotonin , with the corresponding Ki values being 1 . 93 , 0 . 34 , and 1 . 91 microM , respectively . 8 , 9 - Dihydrobarettin interacted exclusively with the P28335 receptor with a Ki value of 4 . 63 microM ; it failed to show affinity to 5 - Q13049 and Q13639 , indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins .\",\n \"Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .\",\n \"P01286 antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro . We investigated the effect of a P01286 antagonist , Q16674 - 602on the metastatic cascade in vitro of three human cancers , DBTRG - 05 glioblastoma , MDA - MB - 468 estrogen - independent breast , and ES - 2 clear cell ovarian cancer . P01286 receptors and their main splice variant , SV1 were detected on all three cell lines . After treatment with Q16674 - 602 , the cell viability decreased significantly , significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased . The attachment of cancer cells to fibronectin and matrigel was severely hindered . Wound - healing experiments demonstrated a reduced cellular motility in all three cell lines . The upregulation of caveolin - 1 and P12830 , and thepowerful downregulation of NF - kappaB and beta - catenin was detected . Our study suggests that the clinical application of highly potent P01286 antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well .\",\n \"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK59___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .\"\n]"},"candidates":{"kind":"list like","value":["___MASK16___","___MASK32___","___MASK45___","___MASK54___","___MASK59___","___MASK68___","___MASK82___","___MASK85___","___MASK97___"],"string":"[\n \"___MASK16___\",\n \"___MASK32___\",\n \"___MASK45___\",\n \"___MASK54___\",\n \"___MASK59___\",\n \"___MASK68___\",\n \"___MASK82___\",\n \"___MASK85___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK59___"},"id":{"kind":"string","value":"MH_train_383"}}},{"rowIdx":384,"cells":{"query":{"kind":"string","value":"interacts_with DB01221?"},"supports":{"kind":"list like","value":["5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .","___MASK63___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK63___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .","Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders .","Role of serotonin in the regulation of interferon - gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter - current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon - gamma ( P01579 ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time - dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 mRNA in the presence of elutriated monocytes . Monocyte - induced inhibition of P01579 production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 production in the presence of monocytes . We conclude that serotonergic P08908 receptors transduce signals that are required for NK cells to produce P01579 in response to P60568 .","Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .","WAY 100635 , a P08908 receptor antagonist , prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7 - chloro - kynurenic acid . The effect of WAY 100635 , a P08908 receptor antagonist , on the impairment of spatial learning caused by intrahippocampal administration of scopolamine , a cholinergic muscarinic receptor antagonist , or 7 - chloro - kynurenic acid , an antagonist at the glycine site associated with the DB01221 receptor complex , was studied in a two - platform spatial discrimination task . DB00747 ( 4 microg / microl ) or 7 - chloro - kynurenic acid ( 3 microg / microl ) , administered bilaterally into the P00915 region of the dorsal hippocampus 10 min before each training session , impaired choice accuracy with no effect on choice latency and errors of omission . Administered subcutaneously at 1 ( but not at 0 . 3 ) mg / kg 30 min before each training session , WAY 100635 did not modify the acquisition of spatial learning , but prevented the impairment of choice accuracy caused by intrahippocampal scopolamine or 7 - chloro - kynurenic acid . These findings suggest that blockade of P08908 receptors can compensate the loss of cholinergic or DB01221 - mediated excitatory input to pyramidal cells in the hippocampus . The mechanisms involved and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed .","Novel therapeutic strategies in major depression : focus on RNAi and ketamine . Major depression is a severe psychiatric syndrome with very high prevalence and - socioeconomic impact . Despite extensive research , its pathophysiology is poorly understood , yet several neurotransmitter systems and brain areas have been implicated . The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin ( 5 - hydroxytryptamine , 5 - HT ) and / or noradrenaline ( NA ) reuptake . These drugs evoke a series of neuronal adaptive mechanisms that limit their full clinical action , making necessary for many patients the use of augmentation strategies . In spite of such strategies , many depressed patients show limited or no improvement , which worsens their quality of life and increases the risk of suicide . Several novel observations in recent years have shaken the antidepressant field , by showing that depressed patients with severe treatment resistance can rapidly experience clinical remission . Hence , deep brain stimulation ( DBS ) of ventral anterior cingulate cortex ( Cg25 ) evokes rapid mood improvements in treatment - resistant patients . Likewise , single doses of the non - competitive N - methyl - D - aspartate ( DB01221 ) receptor antagonist ketamine evoke rapid and long - lasting ( up to 10 days ) antidepressant responses in treatment - resistant patients . On the other hand , new molecular strategies aimed at modulating the expression of certain genes show great potential in the antidepressant field . In particular , RNAi strategies have been used to evoke antidepressant - like effects in laboratory animals by knocking - down the expression of genes involved in antidepressant effects , such as the serotonin transporter ( P31645 ) or the P08908 autoreceptor . Here we review these novel strategies due to their potential impact in the identification of new targets and the further development of new antidepressant drugs .","Neuroprotective effects of serotonin 5 - HT 1A receptor activation against ischemic cell damage in gerbil hippocampus : Involvement of DB01221 receptor Q9UHB4 subunit and P23560 . It is known that the activation of 5 - hydroxytryptamine receptor type 1A ( 5HT ( 1A ) receptor ) may protect against brain damage induced by transient global ischemia . The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated . Given that serotonergic drugs may regulate N - methyl - d - aspartate ( DB01221 ) receptor function , which is implicated in events leading to ischemia - induced neuronal cell death , and also stimulate the expression of brain - derived neurotrophic factor ( P23560 ) , which is down - regulated in cerebral ischemia , we sought to determine the effects of the selective P08908 receptor agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , on the levels of DB01221 receptor Q9UHB4 subunit and P23560 in gerbil hippocampus after transient global cerebral ischemia . Pretreatment with 8 - OH - DPAT ( 1 mg / kg ) prevented the neuronal loss in P00915 subfield 72 h after ischemia and also the dramatic decrease in P23560 immunoreactivity observed in this area at an earlier time . DB01221 receptor Q9UHB4 levels in whole hippocampus were not affected 24 h after ischemia , but the levels of the subunit phosphorylated at the protein kinase A ( PKA ) site , pNR1 ( Ser897 ) , were significantly increased , and this increase was prevented by the same 8 - OH - DPAT dose , a probable consequence of the increased phosphatase 1 ( P50391 ) enzyme activity found in ischemic gerbils pretreated with the 5 - HT ( 1A ) receptor agonist . The results indicate that both Q9UHB4 subunit phosphorylation and the neurotrophin P23560 account , at least in part , for the neuroprotective effect of 8 - OH - DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of P08908 receptor activation in the search for neuroprotective strategies .","The action of 5 - HT on calcium - dependent potassium channels and on the spinal locomotor network in lamprey is mediated by P08908 - like receptors . 5 - HT has a powerful modulatory action on the firing properties of single neurons as well as on locomotor activity . In lamprey , 5 - HT increases the neuronal firing frequency in spinal neurons by reducing the conductance in Ca ( 2 +)- dependent K + channels ( KCa ) underlying the slow afterhyperpolarization ( sAHP ) , and it also lowers the burst frequency of the spinal locomotor network . To elucidate which type of 5 - HT receptor mediates these effects , different specific receptor agonists and antagonists were applied during intracellular current clamp recordings and during DB01221 - induced fictive locomotion in the lamprey spinal cord in vitro preparation . The P08908 receptor agonist 8 - OH - DPAT ( (+/-)- 8 - hydroxy - dipropylaminotetralin hydrobromide ) , the 5 - HT1 receptor agonist 5 - CT ( 5 - carboxyamidotryptamine maleate ) and the 5 - HT2 receptor agonist alpha - CH3 - 5 - HT ( alpha - methylserotonin maleate ) all reproduced the actions of 5 - HT at both the cellular and the network levels . The effects of all agonists were completely or partially blocked by the P08908 and 5 - HT2 receptor antagonist spiperone ( spiroperidol hydrochloride ) while selective 5 - HT2 receptor antagonists were ineffective . The selective P08908 receptor antagonist S (-)- UH301 ( S (-)- 5 - fluoro - 8 - hydroxy - dipropylaminotetralin hydrochloride ) also counteracted the effect of 5 - HT on the sAHP . 5 - Q9H205 and Q13639 receptor agonists and antagonists were without effects . The intracellular coupling mechanism was not sensitive to pertussis toxin nor to the DB02527 dependent protein kinase blocker ( Rp ) - cAMPS . ( ABSTRACT TRUNCATED AT 250 WORDS )","Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .","Functional identification of NR2 subunits contributing to DB01221 receptors on DB05875 receptor - expressing dorsal horn neurons . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers typically composed of two Q9UHB4 and two of four NR2 subunits : Q12879 - 2D . Mice lacking specific NR2 subunits show deficits in pain transmission yet subunit location in the spinal cord remains unclear . We have combined electrophysiological and pharmacological approaches to investigate the composition of functional DB01221 receptors expressed by lamina I , DB05875 receptor - expressing ( P25103 + ) neurons , as well as P25103 - neurons . Under low Mg2 + conditions ( 100 microM ) , the conductance of DB01221 receptors at - 90 mV ( g ( - 90 mV ) ) with Q12879 or Q13224 subunits ( Q12879 / B ) is low compared to conductance measured at the membrane potential where the inward current is maximal or maximal inward current ( MIC ) ( ratio of approximately 0 . 07 calculated from Kuner and Schoepfer , 1996 ) . For Q14957 or O15399 subunits ( Q14957 / D ) , the ratio is higher ( ratio approximately 0 . 4 ) . P25103 + and P25103 - neurons express DB01221 receptors that give ratios approximately 0 . 28 and 0 . 16 , respectively , suggesting both types of subunits are present in both populations of neurons , with P25103 + neurons expressing a higher percentage of Q14957 / D type DB01221 receptors . This was confirmed using EAB318 , an Q12879 / B preferring antagonist , and UBP141 , a mildly selective Q14957 / D antagonist to increase and decrease the g ( - 90 mV ) / g ( MIC ) ratios in both subpopulations of neurons .","Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression - 1 and nuclear - deformed epidermal autoregulatory factor by chronic stress . Chronic stress is known to affect brain areas involved in learning and emotional responses . These changes , thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress - related pathophysiologies . The serotonin - related transcription factors ( Q6P1N0 / Q6P1N0 ; five prime repressor element under dual repression / coiled - coil P06681 domain 1a , and O75398 / Deaf - 1 ; nuclear - deformed epidermal autoregulatory factor ) are two important regulators of the P08908 receptor . Using Western blotting and quantitative real - time polymerase chain reaction ( qPCR ) we examined the expression of mRNA and proteins for Q6P1N0 , O75398 , and the P08908 receptor in the prefrontal cortex ( P27918 ) of male rats exposed to chronic restraint stress ( CRS ; 6 h / day for 21 days ) . After 21 days of CRS , significant reductions in both Q6P1N0 mRNA and protein were observed in the P27918 ( 36 . 8 % and 32 % , respectively ; P < 0 . 001 ) , while the levels of both O75398 protein and mRNA did not change significantly . Consistent with reduced Q6P1N0 protein , P08908 receptor mRNA levels were equally upregulated in the P27918 , while protein levels actually declined , suggesting post - transcriptional receptor downregulation . The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Q6P1N0 and the P08908 receptor in the P27918 of the male rat while having no effect on O75398 . These results point to the importance of understanding the mechanism for the differential regulation of Q6P1N0 and O75398 in the P27918 as a basis for understanding the related effects of chronic stress on the serotonin system ( serotonin - related transcription factors ) and stress - related disorders like depression .","A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK20___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .","Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .","Neurophysiological analysis of circadian rhythm entrainment . We review recent studies in our laboratory that have investigated the neural mechanisms underlying photic entrainment of the mammalian circadian system . The results from studies of extracellular single - unit recordings and of photic induction of Fos - like immunoreactivity ( Fos - lir ) indicate that excitatory amino acid ( EAA ) transmission , and particularly activation of the N - methyl - D - aspartate ( DB01221 ) receptor subtype , is important for conveying photic information to suprachiasmatic nucleus ( SCN ) cells . We have also found that a subregion of the SCN still shows Fos - lir after blockade of EAA receptors , and we have evidence suggesting that these cells are innervated by a distinct subdivision of the retinal projection to the SCN . In addition , we have found that photic responses of cells in the intergeniculate leaflet ( which projects to the SCN ) and of SCN cells are modulated by serotonin ( 5 - HT ) via a receptor that resembles the P08908 subtype .","Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK13___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .","DB09280 - ___MASK32___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .","Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .","Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .","Serotonin suppresses N - methyl - D - aspartate responses in acutely isolated spinal dorsal horn neurons of the rat . In acutely isolated spinal dorsal horn neurons of the rat , effects of serotonin ( 5 - hydroxytryptamine , 5 - HT ) on inward current induced by excitatory amino acids were studied under whole - cell voltage - clamp condition . 5 - HT suppressed the response to N - methyl - D - aspartate ( DB01221 ) , but not the response to kainate or quisqualate . This inhibitory effect of 5 - HT on DB01221 response was present at 5 - HT concentrations as low as 10 (- 15 ) M . Although the 5 - HT effect exhibited similar pharmacology to the P08908 - type receptors , it was not mimicked by increasing intracellular concentration of adenosine 3 ', 5 '- cyclic monophosphate that is the common second messenger for P08908 receptors in the mammalian central nervous system . Glycine strongly antagonized this inhibitory effect of 5 - HT , and 5 - HT reduced opening of DB01221 - gated single channels recorded from the outside - out membrane patch . These lines of evidence are consistent with a possibility that 5 - HT might directly modulate the DB01221 receptor - ion channel complex , either by interacting with the regulatory site ( s ) or by acting on a distinct site .","The role of spinal neurokinin - 1 and glutamate receptors in hyperalgesia and allodynia induced by prostaglandin E ( 2 ) or zymosan in the rat . Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia . This study sought to establish whether neurokinin - 1 ( NK - 1 ) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E2 ( DB00917 ) in rats , and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan , an inflammatory agent which is known to evoke spinal DB00917 release . Spinal application of antagonists of the P25103 , the - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid ( AMPA ) / kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of DB00917 or intraplantar administration of zymosan . The decrease in thermal paw withdrawal response latencies induced by DB00917 , but not by zymosan , was significantly attenuated by spinal administration of an N - methyl -- aspartate ( DB01221 ) receptor antagonist , an AMPA / kainate receptor antagonist , or a metabotropic glutamate receptor antagonist . Allodynia induced by DB00917 was significantly alleviated by antagonists of DB01221 or AMPA / kainate receptors . These results suggest that both DB00917 - induced and zymosan - induced mechanical hyperalgesia are mediated in part through activation of NK - 1 , AMPA / kainate and metabotropic glutamate receptors . DB00917 - induced , but not zymosan - induced , thermal hyperalgesia is mediated in part by activation of DB01221 , AMPA / kainate and metabotropic glutamate receptors . Activation of both DB01221 and AMPA / kainate receptors contribute to DB00917 - induced allodynia .","Effect of tandospirone , a serotonin - 1A receptor partial agonist , on information processing and locomotion in dizocilpine - treated rats . RATIONALE : Augmentation therapy with serotonin - 1A receptor ( P08908 ) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia . OBJECTIVE AND METHODS : The objective of the present study was to examine the effect of repeated administration of tandospirone ( 0 . 05 and 5 mg / kg ) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N - methyl - D - aspartate receptor antagonist MK - 801 , which has been used in animal models of schizophrenia . Furthermore , we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 ( 0 . 3 mg / kg ) , a P08908 receptor antagonist , and whether there is an interaction between haloperidol ( 0 . 1 mg / kg ; a dopamine - D2 receptor antagonist ) and tandospirone . RESULTS : Tandospirone at 5 mg / kg , but not 0 . 05 mg / kg , decreased locomotor activity in saline or MK - 801 - treated rats , which were not affected by co - treatment with WAY 100635 . DB00502 decreased locomotion both in saline and MK - 801 - treated animals , and this effect was not evident in the latter group receiving the higher dose of tandospirone . Tandospirone ( 5 mg / kg ) - induced disruption of sensorimotor gating in saline or MK - 801 - treated animals was reversed by WAY - 100635 , but not by haloperidol . CONCLUSIONS : These findings suggest that behavioural changes induced by tandospirone are not fully blocked by P08908 antagonists and that tandospirone ( 5 mg / kg ) potentiates the effect of MK - 801 . Overall , these findings point to an interaction between DB01221 and 5 - HT ( 1A ) receptors . Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems .","A serotonin - 1A receptor agonist and an N - methyl - D - aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model . The WAG / RIJ rats exhibit spontaneously occurring spike - wave discharges ( SWD ) accompanied by behavioural phenomena , with characteristics similar to the human absence type epilepsy . To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin - 1A ( P08908 ) receptor agonist 8 - hydroxy - 2 -( di - n - propylamino )- tetralin ( 8 - OH - DPAT ) and the N - methyl - D - aspartate ( DB01221 ) receptor antagonist (+)- 5 - methyl - 10 , 11 - dihydro - 5H - dibenzo [ a , d ] cyclohepten - 5 , 10 - imine maleate ( MK - 801 ) . Intracerebroventricular ( i . c . v . ) injection of 8 - OH - DPAT caused marked , dose dependent increase , MK - 801 a decrease in the cumulative duration and number of spike - wave discharges . Pretreatment with MK - 801 ( 10 microg / rat i . c . v . ) abolished the increase caused by 8 - OH - DPAT ( 20 microg / rat i . c . v . ) , but the decrease in SWD to MK - 801 was counterbalanced by 8 - OH - DPAT . These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy .","A possible mechanism of the nucleus accumbens and ventral pallidum P28222 receptors underlying the antidepressant action of ketamine : a PET study with macaques . DB01221 is a unique anesthetic reagent known to produce various psychotic symptoms . DB01221 has recently been reported to elicit a long - lasting antidepressant effect in patients with major depression . Although recent studies provide insight into the molecular mechanisms of the effects of ketamine , the antidepressant mechanism has not been fully elucidated . To understand the involvement of the brain serotonergic system in the actions of ketamine , we performed a positron emission tomography ( PET ) study on non - human primates . Four rhesus monkeys underwent PET studies with two serotonin ( 5 - HT ) - related PET radioligands , [( 11 ) C ] AZ10419369 and [( 11 ) C ] DASB , which are highly selective for the P28222 receptor and serotonin transporter ( P31645 ) , respectively . Voxel - based analysis using standardized brain images revealed that ketamine administration significantly increased P28222 receptor binding in the nucleus accumbens and ventral pallidum , whereas it significantly reduced P31645 binding in these brain regions . DB00574 , a 5 - HT releaser , significantly decreased P28222 receptor binding , but no additional effect was observed when it was administered with ketamine . Furthermore , pretreatment with 2 , 3 - dihydroxy - 6 - nitro - 7 - sulfamoylbenzo ( f ) quinoxaline ( NBQX ) , a potent antagonist of the glutamate α - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid ( AMPA ) receptor , blocked the action of ketamine on the P28222 receptor but not P31645 binding . This indicates the involvement of AMPA receptor activation in ketamine - induced alterations of P28222 receptor binding . Because NBQX is known to block the antidepressant effect of ketamine in rodents , alterations in the serotonergic neurotransmission , particularly upregulation of postsynaptic P28222 receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine .","Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .","Stimulation of the P08908 receptor selectively suppresses DB01221 receptor - mediated synaptic excitation in the rat visual cortex . We have previously found that stimulation of serotonin P08908 receptors inhibits the induction of long - term potentiation ( LTP ) in the rat visual cortex . In the present study , the selective P08908 receptor agonist 8 - hydroxy - 2 -( N , N - dipropylamino ) tetralin ( 8 - OH - DPAT ) significantly reduced N - methyl - d - aspartate ( DB01221 ) receptor - mediated synaptic responses recorded in Mg2 +- free medium in rat visual cortical slices . In addition , there was good correlation between the inhibitory effects of 8 - OH - DPAT on DB01221 responses and LTP . These results suggest that P08908 receptor stimulation inhibits the induction of LTP by suppressing DB01221 receptor - mediated synaptic excitation in the rat visual cortex .","Involvement of extracellular signal - regulated kinase module in HIV - mediated P01730 signals controlling activation of nuclear factor - kappa B and AP - 1 transcription factors . Although the molecular mechanisms by which the HIV - 1 triggers either T cell activation , anergy , or apoptosis remain poorly understood , it is well established that the interaction of HIV - 1 envelope glycoproteins with cell surface P01730 delivers signals to the target cell , resulting in activation of transcription factors such as NF - kappa B and AP - 1 . In this study , we report the first evidence indicating that kinases MEK - 1 ( Q96HU1 kinase / Erk kinase ) and P27361 ( extracellular signal - regulated kinase ) act as intermediates in the cascade of events that regulate NF - kappa B and AP - 1 activation upon HIV - 1 binding to cell surface P01730 . We found that CEM cells transfected with dominant negative forms of MEK - 1 or P27361 do not display NF - kappa B activation after HIV - 1 binding to P01730 . In contrast , NF - kappa B activation was observed in these cells after PMA stimulation . Although the different cell lines studied expressed similar amounts of P01730 and p56 ( lck ) , HIV - 1 replication and HIV - 1 - induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK - 1 or P27361 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK - 1 or wild - type P27361 . In light of recently published data , we propose that a positive signal initiated following oligomerization of P01730 by the virus is likely to involve a recruitment of active forms of p56 ( lck ) , P04049 , MEK - 1 , and P27361 , before AP - 1 and NF - kappa B activation .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK38___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","A pre - and postsynaptic modulatory action of 5 - HT and the 5 - Q13049 , 2C receptor agonist DOB on DB01221 - evoked responses in the rat medial prefrontal cortex . Intracellular recordings were made from pyramidal neurons in layers V and VI of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5 - Q13049 , 2C receptor agonist (-)- 1 - 2 , 5 - dimethoxy - 4 - bromophenol - 2 - aminopropane ( DOB ) and 5 - hydroxytryptamine ( 5 - HT ) on N - methyl - D - aspartate ( DB01221 ) - induced responses . Bath application of either DOB or 5 - HT [ in the presence of antagonists to P08908 , 5 - Q9H205 and gamma - aminobutytric acid ( GABA ) receptors ] produced a concentration - dependent biphasic modulation of the DB01221 responses . They facilitated and inhibited DB01221 responses at low ( + 2 degrees C ) and a small change in T ( cor ) in the moderate toxidrome ( - 1 degrees C < delta Tcor < + 2 degrees C ) . Thus , delta Tcor in response to drugs can be used to estimate the severity of the toxidrome . The second attempt was to identify the receptors mediating those changes . P08908 receptors were involved in the hypothermic response while 5 - Q13049 and DB01221 receptors mediated head shakes , hyperthermia , forepaw treading and Straub tail . Lastly , antidotal effect of cyproheptadine and (+)- MK - 801 was examined . Both drugs blocked hyperthermia and death . However , the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced . These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5 - HT toxidrome .","A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .","Phosphorylation of DB00156 ( 495 ) regulates Ca ( 2 +)/ calmodulin - dependent endothelial nitric oxide synthase activity . The activity of the endothelial nitric oxide synthase ( P29474 ) can be regulated independently of an increase in Ca ( 2 +) by the phosphorylation of DB00133 ( 1177 ) but results only in a low nitric oxide ( NO ) output . In the present study , we assessed whether the agonist - induced ( Ca ( 2 +)- dependent , high - output ) activation of P29474 is associated with changes in the phosphorylation of DB00156 ( 495 ) in the calmodulin ( P62158 ) - binding domain . P29474 DB00156 ( 495 ) was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation . In the same cells , bradykinin enhanced the phosphorylation of DB00133 ( 1177 ) , which was maximal after 5 minutes , and abolished by the P62158 - dependent kinase II ( CaMKII ) inhibitor KN - 93 . Bradykinin also enhanced the association of CaMKII with P29474 . Phosphorylation of DB00156 ( 495 ) was attenuated by the protein kinase C ( PKC ) inhibitor Ro 31 - 8220 and after PKC downregulation using phorbol 12 - myristate 13 - acetate . The agonist - induced dephosphorylation of DB00156 ( 495 ) was completely Ca ( 2 +)- dependent and inhibited by the P50391 inhibitor calyculin A . Little P62158 was bound to P29474 immunoprecipitated from unstimulated cells , but the agonist - induced dephosphorylation of DB00156 ( 495 ) enhanced the association of P62158 . Mutation of DB00156 ( 495 ) to alanine increased P62158 binding to P29474 in the absence of cell stimulation , whereas the corresponding DB00128 ( 495 ) mutant bound almost no P62158 . Accordingly , NO production by the Ala ( 495 ) mutant was more sensitive to Ca ( 2 +)/ P62158 than the aspartate mutant . These results suggest that the dual phosphorylation of DB00133 ( 1177 ) and DB00156 ( 495 ) determines the activity of P29474 in agonist - stimulated endothelial cells . Moreover , the dephosphorylation of DB00156 ( 495 ) by P50391 precedes the phosphorylation of DB00133 ( 1177 ) by CaMKII . The full text of this article is available at http :// www . circresaha . org .","Dissociation between cognitive and motor / motivational deficits in the delayed matching to position test : effects of scopolamine , 8 - OH - DPAT and EAA antagonists . The effects of the muscarinic antagonists scopolamine HBr and MeBr , the P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , and the N - methyl - d - aspartate ( DB01221 ) antagonists MK - 801 and CGS - 19755 on performance of rats in a delayed matching - to - position task were examined . Pretreatment with scopolamine HBr ( 0 . 05 and 0 . 1 mg / kg ) , resulted in a delay - dependent decrease in the percentage of correct responses and discriminability ( log d ) , but had no effect on either the latency to complete trials , or the rate of trial completion during the fixed duration session . DB00747 MeBr ( 0 . 1 mg / kg ) did not impair percent correct or increase the response latency but did decrease the rate of trial completion . 8 - OH - DPAT ( up to 0 . 3 mg / kg ) , had no effect on percent correct , but did induce a small decrease in discriminability . The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion . Both MK - 801 ( 0 . 05 mg / kg ) and CGS 19755 ( 10 mg / kg ) induced a delay - independent impairment in percent correct , discriminability and a reduction in the rate of trial completion without affecting latency . A lower dose of CGS 19755 ( 5 . 0 mg / kg ) induced a slight impairment in discriminability without significantly affecting the other measures . Taken together , these results demonstrate some dissociation between drug - induced cognitive and motor / motivational deficits in the DMTP test . However , the data question the specificity of putative cognitive impairments reported in many previous studies with the P08908 agonist 8 - OH - DPAT .","A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK65___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .","Role of nitric oxide in brain regions related to defensive reactions . DB00435 synthase ( NOS ) positive neurons are located in most brain areas related to defensive reactions , including the dorsolateral periaqueductal grey ( dlPAG ) . NOS inhibitors injected into this structure induce anxiolytic - like responses whereas NO donors promote flight reactions . Intra - dlPAG administration of carboxy - PTIO , a NO scavenger , or ODQ , a soluble guanylate cyclase inhibitor , produced anxiolytic - like effects on rats exposed to the elevated plus - maze ( EPM ) . A double - staining experiment using NADPHd histochemistry and c - Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG , paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus . Cat exposure also increased activation of NOS neurons in the medial amygdala , dorsal pre - mammillary nucleus and bed nucleus of stria terminalis . Local infusion into the dlPAG of a glutamate DB01221 - receptor antagonist ( AP7 ) or a benzodiazepine agonist ( midazolam ) completely prevented the flight reactions induced by intra - dlPAG administration of SIN - 1 , a NO donor . The responses were also inhibited by the 5 - Q13049 / C agonist DOI but not by a P08908 agonist . These results suggest a modulatory role for NO on brain areas related to defensive reactions , probably by interacting with glutamate , serotonin and / or GABA - mediated neurotransmission .","Lowering of body core temperature by exposure to a cold environment and by a P08908 agonist : effects on physiological and psychological variables and blood serotonin levels . The present study was designed to compare the effects of a pharmacologically induced decrease in body core temperature to the effects observed with lowering of body temperature by exposure to a cold environment . Our special interest was the involvement of 5 - HT in thermoregulatory responses . Sixty healthy male volunteers were randomly assigned to one of the following conditions : exposure to normal ambient temperature ( 28 degrees C ) and placebo , exposure to cold ambient temperature ( 5 degrees C ) and placebo , or normal ambient temperature and 10 mg of the partial P08908 agonist ipsapirone . As indicators of physiological responses to lowering of body temperature , tympanic temperature , skin temperature , P15941 , metabolic rate , and heart rate were monitored and saliva cortisol levels and peripheral 5 - HT concentrations were determined . In addition , ratings on ambient temperature , thermal discomfort , and feelings of irritability were obtained . While lowering of body core temperature was associated with marked counterregulations ( decrease of skin temperature , increase in P15941 and metabolic rate ) and feelings of discomfort , this was not observed with ipsapirone . An increase in cortisol levels was primarily observed in the ipsapirone group and was not reflected by respective changes in whole blood or platelet 5 - HT indicating that brain and platelet 5 - HT are not related .","Reduction of DB01221 - induced behaviour after acute and chronic administration of desipramine in mice . The mechanisms of the antinociceptive effect of desipramine ( DB01151 ) are only partly known . It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N - methyl - D - aspartic acid ( DB01221 ) receptor complex . In this study , the modulatory effect of DB01151 on the biting and scratching behaviour induced by intrathecal ( i . th . ) administration of DB01221 ( 0 . 25 nmol ) was investigated . Desipramine was administered acutely , either intrathecally ( 0 . 7 - 35 micrograms ) or intraperitoneally ( i . p . , 10 mg / kg ) , or chronically in the drinking water ( 0 . 15 g / l ) for 3 weeks . The DB01221 - induced behaviour was significantly reduced both after acute and chronic administration of DB01151 . Several studies have shown a functional upregulation of the P08908 receptor after chronic treatment with DB01151 . The activation of this receptor using the P08908 agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin hydrobromide ( 8 - OH - DPAT ) , leads to a reduction in DB01221 - induced behaviour . Using the P08908 antagonist NAN - 190 ( 10 micrograms , i . th . ) , the effect of chronic administration of DB01151 on the DB01221 - induced behaviour was reversed . However , NAN - 190 also increased DB01221 - induced behaviour in the control group , suggesting that a tonic inhibition of this behaviour , mediated by the P08908 receptor , may exist . These findings indicate that DB01151 may reduce glutaminergic transmission at the spinal DB01221 receptor . As this receptor is central in spinal nociceptive transmission , this could be one mechanism for the antinociceptive effect of DB01151 .","Gene - gene interaction analyses between DB01221 receptor subunit and dopamine receptor gene variants and clozapine response . AIMS : To investigate the possible association and gene - gene interaction effects of polymorphisms in DB01221 receptor subunit ( GRIN1 , Q12879 and Q13224 ) and dopamine receptor ( P21728 , P14416 and P35462 ) genes with clozapine response . MATERIALS & METHODS : GRIN1 rs11146020 ( G1001C ) , Q12879 GT - repeat and Q13224 rs10193895 ( G - 200T ) polymorphisms were tested for association in a Caucasian ( n = 183 ) and an African - American ( n = 49 ) sample using χ ( 2 ) and Q9UNW9 tests . Logistic regression and two - way Q9UNW9 were used to explore gene - gene interaction effects with dopamine receptor gene variants . RESULTS & CONCLUSION : This study does not support the involvement of the DB01221 receptor subunit gene polymorphisms in clozapine response . All tests for an association were negative . Gene - gene interaction analyses however yielded promising leads , including an observed effect between P21728 rs686 and P35462 Ser9Gly polymorphisms on clozapine response ( p = 0 . 002 ) .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK85___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .","Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK93___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .","Discriminative stimulus effects of ethanol in rats using a three - choice ethanol - midazolam - water discrimination . Three - choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other . This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma - aminobutyric acid type A ( GABAA ) receptor complex . As an extension to these studies , male Long - Evans rats were trained to discriminate midazolam ( 3 . 0 mg / kg , i . p . ) from ethanol ( 1 . 0 g / kg , i . g . ) from water ( 2 . 3 ml , i . g . ) in a three - lever , food reinforced task . Substitution tests were conducted following administration of GABAA - positive modulators , noncompetitive N - methyl - D - aspartate ( DB01221 ) antagonists , P28222 agonists and isopropanol . Among the GABAA - positive modulators , diazepam was the only drug that completely substituted for midazolam ; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution . The DB01221 antagonist dizocilpine substituted for ethanol , while phencyclidine showed no substitution for either ethanol or midazolam . The serotonin agonists tested also showed no substitution for either ethanol or midazolam . Isopropanol was the only other drug that completely substituted for ethanol . These data extend previous findings from an ethanol - pentobarbital - water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol - like effect .","Cyto - and receptor architecture of area 32 in human and macaque brains . Human area 32 plays crucial roles in emotion and memory consolidation . It has subgenual ( s32 ) , pregenual ( Q9H160 ) , dorsal , and midcingulate components . We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles . The macaque has areas s32 and Q9H160 . In s32 , layer IIIa / b neurons are larger than those of layer IIIc . This relationship is reversed in Q9H160 . Layer Va is thicker and Vb thinner in s32 . Area Q9H160 contains higher kainate , benzodiazepine ( BZ ) , and serotonin ( 5 - HT ) 1A but lower N - methyl - D - aspartate ( DB01221 ) and α2 receptor densities . Most differences were found in layers I , II , and VI . Together , these differences support the dual nature of macaque area 32 . Comparative analysis of human and macaque s32 and Q9H160 supports equivalences in cyto - and receptor architecture . Although there are differences in mean areal receptor densities , there are considerable similarities at the layer level . Laminar receptor distribution patterns in each area are comparable in the two species in layers III - Va for kainate , DB01221 , γ - aminobutyric acid ( GABA ) B , BZ , and P08908 receptors . Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and Q9H160 than to human Q9H160 . Thus , macaque 32 is more complex than hitherto known . Our data suggest a homologous neural architecture in anterior cingulate s32 and Q9H160 in human and macaque brains .","P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .","Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .","Role of serotonin , gamma - aminobutyric acid , and glutamate in the behavioral thermoregulation of female tilapia during the prespawning phase . The role of hypothalamic neurotransmitter systems in behavioral thermoregulation was investigated in the prespawning female tilapia , Oreochromis mossambicus . Intrahypothalamic microinjection with serotonin ( 5 - HT , 3 microliters of 1 . 0 x 10 (- 6 ) M ) resulted in a significant increase in the selected temperature . This effect was mimicked by the agonist of P08908 , 1B , and 2C receptors , N - 3 - trifluoromethylphenyl piperazine . Intrahypothalamic microinjection of tilapia with gamma - aminobutyric acid ( GABA ) resulted in a biphasic effect of the temperature selection , whereas microinjection with muscimol , an agonist of GABAA receptor , had no effect on temperature selection . Both agonist and antagonist of glutamate ( DB00142 ) , N - methyl - D - aspartate ( DB01221 ) , and MK - 801 ( 1 . 0 x 10 (- 6 ) M ) , a noncompetitive blocker of DB01221 receptor , significantly decreased the preferred temperature . These results indicate that the hypothalamic 5 - HT , GABA , and DB00142 systems play a role in the temperature selection of prespawning female tilapia .","Inflammatory cells as source of tachykinin - induced mucus secretion in chronic bronchitis . Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease ( P48444 ) . Tachykinin - induced mucus secretion has been regarded as sensory nerve - dependent so far . We studied the distribution of tachykinin - mRNA and - peptide and its relation to NK - 1 subtype - positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells . RT - PCR demonstrated the expression of tachykinin - and NK - 1 - mRNA in human airway tissues . In situ hybridisation resulted in preprotachykinin ( PPT ) - A mRNA - signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands . NK - 1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT - A mRNA and tachykinin - positive cells . The present data directly demonstrate the presence of both PPT - A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to P25103 positive glandular myoepithelium . Our findings indicate that besides neurally released tachykinins , also inflammatory cell - derived tachykinins may lead to glandular secretion via P25103 stimulation . This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as P48444 or asthma .","Characterization of a novel effect of serotonin P08908 and 5 - Q13049 receptors : increasing cGMP levels in rat frontal cortex . Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years . Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens , the signaling pathways activated by these agents are unclear . Here it is shown that administration of serotonin ( 5 - hydroxytryptamine , 5 - HT ) increased cyclic guanosine monophosphate ( cGMP ) production in frontal cortical slices of rat brain . The effect of 5 - HT was greater than that of N - methyl - D - aspartate ( DB01221 ) , a stimulant of cGMP formation in the central nervous system . The 5 - HT ( 2A / 2C ) receptor phenethylamine agonist , 2 , 5 - dimethoxy - 4 - methylamphetamine ( DOM ) , increased cGMP content in the slices . Additionally 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( DPAT ) , a 5 -( HT1A / 7 ) receptor agonist also increased cGMP production . Stimulation of cGMP formation by DOM was prevented by a 5 - HT ( 2A / 2C ) receptor antagonist , pirenperone , as well as by a 5 - Q13049 receptor selective antagonist , MDL100907 . A P28335 receptor antagonist , SB242084 , did not block the effect of DOM . Stimulation of cGMP production by DPAT was blocked by the P08908 receptor antagonist , WAY100635 . Stimulation of cGMP formation by serotonin could be prevented by pirenperone or WAY100635 . In summary , activation of serotonin P08908 and 5 - Q13049 receptors increase brain cGMP levels .","Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 function in multiple ways . In particular , class 3 mutations such as p . Gly551Asp strongly decrease the time spent by P13569 in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p . Phe508del ) , the most frequent mutation among CF patients ( 70 - 90 % ) , destabilizes the P13569 protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug - like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco ™ ( also known as ___MASK32___ or VX - 770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 ) for the treatment of CF patients carrying at least one P13569 allele with the p . Gly551Asp mutation ( 2 - 5 % of all patients ) . In contrast , the corrector VX - 809 , which significantly improves p . Phe508del - P13569 trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p . Phe508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect .","Innovative approaches for the development of antidepressant drugs : current and future strategies . Depression is a highly debilitating disorder that has been estimated to affect up to 21 % of the world population . Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors ( SSRIs ) and serotonin and norepinephrine reuptake inhibitors ( SNRIs ) , there continue to be many unmet clinical needs with respect to both efficacy and side effects . These needs range from efficacy in treatment resistant patients , to improved onset , to reductions in side effects such as emesis or sexual dysfunction . To address these needs , there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas . There is tremendous diversity in the types of targets and approaches being taken . At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms ( P08908 , P28222 , P28221 , P28335 , alpha - 2A ) . At the other end of the spectrum are more novel targets , such as neurotrophins ( P23560 , IGF ) , based on recent findings that antidepressants induce neurogenesis . In between , there are many approaches that range from directly targeting serotonin receptors ( P28335 , P50406 ) to targeting the multiplicity of potential mechanisms associated with excitatory ( glutamate , DB01221 , Q14416 , P41594 ) or inhibitory amino acid systems ( GABA ) or peptidergic systems ( neurokinin 1 , DB05394 1 , melanin - concentrating hormone 1 , V1b ) . The present review addresses the most exciting approaches and reviews the localization , neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations .","Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .","Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing ' s disease . A 75 - year - old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non - suppressibility to high - dose dexamethasone , responsiveness to P06850 , but not to ___MASK65___ , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 - PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT - PCR revealed abundant expressions of P01189 and SSTR ( - 1 , - 2 , - 5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion .","Acute heat stress induces edema and nitric oxide synthase upregulation and down - regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress .","Activation of the P27361 / 2 signaling cascade by excitotoxic spinal cord injury . The role of the P27361 / 2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury ( SCI ) was examined . Specifically , phosphorylation of P27361 / 2 , activation of transcription factors NF - kB , P54762 - 1 , and CREB , and gene expression of the neurokinin - 1 receptor and DB01221 receptor subunits Q9UHB4 and NR - 2A were investigated . Excitotoxic injury was produced by intraspinal injection of quisqualic acid ( QUIS ) in male Sprague - Dawley rats . Western blots were used to evaluate phosphorylation and activation of P27361 / 2 and transcription factors using phospho - specific or total antibodies . Real - time PCR was used to evaluate gene expression of P25103 , NR - 1 , and NR - 2A . Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior . Excitotoxic spinal injury resulted in : ( 1 ) increased phosphorylation of P27361 / 2 ; ( 2 ) increased activation of NF - kB and phosphorylation of P54762 - 1 ; and ( 3 ) increased gene expression for the P25103 and Q9UHB4 and NR - 2A subunits of the DB01221 receptor . Blockade of the P29323 cascade with the MEK inhibitor PD98059 inhibited phosphorylation of P54762 - 1 , activation of NF - kB and gene expression of Q9UHB4 , NR - 2A and P25103 , and prevented the development of excessive grooming behavior . The results have shown that excitotoxic spinal injury leads to the injury - induced activation of the P29323 --> P54762 - 1 and NF - kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain . Blockade of this intracellular kinase cascade prevented the onset of injury - induced pain behavior ."],"string":"[\n \"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .\",\n \"___MASK63___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK63___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .\",\n \"Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders .\",\n \"Role of serotonin in the regulation of interferon - gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter - current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon - gamma ( P01579 ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time - dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 mRNA in the presence of elutriated monocytes . Monocyte - induced inhibition of P01579 production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 production in the presence of monocytes . We conclude that serotonergic P08908 receptors transduce signals that are required for NK cells to produce P01579 in response to P60568 .\",\n \"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .\",\n \"WAY 100635 , a P08908 receptor antagonist , prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7 - chloro - kynurenic acid . The effect of WAY 100635 , a P08908 receptor antagonist , on the impairment of spatial learning caused by intrahippocampal administration of scopolamine , a cholinergic muscarinic receptor antagonist , or 7 - chloro - kynurenic acid , an antagonist at the glycine site associated with the DB01221 receptor complex , was studied in a two - platform spatial discrimination task . DB00747 ( 4 microg / microl ) or 7 - chloro - kynurenic acid ( 3 microg / microl ) , administered bilaterally into the P00915 region of the dorsal hippocampus 10 min before each training session , impaired choice accuracy with no effect on choice latency and errors of omission . Administered subcutaneously at 1 ( but not at 0 . 3 ) mg / kg 30 min before each training session , WAY 100635 did not modify the acquisition of spatial learning , but prevented the impairment of choice accuracy caused by intrahippocampal scopolamine or 7 - chloro - kynurenic acid . These findings suggest that blockade of P08908 receptors can compensate the loss of cholinergic or DB01221 - mediated excitatory input to pyramidal cells in the hippocampus . The mechanisms involved and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed .\",\n \"Novel therapeutic strategies in major depression : focus on RNAi and ketamine . Major depression is a severe psychiatric syndrome with very high prevalence and - socioeconomic impact . Despite extensive research , its pathophysiology is poorly understood , yet several neurotransmitter systems and brain areas have been implicated . The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin ( 5 - hydroxytryptamine , 5 - HT ) and / or noradrenaline ( NA ) reuptake . These drugs evoke a series of neuronal adaptive mechanisms that limit their full clinical action , making necessary for many patients the use of augmentation strategies . In spite of such strategies , many depressed patients show limited or no improvement , which worsens their quality of life and increases the risk of suicide . Several novel observations in recent years have shaken the antidepressant field , by showing that depressed patients with severe treatment resistance can rapidly experience clinical remission . Hence , deep brain stimulation ( DBS ) of ventral anterior cingulate cortex ( Cg25 ) evokes rapid mood improvements in treatment - resistant patients . Likewise , single doses of the non - competitive N - methyl - D - aspartate ( DB01221 ) receptor antagonist ketamine evoke rapid and long - lasting ( up to 10 days ) antidepressant responses in treatment - resistant patients . On the other hand , new molecular strategies aimed at modulating the expression of certain genes show great potential in the antidepressant field . In particular , RNAi strategies have been used to evoke antidepressant - like effects in laboratory animals by knocking - down the expression of genes involved in antidepressant effects , such as the serotonin transporter ( P31645 ) or the P08908 autoreceptor . Here we review these novel strategies due to their potential impact in the identification of new targets and the further development of new antidepressant drugs .\",\n \"Neuroprotective effects of serotonin 5 - HT 1A receptor activation against ischemic cell damage in gerbil hippocampus : Involvement of DB01221 receptor Q9UHB4 subunit and P23560 . It is known that the activation of 5 - hydroxytryptamine receptor type 1A ( 5HT ( 1A ) receptor ) may protect against brain damage induced by transient global ischemia . The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated . Given that serotonergic drugs may regulate N - methyl - d - aspartate ( DB01221 ) receptor function , which is implicated in events leading to ischemia - induced neuronal cell death , and also stimulate the expression of brain - derived neurotrophic factor ( P23560 ) , which is down - regulated in cerebral ischemia , we sought to determine the effects of the selective P08908 receptor agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , on the levels of DB01221 receptor Q9UHB4 subunit and P23560 in gerbil hippocampus after transient global cerebral ischemia . Pretreatment with 8 - OH - DPAT ( 1 mg / kg ) prevented the neuronal loss in P00915 subfield 72 h after ischemia and also the dramatic decrease in P23560 immunoreactivity observed in this area at an earlier time . DB01221 receptor Q9UHB4 levels in whole hippocampus were not affected 24 h after ischemia , but the levels of the subunit phosphorylated at the protein kinase A ( PKA ) site , pNR1 ( Ser897 ) , were significantly increased , and this increase was prevented by the same 8 - OH - DPAT dose , a probable consequence of the increased phosphatase 1 ( P50391 ) enzyme activity found in ischemic gerbils pretreated with the 5 - HT ( 1A ) receptor agonist . The results indicate that both Q9UHB4 subunit phosphorylation and the neurotrophin P23560 account , at least in part , for the neuroprotective effect of 8 - OH - DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of P08908 receptor activation in the search for neuroprotective strategies .\",\n \"The action of 5 - HT on calcium - dependent potassium channels and on the spinal locomotor network in lamprey is mediated by P08908 - like receptors . 5 - HT has a powerful modulatory action on the firing properties of single neurons as well as on locomotor activity . In lamprey , 5 - HT increases the neuronal firing frequency in spinal neurons by reducing the conductance in Ca ( 2 +)- dependent K + channels ( KCa ) underlying the slow afterhyperpolarization ( sAHP ) , and it also lowers the burst frequency of the spinal locomotor network . To elucidate which type of 5 - HT receptor mediates these effects , different specific receptor agonists and antagonists were applied during intracellular current clamp recordings and during DB01221 - induced fictive locomotion in the lamprey spinal cord in vitro preparation . The P08908 receptor agonist 8 - OH - DPAT ( (+/-)- 8 - hydroxy - dipropylaminotetralin hydrobromide ) , the 5 - HT1 receptor agonist 5 - CT ( 5 - carboxyamidotryptamine maleate ) and the 5 - HT2 receptor agonist alpha - CH3 - 5 - HT ( alpha - methylserotonin maleate ) all reproduced the actions of 5 - HT at both the cellular and the network levels . The effects of all agonists were completely or partially blocked by the P08908 and 5 - HT2 receptor antagonist spiperone ( spiroperidol hydrochloride ) while selective 5 - HT2 receptor antagonists were ineffective . The selective P08908 receptor antagonist S (-)- UH301 ( S (-)- 5 - fluoro - 8 - hydroxy - dipropylaminotetralin hydrochloride ) also counteracted the effect of 5 - HT on the sAHP . 5 - Q9H205 and Q13639 receptor agonists and antagonists were without effects . The intracellular coupling mechanism was not sensitive to pertussis toxin nor to the DB02527 dependent protein kinase blocker ( Rp ) - cAMPS . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .\",\n \"Functional identification of NR2 subunits contributing to DB01221 receptors on DB05875 receptor - expressing dorsal horn neurons . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers typically composed of two Q9UHB4 and two of four NR2 subunits : Q12879 - 2D . Mice lacking specific NR2 subunits show deficits in pain transmission yet subunit location in the spinal cord remains unclear . We have combined electrophysiological and pharmacological approaches to investigate the composition of functional DB01221 receptors expressed by lamina I , DB05875 receptor - expressing ( P25103 + ) neurons , as well as P25103 - neurons . Under low Mg2 + conditions ( 100 microM ) , the conductance of DB01221 receptors at - 90 mV ( g ( - 90 mV ) ) with Q12879 or Q13224 subunits ( Q12879 / B ) is low compared to conductance measured at the membrane potential where the inward current is maximal or maximal inward current ( MIC ) ( ratio of approximately 0 . 07 calculated from Kuner and Schoepfer , 1996 ) . For Q14957 or O15399 subunits ( Q14957 / D ) , the ratio is higher ( ratio approximately 0 . 4 ) . P25103 + and P25103 - neurons express DB01221 receptors that give ratios approximately 0 . 28 and 0 . 16 , respectively , suggesting both types of subunits are present in both populations of neurons , with P25103 + neurons expressing a higher percentage of Q14957 / D type DB01221 receptors . This was confirmed using EAB318 , an Q12879 / B preferring antagonist , and UBP141 , a mildly selective Q14957 / D antagonist to increase and decrease the g ( - 90 mV ) / g ( MIC ) ratios in both subpopulations of neurons .\",\n \"Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression - 1 and nuclear - deformed epidermal autoregulatory factor by chronic stress . Chronic stress is known to affect brain areas involved in learning and emotional responses . These changes , thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress - related pathophysiologies . The serotonin - related transcription factors ( Q6P1N0 / Q6P1N0 ; five prime repressor element under dual repression / coiled - coil P06681 domain 1a , and O75398 / Deaf - 1 ; nuclear - deformed epidermal autoregulatory factor ) are two important regulators of the P08908 receptor . Using Western blotting and quantitative real - time polymerase chain reaction ( qPCR ) we examined the expression of mRNA and proteins for Q6P1N0 , O75398 , and the P08908 receptor in the prefrontal cortex ( P27918 ) of male rats exposed to chronic restraint stress ( CRS ; 6 h / day for 21 days ) . After 21 days of CRS , significant reductions in both Q6P1N0 mRNA and protein were observed in the P27918 ( 36 . 8 % and 32 % , respectively ; P < 0 . 001 ) , while the levels of both O75398 protein and mRNA did not change significantly . Consistent with reduced Q6P1N0 protein , P08908 receptor mRNA levels were equally upregulated in the P27918 , while protein levels actually declined , suggesting post - transcriptional receptor downregulation . The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Q6P1N0 and the P08908 receptor in the P27918 of the male rat while having no effect on O75398 . These results point to the importance of understanding the mechanism for the differential regulation of Q6P1N0 and O75398 in the P27918 as a basis for understanding the related effects of chronic stress on the serotonin system ( serotonin - related transcription factors ) and stress - related disorders like depression .\",\n \"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK20___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .\",\n \"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .\",\n \"Neurophysiological analysis of circadian rhythm entrainment . We review recent studies in our laboratory that have investigated the neural mechanisms underlying photic entrainment of the mammalian circadian system . The results from studies of extracellular single - unit recordings and of photic induction of Fos - like immunoreactivity ( Fos - lir ) indicate that excitatory amino acid ( EAA ) transmission , and particularly activation of the N - methyl - D - aspartate ( DB01221 ) receptor subtype , is important for conveying photic information to suprachiasmatic nucleus ( SCN ) cells . We have also found that a subregion of the SCN still shows Fos - lir after blockade of EAA receptors , and we have evidence suggesting that these cells are innervated by a distinct subdivision of the retinal projection to the SCN . In addition , we have found that photic responses of cells in the intergeniculate leaflet ( which projects to the SCN ) and of SCN cells are modulated by serotonin ( 5 - HT ) via a receptor that resembles the P08908 subtype .\",\n \"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK13___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .\",\n \"DB09280 - ___MASK32___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .\",\n \"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .\",\n \"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .\",\n \"Serotonin suppresses N - methyl - D - aspartate responses in acutely isolated spinal dorsal horn neurons of the rat . In acutely isolated spinal dorsal horn neurons of the rat , effects of serotonin ( 5 - hydroxytryptamine , 5 - HT ) on inward current induced by excitatory amino acids were studied under whole - cell voltage - clamp condition . 5 - HT suppressed the response to N - methyl - D - aspartate ( DB01221 ) , but not the response to kainate or quisqualate . This inhibitory effect of 5 - HT on DB01221 response was present at 5 - HT concentrations as low as 10 (- 15 ) M . Although the 5 - HT effect exhibited similar pharmacology to the P08908 - type receptors , it was not mimicked by increasing intracellular concentration of adenosine 3 ', 5 '- cyclic monophosphate that is the common second messenger for P08908 receptors in the mammalian central nervous system . Glycine strongly antagonized this inhibitory effect of 5 - HT , and 5 - HT reduced opening of DB01221 - gated single channels recorded from the outside - out membrane patch . These lines of evidence are consistent with a possibility that 5 - HT might directly modulate the DB01221 receptor - ion channel complex , either by interacting with the regulatory site ( s ) or by acting on a distinct site .\",\n \"The role of spinal neurokinin - 1 and glutamate receptors in hyperalgesia and allodynia induced by prostaglandin E ( 2 ) or zymosan in the rat . Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia . This study sought to establish whether neurokinin - 1 ( NK - 1 ) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E2 ( DB00917 ) in rats , and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan , an inflammatory agent which is known to evoke spinal DB00917 release . Spinal application of antagonists of the P25103 , the - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid ( AMPA ) / kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of DB00917 or intraplantar administration of zymosan . The decrease in thermal paw withdrawal response latencies induced by DB00917 , but not by zymosan , was significantly attenuated by spinal administration of an N - methyl -- aspartate ( DB01221 ) receptor antagonist , an AMPA / kainate receptor antagonist , or a metabotropic glutamate receptor antagonist . Allodynia induced by DB00917 was significantly alleviated by antagonists of DB01221 or AMPA / kainate receptors . These results suggest that both DB00917 - induced and zymosan - induced mechanical hyperalgesia are mediated in part through activation of NK - 1 , AMPA / kainate and metabotropic glutamate receptors . DB00917 - induced , but not zymosan - induced , thermal hyperalgesia is mediated in part by activation of DB01221 , AMPA / kainate and metabotropic glutamate receptors . Activation of both DB01221 and AMPA / kainate receptors contribute to DB00917 - induced allodynia .\",\n \"Effect of tandospirone , a serotonin - 1A receptor partial agonist , on information processing and locomotion in dizocilpine - treated rats . RATIONALE : Augmentation therapy with serotonin - 1A receptor ( P08908 ) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia . OBJECTIVE AND METHODS : The objective of the present study was to examine the effect of repeated administration of tandospirone ( 0 . 05 and 5 mg / kg ) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N - methyl - D - aspartate receptor antagonist MK - 801 , which has been used in animal models of schizophrenia . Furthermore , we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 ( 0 . 3 mg / kg ) , a P08908 receptor antagonist , and whether there is an interaction between haloperidol ( 0 . 1 mg / kg ; a dopamine - D2 receptor antagonist ) and tandospirone . RESULTS : Tandospirone at 5 mg / kg , but not 0 . 05 mg / kg , decreased locomotor activity in saline or MK - 801 - treated rats , which were not affected by co - treatment with WAY 100635 . DB00502 decreased locomotion both in saline and MK - 801 - treated animals , and this effect was not evident in the latter group receiving the higher dose of tandospirone . Tandospirone ( 5 mg / kg ) - induced disruption of sensorimotor gating in saline or MK - 801 - treated animals was reversed by WAY - 100635 , but not by haloperidol . CONCLUSIONS : These findings suggest that behavioural changes induced by tandospirone are not fully blocked by P08908 antagonists and that tandospirone ( 5 mg / kg ) potentiates the effect of MK - 801 . Overall , these findings point to an interaction between DB01221 and 5 - HT ( 1A ) receptors . Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems .\",\n \"A serotonin - 1A receptor agonist and an N - methyl - D - aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model . The WAG / RIJ rats exhibit spontaneously occurring spike - wave discharges ( SWD ) accompanied by behavioural phenomena , with characteristics similar to the human absence type epilepsy . To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin - 1A ( P08908 ) receptor agonist 8 - hydroxy - 2 -( di - n - propylamino )- tetralin ( 8 - OH - DPAT ) and the N - methyl - D - aspartate ( DB01221 ) receptor antagonist (+)- 5 - methyl - 10 , 11 - dihydro - 5H - dibenzo [ a , d ] cyclohepten - 5 , 10 - imine maleate ( MK - 801 ) . Intracerebroventricular ( i . c . v . ) injection of 8 - OH - DPAT caused marked , dose dependent increase , MK - 801 a decrease in the cumulative duration and number of spike - wave discharges . Pretreatment with MK - 801 ( 10 microg / rat i . c . v . ) abolished the increase caused by 8 - OH - DPAT ( 20 microg / rat i . c . v . ) , but the decrease in SWD to MK - 801 was counterbalanced by 8 - OH - DPAT . These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy .\",\n \"A possible mechanism of the nucleus accumbens and ventral pallidum P28222 receptors underlying the antidepressant action of ketamine : a PET study with macaques . DB01221 is a unique anesthetic reagent known to produce various psychotic symptoms . DB01221 has recently been reported to elicit a long - lasting antidepressant effect in patients with major depression . Although recent studies provide insight into the molecular mechanisms of the effects of ketamine , the antidepressant mechanism has not been fully elucidated . To understand the involvement of the brain serotonergic system in the actions of ketamine , we performed a positron emission tomography ( PET ) study on non - human primates . Four rhesus monkeys underwent PET studies with two serotonin ( 5 - HT ) - related PET radioligands , [( 11 ) C ] AZ10419369 and [( 11 ) C ] DASB , which are highly selective for the P28222 receptor and serotonin transporter ( P31645 ) , respectively . Voxel - based analysis using standardized brain images revealed that ketamine administration significantly increased P28222 receptor binding in the nucleus accumbens and ventral pallidum , whereas it significantly reduced P31645 binding in these brain regions . DB00574 , a 5 - HT releaser , significantly decreased P28222 receptor binding , but no additional effect was observed when it was administered with ketamine . Furthermore , pretreatment with 2 , 3 - dihydroxy - 6 - nitro - 7 - sulfamoylbenzo ( f ) quinoxaline ( NBQX ) , a potent antagonist of the glutamate α - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid ( AMPA ) receptor , blocked the action of ketamine on the P28222 receptor but not P31645 binding . This indicates the involvement of AMPA receptor activation in ketamine - induced alterations of P28222 receptor binding . Because NBQX is known to block the antidepressant effect of ketamine in rodents , alterations in the serotonergic neurotransmission , particularly upregulation of postsynaptic P28222 receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine .\",\n \"Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .\",\n \"Stimulation of the P08908 receptor selectively suppresses DB01221 receptor - mediated synaptic excitation in the rat visual cortex . We have previously found that stimulation of serotonin P08908 receptors inhibits the induction of long - term potentiation ( LTP ) in the rat visual cortex . In the present study , the selective P08908 receptor agonist 8 - hydroxy - 2 -( N , N - dipropylamino ) tetralin ( 8 - OH - DPAT ) significantly reduced N - methyl - d - aspartate ( DB01221 ) receptor - mediated synaptic responses recorded in Mg2 +- free medium in rat visual cortical slices . In addition , there was good correlation between the inhibitory effects of 8 - OH - DPAT on DB01221 responses and LTP . These results suggest that P08908 receptor stimulation inhibits the induction of LTP by suppressing DB01221 receptor - mediated synaptic excitation in the rat visual cortex .\",\n \"Involvement of extracellular signal - regulated kinase module in HIV - mediated P01730 signals controlling activation of nuclear factor - kappa B and AP - 1 transcription factors . Although the molecular mechanisms by which the HIV - 1 triggers either T cell activation , anergy , or apoptosis remain poorly understood , it is well established that the interaction of HIV - 1 envelope glycoproteins with cell surface P01730 delivers signals to the target cell , resulting in activation of transcription factors such as NF - kappa B and AP - 1 . In this study , we report the first evidence indicating that kinases MEK - 1 ( Q96HU1 kinase / Erk kinase ) and P27361 ( extracellular signal - regulated kinase ) act as intermediates in the cascade of events that regulate NF - kappa B and AP - 1 activation upon HIV - 1 binding to cell surface P01730 . We found that CEM cells transfected with dominant negative forms of MEK - 1 or P27361 do not display NF - kappa B activation after HIV - 1 binding to P01730 . In contrast , NF - kappa B activation was observed in these cells after PMA stimulation . Although the different cell lines studied expressed similar amounts of P01730 and p56 ( lck ) , HIV - 1 replication and HIV - 1 - induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK - 1 or P27361 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK - 1 or wild - type P27361 . In light of recently published data , we propose that a positive signal initiated following oligomerization of P01730 by the virus is likely to involve a recruitment of active forms of p56 ( lck ) , P04049 , MEK - 1 , and P27361 , before AP - 1 and NF - kappa B activation .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK38___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"A pre - and postsynaptic modulatory action of 5 - HT and the 5 - Q13049 , 2C receptor agonist DOB on DB01221 - evoked responses in the rat medial prefrontal cortex . Intracellular recordings were made from pyramidal neurons in layers V and VI of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5 - Q13049 , 2C receptor agonist (-)- 1 - 2 , 5 - dimethoxy - 4 - bromophenol - 2 - aminopropane ( DOB ) and 5 - hydroxytryptamine ( 5 - HT ) on N - methyl - D - aspartate ( DB01221 ) - induced responses . Bath application of either DOB or 5 - HT [ in the presence of antagonists to P08908 , 5 - Q9H205 and gamma - aminobutytric acid ( GABA ) receptors ] produced a concentration - dependent biphasic modulation of the DB01221 responses . They facilitated and inhibited DB01221 responses at low ( + 2 degrees C ) and a small change in T ( cor ) in the moderate toxidrome ( - 1 degrees C < delta Tcor < + 2 degrees C ) . Thus , delta Tcor in response to drugs can be used to estimate the severity of the toxidrome . The second attempt was to identify the receptors mediating those changes . P08908 receptors were involved in the hypothermic response while 5 - Q13049 and DB01221 receptors mediated head shakes , hyperthermia , forepaw treading and Straub tail . Lastly , antidotal effect of cyproheptadine and (+)- MK - 801 was examined . Both drugs blocked hyperthermia and death . However , the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced . These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5 - HT toxidrome .\",\n \"A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .\",\n \"Phosphorylation of DB00156 ( 495 ) regulates Ca ( 2 +)/ calmodulin - dependent endothelial nitric oxide synthase activity . The activity of the endothelial nitric oxide synthase ( P29474 ) can be regulated independently of an increase in Ca ( 2 +) by the phosphorylation of DB00133 ( 1177 ) but results only in a low nitric oxide ( NO ) output . In the present study , we assessed whether the agonist - induced ( Ca ( 2 +)- dependent , high - output ) activation of P29474 is associated with changes in the phosphorylation of DB00156 ( 495 ) in the calmodulin ( P62158 ) - binding domain . P29474 DB00156 ( 495 ) was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation . In the same cells , bradykinin enhanced the phosphorylation of DB00133 ( 1177 ) , which was maximal after 5 minutes , and abolished by the P62158 - dependent kinase II ( CaMKII ) inhibitor KN - 93 . Bradykinin also enhanced the association of CaMKII with P29474 . Phosphorylation of DB00156 ( 495 ) was attenuated by the protein kinase C ( PKC ) inhibitor Ro 31 - 8220 and after PKC downregulation using phorbol 12 - myristate 13 - acetate . The agonist - induced dephosphorylation of DB00156 ( 495 ) was completely Ca ( 2 +)- dependent and inhibited by the P50391 inhibitor calyculin A . Little P62158 was bound to P29474 immunoprecipitated from unstimulated cells , but the agonist - induced dephosphorylation of DB00156 ( 495 ) enhanced the association of P62158 . Mutation of DB00156 ( 495 ) to alanine increased P62158 binding to P29474 in the absence of cell stimulation , whereas the corresponding DB00128 ( 495 ) mutant bound almost no P62158 . Accordingly , NO production by the Ala ( 495 ) mutant was more sensitive to Ca ( 2 +)/ P62158 than the aspartate mutant . These results suggest that the dual phosphorylation of DB00133 ( 1177 ) and DB00156 ( 495 ) determines the activity of P29474 in agonist - stimulated endothelial cells . Moreover , the dephosphorylation of DB00156 ( 495 ) by P50391 precedes the phosphorylation of DB00133 ( 1177 ) by CaMKII . The full text of this article is available at http :// www . circresaha . org .\",\n \"Dissociation between cognitive and motor / motivational deficits in the delayed matching to position test : effects of scopolamine , 8 - OH - DPAT and EAA antagonists . The effects of the muscarinic antagonists scopolamine HBr and MeBr , the P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , and the N - methyl - d - aspartate ( DB01221 ) antagonists MK - 801 and CGS - 19755 on performance of rats in a delayed matching - to - position task were examined . Pretreatment with scopolamine HBr ( 0 . 05 and 0 . 1 mg / kg ) , resulted in a delay - dependent decrease in the percentage of correct responses and discriminability ( log d ) , but had no effect on either the latency to complete trials , or the rate of trial completion during the fixed duration session . DB00747 MeBr ( 0 . 1 mg / kg ) did not impair percent correct or increase the response latency but did decrease the rate of trial completion . 8 - OH - DPAT ( up to 0 . 3 mg / kg ) , had no effect on percent correct , but did induce a small decrease in discriminability . The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion . Both MK - 801 ( 0 . 05 mg / kg ) and CGS 19755 ( 10 mg / kg ) induced a delay - independent impairment in percent correct , discriminability and a reduction in the rate of trial completion without affecting latency . A lower dose of CGS 19755 ( 5 . 0 mg / kg ) induced a slight impairment in discriminability without significantly affecting the other measures . Taken together , these results demonstrate some dissociation between drug - induced cognitive and motor / motivational deficits in the DMTP test . However , the data question the specificity of putative cognitive impairments reported in many previous studies with the P08908 agonist 8 - OH - DPAT .\",\n \"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK65___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .\",\n \"Role of nitric oxide in brain regions related to defensive reactions . DB00435 synthase ( NOS ) positive neurons are located in most brain areas related to defensive reactions , including the dorsolateral periaqueductal grey ( dlPAG ) . NOS inhibitors injected into this structure induce anxiolytic - like responses whereas NO donors promote flight reactions . Intra - dlPAG administration of carboxy - PTIO , a NO scavenger , or ODQ , a soluble guanylate cyclase inhibitor , produced anxiolytic - like effects on rats exposed to the elevated plus - maze ( EPM ) . A double - staining experiment using NADPHd histochemistry and c - Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG , paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus . Cat exposure also increased activation of NOS neurons in the medial amygdala , dorsal pre - mammillary nucleus and bed nucleus of stria terminalis . Local infusion into the dlPAG of a glutamate DB01221 - receptor antagonist ( AP7 ) or a benzodiazepine agonist ( midazolam ) completely prevented the flight reactions induced by intra - dlPAG administration of SIN - 1 , a NO donor . The responses were also inhibited by the 5 - Q13049 / C agonist DOI but not by a P08908 agonist . These results suggest a modulatory role for NO on brain areas related to defensive reactions , probably by interacting with glutamate , serotonin and / or GABA - mediated neurotransmission .\",\n \"Lowering of body core temperature by exposure to a cold environment and by a P08908 agonist : effects on physiological and psychological variables and blood serotonin levels . The present study was designed to compare the effects of a pharmacologically induced decrease in body core temperature to the effects observed with lowering of body temperature by exposure to a cold environment . Our special interest was the involvement of 5 - HT in thermoregulatory responses . Sixty healthy male volunteers were randomly assigned to one of the following conditions : exposure to normal ambient temperature ( 28 degrees C ) and placebo , exposure to cold ambient temperature ( 5 degrees C ) and placebo , or normal ambient temperature and 10 mg of the partial P08908 agonist ipsapirone . As indicators of physiological responses to lowering of body temperature , tympanic temperature , skin temperature , P15941 , metabolic rate , and heart rate were monitored and saliva cortisol levels and peripheral 5 - HT concentrations were determined . In addition , ratings on ambient temperature , thermal discomfort , and feelings of irritability were obtained . While lowering of body core temperature was associated with marked counterregulations ( decrease of skin temperature , increase in P15941 and metabolic rate ) and feelings of discomfort , this was not observed with ipsapirone . An increase in cortisol levels was primarily observed in the ipsapirone group and was not reflected by respective changes in whole blood or platelet 5 - HT indicating that brain and platelet 5 - HT are not related .\",\n \"Reduction of DB01221 - induced behaviour after acute and chronic administration of desipramine in mice . The mechanisms of the antinociceptive effect of desipramine ( DB01151 ) are only partly known . It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N - methyl - D - aspartic acid ( DB01221 ) receptor complex . In this study , the modulatory effect of DB01151 on the biting and scratching behaviour induced by intrathecal ( i . th . ) administration of DB01221 ( 0 . 25 nmol ) was investigated . Desipramine was administered acutely , either intrathecally ( 0 . 7 - 35 micrograms ) or intraperitoneally ( i . p . , 10 mg / kg ) , or chronically in the drinking water ( 0 . 15 g / l ) for 3 weeks . The DB01221 - induced behaviour was significantly reduced both after acute and chronic administration of DB01151 . Several studies have shown a functional upregulation of the P08908 receptor after chronic treatment with DB01151 . The activation of this receptor using the P08908 agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin hydrobromide ( 8 - OH - DPAT ) , leads to a reduction in DB01221 - induced behaviour . Using the P08908 antagonist NAN - 190 ( 10 micrograms , i . th . ) , the effect of chronic administration of DB01151 on the DB01221 - induced behaviour was reversed . However , NAN - 190 also increased DB01221 - induced behaviour in the control group , suggesting that a tonic inhibition of this behaviour , mediated by the P08908 receptor , may exist . These findings indicate that DB01151 may reduce glutaminergic transmission at the spinal DB01221 receptor . As this receptor is central in spinal nociceptive transmission , this could be one mechanism for the antinociceptive effect of DB01151 .\",\n \"Gene - gene interaction analyses between DB01221 receptor subunit and dopamine receptor gene variants and clozapine response . AIMS : To investigate the possible association and gene - gene interaction effects of polymorphisms in DB01221 receptor subunit ( GRIN1 , Q12879 and Q13224 ) and dopamine receptor ( P21728 , P14416 and P35462 ) genes with clozapine response . MATERIALS & METHODS : GRIN1 rs11146020 ( G1001C ) , Q12879 GT - repeat and Q13224 rs10193895 ( G - 200T ) polymorphisms were tested for association in a Caucasian ( n = 183 ) and an African - American ( n = 49 ) sample using χ ( 2 ) and Q9UNW9 tests . Logistic regression and two - way Q9UNW9 were used to explore gene - gene interaction effects with dopamine receptor gene variants . RESULTS & CONCLUSION : This study does not support the involvement of the DB01221 receptor subunit gene polymorphisms in clozapine response . All tests for an association were negative . Gene - gene interaction analyses however yielded promising leads , including an observed effect between P21728 rs686 and P35462 Ser9Gly polymorphisms on clozapine response ( p = 0 . 002 ) .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK85___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \\\" febrile episode \\\" cases may also result from the dysfunction of serotonin transmission .\",\n \"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK93___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .\",\n \"Discriminative stimulus effects of ethanol in rats using a three - choice ethanol - midazolam - water discrimination . Three - choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other . This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma - aminobutyric acid type A ( GABAA ) receptor complex . As an extension to these studies , male Long - Evans rats were trained to discriminate midazolam ( 3 . 0 mg / kg , i . p . ) from ethanol ( 1 . 0 g / kg , i . g . ) from water ( 2 . 3 ml , i . g . ) in a three - lever , food reinforced task . Substitution tests were conducted following administration of GABAA - positive modulators , noncompetitive N - methyl - D - aspartate ( DB01221 ) antagonists , P28222 agonists and isopropanol . Among the GABAA - positive modulators , diazepam was the only drug that completely substituted for midazolam ; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution . The DB01221 antagonist dizocilpine substituted for ethanol , while phencyclidine showed no substitution for either ethanol or midazolam . The serotonin agonists tested also showed no substitution for either ethanol or midazolam . Isopropanol was the only other drug that completely substituted for ethanol . These data extend previous findings from an ethanol - pentobarbital - water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol - like effect .\",\n \"Cyto - and receptor architecture of area 32 in human and macaque brains . Human area 32 plays crucial roles in emotion and memory consolidation . It has subgenual ( s32 ) , pregenual ( Q9H160 ) , dorsal , and midcingulate components . We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles . The macaque has areas s32 and Q9H160 . In s32 , layer IIIa / b neurons are larger than those of layer IIIc . This relationship is reversed in Q9H160 . Layer Va is thicker and Vb thinner in s32 . Area Q9H160 contains higher kainate , benzodiazepine ( BZ ) , and serotonin ( 5 - HT ) 1A but lower N - methyl - D - aspartate ( DB01221 ) and α2 receptor densities . Most differences were found in layers I , II , and VI . Together , these differences support the dual nature of macaque area 32 . Comparative analysis of human and macaque s32 and Q9H160 supports equivalences in cyto - and receptor architecture . Although there are differences in mean areal receptor densities , there are considerable similarities at the layer level . Laminar receptor distribution patterns in each area are comparable in the two species in layers III - Va for kainate , DB01221 , γ - aminobutyric acid ( GABA ) B , BZ , and P08908 receptors . Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and Q9H160 than to human Q9H160 . Thus , macaque 32 is more complex than hitherto known . Our data suggest a homologous neural architecture in anterior cingulate s32 and Q9H160 in human and macaque brains .\",\n \"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .\",\n \"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .\",\n \"Role of serotonin , gamma - aminobutyric acid , and glutamate in the behavioral thermoregulation of female tilapia during the prespawning phase . The role of hypothalamic neurotransmitter systems in behavioral thermoregulation was investigated in the prespawning female tilapia , Oreochromis mossambicus . Intrahypothalamic microinjection with serotonin ( 5 - HT , 3 microliters of 1 . 0 x 10 (- 6 ) M ) resulted in a significant increase in the selected temperature . This effect was mimicked by the agonist of P08908 , 1B , and 2C receptors , N - 3 - trifluoromethylphenyl piperazine . Intrahypothalamic microinjection of tilapia with gamma - aminobutyric acid ( GABA ) resulted in a biphasic effect of the temperature selection , whereas microinjection with muscimol , an agonist of GABAA receptor , had no effect on temperature selection . Both agonist and antagonist of glutamate ( DB00142 ) , N - methyl - D - aspartate ( DB01221 ) , and MK - 801 ( 1 . 0 x 10 (- 6 ) M ) , a noncompetitive blocker of DB01221 receptor , significantly decreased the preferred temperature . These results indicate that the hypothalamic 5 - HT , GABA , and DB00142 systems play a role in the temperature selection of prespawning female tilapia .\",\n \"Inflammatory cells as source of tachykinin - induced mucus secretion in chronic bronchitis . Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease ( P48444 ) . Tachykinin - induced mucus secretion has been regarded as sensory nerve - dependent so far . We studied the distribution of tachykinin - mRNA and - peptide and its relation to NK - 1 subtype - positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells . RT - PCR demonstrated the expression of tachykinin - and NK - 1 - mRNA in human airway tissues . In situ hybridisation resulted in preprotachykinin ( PPT ) - A mRNA - signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands . NK - 1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT - A mRNA and tachykinin - positive cells . The present data directly demonstrate the presence of both PPT - A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to P25103 positive glandular myoepithelium . Our findings indicate that besides neurally released tachykinins , also inflammatory cell - derived tachykinins may lead to glandular secretion via P25103 stimulation . This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as P48444 or asthma .\",\n \"Characterization of a novel effect of serotonin P08908 and 5 - Q13049 receptors : increasing cGMP levels in rat frontal cortex . Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years . Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens , the signaling pathways activated by these agents are unclear . Here it is shown that administration of serotonin ( 5 - hydroxytryptamine , 5 - HT ) increased cyclic guanosine monophosphate ( cGMP ) production in frontal cortical slices of rat brain . The effect of 5 - HT was greater than that of N - methyl - D - aspartate ( DB01221 ) , a stimulant of cGMP formation in the central nervous system . The 5 - HT ( 2A / 2C ) receptor phenethylamine agonist , 2 , 5 - dimethoxy - 4 - methylamphetamine ( DOM ) , increased cGMP content in the slices . Additionally 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( DPAT ) , a 5 -( HT1A / 7 ) receptor agonist also increased cGMP production . Stimulation of cGMP formation by DOM was prevented by a 5 - HT ( 2A / 2C ) receptor antagonist , pirenperone , as well as by a 5 - Q13049 receptor selective antagonist , MDL100907 . A P28335 receptor antagonist , SB242084 , did not block the effect of DOM . Stimulation of cGMP production by DPAT was blocked by the P08908 receptor antagonist , WAY100635 . Stimulation of cGMP formation by serotonin could be prevented by pirenperone or WAY100635 . In summary , activation of serotonin P08908 and 5 - Q13049 receptors increase brain cGMP levels .\",\n \"Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 function in multiple ways . In particular , class 3 mutations such as p . Gly551Asp strongly decrease the time spent by P13569 in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p . Phe508del ) , the most frequent mutation among CF patients ( 70 - 90 % ) , destabilizes the P13569 protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug - like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco ™ ( also known as ___MASK32___ or VX - 770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 ) for the treatment of CF patients carrying at least one P13569 allele with the p . Gly551Asp mutation ( 2 - 5 % of all patients ) . In contrast , the corrector VX - 809 , which significantly improves p . Phe508del - P13569 trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p . Phe508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect .\",\n \"Innovative approaches for the development of antidepressant drugs : current and future strategies . Depression is a highly debilitating disorder that has been estimated to affect up to 21 % of the world population . Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors ( SSRIs ) and serotonin and norepinephrine reuptake inhibitors ( SNRIs ) , there continue to be many unmet clinical needs with respect to both efficacy and side effects . These needs range from efficacy in treatment resistant patients , to improved onset , to reductions in side effects such as emesis or sexual dysfunction . To address these needs , there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas . There is tremendous diversity in the types of targets and approaches being taken . At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms ( P08908 , P28222 , P28221 , P28335 , alpha - 2A ) . At the other end of the spectrum are more novel targets , such as neurotrophins ( P23560 , IGF ) , based on recent findings that antidepressants induce neurogenesis . In between , there are many approaches that range from directly targeting serotonin receptors ( P28335 , P50406 ) to targeting the multiplicity of potential mechanisms associated with excitatory ( glutamate , DB01221 , Q14416 , P41594 ) or inhibitory amino acid systems ( GABA ) or peptidergic systems ( neurokinin 1 , DB05394 1 , melanin - concentrating hormone 1 , V1b ) . The present review addresses the most exciting approaches and reviews the localization , neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations .\",\n \"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .\",\n \"Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing ' s disease . A 75 - year - old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non - suppressibility to high - dose dexamethasone , responsiveness to P06850 , but not to ___MASK65___ , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 - PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT - PCR revealed abundant expressions of P01189 and SSTR ( - 1 , - 2 , - 5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion .\",\n \"Acute heat stress induces edema and nitric oxide synthase upregulation and down - regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress .\",\n \"Activation of the P27361 / 2 signaling cascade by excitotoxic spinal cord injury . The role of the P27361 / 2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury ( SCI ) was examined . Specifically , phosphorylation of P27361 / 2 , activation of transcription factors NF - kB , P54762 - 1 , and CREB , and gene expression of the neurokinin - 1 receptor and DB01221 receptor subunits Q9UHB4 and NR - 2A were investigated . Excitotoxic injury was produced by intraspinal injection of quisqualic acid ( QUIS ) in male Sprague - Dawley rats . Western blots were used to evaluate phosphorylation and activation of P27361 / 2 and transcription factors using phospho - specific or total antibodies . Real - time PCR was used to evaluate gene expression of P25103 , NR - 1 , and NR - 2A . Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior . Excitotoxic spinal injury resulted in : ( 1 ) increased phosphorylation of P27361 / 2 ; ( 2 ) increased activation of NF - kB and phosphorylation of P54762 - 1 ; and ( 3 ) increased gene expression for the P25103 and Q9UHB4 and NR - 2A subunits of the DB01221 receptor . Blockade of the P29323 cascade with the MEK inhibitor PD98059 inhibited phosphorylation of P54762 - 1 , activation of NF - kB and gene expression of Q9UHB4 , NR - 2A and P25103 , and prevented the development of excessive grooming behavior . The results have shown that excitotoxic spinal injury leads to the injury - induced activation of the P29323 --> P54762 - 1 and NF - kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain . Blockade of this intracellular kinase cascade prevented the onset of injury - induced pain behavior .\"\n]"},"candidates":{"kind":"list like","value":["___MASK13___","___MASK20___","___MASK32___","___MASK38___","___MASK63___","___MASK65___","___MASK70___","___MASK85___","___MASK93___"],"string":"[\n \"___MASK13___\",\n \"___MASK20___\",\n \"___MASK32___\",\n \"___MASK38___\",\n \"___MASK63___\",\n \"___MASK65___\",\n \"___MASK70___\",\n \"___MASK85___\",\n \"___MASK93___\"\n]"},"answer":{"kind":"string","value":"___MASK32___"},"id":{"kind":"string","value":"MH_train_384"}}},{"rowIdx":385,"cells":{"query":{"kind":"string","value":"interacts_with DB01169?"},"supports":{"kind":"list like","value":["Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK55___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .","Involvement of peroxisome proliferator - activated receptor gamma in gonadal steroidogenesis and steroidogenic acute regulatory protein expression . Peroxisome proliferator - activated receptor ( Q07869 ) gamma belongs to the Q07869 family of nuclear transcription factors whose ligands , such as eicosanoids , fatty acids and prostaglandins , are known to affect gonadal function . Although several of these enhance the expression of the steroidogenic acute regulatory protein ( STAR ) and steroid production , the role of PPARgamma in regulating STAR - mediated steroidogenesis remains unclear . In the present study , we used ciglitazone to selectively activate PPARgamma and examine its role in STAR - mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA - 10 mouse Leydig tumour cells . Cotreatment with both dibutyryl - DB02527 and ciglitazone revealed a dose - dependent , significant increase in progesterone synthesis , Star promoter activity , Star mRNA and STAR protein relative to either compound alone . The overexpression of PPARgamma further increased Star - promoter activity . The ciglitazone - induced activity of the Star - promoter appears to be mediated through the DB02527 - response element half - sites located within its proximal 151 bp . Combined treatment with ciglitazone and dibutyryl - DB02527 significantly increased the expression and activity of transcriptional pathways impacted by the activator protein - 1 family member c - P05412 . The present study demonstrates that ciglitazone and dibutyryl - DB02527 synergistically enhance STAR expression in MA - 10 and KK1 cells . DB09201 - activated PPARgamma appears to increase the sensitivity of Leydig and granulosa cells to DB02527 stimulation , possibly via upregulation of c - P05412 expression .","Metallothionein prevention of arsenic trioxide - induced cardiac cell death is associated with its inhibition of mitogen - activated protein kinases activation in vitro and in vivo . Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent . The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress . Metallothionein ( MT ) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress - induced cardiac damage . To investigate whether and how MT protects against arsenic cardiotoxicity , MT - overexpressing H9c2 ( MT - H9c2 ) cardiac cells and transgenic ( MT - TG ) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide . Cardiac cell apoptosis was detected by molecular indices , including the cleavage of caspase 3 and caspase 12 , Bax / Bcl2 expression ratio , P35638 expression and / or confirmed by a terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assay . DB01169 dose - and time - dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as P27361 / 2 , JNK and p38 , but not in MT - H9c2 cells . Importantly , the protective effect of MT on arsenic trioxide - induced apoptotic cell death was completely recaptured in the heart of MT - TG with a significant prevention of MAPKs activation . These results indicate that arsenic trioxide - upregulated MAPKs might play important role in arsenic trioxide - induced apoptotic cell death in cardiac cells both in vivo and in vitro , and MT ' s suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation . Therefore , selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity .","P04150 - mediated regulation of P14780 gene expression in human ovarian surface epithelial cells . OBJECTIVE : To obtain proof - of - concept that locally produced anti - inflammatory steroids suppress ovulation - associated extracellular matrix proteases in human ovarian surface epithelial ( OSE ) cells . DESIGN : Primary OSE cell cultures treated with interleukin - 1alpha ( IL - 1alpha ) ( 500 pg / mL ) as proxy for inflammation , with / without anti - inflammatory steroid ( cortisol or progesterone [ P ] , 0 . 01 - 1 . 0 microM ) . SETTING : Academic medical center . PATIENT ( S ) : Sixteen premenopausal women ( 29 - 46 years ) undergoing surgery for nonmalignant gynecological conditions . MAIN OUTCOME MEASURE ( S ) : Semiquantitative extracellular matrix protease gene expression profiling with verification by real - time quantitative reverse transcription polymerase chain reaction ( qRT - PCR ) and gelatinase zymography . RESULT ( S ) : Treatment with IL - 1alpha stimulated messenger RNA ( mRNA ) expression of several ovulation - associated matrix metalloproteinase genes by OSE cell cultures , including gelatinase B ( P14780 ) but not gelatinase A ( P08253 ) . The IL - 1alpha - stimulated P14780 mRNA production was suppressed by cortisol but not P . ___MASK81___ but not P also dose - dependently suppressed IL - 1alpha - stimulated P14780 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist DB00834 . CONCLUSION ( S ) : In human OSE cells , stimulation of P14780 gene expression and proteolytic activity by IL - 1alpha is suppressed by anti - inflammatory cortisol through a glucocorticoid receptor - mediated mechanism . Because IL - 1alpha also generates cortisol formation in OSE by stimulating cortisone reductase activity , these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation .","O75915 is required for arsenic trioxide induced apoptosis in HeLa and MCF - 7 cells via reactive oxygen species and mitochondria linked signal pathway . DB01169 , emerging as a standard therapy for refractory acute promyelocytic leukemia , induces apoptosis in a variety of malignant cell lines . O75915 , a novel retinoic acid - inducible gene , is known to be involved in apoptosis induced by various agents , for example , 12 - O - tetradecanoylphorbol 13 - acetate , N - 4 - hydroxy - phenyl - retinamide and arsenic trioxide . However , the molecular mechanisms underlying how O75915 gene is functionally involved in apoptosis remain largely unknown . Herein , our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF - 7 cells in a dose - dependent manner and paralleled with increased O75915 expression . O75915 expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide . Knockdown of O75915 attenuated arsenic trioxide induced apoptosis , and was accompanied by significantly reduced activity of caspase - 9 , enhanced Bad phosphorylation and inhibited Q02750 / 2 , P27361 / 2 and JNK phosphorylations . DB01169 induced loss of mitochondrial transmembrane potential was O75915 - dependent . These findings suggest that O75915 may serve as a pro - apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria - associated signal pathway .","Synergistic inhibition of colon carcinoma cell growth by Hedgehog - Gli1 inhibitor arsenic trioxide and phosphoinositide 3 - kinase inhibitor LY294002 . The Hedgehog ( Hh ) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis , but also in tumorigenesis . Aberrant Hh pathway activation has been reported in a variety of malignant tumors including colon carcinoma . Here , we sought to investigate the regulation of the Hh pathway transcription factor Gli1 by arsenic trioxide and phosphoinositide 3 - kinase ( PI3K ) inhibitor LY294002 in colon carcinoma cells . We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells , which was confirmed by quantitative real - time polymerase chain reaction and Western blots . Knocking down endogenous Gli1 reduced colon carcinoma cell viability through inducing cell apoptosis . Similarly , knocking down Gli2 using short interfering RNA impaired colon carcinoma cell growth in vitro . To elucidate the regulation of Gli1 expression , we found that both Gli inhibitor arsenic trioxide and PI3K inhibitor LY294002 significantly reduced Gli1 protein expression and colon carcinoma cell proliferation . DB01169 treatment also reduced Gli1 downstream target gene expression , such as Bcl2 and P24385 . More importantly , the inhibition of Hedgehog - Gli1 by arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor LY294002 in colon carcinoma cells . Our findings suggest that the Hh pathway transcription factor Gli1 is involved in the regulation of colon carcinoma cell viability . Inhibition of Hedgehog - Gli1 expression by arsenic trioxide and PI3K inhibitor synergistically reduces colon cancer cell proliferation , indicating that they could be used as an effective anti - colon cancer combination therapy .","DB00644 - regulated expression of Jun and P05412 target genes in gonadotropes requires a functional interaction between TCF / LEF family members and beta - catenin . DB00644 regulates gonadotrope function through a complex transcriptional network that includes three members of the immediate early gene family : Egr1 , Jun , and Atf3 . These DNA - binding proteins act alone or in pairs to confer hormonal responsiveness to Cga , Lhb , Fshb , and Gnrhr . Herein we suggest that the transcriptional response of Jun requires a functional interaction between the T - cell factor ( TCF ) / lymphoid enhancer factor ( LEF ) family of DNA - binding proteins and beta - catenin ( officially P35222 ) , a coactivator of TCF / LEF . Supporting data include demonstration that DB00644 increases activity of TOPflash , a TCF / LEF - dependent luciferase reporter , in LbetaT2 cells , a gonadotrope - derived cell line . Additional cotransfection experiments indicate that a dominant - negative form of Q9NQB0 ( TCFDN ) that binds DNA , but not beta - catenin , blocks DB00644 induction of TOPflash . Overexpression of O15169 , an inhibitor of beta - catenin , also reduces DB00644 stimulation of TOPflash . Transduction of LbetaT2 cells with TCFDN adenoviruses diminishes DB00644 stimulation of Jun mRNA without altering expression of Egr1 and Atf3 , two other immediate early genes that confer DB00644 responsiveness . Reduction of beta - catenin in LbetaT2 cells , through stable expression of short hairpin RNA , also selectively compromises DB00644 regulation of Jun expression and levels of P05412 protein . Finally , overexpression of TCFDN attenuates DB00644 regulation of Cga promoter activity , a known downstream target of P05412 . Together , these results indicate that DB00644 regulation of Jun transcription requires a functional interaction between TCF / LEF and beta - catenin and that alteration of either impacts expression of P05412 downstream targets such as Cga .","Dominant negative P13500 blocks human osteoclast differentiation . Human osteoclasts were differentiated using receptor activator of NFκB ligand ( O14788 ) and macrophage colony stimulating factor ( P09603 ) from colony forming unit - granulocyte macrophage ( CFU - GM ) precursors of the myeloid lineage grown from umbilical cord blood . Gene expression profiling using quantitative polymerase chain reaction ( Q - PCR ) showed more than 1 , 000 - fold induction of chemokine P13500 within 24 h of O14788 treatment . P13500 mRNA content exceeds that of other assayed chemokines ( P22362 , 3 , 4 , and 5 ) at all time points up to day 14 of treatment . P13500 induction preceded peak induction of calcium signaling activator calmodulin 1 ( P62158 ) and transcription factors P05412 and P01100 , which were at 3 days . Key osteoclast related transcription factors O95644 and Q13469 showed peak induction at 7 days , while marker genes for osteoclast function cathepsin K and tartrate resistance acid phosphatase ( TRAP ) were maximally induced at 14 days , corresponding with mature osteoclast function . To test whether the early and substantial peak in P13500 expression is part of human osteoclast differentiation events , a dominant negative inhibitor of P13500 ( 7ND ) was added simultaneously with O14788 and P09603 , resulting in blockade of P62158 , P05412 and Q13469 induction and strong inhibition of human osteoclast differentiation . These data show that a cascade of gene expression leading to osteoclast differentiation depends on intact early P13500 induction and signaling in human osteoclasts .","Antitumor activity of arsenic trioxide on retinoblastoma : cell differentiation and apoptosis depending on arsenic trioxide concentration . PURPOSE : DB01169 ( ATO ) targets multiple pathways in malignant cells , resulting in the promotion of differentiation or in the induction of apoptosis . The antitumor activity of ATO on retinoblastoma was investigated . METHODS : Human retinoblastoma cells were incubated with various ATO concentrations . The antiproliferative effect of ATO was evaluated by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay , and the effect of ATO on cell - cycle progression was validated by flow cytometry . At a low concentration , the ATO - induced differentiation of retinoblastoma cells was evaluated by neurofilament expression and extracellular signal - regulated kinase ( P29323 ) 1 / 2 activation , which was confirmed by the inhibition of P27361 / 2 . At a high concentration , ATO - induced H ( 2 ) O ( 2 ) production was investigated with the cell - permeable fluorescent dye 2 ' 7 '- dichlorofluorescein - diacetate , and the relationship of ATO - induced H ( 2 ) O ( 2 ) production with caspase - 3 - dependent apoptosis was validated by Western blot and 4 ' 6 - diamidino - 2 - phenolindole staining , which was confirmed by reactive oxygen species ( ROS ) inhibition . The effect of ATO on tumor formation was assessed with an orthotopic animal model of retinoblastoma . RESULTS : The antitumor activity of ATO in retinoblastoma was related to two main mechanisms , differentiation and apoptosis , which were determined by the level of ATO . At a low dose ( < or = 1 microM ) , ATO induced the differentiation of retinoblastoma cells through P27361 / 2 activation , whereas ROS generation by a high dose ( > or = 2 microM ) of ATO induced apoptosis in retinoblastoma cells . Moreover , ATO at low and high doses effectively inhibited tumor formation . CONCLUSIONS : These results suggest that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma .","Q99706 differentially signals downstream functions in human NK cells through distinct structural modules . Q99706 ( 2DL4 ) is a member of the killer cell Ig - like receptor ( P55040 ) family in human NK cells . It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells , but the mechanism for 2DL4 - mediated signaling remains unclear . In this study we characterized the signaling pathways stimulated by 2DL4 engagement . In a human NK - like cell line , KHYG - 1 , cross - linking of 2DL4 activated MAPKs including JNK , P29323 , and p38 . Furthermore , 2DL4 cross - linking resulted in phosphorylation of O15111 beta ( IKKbeta ) and the phosphorylation and degradation of P25963 , which indicate activation of the classical NF - kappaB pathway . Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes , including P01375 , P01579 , MIP1alpha , MIP1beta , and P10145 . Pharmacological inhibitors of JNK , Q02750 / 2 and p38 , blocked P01579 , P10145 , and MIP1alpha production , suggesting that MAPKs are regulating 2DL4 - mediated cytokine production in a nonredundant manner . Activation of both p38 and P29323 appear to be upstream of the stimulation of NF - kappaB . Mutation of a transmembrane arginine in 2DL4 to glycine ( R / G mutant ) abrogated FcepsilonRI - gamma association , as well as receptor - mediated cytolytic activity and calcium responses . Surprisingly , the R / G mutant still activated MAPKs and the NF - kappaB pathway and selectively stimulated the production of MIP1alpha , but not that of P01579 or P10145 . In conclusion , we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules : 1 ) through transmembrane association with FcepsilonRI - gamma ; and 2 ) through another receptor domain independent of the transmembrane arginine .","[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK13___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK13___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .","Cbl - b is a negative regulator of inflammatory cytokines produced by IgE - activated mast cells . c - Cbl and Cbl - b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow - derived mast cells from c - Cbl and Cbl - b - deficient mice it has recently been shown that Cbl - b is the dominant family member for negatively regulating signaling responses from high - affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl - b - deficient mice is the relatively higher levels of Cbl - b protein over c - Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c - Cbl and Cbl - b - deficient mice and find that loss of Cbl - b , but not c - Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl - b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl - b or c - Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl - b (-/-) mast cells compared with levels produced by c - Cbl (-/-) or wild - type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl - b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions .","Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .","AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 / MAPK , the PI3K / AKT / P42345 and the JAK / P40763 pathways . Here , we tested the efficacy of a P23458 / 2 - inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC - 1 ) , P07949 M918T ( MZ - CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC - 1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and / or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC - 1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC - 1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho - Y1062 P07949 levels , and P42345 effector phospho - S6 , while P23458 / 2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e . g . via JAK / phospho - P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK41___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK41___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK41___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK41___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","___MASK13___ inhibition effect on KITAsn822Lys - mediated signal transduction cascade . OBJECTIVE : Alterations in growth factor signaling pathways may be a frequent collaborating event in Q01196 - Q06455 - mediated leukemogenesis . Gain - of - function P10721 receptor mutations have been reported in adult AML patients , especially those with core binding factor leukemia ( CBFL ) . We have previously reported a new gain - of - function P10721 ( Asn822Lys ) mutation that is constitutively expressed in the Kasumi - 1 CBFL cell line , and has recently been described in two childhood AML patients . To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation , we investigated P10721 downstream signaling in the Kasumi - 1 cell line by means of ___MASK13___ ( Imatinib , Gleevec ) pharmacological inhibition . MATERIALS AND METHODS : We investigated P10721 ( Asn822Lys ) mutant - initiated signaling in Kasumi - 1 cell line , and characterized the inhibitory effect of the ___MASK13___ protein tyrosine kinase inhibitor on downstream signaling . RESULTS : The use of ___MASK13___ - mediated inhibition impaired the tyrosine phosphorylation of P10721 ( Asn822Lys ) and its association with the p85 subunit of phosphatidylinositol 3 '- kinase ( p85PI3K ) . The downstream constitutive phosphorylation of P45983 / 2 and P40763 was also significantly inhibited , but ___MASK13___ had no effect on the constitutive activation of Akt , thus suggesting that it is due to other signaling in Kasumi - 1 cells . ___MASK13___ inhibited the P10721 - mediated proliferation of Kasumi - 1 cells in a dose - dependent manner . CONCLUSIONS : These findings show the role of PI3K in P10721 ( Asn822Lys )- mediated constitutive activation through the Akt - independent downstream signaling pathway of JNK , and also demonstrate the mutant ' s susceptibility to ___MASK13___ , which may therefore have therapeutic potential in CBFL patients with susceptible P10721 mutations .","Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis - related genes peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) , CCAAT / enhancer binding protein - alpha ( C / EBP - α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis - related genes and P27361 / 2 activation in adipocytes .","Proangiogenesis action of the thyroid hormone analog 3 , 5 - diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (- 8 )- 10 (- 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3 , 5 - diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three - dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 )- agarose , as well as basic fibroblast growth factor ( b - FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three - dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b - FGF was blocked by PD 98059 , an inhibitor of the P27361 / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b - FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta3 , and are MAPK dependent .","SnoN / SkiL expression is modulated via arsenic trioxide - induced activation of the PI3K / AKT pathway in ovarian cancer cells . SnoN / SkiL ( TGFβ regulator ) is dysregulated in ovarian cancer , a disease associated with acquired drug - resistance . DB01169 ( As₂O₃ , used in treating APL ) induces SnoN to oppose the apoptotic response in ovarian cancer cells . We now report that As₂O₃ increases phosphorylation of P00533 / p66ShcA and P00533 degradation . As₂O₃ activates Src ( Y416 ) whose activity ( inhibited by Q99463 ) modulates P00533 activation , its interaction with Shc / Grb2 , and p - AKT . Inhibition of PI3K reduces SnoN and cell survival . Although P00533 or P28482 siRNA did not alter SnoN expression , As₂O₃ - induced cleaved PARP was reduced together with increased P98170 . Collectively , As₂O₃ mediates an initial rise in pY - Src ( 416 ) to regulate the PI3K / AKT pathway which increases SnoN and cell survival ; these early events may counter the cell death response associated with increased pY - P00533 / MAPK activation .","DB01169 phosphorylates c - Fos to transactivate P38936 ( P38936 / CIP1 ) expression . An infamous poison , arsenic also has been used as a drug for nearly 2400 years ; in recently years , arsenic has been effective in the treatment of acute promyelocytic leukemia . Increasing evidence suggests that opposite effects of arsenic trioxide ( ATO ) on tumors depend on its concentrations . For this reason , the mechanisms of action of the drug should be elucidated , and it should be used therapeutically only with extreme caution . Previously , we demonstrated the opposing effects of P27361 / 2 and JNK on P38936 ( P38936 / CIP1 ) ( P38936 ) expression in response to ATO in A431 cells . In addition , JNK phosphorylates c - Jun ( DB00133 ( 63 / 73 ) ) to recruit Q15583 / Q13547 to suppress P38936 gene expression . Presently , we demonstrated that a high concentration of ATO sustains P27361 / 2 phosphorylation , and increases c - Fos biosynthesis and stability , which enhances P38936 gene expression . Using site - directed mutagenesis , a DNA affinity precipitation assay , and functional assays , we demonstrated that phosphorylation of the C - terminus of c - Fos ( DB00156 ( 232 ) , DB00156 ( 325 ) , DB00156 ( 331 ) , and DB00133 ( 374 ) ) plays an important role in its binding to the P38936 promoter , and in conjunction with N - terminus phosphorylation of c - Fos ( DB00133 ( 70 ) ) to transactivate P38936 promoter expression . In conclusion , a high concentration of ATO can sustain P27361 / 2 activation to enhance c - Fos expression , then dimerize with dephosphorylated c - Jun ( DB00133 ( 63 / 73 ) ) and recruit p300 / CBP to the Sp1 sites ( - 84 /- 64 ) to activate P38936 gene expression in A431 cells .","DB01169 concentration determines the fate of Ewing ' s sarcoma family tumors and neuroblastoma cells in vitro . DB01169 ( As ( 2 ) O ( 3 ) ) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner . We assessed the effects of As ( 2 ) O ( 3 ) in CADO - ES Ewing ' s sarcoma ( ES ) , JK - GMS peripheral primitive neuroectodermal tumor ( PNET ) , and SH - SY5Y neuroblastoma cells , as they share common histogenetic backgrounds . As ( 2 ) O ( 3 ) at low concentrations ( 0 . 1 - 1 microM ) induced SH - SY5Y differentiation , and whereas PNET cells acquired a slightly differentiated phenotype , change was minimal in ES cells . P28482 ( P28482 ) was activated at low As ( 2 ) O ( 3 ) concentrations , and PD98059 , an inhibitor of MEK - 1 , blocked SH - SY5Y cell differentiation by As ( 2 ) O ( 3 ) . High concentrations ( 2 - 10 microM ) of As ( 2 ) O ( 3 ) induced the apoptosis in all three cell lines , and this was accompanied by the activation of c - jun N - terminal kinase . The generation of H ( 2 ) O ( 2 ) and activation of caspase 3 were identified as critical components of As ( 2 ) O ( 3 )- induced apoptosis in all of the above cell lines . P09038 enhanced As ( 2 ) O ( 3 )- induced apoptosis in JK - GMS cells . The overall effects of As ( 2 ) O ( 3 ) strongly suggest that it has therapeutic potential for the treatment of ES / PNET .","Oxidative stress - induced p53 activity is enhanced by a redox - sensitive Q96A56 SUMOylation . Tumor Protein p53 - Induced Nuclear Protein 1 ( Q96A56 ) is a tumor suppressor that modulates the p53 response to stress . Q96A56 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes . Q96A56 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development . In this work , we report that redox - dependent induction of p53 transcriptional activity is enhanced by the oxidative stress - induced SUMOylation of Q96A56 at lysine 113 . This SUMOylation is mediated by Q9Y6X2 and O00257 , two SUMO ligases especially related to the p53 activation upon DNA damage . Importantly , this modification is reversed by three P63165 - specific proteases Q9P0U3 , 2 and 6 . Moreover , Q96A56 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions . Q96A56 mutation at lysine 113 prevents the pro - apoptotic , antiproliferative and antioxidant effects of Q96A56 by impairing the p53 response on its target genes P38936 , Bax and PUMA . We conclude that Q96A56 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress .","In vitro and in vivo effects of the Q07869 agonists fenofibrate and retinoic acid in endometrial cancer . Fenofibrate , an agonist of Q07869 , in doses above 25 microM , inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells . We show that these effects are potentiated by retinoic acid , an agonist of the retinoid - Q9UBH6 . DNA content analysis shows that P55008 / S phase progression through the cell cycle is inhibited . Independent Component Analysis of gene microarray experiments demonstrated downregulation of P12004 D1 ( P24385 ) and associated changes in cell cycle gene expression . Expression of Q07869 mRNA was reduced by > 75 % using RNA - interference but this resulted in only minor changes in biological effects . A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth . CONCLUSION : The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro .","Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems . This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT - PCR . We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia . Twenty types of chromosomal abnormalities were detected in 42 % from all patients by commercially available multiplex RT - PCR for detecting 28 fusion genes and in 35 % by cytogenetic analysis including Q5TCZ1 analysis . The most common cytogenetic aberrations in acute myeloid leukemia patients was P29590 / PARA , followed by Q01196 / MGT8 and Q03164 , and in acute lymphoid leukemia patients was P11274 / P00519 , followed by P41212 / Q01196 and Q03164 gene rearrangement . Among the negative results for multiplex RT - PCR , clinically significant t ( 3 ; 3 )( q21 ; q26 . 2 ) , t ( 8 ; 14 )( q24 ; q32 ) and i ( 17 )( q10 ) were detected by conventional cytogenetics . The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies , and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems .","Lytic activity of P60568 and IL - 12 stimulated NK cells against Q9UKB1 osteosarcoma cell line . NK cells are CD16 , CD56 positive lymphocytes that spontaneously lyse tumor or virus infected cells . In this study we investigated whether P60568 and / or IL - 12 stimulated NK cells increased their lytic efficiency against Q9UKB1 osteosarcoma cell line . Our results demonstrate that both 18 hour and 5 day incubation times enhanced the lytic activity of human PBL against Q9UKB1 and K562 target cells and that IL - 12 appears to be more efficient than P60568 in augmenting NK cytotoxicity .","Synergism of Q9HC29 and Q96P20 activators promotes a unique transcriptional profile in murine dendritic cells . NLRs are cytoplasmic proteins that sense cellular stress and intracellular damage resulting from pathogen uptake . To date , the role of NLRs has been studied using combinations of NLR and TLR agonists , but the interplay between two different NLRs remains uncharacterized . In this study , we employed microarrays to investigate in DCs the regulation of gene transcription mediated by activation of Q9HC29 and Q96P20 pathways using P16444 and MSU . P16444 and MSU co - stimulation of murine BMDCs up - regulated the expression of genes encoding molecules for antigen presentation and co - stimulation ( MHC class II , P33681 , P42081 ) , integrins ( P05106 , P06756 ) , cytokines ( IL - 1α , IL - 1β , P05231 , P60568 , Q9NPF7 , IL - 12p40 ) , and chemokines ( P09341 , P19875 ) . Transcription of the cytokine genes induced by P16444 and MSU partially depended on Q9HC29 but was independent of Q96P20 . Finally , we showed that P27361 and c - P05412 activation increased upon P16444 and MSU co - stimulation . As a whole , the results indicate that two different NLR activators synergize at the transcriptional level , leading to unique differential expression of genes involved in the innate immune response .","DB01169 inhibits osteosarcoma cell invasiveness via MAPK signaling pathway . DB01169 ( As ( 2 ) O ( 3 ) ) is an active ingredient in traditional Chinese medicine . Recent studies showed that it causes apoptosis in several cancer cells . However , research of As ( 2 ) O ( 3 ) in osteosarcoma is sparse . In our present study , an inhibitory effect of As ( 2 ) O ( 3 ) on osteosarcoma cell adhesion and metastasis was observed with a cell adhesion , migration and invasion test . The impact of As ( 2 ) O ( 3 ) on the activities of P14780 and MAPK pathway - related downstream factors was analyzed by western blotting . Our results showed that As ( 2 ) O ( 3 ) significantly inhibited motility , migration and invasion in Q9UKB1 and MNNG cells in a concentration - dependent manner at concentrations ranging from 0 . 5 - 2 μM , and led to cytoskeletal rearrangements . As ( 2 ) O ( 3 ) exerted an inhibitory effect on the phosphorylation of P27361 / 2 and MEK , which are the members of the MAPK family . Additionally , treatment with As ( 2 ) O ( 3 ) in combination with inhibitors specific for MEK ( U0126 ) in Q9UKB1 and MNNG cells resulted in a marked inhibition of cell invasion and As ( 2 ) O ( 3 ) could significantly reduce PMA - induced invasion . In conclusion , we demonstrate the inhibitory effects of As ( 2 ) O ( 3 ) on the invasiveness of Q9UKB1 and MNNG cells , which may be due at least partly to inactivation of the MAPK signaling pathway .","Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK3___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .","Chronically increased ciliary neurotrophic factor and fibroblast growth factor - 2 expression after spinal contusion in rats . Demyelination and oligodendrocyte loss following spinal cord injury ( SCI ) are well documented . Recently , we showed oligodendrocyte progenitor cell ( OPC ) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders . We have since begun investigating potential mechanisms for this endogenous repair response . Here , we examined ciliary neurotrophic factor ( P26441 ) and fibroblast growth factor - 2 ( P09038 ) expression , because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders . We hypothesized that P26441 and P09038 would increase after SCI , especially in regions of enhanced oligogenesis . First , P26441 protein was quantified using Western blots , which revealed that P26441 protein continually rose through 28 days post injury ( dpi ) . Next , by using immunohistochemistry , we examined the spatiotemporal expression of P26441 in cross - sections spanning the injury site . P26441 immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords . Significantly increased P26441 was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls . By 28 dpi , P26441 expression was significantly higher along lesion borders compared with outlying spared tissue ; a similar distribution of phosphorylated P40763 , a transcription factor up - regulated by P26441 and to a lesser extent P09038 , was also detected . Because P26441 can potentiate P09038 expression , we examined the distribution of P09038 + cells . Significantly more P09038 + cells were noted along lesion borders at 7 and 28 dpi . Thus , both P26441 and P09038 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury - induced gliogenesis .","A metabolic prosurvival role for P29590 in breast cancer . Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression . However , the genetic cues modulating this metabolic switch remain largely undetermined . We identified a metabolic function for the promyelocytic leukemia ( P29590 ) gene , uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival . We found that P29590 acted as both a negative regulator of PPARγ coactivator 1A ( Q9UBK2 ) acetylation and a potent activator of Q07869 signaling and fatty acid oxidation . We further showed that P29590 promoted DB00171 production and inhibited anoikis . Importantly , P29590 expression allowed luminal filling in 3D basement membrane breast culture models , an effect that was reverted by the pharmacological inhibition of fatty acid oxidation . Additionally , immunohistochemical analysis of breast cancer biopsies revealed that P29590 was overexpressed in a subset of breast cancers and enriched in triple - negative cases . Indeed , P29590 expression in breast cancer correlated strikingly with reduced time to recurrence , a gene signature of poor prognosis , and activated Q07869 signaling . These findings have important therapeutic implications , as P29590 and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression , a potential future mode of cancer prevention and treatment .","Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : ___MASK75___ is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2 - mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes .","Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK75___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK75___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .","Systematic review : diet - gene interactions and the risk of colorectal cancer . BACKGROUND : Diet contributes significantly to colorectal cancer ( CRC ) aetiology and may be potentially modifiable . AIM : To review diet - gene interactions , aiming to further the understanding of the underlying biological pathways in CRC development . METHODS : The PubMed and Medline were systematically searched for prospective studies in relation to diet , colorectal cancer and genetics . RESULTS : In a meta - analysis , no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found ( P - value for interaction 0 . 95 ) . We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC . High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype , whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC ( OR = 1 . 25 ; 95 % confidence interval ( CI ) : 0 . 92 - 2 . 01 ) compared with slow acetylators with low meat intake ( reference ) , P - value for interaction = 0 . 07 . Low meat intake in the studied populations may influence the result . Interactions between meat , cruciferous vegetables , fibres , calcium , vitamins , and alcohol and P08183 , P19838 , P09488 , P30711 , P24385 , P11473 , MGTM , P22301 and P37231 are suggested . CONCLUSIONS : A number of interactions between genetic variation and diet are suggested , but the findings need replication in independent , prospective , and well - characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached . When the above criteria are met , studies on diet - gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis .","Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6 . 1 - composed K - DB00171 channels expressed in neural stem cells . BACKGROUND AND PURPOSE : Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases . Iptakalim ( Ipt ) , a novel DB00171 - sensitive potassium ( K - DB00171 ) channel opener , has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro . However , it remains unknown whether Ipt could regulate the adult neurogenesis . METHODS AND RESULTS : Based on the finding that adult neural stem cells ( ANSCs ) in hippocampus expressed Kir6 . 1 / Q09428 - composed K - DB00171 channel , Kir6 . 1 heterozygotic ( Kir6 . 1 (+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis . We showed that administration of Ipt ( 10 mg / kg ) or fluoxetine ( Flx , 10 mg / kg ) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ ) of Kir6 . 1 (+/+) mice but failed to affect those of Kir6 . 1 (+/-) mice . Meanwhile , ANSCs in Kir6 . 1 (+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes . We further found that Kir6 . 1 (+/-) mice showed lower level of brain - derived neurotrophic factor ( P23560 ) in hippocampus compared with Kir6 . 1 (+/+) mice . Furthermore , Ipt increased the levels of P23560 and basic fibroblast growth factor ( P09038 ) throughout the hippocampus in Kir6 . 1 (+/+) mice but not in Kir6 . 1 (+/-) mice . Moreover , Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6 . 1 (+/+) mice . Notably , these effects were completely abolished in Kir6 . 1 (+/-) mice . CONCLUSIONS : Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6 . 1 - composed K - DB00171 channels , which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency , such as major depression .","Effects of leptin and adiponectin on proliferation and protein metabolism of porcine myoblasts . The aim of this study was to show the abundance of leptin and adiponectin receptors ( LEPR , Q96A54 , Q86V24 ) and to determine the direct effects of leptin and adiponectin on the in vitro growth of porcine skeletal muscle cells . Q96A54 and Q86V24 were abundant at mRNA and protein level in proliferating and differentiating myoblast cultures derived from semimembranosus and semitendinosus muscles of newborn piglets , whereas LEPR expression was close to the detection limit . Q15848 ( 10 , 20 , 40 μg / ml ) attenuated the proliferation of porcine myoblasts , measured as [ ( 3 ) H ] - thymidine incorporation and real - time monitoring of the cells in response to 24 - and 48 - h exposure , in a dose - dependent manner . This effect resulted from suppressed basic fibroblast growth factor ( P09038 ) - mediated stimulation of DNA synthesis in serum - free medium ( SFM ) containing P09038 . No effects of leptin ( 5 , 10 , 20 , 40 , 80 ng / ml ) on myoblast proliferation in SFM were detectable . Neither leptin nor adiponectin altered protein synthesis and degradation in differentiating porcine myoblasts cultured in SFM . The results on receptor abundance suggest that porcine skeletal muscle cells may be sensitive to adiponectin and leptin . However , except via inhibitory interaction of adiponectin with P09038 , these adipokines appear not to affect in vitro proliferation and protein metabolism of porcine muscle cells directly under serum - free culture conditions .","Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha - reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha - reductase type I and type II , in androgen - responsive ( LNCaP ) and androgen - unresponsive ( DU145 ) human prostate cancer ( PCa ) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home - made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or = +/- 1 . 5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co - regulators ( AR ; P24385 ) , and signal transduction ( P04626 ; V - P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen - regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real - time PCR assay ( QRT - PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology .","Activation of the p38 MAPK / Akt / P27361 / 2 signal pathways is required for the protein stabilization of Q99741 and cyclin D1 in low - dose arsenite - induced cell proliferation . DB01169 ( ATO ) is a first - line anti - cancer agent for acute promyelocytic leukemia , and induces apoptosis in other solid cancer cell lines including breast cancer cells . However , as with arsenites found in drinking water and used as raw materials for wood preservatives , insecticides , and herbicides , low doses of ATO can induce carcinogenesis after long - term exposure . At 24 h after exposure , ATO ( 0 . 01 - 1 µM ) significantly increased cell proliferation and promoted cell cycle progression from the P55008 to S / G2 phases in the non - tumorigenic MCF10A breast epithelial cell line . The expression of 14 out of 96 cell - cycle - associated genes significantly increased , and seven of these genes including cell division cycle 6 ( Q99741 ) and cyclin D1 ( P24385 ) were closely related to cell cycle progression from P55008 to S phase . Low - dose ATO steadily increased gene transcript and protein levels of both Q99741 and cyclin D1 in a dose - and time - dependent manner . Low - dose ATO produced reactive oxygen species ( ROS ) , and activated the p38 MAPK , Akt , and P27361 / 2 pathways at different time points within 60 min . Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK , Akt , and P27361 / 2 decreased the ATO - increased expression of Q99741 protein . Inhibiting the activation of Akt and P27361 / 2 , but not p38 MAPK , decreased the ATO - induced expression of cyclin D1 protein . This study reports for the first time that p38 MAPK / Akt / P27361 / 2 activation is required for the protein stabilization of Q99741 in addition to cyclin D1 in ATO - induced cell proliferation and cell cycle modulation from P55008 to S phase .","DB01169 induces apoptosis through JNK and P29323 in human mesothelioma cells . Malignant mesothelioma is an aggressive tumor of serosal surfaces , which is refractory to current treatment options . DB01169 ( As2O3 ) is used clinically to treat acute promyelocytic leukemia , and also to inhibit proliferation of several solid tumors including hepatoma , esophageal , and gastric cancer in vitro . Here we found that As2O3 inhibited cell viability of a mesothelioma cell line , NCI - H2052 . As2O3 induced apoptosis of NCI - H2052 cells , which was accompanied by activation of c - Jun NH2 - terminal kinase ( JNK ) 1 / 2 , extracellular signal - regulated kinase ( P29323 ) 1 / 2 , and caspase - 3 . zVAD - fmk , a broad - spectrum caspase inhibitor , inhibited As2O3 - induced apoptosis and activation of caspase - 3 , but not that of P45983 / 2 and P27361 / 2 . Small interfering RNAs ( siRNAs ) targeting P45983 / 2 suppressed As2O3 - induced caspase - 3 activation and apoptosis , indicating that P45983 / 2 regulate As2O3 - induced apoptosis though caspase cascade . Furthermore , P45983 siRNA abrogated As2O3 - induced P45984 phosphorylation and P45984 siRNA abrogated As2O3 - induced P45983 phosphorylation , suggesting that P45983 and P45984 interact with each other . Moreover , P45983 siRNA , but not P45984 siRNA , abrogated As2O3 - induced P27361 / 2 phosphorylation . P45984 siRNA together with PD98059 , a specific MAPK / P29323 kinase inhibitor , suppressed As2O3 - induced apoptosis more significantly than P45984 siRNA alone . These results indicated that As2O3 induces apoptosis of NCI - H2052 cells mainly through P45983 / 2 activation , and that P27361 / 2 is involved in As2O3 - induced apoptosis when P45983 / 2 are inactivated .","Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .","Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK24___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .","___MASK81___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK81___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .","Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .","P06401 membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine - induced matrix metalloproteinase 9 activity in vitro . Progesterone ( P4 ) and the progestin , 17α - hydroxyprogesterone caproate , are clinically used to prevent preterm births ( PTBs ) ; however , their mechanism of action remains unclear . Cytokine - induced matrix metalloproteinase 9 ( P14780 ) activity plays a key role in preterm premature rupture of the membranes and PTB . We demonstrated that the primary chorion cells and the HTR8 / SVneo cells ( cytotrophoblast cell line ) do not express the classical progesterone receptor ( P06401 ) but instead a novel progesterone receptor , progesterone receptor membrane component 1 ( O00264 ) , whose role remains unclear . Using HTR8 / SVneo cells in culture , we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate ( ___MASK41___ ) and dexamethasone ( DB00514 ) but not P4 or 17α - hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α - induced P14780 activity after a 24 - hour incubation period . The inhibitory effect of ___MASK41___ , but not DB00514 , was attenuated when O00264 expression was successfully reduced by O00264 small interfering RNA . Our findings highlight a possible novel role of O00264 in mediating the effects of ___MASK41___ and in modulating cytokine - induced P14780 activity in cytotrophoblast cells in vitro .","Low doses of natural killer T cells provide protection from acute graft - versus - host disease via an P05112 - dependent mechanism . P01730 (+) natural killer T ( NKT ) cells , along with P01730 (+) CD25 (+) regulatory T cells ( Tregs ) , are capable of controlling aberrant immune reactions . We explored the adoptive transfer of highly purified ( > 95 % ) P01730 (+) NKT cells in a murine model of allogeneic hematopoietic cell transplantation ( HCT ) . NKT cells follow a migration and proliferation pattern similar to that of conventional T cells ( Tcons ) , migrating initially to secondary lymphoid organs followed by infiltration of graft - versus - host disease ( GVHD ) target tissues . NKT cells persist for more than 100 days and do not cause significant morbidity or mortality . Doses of NKT cells as low as 1 . 0 × 10 ( 4 ) cells suppress GVHD caused by 5 . 0 × 10 ( 5 ) Tcons in an interleukin - 4 ( P05112 ) - dependent mechanism . Protective doses of NKT cells minimally affect Tcon proliferation , but cause significant reductions in interferon - γ ( IFN - γ ) and tumor necrosis factor - α ( P01375 - α ) production by donor Tcons and in skin , spleen , and gastrointestinal pathology . In addition , NKT cells do not impact the graft - versus - tumor ( GVT ) effect of Tcons against B - cell lymphoma - 1 ( P24385 ) tumors . These studies elucidate the biologic function of donor - type P01730 (+) NKT cells in suppressing GVHD in an allogeneic transplantation setting , demonstrating clinical potential in reducing GVHD in HCT .","Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma . Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia ( P29590 ) gene was significantly upregulated ( 2 . 5 - fold ) in cells positive to prominin - 1 antigen ( CD133 ) , a possible marker for cancer initiating cells . DB01169 ( As ( 2 ) O ( 3 ) ) is known to degrade P29590 protein and has been used for the treatment of patients with acute P29590 . In the present study , the effect of P29590 targeting therapy with As ( 2 ) O ( 3 ) and cytarabine ( DB00987 ) on Daoy medulloblastoma cell proliferation was investigated . Daoy cells were pretreated with As ( 2 ) O ( 3 ) for 6 weeks . The As ( 2 ) O ( 3 )- pretreated Daoy cells were cultured in medium containing DB00987 and cell viability was examined . Next , the As ( 2 ) O ( 3 )- pretreated Daoy cells were inoculated into the nude mouse brain and the effect of DB00987 on the tumor size was evaluated . A significant increase in chemosensitivity to DB00987 was observed in the As ( 2 ) O ( 3 )- pretreated Daoy cells in both in vitro and in vivo conditions . P29590 and P24385 ( cyclin D1 ) protein expression of Daoy medulloblastoma cells was downregulated by As ( 2 ) O ( 3 ) treatment . P29590 has been proposed as a novel therapeutic target to eradicate quiescent leukemia - initiating cells , and P29590 - expressing CD133 - positive cells are similarly a potential therapeutic target of treatment for medulloblastoma .","DB01169 inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells . DB01169 ( As2O3 ) has shown therapeutic effects in some leukemias and solid cancers . However , the molecular mechanisms of its anticancer efficacy have not been clearly elucidated , particularly in solid cancers . Our previous data showed that As2O3 induced apoptosis of human papillomavirus ( HPV ) 16 DNA - immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells . In the present study , we systemically examined the effects of As2O3 on five human cervical cancer cell lines and explored the possible molecular mechanisms . MTT assay showed that HPV - negative C33A cells were more sensitive to growth inhibition induced by As2O3 than HPV - positive cervical cancer cells , and HPV 18 - positive HeLa and C4 - I cells were more sensitive to As2O3 than HPV 16 - positive CaSki and SiHa cells . After As2O3 treatment , both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines . In contrast , p53 and Rb protein levels increased in all tested cell lines . P05412 protein expression decreased significantly in HeLa , CaSki and C33A cells with ELISA method . These results suggest that As2O3 is a potential anticancer drug for cervical cancer .","The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 - thickness , mid - small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c - Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 / CIP1 ) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt - beta - catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration .","Q9Y5V3 mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade . Understanding the molecular events that govern neural progenitor lineage commitment , mitotic arrest , and differentiation into functional progeny are germane to our understanding of neocortical development . Members of the family of bone morphogenetic proteins ( BMPs ) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation . We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that Q9Y5V3 is a mandatory component of the signaling cascade . Q9Y5V3 possesses the ability to bind and function with the TAK1 - Q15750 - P98170 complex facilitating the activation of p38 . Disruption of Q9Y5V3 or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure . The function of Q9Y5V3 is independent of Smad signaling , but the introduction of a dominant - negative Q99717 also rescues neural progenitor apoptosis , suggesting that both canonical and noncanonical pathways can converge and regulate BMP - mediated apoptosis . Collectively , these results establish Q9Y5V3 as an integral component in BMP signaling and clarify its role during neural progenitor development .","P03372 alpha mediates progestin - induced mammary tumor growth by interacting with progesterone receptors at the cyclin D1 / MYC promoters . Synthetic progesterone used in contraception drugs ( progestins ) can promote breast cancer growth , but the mechanisms involved are unknown . Moreover , it remains unclear whether cytoplasmic interactions between the progesterone receptor ( PR ) and estrogen receptor alpha ( ERα ) are required for PR activation . In this study , we used a murine progestin - dependent tumor to investigate the role of ERα in progestin - induced tumor cell proliferation . We found that treatment with the progestin medroxyprogesterone acetate ( ___MASK41___ ) induced the expression and activation of ERα , as well as rapid nuclear colocalization of activated ERα with PR . Treatment with the pure antiestrogen fulvestrant to block ERα disrupted the interaction of ERα and PR in vitro and induced the regression of ___MASK41___ - dependent tumor growth in vivo . ERα blockade also prevented an ___MASK41___ - induced increase in CYCLIN D1 ( P24385 ) and MYC expression . Chromatin immunoprecipitation studies showed that ___MASK41___ triggered binding of ERα and PR to the P24385 and MYC promoters . Interestingly , blockade or RNAi - mediated silencing of ERα inhibited ERα , but not PR binding to both regulatory sequences , indicating that an interaction between ERα and PR at these sites is necessary for ___MASK41___ - induced gene expression and cell proliferation . We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples . Together , our findings argued that ERα - PR association on target gene promoters is essential for progestin - induced cell proliferation .","DB01169 - mediated antiplatelet activity : pivotal role of the phospholipase C gamma 2 - protein kinase C - p38 MAPK cascade . DB01169 produces high rates of complete clinical remission in patients with relapsed / refractory acute promyelocytic leukemia . Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases . Few studies have examined the effects of arsenic trioxide on platelets , and the mechanisms underlying the signaling pathways remain obscure . The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation . DB01169 ( 5 micromol / L ) exhibited more potent activity at inhibiting collagen ( 1 microg / mL ) - induced platelet aggregation than other agonists . DB01169 ( 15 and 25 micromol / L ) inhibited collagen - induced platelet activation accompanied by [ Ca (+ 2 )] i mobilization , thromboxane A ( 2 ) ( TxA ( 2 ) ) formation , phospholipase C ( P98160 ) gamma 2 phosphorylation , and protein kinase C ( PKC ) activation . DB01169 ( 15 and 25 micromol / L ) did not significantly affect cyclic nucleotide - induced vasodilator - stimulated phosphoprotein phosphorylation . Moreover , arsenic trioxide markedly inhibited p38 mitogen - activated protein kinase ( MAPK ) but not P45983 / 2 or P28482 phosphorylation in washed platelets . DB01169 also markedly reduced hydroxyl radical ( OH (.) ) formation in the erythrocyte sedimentation rate ( P03372 ) study . The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the P98160 gamma 2 - PKC - p38 MAPK cascade , thereby leading to inhibition of [ Ca (+ 2 )] i or free radical formation , and finally the inhibition of platelet aggregation .","DB01169 ( ATO ) and Q02750 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells . Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras - mitogen - activated protein kinase ( MAPK ) can confer an aggressive , apoptosis - resistant phenotype to leukemia cells . In this study , we report that acute promyelocytic leukemia ( APL ) cells exploit the Ras - MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad , delaying arsenic trioxide ( ATO ) - induced apoptosis . Both in APL cell line NB4 and in APL primary blasts , the inhibition of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) and Bad phosphorylation by Q02750 inhibitors enhanced apoptosis in ATO - treated cells . We isolated an arsenic - resistant NB4 subline ( NB4 - As ( R ) ) , which showed stronger P27361 / 2 activity ( 2 . 7 - fold increase ) and Bad phosphorylation ( 2 . 4 - fold increase ) compared to parental NB4 cells in response to ATO treatment . Upon ATO exposure , both NB4 and NB4 - As ( R ) cell lines doubled protein levels of the death antagonist Bcl - xL , but the amount of free Bcl - xL that did not heterodimerize with Bad was 1 . 8 - fold greater in NB4 - As ( R ) than in the parental line . Q02750 inhibitors dephosphorylated Bad and inhibited the ATO - induced increase of Bcl - xL , overcoming ATO resistance in NB4 - As ( R ) . These results may provide a rationale to develop combined or sequential Q02750 inhibitors plus ATO therapy in this clinical setting .","[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK73___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .","Parathyroid hormone - responsive P84022 - related factor , Tmem119 , promotes osteoblast differentiation and interacts with the bone morphogenetic protein - Runx2 pathway . The mechanisms whereby the parathyroid hormone ( PTH ) exerts its anabolic action on bone are incompletely understood . We previously showed that inhibition of P27361 / 2 enhanced P84022 - induced bone anabolic action in osteoblasts . These findings suggested the hypothesis that changes in gene expression associated with the altered P84022 - induced signaling brought about by an P27361 / 2 inhibitor would identify novel bone anabolic factors in osteoblasts . We therefore performed a comparative DNA microarray analysis between empty vector - transfected mouse osteoblastic MC3T3 - E1 cells and PD98059 - treated stable P84022 - overexpressing MC3T3 - E1 cells . Among the novel factors , Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF - β . The levels of Tmem119 increased with time in cultures of MC3T3 - E1 cells and mouse mesenchymal ST - 2 cells committed to the osteoblast lineage by P12643 . PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3 - E1 cells . MC3T3 - E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2 , osteocalcin , alkaline phosphatase , and β - catenin , whereas Tmem119 augmented P12643 - induced Runx2 levels in mesenchymal cells . Tmem119 interacted with Runx2 , Q15797 , and Q99717 in C2C12 cells . In conclusion , we identified a P84022 - related factor , Tmem119 , that is induced by PTH and promotes differentiation in mouse osteoblastic cells . Tmem119 is an important molecule in the pathway downstream of PTH and P84022 signaling in osteoblasts .","TG - interacting factor transcriptionally induced by AKT / O43524 is a negative regulator that antagonizes arsenic trioxide - induced cancer cell apoptosis . DB01169 ( ATO ) is a multi - target drug approved by the Food and Drug Administration as the first - line chemotherapeutic agent for the treatment of acute promyelocytic leukemia . In addition , several clinical trials are being conducted with arsenic - based drugs for the treatment of other hematological malignancies and solid tumors . However , ATO ' s modest clinical efficacy on some cancers , and potential toxic effects on humans have been reported . Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue . Previously , we demonstrated that the JNK - induced complex formation of phosphorylated c - Jun and TG - interacting factor ( Q15583 ) antagonizes P29323 - induced cyclin - dependent kinase inhibitor P38936 ( P38936 ( P38936 / CIP1 ) ) expression and resultant apoptosis in response to ATO in A431 cells . Surprisingly , at low - concentrations ( 0 . 1 - 0 . 2 μM ) , ATO increased cellular proliferation , migration and invasion , involving Q15583 expression , however , at high - concentrations ( 5 - 20 μM ) , ATO induced cell apoptosis . Using a promoter analysis , Q15583 was transcriptionally regulated by ATO at the O43524 binding site ( - 1486 to - 1479bp ) via the c - Src / P00533 / AKT pathway . Stable overexpression of Q15583 promoted advancing the cell cycle into the S phase , and attenuated 20 μM ATO - induced apoptosis . Furthermore , blockage of the AKT pathway enhanced ATO - induced P38936 expression and resultant apoptosis in cancer cells , but overexpression of P31749 inhibited P38936 expression . Therefore , we suggest that Q15583 is transcriptionally regulated by the c - Src / P00533 / AKT pathway , which plays a role as a negative regulator in antagonizing ATO - induced P38936 expression and resultant apoptosis . Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO .","P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .","A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .","Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .","The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .","___MASK83___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK83___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK83___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK83___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK83___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .","P28482 , but not P27361 , mediates acquired and \" de novo \" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .","Induction of graft - versus - leukemia ( GVL ) effect without graft - versus - host disease ( GVHD ) by pretransplant donor treatment with immunomodulators . Pretransplant donor treatment with immunomodulators such as complete Freund ' s adjuvant ( O75347 ) or oligodeoxynucleotide sequences expressing CpG motifs ( CpG ) , was applied in sublethally irradiated host mice inoculated with murine models of mammary carcinoma ( 4T1 ) or B cell leukemia ( P24385 ) . Spleen cells or P60568 activated splenocytes ( lymphokine activated killer [ Q96QP1 ] ) derived from donor mice treated with CpG emulsified in incomplete Freund ' s adjuvant ( IFA ) , ( CpG + IFA ) did not cause graft - versus - host disease ( GVHD ) , but were not efficient enough to induce a significant graft - versus - tumor ( GVT ) response against 4T1 cells . In contrast , an efficient graft - versus - leukemia ( GVL ) effect was evident in P24385 - bearing mice inoculated with spleen cells from donors pretreated with O75347 or CpG + IFA . Pretransplant donor treatment with O75347 prolonged survival to a median of 62 days with 3 of 27 mice remaining GVHD - and leukemia - free for > 200 days , compared to GVHD - related death of all mice inoculated with naïve cells ( median 17 days ) , or leukemia - related death of all mice inoculated with leukemia cells ( median of 27 days ) . Pretransplant donor treatment with CpG + IFA exerted a more efficient GVL effect with reduced GVHD resulting in 12 of 26 GVHD - and leukemia - free survivors for > 200 days . Our results suggest that it may be possible to prevent GVHD while sparing an efficient GVL effect by using pretransplant donor treatment with immunomodulators prior to allogeneic stem cell transplantation and / or donor lymphocyte infusions in hematologic malignancies .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK75___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided ."],"string":"[\n \"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK55___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .\",\n \"Involvement of peroxisome proliferator - activated receptor gamma in gonadal steroidogenesis and steroidogenic acute regulatory protein expression . Peroxisome proliferator - activated receptor ( Q07869 ) gamma belongs to the Q07869 family of nuclear transcription factors whose ligands , such as eicosanoids , fatty acids and prostaglandins , are known to affect gonadal function . Although several of these enhance the expression of the steroidogenic acute regulatory protein ( STAR ) and steroid production , the role of PPARgamma in regulating STAR - mediated steroidogenesis remains unclear . In the present study , we used ciglitazone to selectively activate PPARgamma and examine its role in STAR - mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA - 10 mouse Leydig tumour cells . Cotreatment with both dibutyryl - DB02527 and ciglitazone revealed a dose - dependent , significant increase in progesterone synthesis , Star promoter activity , Star mRNA and STAR protein relative to either compound alone . The overexpression of PPARgamma further increased Star - promoter activity . The ciglitazone - induced activity of the Star - promoter appears to be mediated through the DB02527 - response element half - sites located within its proximal 151 bp . Combined treatment with ciglitazone and dibutyryl - DB02527 significantly increased the expression and activity of transcriptional pathways impacted by the activator protein - 1 family member c - P05412 . The present study demonstrates that ciglitazone and dibutyryl - DB02527 synergistically enhance STAR expression in MA - 10 and KK1 cells . DB09201 - activated PPARgamma appears to increase the sensitivity of Leydig and granulosa cells to DB02527 stimulation , possibly via upregulation of c - P05412 expression .\",\n \"Metallothionein prevention of arsenic trioxide - induced cardiac cell death is associated with its inhibition of mitogen - activated protein kinases activation in vitro and in vivo . Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent . The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress . Metallothionein ( MT ) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress - induced cardiac damage . To investigate whether and how MT protects against arsenic cardiotoxicity , MT - overexpressing H9c2 ( MT - H9c2 ) cardiac cells and transgenic ( MT - TG ) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide . Cardiac cell apoptosis was detected by molecular indices , including the cleavage of caspase 3 and caspase 12 , Bax / Bcl2 expression ratio , P35638 expression and / or confirmed by a terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assay . DB01169 dose - and time - dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as P27361 / 2 , JNK and p38 , but not in MT - H9c2 cells . Importantly , the protective effect of MT on arsenic trioxide - induced apoptotic cell death was completely recaptured in the heart of MT - TG with a significant prevention of MAPKs activation . These results indicate that arsenic trioxide - upregulated MAPKs might play important role in arsenic trioxide - induced apoptotic cell death in cardiac cells both in vivo and in vitro , and MT ' s suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation . Therefore , selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity .\",\n \"P04150 - mediated regulation of P14780 gene expression in human ovarian surface epithelial cells . OBJECTIVE : To obtain proof - of - concept that locally produced anti - inflammatory steroids suppress ovulation - associated extracellular matrix proteases in human ovarian surface epithelial ( OSE ) cells . DESIGN : Primary OSE cell cultures treated with interleukin - 1alpha ( IL - 1alpha ) ( 500 pg / mL ) as proxy for inflammation , with / without anti - inflammatory steroid ( cortisol or progesterone [ P ] , 0 . 01 - 1 . 0 microM ) . SETTING : Academic medical center . PATIENT ( S ) : Sixteen premenopausal women ( 29 - 46 years ) undergoing surgery for nonmalignant gynecological conditions . MAIN OUTCOME MEASURE ( S ) : Semiquantitative extracellular matrix protease gene expression profiling with verification by real - time quantitative reverse transcription polymerase chain reaction ( qRT - PCR ) and gelatinase zymography . RESULT ( S ) : Treatment with IL - 1alpha stimulated messenger RNA ( mRNA ) expression of several ovulation - associated matrix metalloproteinase genes by OSE cell cultures , including gelatinase B ( P14780 ) but not gelatinase A ( P08253 ) . The IL - 1alpha - stimulated P14780 mRNA production was suppressed by cortisol but not P . ___MASK81___ but not P also dose - dependently suppressed IL - 1alpha - stimulated P14780 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist DB00834 . CONCLUSION ( S ) : In human OSE cells , stimulation of P14780 gene expression and proteolytic activity by IL - 1alpha is suppressed by anti - inflammatory cortisol through a glucocorticoid receptor - mediated mechanism . Because IL - 1alpha also generates cortisol formation in OSE by stimulating cortisone reductase activity , these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation .\",\n \"O75915 is required for arsenic trioxide induced apoptosis in HeLa and MCF - 7 cells via reactive oxygen species and mitochondria linked signal pathway . DB01169 , emerging as a standard therapy for refractory acute promyelocytic leukemia , induces apoptosis in a variety of malignant cell lines . O75915 , a novel retinoic acid - inducible gene , is known to be involved in apoptosis induced by various agents , for example , 12 - O - tetradecanoylphorbol 13 - acetate , N - 4 - hydroxy - phenyl - retinamide and arsenic trioxide . However , the molecular mechanisms underlying how O75915 gene is functionally involved in apoptosis remain largely unknown . Herein , our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF - 7 cells in a dose - dependent manner and paralleled with increased O75915 expression . O75915 expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide . Knockdown of O75915 attenuated arsenic trioxide induced apoptosis , and was accompanied by significantly reduced activity of caspase - 9 , enhanced Bad phosphorylation and inhibited Q02750 / 2 , P27361 / 2 and JNK phosphorylations . DB01169 induced loss of mitochondrial transmembrane potential was O75915 - dependent . These findings suggest that O75915 may serve as a pro - apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria - associated signal pathway .\",\n \"Synergistic inhibition of colon carcinoma cell growth by Hedgehog - Gli1 inhibitor arsenic trioxide and phosphoinositide 3 - kinase inhibitor LY294002 . The Hedgehog ( Hh ) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis , but also in tumorigenesis . Aberrant Hh pathway activation has been reported in a variety of malignant tumors including colon carcinoma . Here , we sought to investigate the regulation of the Hh pathway transcription factor Gli1 by arsenic trioxide and phosphoinositide 3 - kinase ( PI3K ) inhibitor LY294002 in colon carcinoma cells . We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells , which was confirmed by quantitative real - time polymerase chain reaction and Western blots . Knocking down endogenous Gli1 reduced colon carcinoma cell viability through inducing cell apoptosis . Similarly , knocking down Gli2 using short interfering RNA impaired colon carcinoma cell growth in vitro . To elucidate the regulation of Gli1 expression , we found that both Gli inhibitor arsenic trioxide and PI3K inhibitor LY294002 significantly reduced Gli1 protein expression and colon carcinoma cell proliferation . DB01169 treatment also reduced Gli1 downstream target gene expression , such as Bcl2 and P24385 . More importantly , the inhibition of Hedgehog - Gli1 by arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor LY294002 in colon carcinoma cells . Our findings suggest that the Hh pathway transcription factor Gli1 is involved in the regulation of colon carcinoma cell viability . Inhibition of Hedgehog - Gli1 expression by arsenic trioxide and PI3K inhibitor synergistically reduces colon cancer cell proliferation , indicating that they could be used as an effective anti - colon cancer combination therapy .\",\n \"DB00644 - regulated expression of Jun and P05412 target genes in gonadotropes requires a functional interaction between TCF / LEF family members and beta - catenin . DB00644 regulates gonadotrope function through a complex transcriptional network that includes three members of the immediate early gene family : Egr1 , Jun , and Atf3 . These DNA - binding proteins act alone or in pairs to confer hormonal responsiveness to Cga , Lhb , Fshb , and Gnrhr . Herein we suggest that the transcriptional response of Jun requires a functional interaction between the T - cell factor ( TCF ) / lymphoid enhancer factor ( LEF ) family of DNA - binding proteins and beta - catenin ( officially P35222 ) , a coactivator of TCF / LEF . Supporting data include demonstration that DB00644 increases activity of TOPflash , a TCF / LEF - dependent luciferase reporter , in LbetaT2 cells , a gonadotrope - derived cell line . Additional cotransfection experiments indicate that a dominant - negative form of Q9NQB0 ( TCFDN ) that binds DNA , but not beta - catenin , blocks DB00644 induction of TOPflash . Overexpression of O15169 , an inhibitor of beta - catenin , also reduces DB00644 stimulation of TOPflash . Transduction of LbetaT2 cells with TCFDN adenoviruses diminishes DB00644 stimulation of Jun mRNA without altering expression of Egr1 and Atf3 , two other immediate early genes that confer DB00644 responsiveness . Reduction of beta - catenin in LbetaT2 cells , through stable expression of short hairpin RNA , also selectively compromises DB00644 regulation of Jun expression and levels of P05412 protein . Finally , overexpression of TCFDN attenuates DB00644 regulation of Cga promoter activity , a known downstream target of P05412 . Together , these results indicate that DB00644 regulation of Jun transcription requires a functional interaction between TCF / LEF and beta - catenin and that alteration of either impacts expression of P05412 downstream targets such as Cga .\",\n \"Dominant negative P13500 blocks human osteoclast differentiation . Human osteoclasts were differentiated using receptor activator of NFκB ligand ( O14788 ) and macrophage colony stimulating factor ( P09603 ) from colony forming unit - granulocyte macrophage ( CFU - GM ) precursors of the myeloid lineage grown from umbilical cord blood . Gene expression profiling using quantitative polymerase chain reaction ( Q - PCR ) showed more than 1 , 000 - fold induction of chemokine P13500 within 24 h of O14788 treatment . P13500 mRNA content exceeds that of other assayed chemokines ( P22362 , 3 , 4 , and 5 ) at all time points up to day 14 of treatment . P13500 induction preceded peak induction of calcium signaling activator calmodulin 1 ( P62158 ) and transcription factors P05412 and P01100 , which were at 3 days . Key osteoclast related transcription factors O95644 and Q13469 showed peak induction at 7 days , while marker genes for osteoclast function cathepsin K and tartrate resistance acid phosphatase ( TRAP ) were maximally induced at 14 days , corresponding with mature osteoclast function . To test whether the early and substantial peak in P13500 expression is part of human osteoclast differentiation events , a dominant negative inhibitor of P13500 ( 7ND ) was added simultaneously with O14788 and P09603 , resulting in blockade of P62158 , P05412 and Q13469 induction and strong inhibition of human osteoclast differentiation . These data show that a cascade of gene expression leading to osteoclast differentiation depends on intact early P13500 induction and signaling in human osteoclasts .\",\n \"Antitumor activity of arsenic trioxide on retinoblastoma : cell differentiation and apoptosis depending on arsenic trioxide concentration . PURPOSE : DB01169 ( ATO ) targets multiple pathways in malignant cells , resulting in the promotion of differentiation or in the induction of apoptosis . The antitumor activity of ATO on retinoblastoma was investigated . METHODS : Human retinoblastoma cells were incubated with various ATO concentrations . The antiproliferative effect of ATO was evaluated by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay , and the effect of ATO on cell - cycle progression was validated by flow cytometry . At a low concentration , the ATO - induced differentiation of retinoblastoma cells was evaluated by neurofilament expression and extracellular signal - regulated kinase ( P29323 ) 1 / 2 activation , which was confirmed by the inhibition of P27361 / 2 . At a high concentration , ATO - induced H ( 2 ) O ( 2 ) production was investigated with the cell - permeable fluorescent dye 2 ' 7 '- dichlorofluorescein - diacetate , and the relationship of ATO - induced H ( 2 ) O ( 2 ) production with caspase - 3 - dependent apoptosis was validated by Western blot and 4 ' 6 - diamidino - 2 - phenolindole staining , which was confirmed by reactive oxygen species ( ROS ) inhibition . The effect of ATO on tumor formation was assessed with an orthotopic animal model of retinoblastoma . RESULTS : The antitumor activity of ATO in retinoblastoma was related to two main mechanisms , differentiation and apoptosis , which were determined by the level of ATO . At a low dose ( < or = 1 microM ) , ATO induced the differentiation of retinoblastoma cells through P27361 / 2 activation , whereas ROS generation by a high dose ( > or = 2 microM ) of ATO induced apoptosis in retinoblastoma cells . Moreover , ATO at low and high doses effectively inhibited tumor formation . CONCLUSIONS : These results suggest that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma .\",\n \"Q99706 differentially signals downstream functions in human NK cells through distinct structural modules . Q99706 ( 2DL4 ) is a member of the killer cell Ig - like receptor ( P55040 ) family in human NK cells . It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells , but the mechanism for 2DL4 - mediated signaling remains unclear . In this study we characterized the signaling pathways stimulated by 2DL4 engagement . In a human NK - like cell line , KHYG - 1 , cross - linking of 2DL4 activated MAPKs including JNK , P29323 , and p38 . Furthermore , 2DL4 cross - linking resulted in phosphorylation of O15111 beta ( IKKbeta ) and the phosphorylation and degradation of P25963 , which indicate activation of the classical NF - kappaB pathway . Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes , including P01375 , P01579 , MIP1alpha , MIP1beta , and P10145 . Pharmacological inhibitors of JNK , Q02750 / 2 and p38 , blocked P01579 , P10145 , and MIP1alpha production , suggesting that MAPKs are regulating 2DL4 - mediated cytokine production in a nonredundant manner . Activation of both p38 and P29323 appear to be upstream of the stimulation of NF - kappaB . Mutation of a transmembrane arginine in 2DL4 to glycine ( R / G mutant ) abrogated FcepsilonRI - gamma association , as well as receptor - mediated cytolytic activity and calcium responses . Surprisingly , the R / G mutant still activated MAPKs and the NF - kappaB pathway and selectively stimulated the production of MIP1alpha , but not that of P01579 or P10145 . In conclusion , we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules : 1 ) through transmembrane association with FcepsilonRI - gamma ; and 2 ) through another receptor domain independent of the transmembrane arginine .\",\n \"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK13___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK13___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .\",\n \"Cbl - b is a negative regulator of inflammatory cytokines produced by IgE - activated mast cells . c - Cbl and Cbl - b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow - derived mast cells from c - Cbl and Cbl - b - deficient mice it has recently been shown that Cbl - b is the dominant family member for negatively regulating signaling responses from high - affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl - b - deficient mice is the relatively higher levels of Cbl - b protein over c - Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c - Cbl and Cbl - b - deficient mice and find that loss of Cbl - b , but not c - Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl - b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl - b or c - Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl - b (-/-) mast cells compared with levels produced by c - Cbl (-/-) or wild - type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl - b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions .\",\n \"Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .\",\n \"AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 / MAPK , the PI3K / AKT / P42345 and the JAK / P40763 pathways . Here , we tested the efficacy of a P23458 / 2 - inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC - 1 ) , P07949 M918T ( MZ - CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC - 1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and / or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC - 1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC - 1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho - Y1062 P07949 levels , and P42345 effector phospho - S6 , while P23458 / 2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e . g . via JAK / phospho - P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK41___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK41___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK41___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK41___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"___MASK13___ inhibition effect on KITAsn822Lys - mediated signal transduction cascade . OBJECTIVE : Alterations in growth factor signaling pathways may be a frequent collaborating event in Q01196 - Q06455 - mediated leukemogenesis . Gain - of - function P10721 receptor mutations have been reported in adult AML patients , especially those with core binding factor leukemia ( CBFL ) . We have previously reported a new gain - of - function P10721 ( Asn822Lys ) mutation that is constitutively expressed in the Kasumi - 1 CBFL cell line , and has recently been described in two childhood AML patients . To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation , we investigated P10721 downstream signaling in the Kasumi - 1 cell line by means of ___MASK13___ ( Imatinib , Gleevec ) pharmacological inhibition . MATERIALS AND METHODS : We investigated P10721 ( Asn822Lys ) mutant - initiated signaling in Kasumi - 1 cell line , and characterized the inhibitory effect of the ___MASK13___ protein tyrosine kinase inhibitor on downstream signaling . RESULTS : The use of ___MASK13___ - mediated inhibition impaired the tyrosine phosphorylation of P10721 ( Asn822Lys ) and its association with the p85 subunit of phosphatidylinositol 3 '- kinase ( p85PI3K ) . The downstream constitutive phosphorylation of P45983 / 2 and P40763 was also significantly inhibited , but ___MASK13___ had no effect on the constitutive activation of Akt , thus suggesting that it is due to other signaling in Kasumi - 1 cells . ___MASK13___ inhibited the P10721 - mediated proliferation of Kasumi - 1 cells in a dose - dependent manner . CONCLUSIONS : These findings show the role of PI3K in P10721 ( Asn822Lys )- mediated constitutive activation through the Akt - independent downstream signaling pathway of JNK , and also demonstrate the mutant ' s susceptibility to ___MASK13___ , which may therefore have therapeutic potential in CBFL patients with susceptible P10721 mutations .\",\n \"Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis - related genes peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) , CCAAT / enhancer binding protein - alpha ( C / EBP - α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis - related genes and P27361 / 2 activation in adipocytes .\",\n \"Proangiogenesis action of the thyroid hormone analog 3 , 5 - diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (- 8 )- 10 (- 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3 , 5 - diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three - dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 )- agarose , as well as basic fibroblast growth factor ( b - FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three - dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b - FGF was blocked by PD 98059 , an inhibitor of the P27361 / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b - FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta3 , and are MAPK dependent .\",\n \"SnoN / SkiL expression is modulated via arsenic trioxide - induced activation of the PI3K / AKT pathway in ovarian cancer cells . SnoN / SkiL ( TGFβ regulator ) is dysregulated in ovarian cancer , a disease associated with acquired drug - resistance . DB01169 ( As₂O₃ , used in treating APL ) induces SnoN to oppose the apoptotic response in ovarian cancer cells . We now report that As₂O₃ increases phosphorylation of P00533 / p66ShcA and P00533 degradation . As₂O₃ activates Src ( Y416 ) whose activity ( inhibited by Q99463 ) modulates P00533 activation , its interaction with Shc / Grb2 , and p - AKT . Inhibition of PI3K reduces SnoN and cell survival . Although P00533 or P28482 siRNA did not alter SnoN expression , As₂O₃ - induced cleaved PARP was reduced together with increased P98170 . Collectively , As₂O₃ mediates an initial rise in pY - Src ( 416 ) to regulate the PI3K / AKT pathway which increases SnoN and cell survival ; these early events may counter the cell death response associated with increased pY - P00533 / MAPK activation .\",\n \"DB01169 phosphorylates c - Fos to transactivate P38936 ( P38936 / CIP1 ) expression . An infamous poison , arsenic also has been used as a drug for nearly 2400 years ; in recently years , arsenic has been effective in the treatment of acute promyelocytic leukemia . Increasing evidence suggests that opposite effects of arsenic trioxide ( ATO ) on tumors depend on its concentrations . For this reason , the mechanisms of action of the drug should be elucidated , and it should be used therapeutically only with extreme caution . Previously , we demonstrated the opposing effects of P27361 / 2 and JNK on P38936 ( P38936 / CIP1 ) ( P38936 ) expression in response to ATO in A431 cells . In addition , JNK phosphorylates c - Jun ( DB00133 ( 63 / 73 ) ) to recruit Q15583 / Q13547 to suppress P38936 gene expression . Presently , we demonstrated that a high concentration of ATO sustains P27361 / 2 phosphorylation , and increases c - Fos biosynthesis and stability , which enhances P38936 gene expression . Using site - directed mutagenesis , a DNA affinity precipitation assay , and functional assays , we demonstrated that phosphorylation of the C - terminus of c - Fos ( DB00156 ( 232 ) , DB00156 ( 325 ) , DB00156 ( 331 ) , and DB00133 ( 374 ) ) plays an important role in its binding to the P38936 promoter , and in conjunction with N - terminus phosphorylation of c - Fos ( DB00133 ( 70 ) ) to transactivate P38936 promoter expression . In conclusion , a high concentration of ATO can sustain P27361 / 2 activation to enhance c - Fos expression , then dimerize with dephosphorylated c - Jun ( DB00133 ( 63 / 73 ) ) and recruit p300 / CBP to the Sp1 sites ( - 84 /- 64 ) to activate P38936 gene expression in A431 cells .\",\n \"DB01169 concentration determines the fate of Ewing ' s sarcoma family tumors and neuroblastoma cells in vitro . DB01169 ( As ( 2 ) O ( 3 ) ) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner . We assessed the effects of As ( 2 ) O ( 3 ) in CADO - ES Ewing ' s sarcoma ( ES ) , JK - GMS peripheral primitive neuroectodermal tumor ( PNET ) , and SH - SY5Y neuroblastoma cells , as they share common histogenetic backgrounds . As ( 2 ) O ( 3 ) at low concentrations ( 0 . 1 - 1 microM ) induced SH - SY5Y differentiation , and whereas PNET cells acquired a slightly differentiated phenotype , change was minimal in ES cells . P28482 ( P28482 ) was activated at low As ( 2 ) O ( 3 ) concentrations , and PD98059 , an inhibitor of MEK - 1 , blocked SH - SY5Y cell differentiation by As ( 2 ) O ( 3 ) . High concentrations ( 2 - 10 microM ) of As ( 2 ) O ( 3 ) induced the apoptosis in all three cell lines , and this was accompanied by the activation of c - jun N - terminal kinase . The generation of H ( 2 ) O ( 2 ) and activation of caspase 3 were identified as critical components of As ( 2 ) O ( 3 )- induced apoptosis in all of the above cell lines . P09038 enhanced As ( 2 ) O ( 3 )- induced apoptosis in JK - GMS cells . The overall effects of As ( 2 ) O ( 3 ) strongly suggest that it has therapeutic potential for the treatment of ES / PNET .\",\n \"Oxidative stress - induced p53 activity is enhanced by a redox - sensitive Q96A56 SUMOylation . Tumor Protein p53 - Induced Nuclear Protein 1 ( Q96A56 ) is a tumor suppressor that modulates the p53 response to stress . Q96A56 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes . Q96A56 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development . In this work , we report that redox - dependent induction of p53 transcriptional activity is enhanced by the oxidative stress - induced SUMOylation of Q96A56 at lysine 113 . This SUMOylation is mediated by Q9Y6X2 and O00257 , two SUMO ligases especially related to the p53 activation upon DNA damage . Importantly , this modification is reversed by three P63165 - specific proteases Q9P0U3 , 2 and 6 . Moreover , Q96A56 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions . Q96A56 mutation at lysine 113 prevents the pro - apoptotic , antiproliferative and antioxidant effects of Q96A56 by impairing the p53 response on its target genes P38936 , Bax and PUMA . We conclude that Q96A56 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress .\",\n \"In vitro and in vivo effects of the Q07869 agonists fenofibrate and retinoic acid in endometrial cancer . Fenofibrate , an agonist of Q07869 , in doses above 25 microM , inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells . We show that these effects are potentiated by retinoic acid , an agonist of the retinoid - Q9UBH6 . DNA content analysis shows that P55008 / S phase progression through the cell cycle is inhibited . Independent Component Analysis of gene microarray experiments demonstrated downregulation of P12004 D1 ( P24385 ) and associated changes in cell cycle gene expression . Expression of Q07869 mRNA was reduced by > 75 % using RNA - interference but this resulted in only minor changes in biological effects . A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth . CONCLUSION : The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro .\",\n \"Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems . This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT - PCR . We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia . Twenty types of chromosomal abnormalities were detected in 42 % from all patients by commercially available multiplex RT - PCR for detecting 28 fusion genes and in 35 % by cytogenetic analysis including Q5TCZ1 analysis . The most common cytogenetic aberrations in acute myeloid leukemia patients was P29590 / PARA , followed by Q01196 / MGT8 and Q03164 , and in acute lymphoid leukemia patients was P11274 / P00519 , followed by P41212 / Q01196 and Q03164 gene rearrangement . Among the negative results for multiplex RT - PCR , clinically significant t ( 3 ; 3 )( q21 ; q26 . 2 ) , t ( 8 ; 14 )( q24 ; q32 ) and i ( 17 )( q10 ) were detected by conventional cytogenetics . The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies , and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems .\",\n \"Lytic activity of P60568 and IL - 12 stimulated NK cells against Q9UKB1 osteosarcoma cell line . NK cells are CD16 , CD56 positive lymphocytes that spontaneously lyse tumor or virus infected cells . In this study we investigated whether P60568 and / or IL - 12 stimulated NK cells increased their lytic efficiency against Q9UKB1 osteosarcoma cell line . Our results demonstrate that both 18 hour and 5 day incubation times enhanced the lytic activity of human PBL against Q9UKB1 and K562 target cells and that IL - 12 appears to be more efficient than P60568 in augmenting NK cytotoxicity .\",\n \"Synergism of Q9HC29 and Q96P20 activators promotes a unique transcriptional profile in murine dendritic cells . NLRs are cytoplasmic proteins that sense cellular stress and intracellular damage resulting from pathogen uptake . To date , the role of NLRs has been studied using combinations of NLR and TLR agonists , but the interplay between two different NLRs remains uncharacterized . In this study , we employed microarrays to investigate in DCs the regulation of gene transcription mediated by activation of Q9HC29 and Q96P20 pathways using P16444 and MSU . P16444 and MSU co - stimulation of murine BMDCs up - regulated the expression of genes encoding molecules for antigen presentation and co - stimulation ( MHC class II , P33681 , P42081 ) , integrins ( P05106 , P06756 ) , cytokines ( IL - 1α , IL - 1β , P05231 , P60568 , Q9NPF7 , IL - 12p40 ) , and chemokines ( P09341 , P19875 ) . Transcription of the cytokine genes induced by P16444 and MSU partially depended on Q9HC29 but was independent of Q96P20 . Finally , we showed that P27361 and c - P05412 activation increased upon P16444 and MSU co - stimulation . As a whole , the results indicate that two different NLR activators synergize at the transcriptional level , leading to unique differential expression of genes involved in the innate immune response .\",\n \"DB01169 inhibits osteosarcoma cell invasiveness via MAPK signaling pathway . DB01169 ( As ( 2 ) O ( 3 ) ) is an active ingredient in traditional Chinese medicine . Recent studies showed that it causes apoptosis in several cancer cells . However , research of As ( 2 ) O ( 3 ) in osteosarcoma is sparse . In our present study , an inhibitory effect of As ( 2 ) O ( 3 ) on osteosarcoma cell adhesion and metastasis was observed with a cell adhesion , migration and invasion test . The impact of As ( 2 ) O ( 3 ) on the activities of P14780 and MAPK pathway - related downstream factors was analyzed by western blotting . Our results showed that As ( 2 ) O ( 3 ) significantly inhibited motility , migration and invasion in Q9UKB1 and MNNG cells in a concentration - dependent manner at concentrations ranging from 0 . 5 - 2 μM , and led to cytoskeletal rearrangements . As ( 2 ) O ( 3 ) exerted an inhibitory effect on the phosphorylation of P27361 / 2 and MEK , which are the members of the MAPK family . Additionally , treatment with As ( 2 ) O ( 3 ) in combination with inhibitors specific for MEK ( U0126 ) in Q9UKB1 and MNNG cells resulted in a marked inhibition of cell invasion and As ( 2 ) O ( 3 ) could significantly reduce PMA - induced invasion . In conclusion , we demonstrate the inhibitory effects of As ( 2 ) O ( 3 ) on the invasiveness of Q9UKB1 and MNNG cells , which may be due at least partly to inactivation of the MAPK signaling pathway .\",\n \"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK3___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .\",\n \"Chronically increased ciliary neurotrophic factor and fibroblast growth factor - 2 expression after spinal contusion in rats . Demyelination and oligodendrocyte loss following spinal cord injury ( SCI ) are well documented . Recently , we showed oligodendrocyte progenitor cell ( OPC ) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders . We have since begun investigating potential mechanisms for this endogenous repair response . Here , we examined ciliary neurotrophic factor ( P26441 ) and fibroblast growth factor - 2 ( P09038 ) expression , because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders . We hypothesized that P26441 and P09038 would increase after SCI , especially in regions of enhanced oligogenesis . First , P26441 protein was quantified using Western blots , which revealed that P26441 protein continually rose through 28 days post injury ( dpi ) . Next , by using immunohistochemistry , we examined the spatiotemporal expression of P26441 in cross - sections spanning the injury site . P26441 immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords . Significantly increased P26441 was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls . By 28 dpi , P26441 expression was significantly higher along lesion borders compared with outlying spared tissue ; a similar distribution of phosphorylated P40763 , a transcription factor up - regulated by P26441 and to a lesser extent P09038 , was also detected . Because P26441 can potentiate P09038 expression , we examined the distribution of P09038 + cells . Significantly more P09038 + cells were noted along lesion borders at 7 and 28 dpi . Thus , both P26441 and P09038 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury - induced gliogenesis .\",\n \"A metabolic prosurvival role for P29590 in breast cancer . Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression . However , the genetic cues modulating this metabolic switch remain largely undetermined . We identified a metabolic function for the promyelocytic leukemia ( P29590 ) gene , uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival . We found that P29590 acted as both a negative regulator of PPARγ coactivator 1A ( Q9UBK2 ) acetylation and a potent activator of Q07869 signaling and fatty acid oxidation . We further showed that P29590 promoted DB00171 production and inhibited anoikis . Importantly , P29590 expression allowed luminal filling in 3D basement membrane breast culture models , an effect that was reverted by the pharmacological inhibition of fatty acid oxidation . Additionally , immunohistochemical analysis of breast cancer biopsies revealed that P29590 was overexpressed in a subset of breast cancers and enriched in triple - negative cases . Indeed , P29590 expression in breast cancer correlated strikingly with reduced time to recurrence , a gene signature of poor prognosis , and activated Q07869 signaling . These findings have important therapeutic implications , as P29590 and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression , a potential future mode of cancer prevention and treatment .\",\n \"Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : ___MASK75___ is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2 - mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes .\",\n \"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK75___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK75___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .\",\n \"Systematic review : diet - gene interactions and the risk of colorectal cancer . BACKGROUND : Diet contributes significantly to colorectal cancer ( CRC ) aetiology and may be potentially modifiable . AIM : To review diet - gene interactions , aiming to further the understanding of the underlying biological pathways in CRC development . METHODS : The PubMed and Medline were systematically searched for prospective studies in relation to diet , colorectal cancer and genetics . RESULTS : In a meta - analysis , no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found ( P - value for interaction 0 . 95 ) . We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC . High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype , whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC ( OR = 1 . 25 ; 95 % confidence interval ( CI ) : 0 . 92 - 2 . 01 ) compared with slow acetylators with low meat intake ( reference ) , P - value for interaction = 0 . 07 . Low meat intake in the studied populations may influence the result . Interactions between meat , cruciferous vegetables , fibres , calcium , vitamins , and alcohol and P08183 , P19838 , P09488 , P30711 , P24385 , P11473 , MGTM , P22301 and P37231 are suggested . CONCLUSIONS : A number of interactions between genetic variation and diet are suggested , but the findings need replication in independent , prospective , and well - characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached . When the above criteria are met , studies on diet - gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis .\",\n \"Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6 . 1 - composed K - DB00171 channels expressed in neural stem cells . BACKGROUND AND PURPOSE : Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases . Iptakalim ( Ipt ) , a novel DB00171 - sensitive potassium ( K - DB00171 ) channel opener , has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro . However , it remains unknown whether Ipt could regulate the adult neurogenesis . METHODS AND RESULTS : Based on the finding that adult neural stem cells ( ANSCs ) in hippocampus expressed Kir6 . 1 / Q09428 - composed K - DB00171 channel , Kir6 . 1 heterozygotic ( Kir6 . 1 (+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis . We showed that administration of Ipt ( 10 mg / kg ) or fluoxetine ( Flx , 10 mg / kg ) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ ) of Kir6 . 1 (+/+) mice but failed to affect those of Kir6 . 1 (+/-) mice . Meanwhile , ANSCs in Kir6 . 1 (+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes . We further found that Kir6 . 1 (+/-) mice showed lower level of brain - derived neurotrophic factor ( P23560 ) in hippocampus compared with Kir6 . 1 (+/+) mice . Furthermore , Ipt increased the levels of P23560 and basic fibroblast growth factor ( P09038 ) throughout the hippocampus in Kir6 . 1 (+/+) mice but not in Kir6 . 1 (+/-) mice . Moreover , Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6 . 1 (+/+) mice . Notably , these effects were completely abolished in Kir6 . 1 (+/-) mice . CONCLUSIONS : Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6 . 1 - composed K - DB00171 channels , which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency , such as major depression .\",\n \"Effects of leptin and adiponectin on proliferation and protein metabolism of porcine myoblasts . The aim of this study was to show the abundance of leptin and adiponectin receptors ( LEPR , Q96A54 , Q86V24 ) and to determine the direct effects of leptin and adiponectin on the in vitro growth of porcine skeletal muscle cells . Q96A54 and Q86V24 were abundant at mRNA and protein level in proliferating and differentiating myoblast cultures derived from semimembranosus and semitendinosus muscles of newborn piglets , whereas LEPR expression was close to the detection limit . Q15848 ( 10 , 20 , 40 μg / ml ) attenuated the proliferation of porcine myoblasts , measured as [ ( 3 ) H ] - thymidine incorporation and real - time monitoring of the cells in response to 24 - and 48 - h exposure , in a dose - dependent manner . This effect resulted from suppressed basic fibroblast growth factor ( P09038 ) - mediated stimulation of DNA synthesis in serum - free medium ( SFM ) containing P09038 . No effects of leptin ( 5 , 10 , 20 , 40 , 80 ng / ml ) on myoblast proliferation in SFM were detectable . Neither leptin nor adiponectin altered protein synthesis and degradation in differentiating porcine myoblasts cultured in SFM . The results on receptor abundance suggest that porcine skeletal muscle cells may be sensitive to adiponectin and leptin . However , except via inhibitory interaction of adiponectin with P09038 , these adipokines appear not to affect in vitro proliferation and protein metabolism of porcine muscle cells directly under serum - free culture conditions .\",\n \"Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha - reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha - reductase type I and type II , in androgen - responsive ( LNCaP ) and androgen - unresponsive ( DU145 ) human prostate cancer ( PCa ) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home - made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or = +/- 1 . 5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co - regulators ( AR ; P24385 ) , and signal transduction ( P04626 ; V - P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen - regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real - time PCR assay ( QRT - PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology .\",\n \"Activation of the p38 MAPK / Akt / P27361 / 2 signal pathways is required for the protein stabilization of Q99741 and cyclin D1 in low - dose arsenite - induced cell proliferation . DB01169 ( ATO ) is a first - line anti - cancer agent for acute promyelocytic leukemia , and induces apoptosis in other solid cancer cell lines including breast cancer cells . However , as with arsenites found in drinking water and used as raw materials for wood preservatives , insecticides , and herbicides , low doses of ATO can induce carcinogenesis after long - term exposure . At 24 h after exposure , ATO ( 0 . 01 - 1 µM ) significantly increased cell proliferation and promoted cell cycle progression from the P55008 to S / G2 phases in the non - tumorigenic MCF10A breast epithelial cell line . The expression of 14 out of 96 cell - cycle - associated genes significantly increased , and seven of these genes including cell division cycle 6 ( Q99741 ) and cyclin D1 ( P24385 ) were closely related to cell cycle progression from P55008 to S phase . Low - dose ATO steadily increased gene transcript and protein levels of both Q99741 and cyclin D1 in a dose - and time - dependent manner . Low - dose ATO produced reactive oxygen species ( ROS ) , and activated the p38 MAPK , Akt , and P27361 / 2 pathways at different time points within 60 min . Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK , Akt , and P27361 / 2 decreased the ATO - increased expression of Q99741 protein . Inhibiting the activation of Akt and P27361 / 2 , but not p38 MAPK , decreased the ATO - induced expression of cyclin D1 protein . This study reports for the first time that p38 MAPK / Akt / P27361 / 2 activation is required for the protein stabilization of Q99741 in addition to cyclin D1 in ATO - induced cell proliferation and cell cycle modulation from P55008 to S phase .\",\n \"DB01169 induces apoptosis through JNK and P29323 in human mesothelioma cells . Malignant mesothelioma is an aggressive tumor of serosal surfaces , which is refractory to current treatment options . DB01169 ( As2O3 ) is used clinically to treat acute promyelocytic leukemia , and also to inhibit proliferation of several solid tumors including hepatoma , esophageal , and gastric cancer in vitro . Here we found that As2O3 inhibited cell viability of a mesothelioma cell line , NCI - H2052 . As2O3 induced apoptosis of NCI - H2052 cells , which was accompanied by activation of c - Jun NH2 - terminal kinase ( JNK ) 1 / 2 , extracellular signal - regulated kinase ( P29323 ) 1 / 2 , and caspase - 3 . zVAD - fmk , a broad - spectrum caspase inhibitor , inhibited As2O3 - induced apoptosis and activation of caspase - 3 , but not that of P45983 / 2 and P27361 / 2 . Small interfering RNAs ( siRNAs ) targeting P45983 / 2 suppressed As2O3 - induced caspase - 3 activation and apoptosis , indicating that P45983 / 2 regulate As2O3 - induced apoptosis though caspase cascade . Furthermore , P45983 siRNA abrogated As2O3 - induced P45984 phosphorylation and P45984 siRNA abrogated As2O3 - induced P45983 phosphorylation , suggesting that P45983 and P45984 interact with each other . Moreover , P45983 siRNA , but not P45984 siRNA , abrogated As2O3 - induced P27361 / 2 phosphorylation . P45984 siRNA together with PD98059 , a specific MAPK / P29323 kinase inhibitor , suppressed As2O3 - induced apoptosis more significantly than P45984 siRNA alone . These results indicated that As2O3 induces apoptosis of NCI - H2052 cells mainly through P45983 / 2 activation , and that P27361 / 2 is involved in As2O3 - induced apoptosis when P45983 / 2 are inactivated .\",\n \"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .\",\n \"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK24___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .\",\n \"___MASK81___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK81___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .\",\n \"Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .\",\n \"P06401 membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine - induced matrix metalloproteinase 9 activity in vitro . Progesterone ( P4 ) and the progestin , 17α - hydroxyprogesterone caproate , are clinically used to prevent preterm births ( PTBs ) ; however , their mechanism of action remains unclear . Cytokine - induced matrix metalloproteinase 9 ( P14780 ) activity plays a key role in preterm premature rupture of the membranes and PTB . We demonstrated that the primary chorion cells and the HTR8 / SVneo cells ( cytotrophoblast cell line ) do not express the classical progesterone receptor ( P06401 ) but instead a novel progesterone receptor , progesterone receptor membrane component 1 ( O00264 ) , whose role remains unclear . Using HTR8 / SVneo cells in culture , we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate ( ___MASK41___ ) and dexamethasone ( DB00514 ) but not P4 or 17α - hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α - induced P14780 activity after a 24 - hour incubation period . The inhibitory effect of ___MASK41___ , but not DB00514 , was attenuated when O00264 expression was successfully reduced by O00264 small interfering RNA . Our findings highlight a possible novel role of O00264 in mediating the effects of ___MASK41___ and in modulating cytokine - induced P14780 activity in cytotrophoblast cells in vitro .\",\n \"Low doses of natural killer T cells provide protection from acute graft - versus - host disease via an P05112 - dependent mechanism . P01730 (+) natural killer T ( NKT ) cells , along with P01730 (+) CD25 (+) regulatory T cells ( Tregs ) , are capable of controlling aberrant immune reactions . We explored the adoptive transfer of highly purified ( > 95 % ) P01730 (+) NKT cells in a murine model of allogeneic hematopoietic cell transplantation ( HCT ) . NKT cells follow a migration and proliferation pattern similar to that of conventional T cells ( Tcons ) , migrating initially to secondary lymphoid organs followed by infiltration of graft - versus - host disease ( GVHD ) target tissues . NKT cells persist for more than 100 days and do not cause significant morbidity or mortality . Doses of NKT cells as low as 1 . 0 × 10 ( 4 ) cells suppress GVHD caused by 5 . 0 × 10 ( 5 ) Tcons in an interleukin - 4 ( P05112 ) - dependent mechanism . Protective doses of NKT cells minimally affect Tcon proliferation , but cause significant reductions in interferon - γ ( IFN - γ ) and tumor necrosis factor - α ( P01375 - α ) production by donor Tcons and in skin , spleen , and gastrointestinal pathology . In addition , NKT cells do not impact the graft - versus - tumor ( GVT ) effect of Tcons against B - cell lymphoma - 1 ( P24385 ) tumors . These studies elucidate the biologic function of donor - type P01730 (+) NKT cells in suppressing GVHD in an allogeneic transplantation setting , demonstrating clinical potential in reducing GVHD in HCT .\",\n \"Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma . Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia ( P29590 ) gene was significantly upregulated ( 2 . 5 - fold ) in cells positive to prominin - 1 antigen ( CD133 ) , a possible marker for cancer initiating cells . DB01169 ( As ( 2 ) O ( 3 ) ) is known to degrade P29590 protein and has been used for the treatment of patients with acute P29590 . In the present study , the effect of P29590 targeting therapy with As ( 2 ) O ( 3 ) and cytarabine ( DB00987 ) on Daoy medulloblastoma cell proliferation was investigated . Daoy cells were pretreated with As ( 2 ) O ( 3 ) for 6 weeks . The As ( 2 ) O ( 3 )- pretreated Daoy cells were cultured in medium containing DB00987 and cell viability was examined . Next , the As ( 2 ) O ( 3 )- pretreated Daoy cells were inoculated into the nude mouse brain and the effect of DB00987 on the tumor size was evaluated . A significant increase in chemosensitivity to DB00987 was observed in the As ( 2 ) O ( 3 )- pretreated Daoy cells in both in vitro and in vivo conditions . P29590 and P24385 ( cyclin D1 ) protein expression of Daoy medulloblastoma cells was downregulated by As ( 2 ) O ( 3 ) treatment . P29590 has been proposed as a novel therapeutic target to eradicate quiescent leukemia - initiating cells , and P29590 - expressing CD133 - positive cells are similarly a potential therapeutic target of treatment for medulloblastoma .\",\n \"DB01169 inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells . DB01169 ( As2O3 ) has shown therapeutic effects in some leukemias and solid cancers . However , the molecular mechanisms of its anticancer efficacy have not been clearly elucidated , particularly in solid cancers . Our previous data showed that As2O3 induced apoptosis of human papillomavirus ( HPV ) 16 DNA - immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells . In the present study , we systemically examined the effects of As2O3 on five human cervical cancer cell lines and explored the possible molecular mechanisms . MTT assay showed that HPV - negative C33A cells were more sensitive to growth inhibition induced by As2O3 than HPV - positive cervical cancer cells , and HPV 18 - positive HeLa and C4 - I cells were more sensitive to As2O3 than HPV 16 - positive CaSki and SiHa cells . After As2O3 treatment , both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines . In contrast , p53 and Rb protein levels increased in all tested cell lines . P05412 protein expression decreased significantly in HeLa , CaSki and C33A cells with ELISA method . These results suggest that As2O3 is a potential anticancer drug for cervical cancer .\",\n \"The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 - thickness , mid - small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c - Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 / CIP1 ) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt - beta - catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration .\",\n \"Q9Y5V3 mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade . Understanding the molecular events that govern neural progenitor lineage commitment , mitotic arrest , and differentiation into functional progeny are germane to our understanding of neocortical development . Members of the family of bone morphogenetic proteins ( BMPs ) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation . We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that Q9Y5V3 is a mandatory component of the signaling cascade . Q9Y5V3 possesses the ability to bind and function with the TAK1 - Q15750 - P98170 complex facilitating the activation of p38 . Disruption of Q9Y5V3 or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure . The function of Q9Y5V3 is independent of Smad signaling , but the introduction of a dominant - negative Q99717 also rescues neural progenitor apoptosis , suggesting that both canonical and noncanonical pathways can converge and regulate BMP - mediated apoptosis . Collectively , these results establish Q9Y5V3 as an integral component in BMP signaling and clarify its role during neural progenitor development .\",\n \"P03372 alpha mediates progestin - induced mammary tumor growth by interacting with progesterone receptors at the cyclin D1 / MYC promoters . Synthetic progesterone used in contraception drugs ( progestins ) can promote breast cancer growth , but the mechanisms involved are unknown . Moreover , it remains unclear whether cytoplasmic interactions between the progesterone receptor ( PR ) and estrogen receptor alpha ( ERα ) are required for PR activation . In this study , we used a murine progestin - dependent tumor to investigate the role of ERα in progestin - induced tumor cell proliferation . We found that treatment with the progestin medroxyprogesterone acetate ( ___MASK41___ ) induced the expression and activation of ERα , as well as rapid nuclear colocalization of activated ERα with PR . Treatment with the pure antiestrogen fulvestrant to block ERα disrupted the interaction of ERα and PR in vitro and induced the regression of ___MASK41___ - dependent tumor growth in vivo . ERα blockade also prevented an ___MASK41___ - induced increase in CYCLIN D1 ( P24385 ) and MYC expression . Chromatin immunoprecipitation studies showed that ___MASK41___ triggered binding of ERα and PR to the P24385 and MYC promoters . Interestingly , blockade or RNAi - mediated silencing of ERα inhibited ERα , but not PR binding to both regulatory sequences , indicating that an interaction between ERα and PR at these sites is necessary for ___MASK41___ - induced gene expression and cell proliferation . We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples . Together , our findings argued that ERα - PR association on target gene promoters is essential for progestin - induced cell proliferation .\",\n \"DB01169 - mediated antiplatelet activity : pivotal role of the phospholipase C gamma 2 - protein kinase C - p38 MAPK cascade . DB01169 produces high rates of complete clinical remission in patients with relapsed / refractory acute promyelocytic leukemia . Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases . Few studies have examined the effects of arsenic trioxide on platelets , and the mechanisms underlying the signaling pathways remain obscure . The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation . DB01169 ( 5 micromol / L ) exhibited more potent activity at inhibiting collagen ( 1 microg / mL ) - induced platelet aggregation than other agonists . DB01169 ( 15 and 25 micromol / L ) inhibited collagen - induced platelet activation accompanied by [ Ca (+ 2 )] i mobilization , thromboxane A ( 2 ) ( TxA ( 2 ) ) formation , phospholipase C ( P98160 ) gamma 2 phosphorylation , and protein kinase C ( PKC ) activation . DB01169 ( 15 and 25 micromol / L ) did not significantly affect cyclic nucleotide - induced vasodilator - stimulated phosphoprotein phosphorylation . Moreover , arsenic trioxide markedly inhibited p38 mitogen - activated protein kinase ( MAPK ) but not P45983 / 2 or P28482 phosphorylation in washed platelets . DB01169 also markedly reduced hydroxyl radical ( OH (.) ) formation in the erythrocyte sedimentation rate ( P03372 ) study . The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the P98160 gamma 2 - PKC - p38 MAPK cascade , thereby leading to inhibition of [ Ca (+ 2 )] i or free radical formation , and finally the inhibition of platelet aggregation .\",\n \"DB01169 ( ATO ) and Q02750 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells . Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras - mitogen - activated protein kinase ( MAPK ) can confer an aggressive , apoptosis - resistant phenotype to leukemia cells . In this study , we report that acute promyelocytic leukemia ( APL ) cells exploit the Ras - MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad , delaying arsenic trioxide ( ATO ) - induced apoptosis . Both in APL cell line NB4 and in APL primary blasts , the inhibition of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) and Bad phosphorylation by Q02750 inhibitors enhanced apoptosis in ATO - treated cells . We isolated an arsenic - resistant NB4 subline ( NB4 - As ( R ) ) , which showed stronger P27361 / 2 activity ( 2 . 7 - fold increase ) and Bad phosphorylation ( 2 . 4 - fold increase ) compared to parental NB4 cells in response to ATO treatment . Upon ATO exposure , both NB4 and NB4 - As ( R ) cell lines doubled protein levels of the death antagonist Bcl - xL , but the amount of free Bcl - xL that did not heterodimerize with Bad was 1 . 8 - fold greater in NB4 - As ( R ) than in the parental line . Q02750 inhibitors dephosphorylated Bad and inhibited the ATO - induced increase of Bcl - xL , overcoming ATO resistance in NB4 - As ( R ) . These results may provide a rationale to develop combined or sequential Q02750 inhibitors plus ATO therapy in this clinical setting .\",\n \"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK73___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .\",\n \"Parathyroid hormone - responsive P84022 - related factor , Tmem119 , promotes osteoblast differentiation and interacts with the bone morphogenetic protein - Runx2 pathway . The mechanisms whereby the parathyroid hormone ( PTH ) exerts its anabolic action on bone are incompletely understood . We previously showed that inhibition of P27361 / 2 enhanced P84022 - induced bone anabolic action in osteoblasts . These findings suggested the hypothesis that changes in gene expression associated with the altered P84022 - induced signaling brought about by an P27361 / 2 inhibitor would identify novel bone anabolic factors in osteoblasts . We therefore performed a comparative DNA microarray analysis between empty vector - transfected mouse osteoblastic MC3T3 - E1 cells and PD98059 - treated stable P84022 - overexpressing MC3T3 - E1 cells . Among the novel factors , Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF - β . The levels of Tmem119 increased with time in cultures of MC3T3 - E1 cells and mouse mesenchymal ST - 2 cells committed to the osteoblast lineage by P12643 . PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3 - E1 cells . MC3T3 - E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2 , osteocalcin , alkaline phosphatase , and β - catenin , whereas Tmem119 augmented P12643 - induced Runx2 levels in mesenchymal cells . Tmem119 interacted with Runx2 , Q15797 , and Q99717 in C2C12 cells . In conclusion , we identified a P84022 - related factor , Tmem119 , that is induced by PTH and promotes differentiation in mouse osteoblastic cells . Tmem119 is an important molecule in the pathway downstream of PTH and P84022 signaling in osteoblasts .\",\n \"TG - interacting factor transcriptionally induced by AKT / O43524 is a negative regulator that antagonizes arsenic trioxide - induced cancer cell apoptosis . DB01169 ( ATO ) is a multi - target drug approved by the Food and Drug Administration as the first - line chemotherapeutic agent for the treatment of acute promyelocytic leukemia . In addition , several clinical trials are being conducted with arsenic - based drugs for the treatment of other hematological malignancies and solid tumors . However , ATO ' s modest clinical efficacy on some cancers , and potential toxic effects on humans have been reported . Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue . Previously , we demonstrated that the JNK - induced complex formation of phosphorylated c - Jun and TG - interacting factor ( Q15583 ) antagonizes P29323 - induced cyclin - dependent kinase inhibitor P38936 ( P38936 ( P38936 / CIP1 ) ) expression and resultant apoptosis in response to ATO in A431 cells . Surprisingly , at low - concentrations ( 0 . 1 - 0 . 2 μM ) , ATO increased cellular proliferation , migration and invasion , involving Q15583 expression , however , at high - concentrations ( 5 - 20 μM ) , ATO induced cell apoptosis . Using a promoter analysis , Q15583 was transcriptionally regulated by ATO at the O43524 binding site ( - 1486 to - 1479bp ) via the c - Src / P00533 / AKT pathway . Stable overexpression of Q15583 promoted advancing the cell cycle into the S phase , and attenuated 20 μM ATO - induced apoptosis . Furthermore , blockage of the AKT pathway enhanced ATO - induced P38936 expression and resultant apoptosis in cancer cells , but overexpression of P31749 inhibited P38936 expression . Therefore , we suggest that Q15583 is transcriptionally regulated by the c - Src / P00533 / AKT pathway , which plays a role as a negative regulator in antagonizing ATO - induced P38936 expression and resultant apoptosis . Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO .\",\n \"P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .\",\n \"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .\",\n \"Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .\",\n \"The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .\",\n \"___MASK83___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK83___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK83___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK83___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK83___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .\",\n \"P28482 , but not P27361 , mediates acquired and \\\" de novo \\\" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .\",\n \"Induction of graft - versus - leukemia ( GVL ) effect without graft - versus - host disease ( GVHD ) by pretransplant donor treatment with immunomodulators . Pretransplant donor treatment with immunomodulators such as complete Freund ' s adjuvant ( O75347 ) or oligodeoxynucleotide sequences expressing CpG motifs ( CpG ) , was applied in sublethally irradiated host mice inoculated with murine models of mammary carcinoma ( 4T1 ) or B cell leukemia ( P24385 ) . Spleen cells or P60568 activated splenocytes ( lymphokine activated killer [ Q96QP1 ] ) derived from donor mice treated with CpG emulsified in incomplete Freund ' s adjuvant ( IFA ) , ( CpG + IFA ) did not cause graft - versus - host disease ( GVHD ) , but were not efficient enough to induce a significant graft - versus - tumor ( GVT ) response against 4T1 cells . In contrast , an efficient graft - versus - leukemia ( GVL ) effect was evident in P24385 - bearing mice inoculated with spleen cells from donors pretreated with O75347 or CpG + IFA . Pretransplant donor treatment with O75347 prolonged survival to a median of 62 days with 3 of 27 mice remaining GVHD - and leukemia - free for > 200 days , compared to GVHD - related death of all mice inoculated with naïve cells ( median 17 days ) , or leukemia - related death of all mice inoculated with leukemia cells ( median of 27 days ) . Pretransplant donor treatment with CpG + IFA exerted a more efficient GVL effect with reduced GVHD resulting in 12 of 26 GVHD - and leukemia - free survivors for > 200 days . Our results suggest that it may be possible to prevent GVHD while sparing an efficient GVL effect by using pretransplant donor treatment with immunomodulators prior to allogeneic stem cell transplantation and / or donor lymphocyte infusions in hematologic malignancies .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK75___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .\"\n]"},"candidates":{"kind":"list like","value":["___MASK13___","___MASK24___","___MASK3___","___MASK41___","___MASK55___","___MASK73___","___MASK75___","___MASK81___","___MASK83___"],"string":"[\n \"___MASK13___\",\n \"___MASK24___\",\n \"___MASK3___\",\n \"___MASK41___\",\n \"___MASK55___\",\n \"___MASK73___\",\n \"___MASK75___\",\n \"___MASK81___\",\n \"___MASK83___\"\n]"},"answer":{"kind":"string","value":"___MASK75___"},"id":{"kind":"string","value":"MH_train_385"}}},{"rowIdx":386,"cells":{"query":{"kind":"string","value":"interacts_with DB01088?"},"supports":{"kind":"list like","value":["Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of P04626 . We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity . Five of these genes failed to score in transformation assays ; however , novel recurring extracellular domain mutations of the receptor tyrosine kinase gene P04626 were potently oncogenic . These P04626 extracellular domain mutants were activated by two distinct mechanisms , characterized by elevated C - terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation . These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins , impacting cell motility . Survival of Ba / P13726 cells transformed to P08700 independence by the P04626 extracellular domain mutants was abrogated by treatment with small - molecule inhibitors of P04626 , raising the possibility that patients harboring such mutations could benefit from P04626 - directed therapy .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .","DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .","Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK93___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .","Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .","Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high - affinity ( KD = 36 +/- 3 nM ) and low - affinity ( KD = 2 . 1 +/- 0 . 8 microM ) prostacyclin ( DB01240 ) - receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [ 3H ] iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5 - 10 - fold increase in the number of both the low - and the high - affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5 - fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 - G2 - adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor .","Regulation of cyclooxygenase - 2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c - kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells . Emerging evidence has suggested the pivotal role of mast cells in a host defense against bacterial infection . In this paper , we report that bacterial lipopolysaccharide ( LPS ) is a potent enhancer of the cytokine - and IgE - dependent delayed responses of P08700 - dependent mouse bone marrow - derived cultured mast cells ( BMMC ) . LPS , although showing minimal effects , significantly augmented the c - kit ligand ( KL ) - or IgE - dependent expression of cyclooxygenase ( P36551 ) - 2 and the attendant delayed PGD2 generation , with P22301 and P05112 acting as potentiating and inhibitory cytokines , respectively . The P35354 - inducing activity of LPS was mimicked by exogenous P01584 . Assessment of endogenous cytokine induction revealed that P01584 expression was stimulated by either LPS or exogenous P01584 . P05231 expression occurred in parallel with P35354 expression . P22301 expression , which lagged behind P35354 expression , depended on exogenous P22301 , but not on LPS and P01584 . Thus , LPS and P01584 exhibited similar biological activities in terms of P35354 and endogenous cytokine expression . However , adding an antibody against the type I IL - 1 receptor to BMMC , which abrogated the effects of P01584 , failed to neutralize the effects of LPS . These results suggest that LPS activates BMMC through the signal transduction pathway shared with exogenous P01584 , rather than exerting its action indirectly via the production of endogenous P01584 .","___MASK50___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK50___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .","[ Thrombocyte prostacyclin receptors in gestational hypertension and pre - eclampsia ] . OBJECTIVE : To determine prostacyclin ( DB01240 ) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome . METHODS : Radioligand binding studies with [ 3H ] - DB01088 were performed to measure receptor capacity ( Bmax ) and affinity ( Kd - 1 ) using platelet membranes from patients with preeclampsia , gestational hypertension or normal pregnancy . RESULTS : P43119 capacity did not differ between the patient groups . In contrast , P43119 affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy . A similar pattern was found in fetal growth ( normal pregnancy > gestational hypertension > preeclampsia ) . Furthermore , the rate of low Apgar scores and acidosis was increased in preeclampsia . CONCLUSIONS : In preeclampsia reduced platelet P43119 affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy , whereas these differences were less pronounced in gestational hypertension . This suggests a role of DB01240 and its receptor in gestational hypertension and in particular in preeclampsia .","Dopamine receptors D1 and D2 are related to observed maternal behavior . The dopamine pathway and especially the dopamine receptors 1 and 2 ( P21728 and P14416 ) are implicated in the regulation of mothering in rats . Evidence for this in humans is lacking . Here , we show that genetic variation in both P21728 and P14416 genes in a sample of 187 Caucasian mothers predicts variation in distinct maternal behaviors during a 30 - min mother - infant interaction at 6 months postpartum . Two P21728 single - nucleotide polymorphisms ( SNPs rs265981 and rs686 ) significantly associated with maternal orienting away from the infant ( P = 0 . 002 and P = 0 . 003 , respectively ) , as did P21728 haplotypes ( P = 0 . 03 ) . Two P14416 SNPs ( rs1799732 and rs6277 ) significantly associated with maternal infant - directed vocalizing ( P = 0 . 001 and P = 0 . 04 , respectively ) , as did P14416 haplotypes ( P = 0 . 01 ) . We present evidence for heterosis in P21728 where heterozygote mothers orient away from their infants significantly less than either homozygote group . Our findings provide important evidence that genetic variation in receptors critical for mothering in non - human species also affect human maternal behaviors . The findings also highlight the importance of exploring multiple dimensions of the complex human mothering phenotype .","[ Detection of a high - affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high - and a low - affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low - affinity binding sites disappear totally and the specific high - affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto ' s and Riedl ' s thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key - role of DB01240 in thyroid intermediary metabolism .","[ ___MASK5___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK5___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .","P01236 : a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage . Recent studies have shown that the anterior pituitary hormone prolactin , together with various cytokines , plays an important role in maintaining normal immune responses . Although there is evidence that prolactin may be a significant immunotropic hormone that can counteract the immunosuppressive effects of drugs such as cyclosporine , morphine , or glucocorticoids , it remains unknown whether prolactin administration has any salutary effects on the depressed immune responses following severe hemorrhage . To study this , mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min , then adequately resuscitated and segregated into two groups . One group received saline - vehicle ( hem - SS ) ; animals in the other group were treated with prolactin ( hem - PRL ) ( 100 micrograms per 25 g BW , subcutaneously ) immediately before resuscitation . Two hours following saline or prolactin injection , splenocytes ( SPL ) were harvested and assessed for proliferative capacity ( PC ) and their ability to release P60568 and P08700 . Supernatant lymphokine levels were determined by bioassay . The proliferative capacity of the splenocytes , as well as their ability to release P60568 and P08700 , was significantly depressed in the vehicle - treated hemorrhaged animals , compared to shams . Treatment with prolactin restored the depressed splenocyte functions seen after severe hemorrhage . These results support the notion that the immunosuppression following hemorrhage and trauma may be mediated by hormones from the hypothalamic - pituitary - adrenal axis . Furthermore , our results suggest that the use of prolactin , which did not produce any adverse hemodynamic effects , represents a novel and safe immunomodulating hormone for the treatment of immunodepression following severe blood loss .","P01308 generates free radicals in human fibroblasts ex vivo by a protein kinase C - dependent mechanism , which is inhibited by pravastatin . P01308 can generate oxygen free radicals . Statins , P04035 inhibitors , exert a powerful antioxidant effect . The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects . In cultured skin fibroblasts from human volunteers exposed to high insulin concentration , either in the presence or in the absence of pravastatin , insulin induced translocation of the p47 ( phox ) subunit of NAD ( P ) H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta - dependent mechanism . The insulin - induced translocation of p47 ( phox ) was PKC delta dependent and attenuated by pravastatin , but independent of the activation of Akt and Rac1 . P01308 - induced Akt phosphorylation was increased by pravastatin and P27361 / 2 phosphorylation attenuated . The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts , ex vivo . It involves phosphatidylinositol 3 - kinase , PKC delta , and p47 ( phox ) translocation and promotes P27361 / 2 phosphorylation . ___MASK28___ inhibited radical oxygen species production by inhibiting PKC delta . These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome .","P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .","Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug - induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G - P04141 and P15692 . This stimulation was associated with drug - induced activation of NF - kappaB , AP - 1 , P05549 , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 - 2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 - 3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug - mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 / neu signaling ( Herceptin / ___MASK99___ ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug - stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth - stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .","Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK8___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .","Control of vascular tube morphogenesis and maturation in 3D extracellular matrices by endothelial cells and pericytes . An important advance using in vitro EC tube morphogenesis and maturation models has been the development of systems using serum - free defined media . Using this approach , the growth factors and cytokines which are actually necessary for these events can be determined . The first model developed by our laboratory was such a system where we showed that phorbol ester was needed in order to promote survival and tube morphogenesis in 3D collagen matrices . Recently , we have developed a new system in which the hematopoietic stem cell cytokines , stem cell factor ( P21583 ) , interleukin - 3 ( P08700 ) , and stromal derived factor - 1α ( SDF - 1α ) were added in conjunction with P09038 to promote human EC tube morphogenesis in 3D collagen matrices under serum - free defined conditions . This new model using P21583 , P08700 , SDF - 1α , and P09038 also works well following the addition of pericytes where EC tube formation occurs , pericytes are recruited to the tubes , and vascular basement membrane matrix assembly occurs following EC - pericyte interactions . In this chapter , we describe several in vitro assay models that we routinely utilize to investigate the molecular requirements that are critical to EC tube formation and maturation events in 3D extracellular matrix environments .","Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .","Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK94___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .","Expression of prostacyclin receptors in luteinizing hormone - releasing hormone immortalized neurons : role in the control of hormone secretion . PGs of the E series are involved in the control of P01148 secretion . The present experiments were conducted to clarify whether DB01240 ( prostacyclin ) might be also involved in such a control , using multiple methodological approaches on immortalized P01148 - secreting neurons . A RT - PCR procedure to detect mouse P43119 ( IP ) messenger RNA was first applied , and the results obtained showed the presence of a specific transcript in two cell lines of immortalized P01148 neurons ( GT1 - 1 and GN11 cell lines ) . Receptor binding assays on membrane preparations from GT1 - 1 cells showed the presence of a single specific and saturable class of binding sites ( Kd = 4 . 6 nM ; 10 , 000 sites / cell ) for [ 3H ] iloprost , a stable analog of DB01240 . Competition experiments showed that the binding sites labeled by [ 3H ] iloprost possess the pharmacological characteristics of IP receptors . In functional studies , DB01240 and its analogs , iloprost and cicaprost , were able to stimulate P01148 release from the GT1 - 1 cells with elevated potencies ( EC50 = 0 . 6 - 4 . 3 nM ) ; PGE1 was only slightly less active ( EC50 = 28 . 5 nM ) , whereas DB00917 , considered the major PG involved in P01148 secretion , was poorly effective ( EC50 = 921 nM ) . The relative potencies ( EC50 ) of these compounds in stimulating the intracellular accumulation of DB02527 were in line with their P01148 - releasing activities . In conclusion , these results indicate that immortalized P01148 - secreting neurons express IP receptors through which DB01240 may exert relevant effects on P01148 release .","Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .","___MASK99___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK99___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .","DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .","___MASK28___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK28___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .","P35354 - derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up - regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females .","Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK99___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK99___ is also being investigated as part of triplet drug regimens . ___MASK99___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .","___MASK28___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .","Critical role of the interleukin 2 ( P60568 ) receptor gamma - chain - associated Jak3 in the P60568 - induced c - fos and c - myc , but not bcl - 2 , gene induction . The interleukin 2 receptor ( IL - 2R ) consists of three subunits , the IL - 2R alpha , IL - 2R beta c , and IL - 2R gamma c chains . Two Janus family protein tyrosine kinases ( PTKs ) , Jak1 and Jak3 , were shown to associate with IL - 2R beta c and IL - 2R gamma c , respectively , and their PTK activities are increased after P60568 stimulation . A Jak3 mutant with truncation of the C - terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL - 2R gamma c . In a hematopoietic cell line , P08709 , that responds to either P60568 or P08700 , overexpression of this Jak3 mutant results in selective inhibition of the P60568 - induced activation of Jak1 / Jak3 PTKs and of cell proliferation . Of the three target nuclear protooncogenes of the P60568 signaling , c - fos and c - myc genes , but not the bcl - 2 gene , were found to be impaired . On the other hand , overexpression of the dominant negative form of the IL - 2R gamma c chain , which lacks most of its cytoplasmic domain , in P08709 cells resulted in the inhibition of all three protooncogenes . These results provide a further molecular basis for the critical role of Jak3 in P60568 signaling and also suggest a Jak PTK - independent signaling pathway ( s ) for the bcl - 2 gene induction by IL - 2R .","Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK11___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .","Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK88___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .","Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK8___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .","Two types of prostacyclin receptor coupling to stimulation of adenylate cyclase and phosphatidylinositol hydrolysis in a cultured mast cell line , BNu - 2cl3 cells . DB01240 ( DB01240 ) - mediated signal transduction was examined in interleukin 3 ( P08700 ) - dependent BNu - 2cl3 mast cells . DB01088 , a stable DB01240 analogue , induced the accumulation of intracellular DB02527 and IP3 , and an increase in the intracellular Ca2 + concentration . Pretreatment of the cells with a protein kinase C activator , 12 - O - tetradecanoyl phorbol 13 - acetate , suppressed the iloprost - induced IP3 accumulation and Ca2 + mobilization , but inversely potentiated the DB02527 accumulation , suggesting that neither of these signal transduction pathways of iloprosts is the result of a secondary effect of activation of the other . Removal of P08700 from the culture medium reduced the iloprost - induced IP3 accumulation and Ca2 + mobilization , while it had no effect on the iloprost - induced DB02527 accumulation at all . These results taken together suggest that BNu - 2cl3 cells express two types of P43119 ; one couples to stimulation of adenylate cyclase , its expression being independent of P08700 , while the other couples to phosphatidylinositol hydrolysis , its expression being dependent on P08700 .","Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK5___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )","HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT - PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF - beta ) , macrophage colony - stimulating factor ( P09603 ) , oncostatin - M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL - 11 , IL - 12 and P05231 receptor ( IL - 6R ) . At the same time the expression of IL - 1 , P60568 , P08700 , P05231 , P29965 and IL - 2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro - and anti - inflammatory and other regulatory cytokines .","P01148 antagonist DB00050 reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia . BACKGROUND : Recent findings suggest that BPH has an inflammatory component . Clinical trials have documented that therapy with P01148 antagonist DB00050 causes a marked and prolonged improvement in LUTS in men with symptomatic BPH . We investigated the mechanism of action and effect of DB00050 in a rat model of BPH . METHODS : Adult male Wistar rats were used . BPH was induced in rats by subcutaneous injections of TE 2 mg / day for 4 weeks . Control animals received injections of corn oil . After induction of BPH , rats received depot DB00050 pamoate at the doses of 0 . 625 , 1 . 25 , and 12 . 5 mg / kg on days 1 and 22 and TE - control rats received vehicle injections . Whole prostates were weighed and processed for RNA and protein . Real - time RT - PCR assays for numerous inflammatory cytokines and growth factors were performed . Quantitative analyses of prostatic P01148 receptor , P01148 , androgen receptor ( AR ) and 5α - reductase 2 were done by real - time RT - PCR and immunoblotting ; serum DB02901 , LH , PSA , and DB01277 by immunoassays . RESULTS : mRNA levels for inflammatory cytokines IFN - γ , P08700 , P05112 , P05113 , P05231 , P10145 , P35225 , P40933 , and Q16552 and for growth factors P01133 , P09038 , FGF - 7 , P55075 , Q92915 , TGF - β1 , and P15692 were significantly reduced by DB00050 0 . 625 mg / kg ( P < 0 . 05 ) . Prostate weights were also significantly lowered by any dose of DB00050 . CONCLUSIONS : This study suggests that DB00050 reduces various inflammatory cytokines and growth factors in rat prostate and , at doses which do not induce castration levels of testosterone , can lower prostate weights . Our findings shed light on the mechanism of action of P01148 antagonists in BPH ."],"string":"[\n \"Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of P04626 . We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity . Five of these genes failed to score in transformation assays ; however , novel recurring extracellular domain mutations of the receptor tyrosine kinase gene P04626 were potently oncogenic . These P04626 extracellular domain mutants were activated by two distinct mechanisms , characterized by elevated C - terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation . These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins , impacting cell motility . Survival of Ba / P13726 cells transformed to P08700 independence by the P04626 extracellular domain mutants was abrogated by treatment with small - molecule inhibitors of P04626 , raising the possibility that patients harboring such mutations could benefit from P04626 - directed therapy .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .\",\n \"DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .\",\n \"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK93___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .\",\n \"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .\",\n \"Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high - affinity ( KD = 36 +/- 3 nM ) and low - affinity ( KD = 2 . 1 +/- 0 . 8 microM ) prostacyclin ( DB01240 ) - receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [ 3H ] iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5 - 10 - fold increase in the number of both the low - and the high - affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5 - fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 - G2 - adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor .\",\n \"Regulation of cyclooxygenase - 2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c - kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells . Emerging evidence has suggested the pivotal role of mast cells in a host defense against bacterial infection . In this paper , we report that bacterial lipopolysaccharide ( LPS ) is a potent enhancer of the cytokine - and IgE - dependent delayed responses of P08700 - dependent mouse bone marrow - derived cultured mast cells ( BMMC ) . LPS , although showing minimal effects , significantly augmented the c - kit ligand ( KL ) - or IgE - dependent expression of cyclooxygenase ( P36551 ) - 2 and the attendant delayed PGD2 generation , with P22301 and P05112 acting as potentiating and inhibitory cytokines , respectively . The P35354 - inducing activity of LPS was mimicked by exogenous P01584 . Assessment of endogenous cytokine induction revealed that P01584 expression was stimulated by either LPS or exogenous P01584 . P05231 expression occurred in parallel with P35354 expression . P22301 expression , which lagged behind P35354 expression , depended on exogenous P22301 , but not on LPS and P01584 . Thus , LPS and P01584 exhibited similar biological activities in terms of P35354 and endogenous cytokine expression . However , adding an antibody against the type I IL - 1 receptor to BMMC , which abrogated the effects of P01584 , failed to neutralize the effects of LPS . These results suggest that LPS activates BMMC through the signal transduction pathway shared with exogenous P01584 , rather than exerting its action indirectly via the production of endogenous P01584 .\",\n \"___MASK50___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK50___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .\",\n \"[ Thrombocyte prostacyclin receptors in gestational hypertension and pre - eclampsia ] . OBJECTIVE : To determine prostacyclin ( DB01240 ) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome . METHODS : Radioligand binding studies with [ 3H ] - DB01088 were performed to measure receptor capacity ( Bmax ) and affinity ( Kd - 1 ) using platelet membranes from patients with preeclampsia , gestational hypertension or normal pregnancy . RESULTS : P43119 capacity did not differ between the patient groups . In contrast , P43119 affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy . A similar pattern was found in fetal growth ( normal pregnancy > gestational hypertension > preeclampsia ) . Furthermore , the rate of low Apgar scores and acidosis was increased in preeclampsia . CONCLUSIONS : In preeclampsia reduced platelet P43119 affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy , whereas these differences were less pronounced in gestational hypertension . This suggests a role of DB01240 and its receptor in gestational hypertension and in particular in preeclampsia .\",\n \"Dopamine receptors D1 and D2 are related to observed maternal behavior . The dopamine pathway and especially the dopamine receptors 1 and 2 ( P21728 and P14416 ) are implicated in the regulation of mothering in rats . Evidence for this in humans is lacking . Here , we show that genetic variation in both P21728 and P14416 genes in a sample of 187 Caucasian mothers predicts variation in distinct maternal behaviors during a 30 - min mother - infant interaction at 6 months postpartum . Two P21728 single - nucleotide polymorphisms ( SNPs rs265981 and rs686 ) significantly associated with maternal orienting away from the infant ( P = 0 . 002 and P = 0 . 003 , respectively ) , as did P21728 haplotypes ( P = 0 . 03 ) . Two P14416 SNPs ( rs1799732 and rs6277 ) significantly associated with maternal infant - directed vocalizing ( P = 0 . 001 and P = 0 . 04 , respectively ) , as did P14416 haplotypes ( P = 0 . 01 ) . We present evidence for heterosis in P21728 where heterozygote mothers orient away from their infants significantly less than either homozygote group . Our findings provide important evidence that genetic variation in receptors critical for mothering in non - human species also affect human maternal behaviors . The findings also highlight the importance of exploring multiple dimensions of the complex human mothering phenotype .\",\n \"[ Detection of a high - affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high - and a low - affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low - affinity binding sites disappear totally and the specific high - affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto ' s and Riedl ' s thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key - role of DB01240 in thyroid intermediary metabolism .\",\n \"[ ___MASK5___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK5___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .\",\n \"P01236 : a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage . Recent studies have shown that the anterior pituitary hormone prolactin , together with various cytokines , plays an important role in maintaining normal immune responses . Although there is evidence that prolactin may be a significant immunotropic hormone that can counteract the immunosuppressive effects of drugs such as cyclosporine , morphine , or glucocorticoids , it remains unknown whether prolactin administration has any salutary effects on the depressed immune responses following severe hemorrhage . To study this , mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min , then adequately resuscitated and segregated into two groups . One group received saline - vehicle ( hem - SS ) ; animals in the other group were treated with prolactin ( hem - PRL ) ( 100 micrograms per 25 g BW , subcutaneously ) immediately before resuscitation . Two hours following saline or prolactin injection , splenocytes ( SPL ) were harvested and assessed for proliferative capacity ( PC ) and their ability to release P60568 and P08700 . Supernatant lymphokine levels were determined by bioassay . The proliferative capacity of the splenocytes , as well as their ability to release P60568 and P08700 , was significantly depressed in the vehicle - treated hemorrhaged animals , compared to shams . Treatment with prolactin restored the depressed splenocyte functions seen after severe hemorrhage . These results support the notion that the immunosuppression following hemorrhage and trauma may be mediated by hormones from the hypothalamic - pituitary - adrenal axis . Furthermore , our results suggest that the use of prolactin , which did not produce any adverse hemodynamic effects , represents a novel and safe immunomodulating hormone for the treatment of immunodepression following severe blood loss .\",\n \"P01308 generates free radicals in human fibroblasts ex vivo by a protein kinase C - dependent mechanism , which is inhibited by pravastatin . P01308 can generate oxygen free radicals . Statins , P04035 inhibitors , exert a powerful antioxidant effect . The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects . In cultured skin fibroblasts from human volunteers exposed to high insulin concentration , either in the presence or in the absence of pravastatin , insulin induced translocation of the p47 ( phox ) subunit of NAD ( P ) H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta - dependent mechanism . The insulin - induced translocation of p47 ( phox ) was PKC delta dependent and attenuated by pravastatin , but independent of the activation of Akt and Rac1 . P01308 - induced Akt phosphorylation was increased by pravastatin and P27361 / 2 phosphorylation attenuated . The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts , ex vivo . It involves phosphatidylinositol 3 - kinase , PKC delta , and p47 ( phox ) translocation and promotes P27361 / 2 phosphorylation . ___MASK28___ inhibited radical oxygen species production by inhibiting PKC delta . These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome .\",\n \"P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .\",\n \"Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug - induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G - P04141 and P15692 . This stimulation was associated with drug - induced activation of NF - kappaB , AP - 1 , P05549 , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 - 2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 - 3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug - mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 / neu signaling ( Herceptin / ___MASK99___ ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug - stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth - stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .\",\n \"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK8___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .\",\n \"Control of vascular tube morphogenesis and maturation in 3D extracellular matrices by endothelial cells and pericytes . An important advance using in vitro EC tube morphogenesis and maturation models has been the development of systems using serum - free defined media . Using this approach , the growth factors and cytokines which are actually necessary for these events can be determined . The first model developed by our laboratory was such a system where we showed that phorbol ester was needed in order to promote survival and tube morphogenesis in 3D collagen matrices . Recently , we have developed a new system in which the hematopoietic stem cell cytokines , stem cell factor ( P21583 ) , interleukin - 3 ( P08700 ) , and stromal derived factor - 1α ( SDF - 1α ) were added in conjunction with P09038 to promote human EC tube morphogenesis in 3D collagen matrices under serum - free defined conditions . This new model using P21583 , P08700 , SDF - 1α , and P09038 also works well following the addition of pericytes where EC tube formation occurs , pericytes are recruited to the tubes , and vascular basement membrane matrix assembly occurs following EC - pericyte interactions . In this chapter , we describe several in vitro assay models that we routinely utilize to investigate the molecular requirements that are critical to EC tube formation and maturation events in 3D extracellular matrix environments .\",\n \"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .\",\n \"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK94___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .\",\n \"Expression of prostacyclin receptors in luteinizing hormone - releasing hormone immortalized neurons : role in the control of hormone secretion . PGs of the E series are involved in the control of P01148 secretion . The present experiments were conducted to clarify whether DB01240 ( prostacyclin ) might be also involved in such a control , using multiple methodological approaches on immortalized P01148 - secreting neurons . A RT - PCR procedure to detect mouse P43119 ( IP ) messenger RNA was first applied , and the results obtained showed the presence of a specific transcript in two cell lines of immortalized P01148 neurons ( GT1 - 1 and GN11 cell lines ) . Receptor binding assays on membrane preparations from GT1 - 1 cells showed the presence of a single specific and saturable class of binding sites ( Kd = 4 . 6 nM ; 10 , 000 sites / cell ) for [ 3H ] iloprost , a stable analog of DB01240 . Competition experiments showed that the binding sites labeled by [ 3H ] iloprost possess the pharmacological characteristics of IP receptors . In functional studies , DB01240 and its analogs , iloprost and cicaprost , were able to stimulate P01148 release from the GT1 - 1 cells with elevated potencies ( EC50 = 0 . 6 - 4 . 3 nM ) ; PGE1 was only slightly less active ( EC50 = 28 . 5 nM ) , whereas DB00917 , considered the major PG involved in P01148 secretion , was poorly effective ( EC50 = 921 nM ) . The relative potencies ( EC50 ) of these compounds in stimulating the intracellular accumulation of DB02527 were in line with their P01148 - releasing activities . In conclusion , these results indicate that immortalized P01148 - secreting neurons express IP receptors through which DB01240 may exert relevant effects on P01148 release .\",\n \"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .\",\n \"___MASK99___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK99___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .\",\n \"DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .\",\n \"___MASK28___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK28___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .\",\n \"P35354 - derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up - regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females .\",\n \"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK99___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK99___ is also being investigated as part of triplet drug regimens . ___MASK99___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .\",\n \"___MASK28___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .\",\n \"Critical role of the interleukin 2 ( P60568 ) receptor gamma - chain - associated Jak3 in the P60568 - induced c - fos and c - myc , but not bcl - 2 , gene induction . The interleukin 2 receptor ( IL - 2R ) consists of three subunits , the IL - 2R alpha , IL - 2R beta c , and IL - 2R gamma c chains . Two Janus family protein tyrosine kinases ( PTKs ) , Jak1 and Jak3 , were shown to associate with IL - 2R beta c and IL - 2R gamma c , respectively , and their PTK activities are increased after P60568 stimulation . A Jak3 mutant with truncation of the C - terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL - 2R gamma c . In a hematopoietic cell line , P08709 , that responds to either P60568 or P08700 , overexpression of this Jak3 mutant results in selective inhibition of the P60568 - induced activation of Jak1 / Jak3 PTKs and of cell proliferation . Of the three target nuclear protooncogenes of the P60568 signaling , c - fos and c - myc genes , but not the bcl - 2 gene , were found to be impaired . On the other hand , overexpression of the dominant negative form of the IL - 2R gamma c chain , which lacks most of its cytoplasmic domain , in P08709 cells resulted in the inhibition of all three protooncogenes . These results provide a further molecular basis for the critical role of Jak3 in P60568 signaling and also suggest a Jak PTK - independent signaling pathway ( s ) for the bcl - 2 gene induction by IL - 2R .\",\n \"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK11___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .\",\n \"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK88___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .\",\n \"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK8___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .\",\n \"Two types of prostacyclin receptor coupling to stimulation of adenylate cyclase and phosphatidylinositol hydrolysis in a cultured mast cell line , BNu - 2cl3 cells . DB01240 ( DB01240 ) - mediated signal transduction was examined in interleukin 3 ( P08700 ) - dependent BNu - 2cl3 mast cells . DB01088 , a stable DB01240 analogue , induced the accumulation of intracellular DB02527 and IP3 , and an increase in the intracellular Ca2 + concentration . Pretreatment of the cells with a protein kinase C activator , 12 - O - tetradecanoyl phorbol 13 - acetate , suppressed the iloprost - induced IP3 accumulation and Ca2 + mobilization , but inversely potentiated the DB02527 accumulation , suggesting that neither of these signal transduction pathways of iloprosts is the result of a secondary effect of activation of the other . Removal of P08700 from the culture medium reduced the iloprost - induced IP3 accumulation and Ca2 + mobilization , while it had no effect on the iloprost - induced DB02527 accumulation at all . These results taken together suggest that BNu - 2cl3 cells express two types of P43119 ; one couples to stimulation of adenylate cyclase , its expression being independent of P08700 , while the other couples to phosphatidylinositol hydrolysis , its expression being dependent on P08700 .\",\n \"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK5___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT - PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF - beta ) , macrophage colony - stimulating factor ( P09603 ) , oncostatin - M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL - 11 , IL - 12 and P05231 receptor ( IL - 6R ) . At the same time the expression of IL - 1 , P60568 , P08700 , P05231 , P29965 and IL - 2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro - and anti - inflammatory and other regulatory cytokines .\",\n \"P01148 antagonist DB00050 reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia . BACKGROUND : Recent findings suggest that BPH has an inflammatory component . Clinical trials have documented that therapy with P01148 antagonist DB00050 causes a marked and prolonged improvement in LUTS in men with symptomatic BPH . We investigated the mechanism of action and effect of DB00050 in a rat model of BPH . METHODS : Adult male Wistar rats were used . BPH was induced in rats by subcutaneous injections of TE 2 mg / day for 4 weeks . Control animals received injections of corn oil . After induction of BPH , rats received depot DB00050 pamoate at the doses of 0 . 625 , 1 . 25 , and 12 . 5 mg / kg on days 1 and 22 and TE - control rats received vehicle injections . Whole prostates were weighed and processed for RNA and protein . Real - time RT - PCR assays for numerous inflammatory cytokines and growth factors were performed . Quantitative analyses of prostatic P01148 receptor , P01148 , androgen receptor ( AR ) and 5α - reductase 2 were done by real - time RT - PCR and immunoblotting ; serum DB02901 , LH , PSA , and DB01277 by immunoassays . RESULTS : mRNA levels for inflammatory cytokines IFN - γ , P08700 , P05112 , P05113 , P05231 , P10145 , P35225 , P40933 , and Q16552 and for growth factors P01133 , P09038 , FGF - 7 , P55075 , Q92915 , TGF - β1 , and P15692 were significantly reduced by DB00050 0 . 625 mg / kg ( P < 0 . 05 ) . Prostate weights were also significantly lowered by any dose of DB00050 . CONCLUSIONS : This study suggests that DB00050 reduces various inflammatory cytokines and growth factors in rat prostate and , at doses which do not induce castration levels of testosterone , can lower prostate weights . Our findings shed light on the mechanism of action of P01148 antagonists in BPH .\"\n]"},"candidates":{"kind":"list like","value":["___MASK11___","___MASK28___","___MASK50___","___MASK5___","___MASK88___","___MASK8___","___MASK93___","___MASK94___","___MASK99___"],"string":"[\n \"___MASK11___\",\n \"___MASK28___\",\n \"___MASK50___\",\n \"___MASK5___\",\n \"___MASK88___\",\n \"___MASK8___\",\n \"___MASK93___\",\n \"___MASK94___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK8___"},"id":{"kind":"string","value":"MH_train_386"}}},{"rowIdx":387,"cells":{"query":{"kind":"string","value":"interacts_with DB00074?"},"supports":{"kind":"list like","value":["Human chromosome 10 loci map to three different sheep chromosomes . The interleukin 2 receptor ( P01589 ) , a human Chromosome ( Chr ) 10p locus , was mapped to sheep Chr 13q12 - q15 by in situ hybridization . Two loci from human Chr 10q , cytochrome P450 subfamily XVII ( P05093 ) and the tachykinin 2 receptor ( P21452 ) , were assigned to sheep Chrs 22q21 - q23 and 25q14 - q23 respectively . The assignment of P01589 allows the provisional assignment of the previously unassigned sheep syntenic group U15 to sheep Chr 13 . Sheep linkage group 5 is predicted to be located on sheep Chr 25 on the basis of the P21452 assignment .","Lactobacillus acidophilus L - 92 Cells Activate Expression of Immunomodulatory Genes in THP - 1 Cells . To understand the immunomodulatory effects of Lactobacillus acidophilus L - 92 cells suggested from our previous study of in vivo anti - allergy and anti - virus effects , host immune responses in macrophage - like THP - 1 cells after 4 h ( the early phase ) and 24 h ( the late phase ) of cocultivation with L - 92 cells were investigated by transcriptome analysis . In the early phase of L - 92 treatment , various transcription regulator genes , such as , NFkB1 , NFkB2 , P05412 , P31629 and Q01201 , and genes encoding chemokines and cytokines , such as P13236 , O14625 , P10147 and P01375 , were upregulated . Two transmembrane receptor genes , Q9NYK1 and P05362 , were also upregulated in the early phase of treatment . In contrast , many transmembrane receptor genes , such as P16871 , P33681 , Q9HC73 , P42081 , P06127 , HLA - DQA1 , P01589 , Q13261 and P15509 , and some cytokine genes , including P05231 , Q9NPF7 and O00626 , were significantly upregulated in the late phase after L - 92 exposure . Some genes encoding cytokines , such as P01583 , P01584 and P10145 , and the enzyme P14902 were upregulated at both the early and the late phases of treatment . These results suggest that probiotic L - 92 might promote Th1 and regulatory T - cell responses by activation of the MAPK signaling pathway , followed by the NOD - like receptor signaling pathway in THP - 1 cells .","Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .","Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK93___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .","Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK25___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .","Induction therapy with interleukin - 2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function . PURPOSE : To determine the effectiveness of induction immunotherapy with interleukin - 2 receptor antagonists ( P01589 ) after intestinal transplantation ( IT ) . METHODS : A single - center , retrospective study was undertaken of all patients undergoing IT using existing medical records and database . Immunotherapy was either triple ( standard maintenance triple therapy [ SMTT ] ) or P01589 [ induction P01589 plus SMTTx ] or OKT3 [ induction antilymphocyte preparations plus SMTTx ] ) . Data was collected for the first 175 postoperative days . Outcomes included pretransplant renal function , posttransplant serum creatinine normalized to age ( nl - sCR ) , rejection ( P10323 ) , and survival . Standard statistical analysis was undertaken . RESULTS : There were no significant differences in the groups : triple ( n = 10 , median age 3 . 5 years , cGFR 106 +/- 44 mL / min ) , P01589 ( n = 13 , median age 3 . 2 years , cGFR 101 +/- 61 mL / min ) , OKT3 ( n = 4 , median age 7 . 7 years , cGFR 104 +/- 27 mL / min ) . nl - sCR was significantly ( P < . 01 ) lower in P01589 at most postoperative weeks . P01589 had significantly fewer rejection and infectious episodes than the other two groups . Three - year patient survival was 92 % in P01589 versus 50 % triple and OKT3 . CONCLUSIONS : P01589 immunotherapy after IT is associated with a lower incidence of renal dysfunction as compared with historical controls . Furthermore , P01589 therapy resulted in a lower incidence of rejection and improved survival . P01589 should be considered in select patients undergoing IT .","Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .","___MASK64___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK64___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .","___MASK57___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK57___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .","Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK27___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK27___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK27___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK27___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK27___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK27___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK27___ .","___MASK68___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .","___MASK47___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK47___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK47___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .","___MASK32___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK32___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK32___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK32___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .","Gene expression analysis of ELF - MF exposed human monocytes indicating the involvement of the alternative activation pathway . This study focused on the cell activating capacity of extremely low frequency magnetic fields ( ELF - MF ) on human umbilical cord blood - derived monocytes . Our results confirm the previous findings of cell activating capacity of ELF - MF ( 1 . 0 mT ) in human monocytes , which was detected as an increased ROS release . Furthermore , gene expression profiling ( whole - genome cDNA array Human Unigene RZPD - 2 ) was performed to achieve a comprehensive view of involved genes during the cell activation process after 45 min ELF - MF exposure . Our results indicate the alteration of 986 genes involved in metabolism , cellular physiological processes , signal transduction and immune response . Significant regulations could be analyzed for 5 genes ( expression > 2 - or < 0 . 5 - fold ) : Q13261 ( Interleukin 15 receptor , alpha chain ) , Q9UBC2 ( P00533 pathway substrate 15 - like 1 ) , Q9Y6K1 ( Hypothetical protein MGC16121 ) , Q9Y6K1 ( DNA ( cytosine - 5 ) methyltransferase 3 alpha ) , and one gene with no match to known genes , DKFZP586J1624 . Real - time RT - PCR analysis of the kinetic of the expression of Q13261 , and Q13651 during 45 min ELF - MF exposure indicates the regulation of cell activation via the alternative pathway , whereas the delayed gene expression of P01100 , P01589 and the melatonin synthesizing enzyme P46597 suggests the suppression of inflammatory processes . Accordingly , we suggest that ELF - MF activates human monocytes via the alternative pathway .","Non - HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients . Autoimmune Polyglandular Syndrome Type II ( APSII ) is characterized by the co - occurrence of clinical insufficiency of at least two endocrine glands . Although , HLA determinants of APSII predisposition have been identified , little attention has been paid to non - HLA genes . Here , we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co - occurrence of Autoimmune Thyroid Disease ( AITD ) and Type 1 Diabetes ( T1D ) and lower frequency of Addison ' s disease ( AD ) . We tested the high a priori possibility that well - established non - HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII , namely : ( 1 ) two T1D - associated SNPs , in P16410 and P01589 , suggest their involvement in T1D pathogenesis in this cohort ; ( 2 ) two SNPs in Q14765 and P40933 not previously associated to endocrinopathies , are possibly involved in co - occurrence of organ autoimmunity in APSII , and ; ( 3 ) one SNP in P01375 alpha showed association to APSII irrespective of AD . While this work was performed in a relatively small cohort , these results support the notion that the non - HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co - occurrence of multiple autoimmune endocrinopathies .","Human T - cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF - kappaB . Adult T - cell leukemia ( ATL ) is a highly aggressive T - cell malignancy caused by human T - cell leukemia virus type 1 ( HTLV - 1 ) . The activation of NF - kappaB by Tax has been reported to play a crucial role in HTLV - 1 - induced transformation . The HTLV - 1 bZIP factor ( P02008 ) , which is encoded by an mRNA of the opposite polarity of the viral genomic RNA , is involved in both T cell proliferation and suppression of Tax - mediated viral gene transcription , suggesting that P02008 cooperates closely with Tax . In the present study , we observed that P02008 specifically suppressed NF - kappaB - driven transcription mediated by p65 ( the classical pathway ) without inhibiting the alternative NF - kappaB signaling pathway . In an immunoprecipitation assay , P02008 bound to p65 and diminished the DNA binding capacity of p65 . In addition , P02008 induced p65 degradation through increasing the expression of the Q96JY6 gene , which encodes a ubiquitin E3 ligase for p65 . Finally , P02008 actually repressed the transcription of some classical NF - kappaB target genes , such as P10145 , P01589 , Q15306 , P19320 , and P15692 . Selective suppression of the classical NF - kappaB pathway by P02008 renders the alternative NF - kappaB pathway predominant after activation of NF - kappaB by Tax or other stimuli , which might be critical for oncogenesis .","Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .","Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK21___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .","DB00074 induction in patients receiving tacrolimus - based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine - based immunosuppression . However , its clinical utility in patients receiving tacrolimus - based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 ) , and 132 patients received tacrolimus without basiliximab ( TAC - No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 compared to TAC - IL - 2RA and TAC - No Groups ( 33 vs . 14 . 9 vs . 14 . 3 % , p < 0 . 001 ) . Inferior creatinine clearance was observed in dTAC - P01589 Group compared to TAC - P01589 and TAC - No Groups at months 1 ( 41 . 6 vs . 49 . 9 vs . 44 . 8 mL / min , p = 0 . 004 ) , 3 ( 49 . 8 vs . 57 . 2 vs . 53 . 5 mL / min , p = 0 . 017 ) , and 6 ( 53 . 1 vs . 61 . 8 vs . 57 . 0 mL / min , p = 0 . 001 ) . Patients who received basiliximab ( TAC - P01589 and dTAC - P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39 . 3 % , p = 0 . 009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction ."],"string":"[\n \"Human chromosome 10 loci map to three different sheep chromosomes . The interleukin 2 receptor ( P01589 ) , a human Chromosome ( Chr ) 10p locus , was mapped to sheep Chr 13q12 - q15 by in situ hybridization . Two loci from human Chr 10q , cytochrome P450 subfamily XVII ( P05093 ) and the tachykinin 2 receptor ( P21452 ) , were assigned to sheep Chrs 22q21 - q23 and 25q14 - q23 respectively . The assignment of P01589 allows the provisional assignment of the previously unassigned sheep syntenic group U15 to sheep Chr 13 . Sheep linkage group 5 is predicted to be located on sheep Chr 25 on the basis of the P21452 assignment .\",\n \"Lactobacillus acidophilus L - 92 Cells Activate Expression of Immunomodulatory Genes in THP - 1 Cells . To understand the immunomodulatory effects of Lactobacillus acidophilus L - 92 cells suggested from our previous study of in vivo anti - allergy and anti - virus effects , host immune responses in macrophage - like THP - 1 cells after 4 h ( the early phase ) and 24 h ( the late phase ) of cocultivation with L - 92 cells were investigated by transcriptome analysis . In the early phase of L - 92 treatment , various transcription regulator genes , such as , NFkB1 , NFkB2 , P05412 , P31629 and Q01201 , and genes encoding chemokines and cytokines , such as P13236 , O14625 , P10147 and P01375 , were upregulated . Two transmembrane receptor genes , Q9NYK1 and P05362 , were also upregulated in the early phase of treatment . In contrast , many transmembrane receptor genes , such as P16871 , P33681 , Q9HC73 , P42081 , P06127 , HLA - DQA1 , P01589 , Q13261 and P15509 , and some cytokine genes , including P05231 , Q9NPF7 and O00626 , were significantly upregulated in the late phase after L - 92 exposure . Some genes encoding cytokines , such as P01583 , P01584 and P10145 , and the enzyme P14902 were upregulated at both the early and the late phases of treatment . These results suggest that probiotic L - 92 might promote Th1 and regulatory T - cell responses by activation of the MAPK signaling pathway , followed by the NOD - like receptor signaling pathway in THP - 1 cells .\",\n \"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .\",\n \"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK93___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .\",\n \"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK25___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .\",\n \"Induction therapy with interleukin - 2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function . PURPOSE : To determine the effectiveness of induction immunotherapy with interleukin - 2 receptor antagonists ( P01589 ) after intestinal transplantation ( IT ) . METHODS : A single - center , retrospective study was undertaken of all patients undergoing IT using existing medical records and database . Immunotherapy was either triple ( standard maintenance triple therapy [ SMTT ] ) or P01589 [ induction P01589 plus SMTTx ] or OKT3 [ induction antilymphocyte preparations plus SMTTx ] ) . Data was collected for the first 175 postoperative days . Outcomes included pretransplant renal function , posttransplant serum creatinine normalized to age ( nl - sCR ) , rejection ( P10323 ) , and survival . Standard statistical analysis was undertaken . RESULTS : There were no significant differences in the groups : triple ( n = 10 , median age 3 . 5 years , cGFR 106 +/- 44 mL / min ) , P01589 ( n = 13 , median age 3 . 2 years , cGFR 101 +/- 61 mL / min ) , OKT3 ( n = 4 , median age 7 . 7 years , cGFR 104 +/- 27 mL / min ) . nl - sCR was significantly ( P < . 01 ) lower in P01589 at most postoperative weeks . P01589 had significantly fewer rejection and infectious episodes than the other two groups . Three - year patient survival was 92 % in P01589 versus 50 % triple and OKT3 . CONCLUSIONS : P01589 immunotherapy after IT is associated with a lower incidence of renal dysfunction as compared with historical controls . Furthermore , P01589 therapy resulted in a lower incidence of rejection and improved survival . P01589 should be considered in select patients undergoing IT .\",\n \"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .\",\n \"___MASK64___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK64___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .\",\n \"___MASK57___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK57___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .\",\n \"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK27___ and its - in terms of P36551 - inhibition - \\\" inactive \\\" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK27___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK27___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK27___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK27___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK27___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK27___ .\",\n \"___MASK68___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .\",\n \"___MASK47___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK47___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK47___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .\",\n \"___MASK32___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK32___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK32___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK32___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .\",\n \"Gene expression analysis of ELF - MF exposed human monocytes indicating the involvement of the alternative activation pathway . This study focused on the cell activating capacity of extremely low frequency magnetic fields ( ELF - MF ) on human umbilical cord blood - derived monocytes . Our results confirm the previous findings of cell activating capacity of ELF - MF ( 1 . 0 mT ) in human monocytes , which was detected as an increased ROS release . Furthermore , gene expression profiling ( whole - genome cDNA array Human Unigene RZPD - 2 ) was performed to achieve a comprehensive view of involved genes during the cell activation process after 45 min ELF - MF exposure . Our results indicate the alteration of 986 genes involved in metabolism , cellular physiological processes , signal transduction and immune response . Significant regulations could be analyzed for 5 genes ( expression > 2 - or < 0 . 5 - fold ) : Q13261 ( Interleukin 15 receptor , alpha chain ) , Q9UBC2 ( P00533 pathway substrate 15 - like 1 ) , Q9Y6K1 ( Hypothetical protein MGC16121 ) , Q9Y6K1 ( DNA ( cytosine - 5 ) methyltransferase 3 alpha ) , and one gene with no match to known genes , DKFZP586J1624 . Real - time RT - PCR analysis of the kinetic of the expression of Q13261 , and Q13651 during 45 min ELF - MF exposure indicates the regulation of cell activation via the alternative pathway , whereas the delayed gene expression of P01100 , P01589 and the melatonin synthesizing enzyme P46597 suggests the suppression of inflammatory processes . Accordingly , we suggest that ELF - MF activates human monocytes via the alternative pathway .\",\n \"Non - HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients . Autoimmune Polyglandular Syndrome Type II ( APSII ) is characterized by the co - occurrence of clinical insufficiency of at least two endocrine glands . Although , HLA determinants of APSII predisposition have been identified , little attention has been paid to non - HLA genes . Here , we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co - occurrence of Autoimmune Thyroid Disease ( AITD ) and Type 1 Diabetes ( T1D ) and lower frequency of Addison ' s disease ( AD ) . We tested the high a priori possibility that well - established non - HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII , namely : ( 1 ) two T1D - associated SNPs , in P16410 and P01589 , suggest their involvement in T1D pathogenesis in this cohort ; ( 2 ) two SNPs in Q14765 and P40933 not previously associated to endocrinopathies , are possibly involved in co - occurrence of organ autoimmunity in APSII , and ; ( 3 ) one SNP in P01375 alpha showed association to APSII irrespective of AD . While this work was performed in a relatively small cohort , these results support the notion that the non - HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co - occurrence of multiple autoimmune endocrinopathies .\",\n \"Human T - cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF - kappaB . Adult T - cell leukemia ( ATL ) is a highly aggressive T - cell malignancy caused by human T - cell leukemia virus type 1 ( HTLV - 1 ) . The activation of NF - kappaB by Tax has been reported to play a crucial role in HTLV - 1 - induced transformation . The HTLV - 1 bZIP factor ( P02008 ) , which is encoded by an mRNA of the opposite polarity of the viral genomic RNA , is involved in both T cell proliferation and suppression of Tax - mediated viral gene transcription , suggesting that P02008 cooperates closely with Tax . In the present study , we observed that P02008 specifically suppressed NF - kappaB - driven transcription mediated by p65 ( the classical pathway ) without inhibiting the alternative NF - kappaB signaling pathway . In an immunoprecipitation assay , P02008 bound to p65 and diminished the DNA binding capacity of p65 . In addition , P02008 induced p65 degradation through increasing the expression of the Q96JY6 gene , which encodes a ubiquitin E3 ligase for p65 . Finally , P02008 actually repressed the transcription of some classical NF - kappaB target genes , such as P10145 , P01589 , Q15306 , P19320 , and P15692 . Selective suppression of the classical NF - kappaB pathway by P02008 renders the alternative NF - kappaB pathway predominant after activation of NF - kappaB by Tax or other stimuli , which might be critical for oncogenesis .\",\n \"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .\",\n \"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK21___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .\",\n \"DB00074 induction in patients receiving tacrolimus - based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine - based immunosuppression . However , its clinical utility in patients receiving tacrolimus - based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 ) , and 132 patients received tacrolimus without basiliximab ( TAC - No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 compared to TAC - IL - 2RA and TAC - No Groups ( 33 vs . 14 . 9 vs . 14 . 3 % , p < 0 . 001 ) . Inferior creatinine clearance was observed in dTAC - P01589 Group compared to TAC - P01589 and TAC - No Groups at months 1 ( 41 . 6 vs . 49 . 9 vs . 44 . 8 mL / min , p = 0 . 004 ) , 3 ( 49 . 8 vs . 57 . 2 vs . 53 . 5 mL / min , p = 0 . 017 ) , and 6 ( 53 . 1 vs . 61 . 8 vs . 57 . 0 mL / min , p = 0 . 001 ) . Patients who received basiliximab ( TAC - P01589 and dTAC - P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39 . 3 % , p = 0 . 009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction .\"\n]"},"candidates":{"kind":"list like","value":["___MASK21___","___MASK25___","___MASK27___","___MASK32___","___MASK47___","___MASK57___","___MASK64___","___MASK68___","___MASK93___"],"string":"[\n \"___MASK21___\",\n \"___MASK25___\",\n \"___MASK27___\",\n \"___MASK32___\",\n \"___MASK47___\",\n \"___MASK57___\",\n \"___MASK64___\",\n \"___MASK68___\",\n \"___MASK93___\"\n]"},"answer":{"kind":"string","value":"___MASK47___"},"id":{"kind":"string","value":"MH_train_387"}}},{"rowIdx":388,"cells":{"query":{"kind":"string","value":"interacts_with DB06663?"},"supports":{"kind":"list like","value":["Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK49___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .","Effects of chimeric somatostatin - dopamine molecules on human peripheral blood lymphocytes activation . O43521 23A761 , selective for somatostatin receptors subtypes 2 , 5 and the dopamine receptor subtype 2 , and O43521 23A757 with affinity for P30874 and DAR2 were studied on human PBL proliferation and activation . O43521 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen , while O43521 23A757 was more potent than specific P30874 and DAR2 agonists in suppressing antigen induced proliferation only . Both molecules displayed enhanced potency in suppressing IFNgamma and P05231 secretion compared with the SSTR and DAR2 analogs , while only O43521 23A761 was able to inhibit P60568 secretion and its effect is more potent than the control analogs . Furthermore O43521 23A761 inhibit cell progression into the S phase and then into the G2 / M , while O43521 23A757 inhibited bromodeoxyuridine incorporation only during the S phase . Both chimeric molecules resulted significantly more effective than the respective controls .","Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK93___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .","Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( ___MASK26___ ) reduces hyperactive - impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate ___MASK26___ effects in P51689 , as in typically developing children with attention - deficit / hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to ___MASK26___ during a 1 - week safety / tolerability lead - in phase and 58 who went on to be randomized to placebo and three doses of ___MASK26___ during a 4 - week blinded , crossover study . Outcome measures included the Clinical Global Impression - Improvement ( CGI - I ) scale and the Aberrant Behavior Checklist ( ABC - hyperactivity index ) . A total of 14 subjects discontinued the study because of ___MASK26___ side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty - nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P = 0 . 006 ) , P08913 ( P < 0 . 02 ) , P21964 ( P < 0 . 04 ) , P35462 ( P < 0 . 05 ) , P21917 ( P < 0 . 05 ) , Q01959 ( P < 0 . 05 ) and P31645 ( P < 0 . 05 ) genotypes were found for responders versus non - responders . Variants in P14416 ( P < 0 . 001 ) and P35462 ( P < 0 . 04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first ___MASK26___ pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in ___MASK26___ ' s efficacy and tolerability .","Modulation of expression of somatostatin receptor subtypes in Graves ' ophthalmopathy orbits : relevance to novel analogs . Apart from evaluating orbital inflammation in Graves ' ophthalmopathy ( GO ) , somatostatin ( P61278 ) analogs have been proposed as a therapy , but recent trials were disappointing . We aimed to measure somatostatin receptor ( SSTR ) expression in orbital tissues ex vivo and determine whether the new broad - affinity analog DB06663 might be of therapeutic use . Orbital adipose / connective tissues from 29 GO patients and 10 normal individuals were analyzed . Transcripts were quantified using SYBR Green and a light cycler . In vitro models were used to investigate whether thyrotropin receptor activation ( as occurs via thyroid stimulating antibodies ) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and DB06663 in their modulation . The expression of P30872 was significantly higher in GO patients than normal controls ( P = 0 . 024 ) . Although differences in the expression of P30874 were not significant , 39 % of GO samples had levels above the 97th percentile of the controls . P32745 , - 4 , and - 5 were at or below the limit of detection ( LOD ) . The lymphocyte contribution was minimal , since CD3alpha transcripts were at the LOD . DB00024 receptor activation did not modulate SSTR expression . An in vitro model of adipogenesis indicated upregulation of P30872 and P30874 during differentiation . DB06663 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide . Ex vivo analysis of orbital tissues reveals upregulation of P30872 and - 2 in a group of GO patients . Adipogenesis , a process occurring in GO orbits , provides one possible explanation for some of the observed increase .","Filamin A in somatostatin and dopamine receptor regulation in pituitary and the role of DB02527 / PKA dependent phosphorylation . Molecular mechanisms underlying resistance of pituitary tumors to somatostatin ( SS ) and dopamine ( DA ) analogues treatment are not completely understood . Resistance has been associated with defective expression of functional somatostatin and dopamine receptors P30874 , P35346 , and P14416 , respectively . Recently , a role of cytoskeleton protein filamin A ( P21333 ) in P14416 and SSTR receptors expression and signaling in PRL - and GH - secreting tumors , respectively , has been demonstrated , first revealing a link between P21333 expression and responsiveness of pituitary tumors to pharmacological therapy . No molecular events underlying the reduction of P21333 levels in resistant tumors have been so far identified . P21333 can be phosphorylated by PKA on Ser2152 , with increased P21333 resistance to cleavage by calpain and conformational changes affecting P21333 regions involved in P30874 and P14416 binding and signal transduction . In this respect , the effect of DB02527 / PKA pathway in the regulation of P21333 stability and / or function by modulating its phosphorylation status could assume particular importance in pituitary , where DB02527 cascade plays a crucial role in pituitary cell functions and tumorigenesis . This review will discuss the role of P21333 in the regulation of the main GPCRs target of pharmacological treatment of pituitary tumors , that is , P30874 and P14416 , focusing on the effects of DB02527 / PKA - mediated P21333 phosphorylation on P21333 biological functions .","Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK93___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .","No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK26___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK26___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK26___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK26___ among adults with ADHD .","Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors . AIMS : To evaluate the frequency of somatostatin - receptor 5 ( SSTR 5 ) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies . MATERIAL AND METHOD : we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal ( clone UMB - 4 ) and polyclonal SSTR 5 - antibodies . Immunoreactive score ( P41252 ) and DAKO - score Her2 / neu were evaluated . RESULTS : Immunohistochemistry analysis demonstrated for the P41252 a significant higher staining of all specimen using the monoclonal antibodies ( P41252 P35346 poly vs P41252 SSTR 5 mono ; 20 . 0 % vs 30 . 3 % p < 0 . 001 ) by a correlation of 0 . 21 ; p = 0 . 04 . For the P04626 score there was also a significant higher staining in the monoclonal group ( Her2 SSTR 5 poly vs Her2 SSTR 5 mono ; 21 . 5 % vs 28 . 8 % p < 0 . 001 ) by a correlation of 0 . 20 ; p = 0 . 08 . CONCLUSION : Both antibodies are useful in staining of SSTR , although UMB - 4 demonstrated a 10 % higher SSTR 5 staining . Due to the previous underestimated expression rate of SSTR 5 , current standards in diagnostics and therapy should be reconsidered . The increasing usage of long - acting pansomatostatin receptor analogues will rise the adverse effects connected to P35346 binding .","Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .","P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .","___MASK47___ induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase - 5 ( O76074 ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1 - 20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin - 1 ( P10599 - 1 ) , hemeoxygenase - 1 ( P09601 ) and P15692 . ___MASK47___ induced P15692 and angiopoietin specific receptors such as P35968 , Tie - 1 and Tie - 2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 enzyme activity . ___MASK47___ below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . ___MASK47___ along with SnPP inhibited both P15692 and Q15389 ( Ang - 1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro - angiogenic factor .","Somatostatin activation of mitogen - activated protein kinase via somatostatin receptor 1 ( P30872 ) . Hormones and growth factors regulate cell growth via the mitogen - activated protein ( Q96HU1 ) kinase cascade . Here we examine the actions of the hormone somatostatin on the Q96HU1 kinase cascade through one of its two major receptor subtypes , the somatostatin receptor 1 ( P30872 ) stably expressed in CHO - P04264 cells . Somatostatin antagonizes the proliferative effects of fibroblast growth factor in CHO - P30872 cells via the P30872 receptor . However , in these cells , somatostatin robustly activates Q96HU1 kinase ( also called extracellular signal regulated kinase ; P29323 ) and augments fibroblast growth factor - stimulated P29323 activity . We show that the activation of P29323 via P30872 is pertussis toxin sensitive and requires the small G protein Ras , phosphatidylinositol 3 - kinase , the serine / threonine kinase P04049 , and the protein tyrosine phosphatase Q06124 . The activation of P29323 by P30872 increased the expression of the cyclin - dependent protein kinase inhibitor P38936 ( cip1 / P38936 ) . Previous studies have suggested that somatostatin - stimulated protein tyrosine phosphatase activity mediates the growth effects of somatostatin . Our data suggest that Q06124 stimulation by P30872 may mediate some of these effects through the activation of the Q96HU1 kinase cascade and the expression of P38936 ( cip1 / P38936 ) .","___MASK49___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .","___MASK94___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK94___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK94___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK94___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK94___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK94___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .","Regeneration of insulin - producing pancreatic cells using a volatile bioactive compound and human teeth . Transplantation of insulin ( P01308 ) - secreting cells differentiated in vitro from stem cells promises a safer and easier treatment of severe diabetes mellitus . A volatile bioactive compound , hydrogen sulfide ( H2S ) , promotes cell differentiation ; human tooth - pulp stem cells undergo hepatic differentiation . The aim of this study is to develop a novel protocol using H2S to enhance pancreatic differentiation from the CD117 (+) cell fraction of human tooth pulp . During the differentiation , the cells were exposed to 0 . 1 ng ml (- 1 ) H2S . Immunocytochemistry , RT - PCR , determination of P01308 c - peptide content and flow cytometry of pancreatically related markers were carried out . Expression of WNT and the PI3K / AKT signaling pathway were also determined by PCR array . After differentiation , P01308 , glucagon ( P01275 ) , somatostatin ( P61278 ) and pancreatic polypeptide ( P01298 ) were positive when examined by immunofluorescence . P01308 and P01275 were also determined flow - cytometrically . Only the cells expressing P01308 increased after H2S exposure . The number of cells expressing P01275 was significantly decreased . Genes involved in canonical WNT and the WNT / calcium pathways were highly expressed after H2S exposure . H2S accelerated P01308 synthesis and secretion by regenerated P01308 - producing cells from human teeth . All signaling pathway functions of the PI3K - AKT pathway were extremely activated by H2S exposure . The matured P01308 - producing cells originating in human teeth were increased by H2S in order to control blood - glucose level .","Somatostatin ameliorates lipopolysaccharide - induced tight junction damage via the P29323 - MAPK pathway in Caco2 cells . Dysfunction of the epithelial barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut . Somatostatin ( P61278 ) has been demonstrated to reduce local and systemic inflammation reactions and maintain the integrity of the blood - brain barrier ( BBB ) . To determine the beneficial effect of P61278 on lipopolysaccharide ( LPS ) - induced damage of the tight junction ( TJ ) and its mechanisms , Caco2 cells pretreated with P61278 ( 1nM ) or MEK inhibitor U0126 ( 10μM ) were exposed to LPS . LPS significantly reduced the expression of TJ proteins in a dose - dependent way . LPS ( 100μg / ml ) greatly induced Caco2 monolayer barrier dysfunction by decreasing transepithelial resistance and increasing epithelial permeability . Pretreatment with P61278 effectively improved the barrier dysfunction of Caco2 cells . P61278 significantly increased the expression of TJ proteins occludin and ZO - 1 and inhibited the redistribution of TJ proteins due to LPS stimulation . Furthermore , P61278 decreased the LPS - induced phosphorylation of P27361 / 2 , and a selective MEK inhibitor markedly protected the barrier function against LPS disturbance by blocking the activation of the P29323 - MAPK pathway in Caco2 cells . Besides , LPS significantly increased the mRNA level of P35346 , which was partly inhibited by pretreatment with P61278 . In conclusion , the present study indicates that P61278 protects the Caco2 monolayer barrier against LPS - induced tight junction breakdown by down - regulating the activation of the P29323 - MAPK pathway and suppression the activation of P35346 .","ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .","Corynoxine , a natural autophagy enhancer , promotes the clearance of alpha - synuclein via Akt / P42345 pathway . Parkinson ' s disease ( PD ) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates ( namely Lewy bodies ) in dopaminergic neurons in the substantia nigra region of the brain . P37840 ( α - syn ) is the major component of Lewy bodies in PD patients , and impairment of the autophagy - lysosomal system has been linked to its accumulation . In our previous study , we identified an oxindole alkaloid Corynoxine B ( Cory B ) , isolated from Uncaria rhynchophylla ( Miq . ) Jacks ( Gouteng in Chinese ) , as a Q14457 - dependent autophagy inducer . In this work , we show that Cory , an enantiomer of Cory B , also induces autophagy in different neuronal cell lines , including N2a and SHSY - 5Y cells , which is paralleled with increased lysosomal enzyme cathepsin D . In vivo , Cory promotes the formation of autophagosomes in the fat bodies of Drosophila . By inducing autophagy , Cory promotes the clearance of wild - type and A53T α - syn in inducible PC12 cells . Interestingly , different from its enantiomer Cory B , Cory induces autophagy through the Akt / P42345 pathway as evidenced by the reduction in the levels of phospho - Akt , phospho - P42345 and phospho - P08133 S6 Kinase . Collectively , our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine , which may have potential application in the prevention or treatment of PD .","Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK37___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK37___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK37___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .","Inhibitory effect of somatostatin - 14 and some analogues on human natural killer cell activity . The effect of somatostatin - 14 ( P61278 ) and the P61278 analogues P52788 and RC160 on human natural killer ( NK ) activity mediated by large granular lymphocytes ( LGL ) , as well as on P60568 - and / or anti - CD16 monoclonal antibody ( mAb ) - induced activation of these cells , was investigated . The NK activity of LGL was studied by the release of 51Cr by the erythroleukemia - derived cell line K562 , whereas 51Cr release by the P815 murine mastocytoma - derived cell line , for which lysis was redirected by the use of an anti - CD16 mAb , was used to study the cytolytic potential of these cells . P60568 was used at the final concentration of 100 IU and was incubated overnight with LGL . P61278 and the analogues , added to these systems at final doses ranging from 10 (- 12 ) to 10 (- 5 ) M , were inhibitory of the NK cell activity to K562 , with a dose - response curve starting from 10 (- 8 ) M and reaching a significant level at 10 (- 6 ) M . On the contrary , no effect was observed on the redirected killing assay to P815 and on the P60568 - induced activation of NK cells . These results provide additional evidence for the immunomodulatory action of somatostatin .","Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .","DB06663 , a multiple somatostatin receptor subtypes ligand , reduces cell viability in non - functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion . Somatostatin ( SRIF ) analogs have been employed in medical therapy of non - functioning pituitary adenomas ( DB04552 ) , with contrasting results . Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor ( P15692 ) secretion and action , and that P15692 expression may be related to pituitary tumor growth . The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on P15692 secretion and cell proliferation in human DB04552 primary cultures . We assessed the expression of SRIF receptors ( P30872 - 5 ) , the in vitro effects on P15692 secretion , and on cell viability of SRIF and of the stable SRIF analog pasireotide ( DB06663 ) , which activates P30872 , 2 , 3 , and 5 . Twenty - five DB04552 were examined by RT - PCR for expression of alpha - subunit , SSTR , P15692 , and P15692 receptors 1 ( P15692 - Q96GN5 ) and 2 ( P15692 - R2 ) . Primary cultures were tested with SRIF and with pasireotide . All DB04552 samples expressed alpha - sub , P15692 and P17948 and 2 , while SSTR expression pattern was highly variable . Two different groups were identified according to P15692 secretion inhibition by SRIF . P15692 secretion and cell viability were reduced by SRIF and pasireotide in the ' responder ' group , but not in the ' non - responder ' group , including DB04552 expressing P35346 . SRIF and pasireotide completely blocked forskolin - induced P15692 secretion . In addition , SRIF and pasireotide completely abrogated the promoting effects of P15692 on DB04552 cell viability . Our data demonstrate that pasireotide can inhibit DB04552 cell viability by inhibiting P15692 secretion , and suggest that the multireceptor - SSTR agonist pasireotide might be useful in medical therapy of selected DB04552 .","Effect of DB06663 ( pasireotide ) on corticotropic cells : action in dogs with Cushing ' s disease . DB06663 ( pasireotide ) is a multiligand somatostatin ( SRIF ) analog able to bind to somatostatin receptor ( SSTR ) subtypes 1 , 2 , 3 and 5 , and trigger antisecretory and antiproliferative signaling cascades . Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing ' s disease in a spontaneous manner , due to adrenocorticotropic hormone ( DB01285 ) - producing pituitary adenomas . Different levels of expression of P30874 and P35346 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells . The objective of this study was to evaluate whether DB06663 controls both tumor cell growth and hormone synthesis , therefore controlling the disease . DB06663 was tested in dogs suffering from Cushing ' s disease ( 10 animals were treated continuously during 6 months , and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2 - month rest period ) . A significant decrease in DB01285 , urinary cortisol creatinine ratio , adenoma size ( magnetic nuclear resonance ) and improvement of clinical signs were obtained , without side effects . AtT20 cells treated with DB06663 suppressed pro - opiomelanocortin ( P01189 ) promoter activity through P30874 , via the G ( i ) α - subunit , and reduced P22736 / Nurr1 transcriptional activity . We conclude that DB06663 , in addition to its well - described antisecretory effects , inhibits , as shown in AtT20 cells , DB01285 synthesis at the P01189 transcriptional level , an effect mediated mainly through P30874 , and limits tumor growth . The controlled Cushing ' s disease in the dogs that received the treatment indicates that DB06663 has a potential therapeutic use in humans suffering from Cushing ' s disease .","Effect of chronic ___MASK47___ treatment on the prostate of C57Bl / 6 mice . ___MASK47___ is a potent and selective inhibitor of phosphodiesterase - 5 ( O76074 ) and is considered first - line therapy for erectile dysfunction . Nowadays , ___MASK47___ is used extensively throughout the world on patients with pulmonary hypertension . However , few studies have evaluated the possible side effects of chronic ___MASK47___ treatment on the male reproductive system , specifically in the prostate . In the present study , it was demonstrated via morphological and ultrastructural analysis that chronic treatment with ___MASK47___ induced an enhancement of the glandular activity of the prostate . In addition , mice treated with ___MASK47___ showed a significant increase in testosterone serum levels . However , no statistically significant differences were observed in nitric oxide serum levels , or in sGC , P29474 , PSA and TGF - β prostatic expression . In conclusion , the present study suggests that chronic use of ___MASK47___ does not cause evident prostatic damage , and therefore , can be used pharmacologically to treat a variety of disorders .","Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK54___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .","[ New medical treatments in Cushing disease ] . The standard treatment of Cushing disease is surgery . Radiotherapy and steroïdogenesis inhibitors are second - line treatments . The new multi - ligand somatostatin analogs , such as DB06663 , having a much higher affinity with several receptors of somatostatin ( P30872 , 3 , and 5 ) than octreotid ( mostly a P30874 receptor ) have been synthetized . Some studies have shown that P35346 is predominantly expressed in corticotroph pituitary adenomas and that DB06663 has more efficacy than octreotid in the treatment of Cushing disease . It has been suggested that the thiazolinidinediones , P37231 agonists , might also be useful in the treatment of this disease , but studies are still limited and give conflicting results . In a recent study conducted on dogs , Castillo et al have shown that the retinoïds give encouraging results and might open a new pathway in the treatment of Cushing disease . But further studies , especially on humans , are necessary before conclusions can be reached . Labeur and his team have contributed a study on the use of gamma - interferon on murine pituitary cells and on human and murine corticotroph pituitary adenoma cells , and they have evidenced a 20 to 60 % decrease in the production of DB01285 in 5 cases out of 7 in the tumoral cells treated -- versus the non - treated ones . Eventually , Pivonello and his team have confirmed the D2 dopaminergic receptor expression in corticotroph pituitary cells , mainly in the intermediary zone . Thus they have suggested that the dopaminergic agonists -- such as cabergoline - could be used in corticotroph pituitary adenomas derivated from the intermediary zone .","Brucine suppresses colon cancer cells growth via mediating P35968 signalling pathway . Angiogenesis plays an important role in colon cancer development . This study aimed to demonstrate the effect of brucine on tumour angiogenesis and its mechanism of action . The anti - angiogenic effect was evaluated on the chicken chorioallantoic membrane ( P62158 ) model and tube formation . The mechanism was demonstrated through detecting mRNA and protein expressions of P35968 ( P35968 ) , PKCα , PLCγ and Raf1 by reverse transcription - polymerase chain reaction ( RT - PCR ) and Western blot ( WB ) , as well as expressions of P15692 and PKCβ and P42345 by ELISA and WB . The results showed that brucine significantly reduced angiogenesis of P62158 and tube formation , inhibited the P15692 secretion and P42345 expression in LoVo cell and down - regulated the mRNA and phosphorylation protein expressions of P35968 , PKCα , PLCγ and Raf1 . In addition , the effects of brucine on P35968 kinase activity , viability of LoVo cell and gene knockdown cell were detected with the Lance ™ assay , WST - 1 assay and instantaneous siRNA . Compared to that of normal LoVo cells , the inhibition on proliferation of knockdown cells by brucine decreased significantly . These results suggest that brucine could inhibit angiogenesis and be a useful therapeutic candidate for colon cancer intervention .","Distinct patterns of neuropeptide gene expression in the lateral hypothalamic area and arcuate nucleus are associated with dehydration - induced anorexia . We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration - associated anorexia . In situ hybridization and hormone analyses of anorexic and paired food - restricted rats revealed two distinct profiles . First , both groups had the characteristic gene expression and endocrine signatures usually associated with starvation : increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus ( Q5SW96 ) ; increased circulating glucocorticoid but reduced leptin and insulin . Dehydrated animals are strongly anorexic despite these attributes , showing that the output of leptin - and insulin - sensitive Q5SW96 neurons that ordinarily stimulate eating must be inhibited . The second pattern occurred only in anorexic animals and had two components : ( 1 ) reduced corticotropin - releasing hormone ( P06850 ) mRNA in the neuroendocrine paraventricular nucleus ( PVH ) and ( 2 ) increased P06850 and neurotensin mRNAs in the lateral hypothalamic ( LHA ) and retrochiasmatic areas . However , neither corticosterone nor suppressed PVH P06850 gene expression is required for anorexia after dehydration because PVH P06850 mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls . We also showed that LHA P06850 mRNA was strongly correlated with the intensity of anorexia , increased LHA P06850 gene expression preceded the onset of anorexia , and dehydrated adrenalectomized animals ( which also develop anorexia ) had elevated LHA P06850 gene expression with a distribution pattern similar to intact animals . Finally , we identified specific efferents from the P06850 - containing region of the LHA to the PVH , thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the Q5SW96 and the LHA . Together , these observations suggest that P06850 and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects .","Effects of vasoactive intestinal peptide ( P01282 ) and somatostatin ( P61278 ) on lipoprotein receptor expression by A431 tumor cells . A variety of tumor cells have been shown to express lipoprotein receptors . Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells . We investigated the effects of vasoactive intestinal peptide ( P01282 ) and somatostatin - 14 ( P61278 - 14 ) on the binding of 111Indium - labeled lipoproteins [ ( 111 ) In - low density lipoprotein ( ( 111 ) In - LDL ) , ( 111 ) In - high density lipoprotein ( ( 111 ) In - HDL ) and ( 111 ) In - very low density lipoprotein ( ( 111 ) In - VLDL ) ] onto the epidermoid mammary carcinoma cell line A431 . Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL , HDL and VLDL expressed by A431 cells , respectively . P01282 increased significantly the binding capacity for ( 111 ) In - LDL on A431 cells . The P01282 - induced increase of ( 111 ) In - LDL binding sites was inhibited by P61278 - 14 . Furthermore , P61278 - 14 inhibited P01282 - induced 3H - thymidine incorporation and adenosine 3 '- 5 ' cyclic monophosphate ( DB02527 ) formation in A431 cells with IC50 values in the range of 5 - 7 nM . However , P61278 - 14 showed no effect on dibutyryl - DB02527 - induced increase of ( 111 ) In - LDL binding sites expressed on A431 cells . In contrast to ( 111 ) In - LDL binding , no effects of P01282 or P61278 - 14 on HDL or VLDL binding to A431 tumor cells were found . Our results suggest a direct effect of P01282 and P61278 - 14 on LDL - binding onto tumor cells . The complex interactions between P01282 and P61278 - 14 on P01130 expression of tumor cells may play a role in tumor cell lipid metabolism .","Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK94___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .","___MASK37___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .","P01308 - like growth factor pathway genes and blood concentrations , dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin - like growth factor 1 ( DB01277 ) . Several single nucleotide polymorphisms ( SNPs ) have been weakly associated with circulating concentrations of DB01277 and IGF binding protein 3 ( P17936 ) , but none of these SNPs was associated with risk of prostate cancer . We examined whether an association between 16 SNPs associated with circulating DB01277 or P17936 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5 , 253 cases and 4 , 963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . The BPC3 includes nested case - control studies within large North - American and European cohorts . Per - allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake , which was expressed as the percentage of energy derived from total , animal , dairy or plant protein sources , using conditional logistic regression models . Total , animal , dairy and plant protein intakes were significantly positively associated with blood DB01277 ( p < 0 . 01 ) , but not with P17936 concentrations ( p > 0 . 10 ) or with risk of prostate cancer ( p > 0 . 20 ) . After adjusting for multiple testing , the SNP - prostate cancer associations did not differ by intakes of protein , although two interactions by intake of plant protein were of marginal statistical significance [ P35346 ( somatostatin receptor 5 ) - rs197056 ( uncorrected p for interaction , 0 . 001 ) ; P35346 - rs197057 ( uncorrected p for interaction , 0 . 002 ) ] . We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein .","Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .","Expression of somatostatin receptors in human melanoma cell lines : effect of two different somatostatin analogues , octreotide and DB06663 , on cell proliferation . Somatostatin analogues ( SAs ) are potential anticancer agents . This study was designed to investigate the expression of somatostatin receptors ( SSTRs ) in melanoma cells and the effect of two SAs on cell proliferation and viability . Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and DB06663 . Expression of P30872 , P30874 , P32745 and P35346 was assessed by real - time polymerase chain reaction . Proliferation , viability and cell death were assessed using standard assays . Inhibition was modelled by mixed - effect regression . Melanoma cells expressed one or more SSTR . Both SAs inhibited proliferation of most melanoma cell lines , but inhibition was < 50 % . Neither SA affected cell viability or induced cell death . The results suggest that melanoma cell lines express SSTRs . The SAs investigated , under the conditions used in this study , did not , however , significantly inhibit melanoma growth or induce cell death . Novel SAs , combination therapy with SAs and their anti - angiogenic properties should be further investigated .","Modulation by cytokines of glucocorticoid action . Glucocorticoids ( GC ) are potent modulators of the inflammatory response . Their effects serve to down - regulate the inflammatory response and are mediated by genomic pathways that follow the interaction with specific receptors ( glucocorticoid receptors , GR ) . Interleukin ( IL ) - 1 , P60568 , and P05231 are able to increase GC secretion by enhancing synthesis and release of P06850 and DB01285 . Cytokine effects upon steroidogenesis also occur at the adrenal level . The role of cytokines as modulators of GR has received scarce attention . IL - 1 has been shown to up - regulate GR mRNA expression in hypothalamic P06850 secreting cells . On the other hand , macrophage migration inhibitory factor ( MIF ) , a T - cell product inducible by inflammatory substances including other cytokines , counterregulates GC action within the immune system . Besides immunocytes and neurons , bone cells are a sensitive target for GC and cytokines . We have found that P60568 and P05231 up - regulate remarkably the number of GR binding sites and the expression of GR mRNA in peripheral blood mononuclear cells and in osteoblast - like Saos - 2 cells . Available data suggest that inflammatory cytokines have both direct and indirect effects on GC action at the target level . Autocrine - induced transcription of GR in immunocytes and / or osteoblasts could be a mechanism that restrains excess cytokine production .","Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK94___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .","New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .","Ca2 + regulates hormone secretion and proopiomelanocortin gene expression in melanotrope cells via the calmodulin and the protein kinase C pathways . The mechanism by which Ca2 + regulates proopiomelanocortin ( P01189 ) - derived peptide secretion and P01189 mRNA levels was investigated in primary cultures of porcine intermediate lobe ( IL ) cells maintained in serum - free medium . P01189 gene expression was evaluated by the dot blot hybridization assay with a 32P - labeled DNA probe complementary to the full - length sequence of porcine P01189 mRNA . Treatment of IL cells for 24 h with the calmodulin ( P62158 ) antagonists W7 and W13 reduced P01189 mRNA levels by a maximum of 50 % in a dose - dependent manner ( ED50 approximately 10 (- 8 ) M ) . Accumulation of alpha - melanocyte - stimulating hormone ( alpha - MSH ) in the medium was also depressed by 50 % after 8 h of treatment . The role of protein kinase C ( PKC ) was investigated by depleting the IL cell PKC content with phorbol ester treatment . Phorbol 12 - myristate 13 - acetate ( PMA ) at 5 X 10 (- 8 ) M induced a rapid translocation of cytoplasmic PKC activity toward the membrane . After 12 h of PMA treatment , PKC activity was undetectable in either the cytoplasmic or the particulate fractions . The same dose of PMA induced a time - dependent decrease in P01189 mRNA levels ( 50 % inhibition after 24 h ) . The same effect was seen with the phorbol ester phorbol 12 , 13 - dibutyrate at 5 X 10 (- 8 ) M , whereas the inactive phorbol ester 4 alpha - phorbol at 5 X 10 (- 8 ) M was without effect after 24 h of treatment . PMA treatment had a biphasic effect on alpha - MSH secretion . ( ABSTRACT TRUNCATED AT 250 WORDS )","Fluvoxamine exerts anorexic effect in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m - chlorophenylpiperazine ( mCPP ) and fenfluramine . We previously reported that fluvoxamine , a selective serotonin reuptake inhibitor , together with pharmacological inactivation of P28335 receptors exert feeding suppression through activation of P28222 receptors in mice . Here , we report that fluvoxamine exerted anorexic effects in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene ( 2CREnd mice ) , whereas fluvoxamine had no effect on food intake in age - matched wild - type mice and P28335 receptor mutant mice , which are associated with decreases in hypothalamic proopiomelanocortin ( P01189 ) expression . mCPP suppressed food intake in P28335 receptor mutant mice , 2CREnd mice and age - matched wild - type mice . These results suggest that fluvoxamine - induced feeding suppression requires a perturbation of P28335 receptor and beta - endorphin signalling plus functional hypothalamic P01189 activity , whereas mCPP - induced feeding suppression does not always require functional P28335 receptor , beta - endorphin , and P01189 activity in mice .","DB00428 - induced increase in cholesterol ester transfer protein ( P11597 ) and its reversal by insulin in transgenic mice expressing human P11597 . High plasma triacylglycerol and low high - density lipoprotein levels are risk factors for cardiovascular disease in diabetes . Plasma high - density lipoprotein levels are regulated by cholesterol ester transfer protein ( P11597 ) . The regulation of P11597 under diabetic conditions is not clear , and this is due to a lack of appropriate models . We used transgenic mice expressing human P11597 to study the regulation of this protein under type - 1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes . Mice expressing human P11597 under the control of its natural flanking region and age - matched littermates not expressing this protein were made diabetic by injecting streptozotocin , and the reversal of diabetes was assessed by injecting insulin . The plasma total cholesterol , low - density lipoprotein - cholesterol , and triacylglycerol concentrations were elevated , whereas high - density lipoprotein - cholesterol concentrations were reduced after the onset of diabetes . P01308 injection partially recovered this effect . The plasma cholesterol ester transfer activity , P11597 mass , and hepatic P11597 mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration . There was a strong correlation between high - density lipoprotein - cholesterol concentrations and cholesterol ester transfer activity . These results suggest that an increase in P11597 under diabetic conditions might be a major factor responsible for increased incidence of diabetes - induced atherosclerosis .","P30872 and P35346 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors . The effectiveness of the long acting somatostatin analogues like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells . The immunohistochemical method performed on surgically removed tumors searches the expression of receptors at the level of receptor protein and gives us insight into receptor ' s cellular localization . The aim of study was to assess the presence of all the 5 subtypes of SSTR 1 - 5 ( including 2A and 2B SSTR isoforms ) in surgically treated human neuroendocrine tumors ( NETs ) to establish which receptor subtype is the dominant form of somatostatin receptor in particular tumor and thus to be able to predict which somatostatin analog will be effective in NETs treatment . 18 samples of neuroendocrine tumors ( surgically excised tumors or biopsies ) were immunostained with specific antibodies . Expression of SSTR was scored semiquantitatively . Only strong or moderate immunostaining was considered as positive reaction . The summarized expression pattern of SSTR in the investigated neuroendocrine tumors in our material was : SSTR 1 > SSTR 5 > SSTR 3 > SSTR 2A > SSTR 2B . The receptors were distributed mainly in the area of cells cytoplasm with a few specimens showing only membranous or mixed : membranous -- cytoplasmic localization . The observed pattern suggests that apart from octreotide and lanreotide , newly synthesized multiligand analogs such as DB06663 , KE 108 or SSTR 1 and SSTR 5 selective analogs could be effective in NETs treatment .","___MASK47___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .","Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .","Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin - dependent kinase ( CDK ) inhibitor . Cushing disease caused by adrenocorticotropin ( DB01285 ) - secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes , hypertension , osteoporosis , central obesity , cardiovascular morbidity , and increased mortality . There is no effective pituitary targeted pharmacotherapy for Cushing disease . Here , we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene ( O95997 / securin ) targeted to the adenohypophyseal proopiomelanocortin ( P01189 ) lineage , which recapitulated early features pathognomonic of corticotroph adenomas , including corticotroph expansion and partial glucocorticoid resistance . Adult Tg : Pomc - Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up - regulation , as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease . Early development of corticotroph pathologies in Tg : Pomc - Pttg embryos facilitated drug testing in vivo . We identified a pharmacologic P24941 / cyclin E inhibitor , R - roscovitine ( seliciclib ; CYC202 ) , which specifically reversed corticotroph expansion in live Tg : Pomc - Pttg embryos . We further validated that orally administered R - roscovitine suppresses DB01285 and corticosterone levels , and also restrained tumor growth in a mouse model of DB01285 - secreting pituitary adenomas . Molecular analyses in vitro and in vivo showed that R - roscovitine suppresses DB01285 expression , induces corticotroph tumor cell senescence and cell cycle exit by up - regulating p27 , P38936 and p57 , and downregulates cyclin E expression . The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion .","Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK74___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK78___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .","Inhibition of the tumour necrosis factor - alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs . Several autocrine soluble factors , including macrophage inflammatory protein - 1α and tumour necrosis factor - alpha ( P01375 - α ) , promote the survival and growth of multiple myeloma ( MM ) cells . We hypothesised that inhibition of the P01375 - α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines . In the present study , a P01375 - α - neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells . In addition , combination treatment with the P01375 - α - neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor κB ( NF - κB ) p65 nuclear translocation and mammalian target of rapamycin ( P42345 ) activation and upregulated the expression of Bax and Bim . Treatment of Q5SW96 - 77 cells with the NF - κB inhibitor dimethyl fumarate or the P42345 inhibitor rapamycin suppressed NF - κB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan . Furthermore , infliximab , a monoclonal antibody against P01375 - α , also enhanced the cytotoxic effect of anticancer drugs in Q5SW96 - 77 cells . These results indicated that P01375 - α - neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the P01375 receptor / P42345 / NF - κB pathways . The inhibition of P01375 - α may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients .","Somatostatin modulates PI3K - Akt , P29474 and NHE activity in the ciliary epithelium . Somatostatin ( P61278 ) is a biologically active peptide produced in neuroendocrine cells . In the present study , we provide evidence of pro - P61278 and P61278 receptor ( P30872 and 2A ) mRNA expression in ocular ciliary epithelium ( CE ) . P61278 or P61278 - like immunoreactivity was detected by radioimmunoassay in tissue extract from ciliary processes and in aqueous humor . The distinct immunolabeling of CE with P61278 and proprotein convertases PC1 and P16519 antibodies suggested a tissue and cell - specific processing of pro - P61278 . P61278 ( 10 (- 8 ) to 10 (- 4 ) M ) added exogenously to the CE , elicited the following effects : ( i ) a dose - dependent attenuation of Na +/ H +- exchanger ( NHE ) activity ; ( ii ) up to a two - fold increase phosphorylation of p - Akt - Ser473 and of p - P29474 - Ser617 , and ( iii ) lack of response on intracellular cyclic GMP production . LY294002 , a PI3K - inhibitor , blocked P61278 - induced p - Akt - Ser473 and partially p - P29474 - Ser617 , however , it did not reverse P61278 - induced NHE attenuation . Collectively , these results suggested involvement of P61278 in multiple intracellular signaling pathways in the CE .","Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune - mediated arthritis . OBJECTIVE : Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties . However , it is not known which of the 5 somatostatin receptor subtypes ( SSTRs 1 - 5 ) is involved in these actions . The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide ( DB06663 ) in a mouse model of antigen - induced arthritis ( AIA ) . METHODS : Studies were performed in P30874 - deficient mice ( P30874 (-/-) ) and their wild - type littermates ( P30874 (+/+) ) . The expression of P30872 , SSTR2A , P32745 , and P35346 in dorsal root ganglia was examined by immunohistochemistry . RESULTS : Untreated P30874 (-/-) mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in P30874 (+/+) mice . In wild - type mice , both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone . In P30874 (-/-) mice , the antiinflammatory effects of both octreotide and pasireotide were completely abrogated . Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions . In addition , both octreotide and pasireotide reduced inflammatory hyperalgesia . The antinociceptive actions of octreotide were abolished in P30874 (-/-) mice , but those of pasireotide were retained . In dorsal root ganglia of naive wild - type mice , only P30872 and SSTR2A , but not P32745 or P35346 , were detected in a subset of small - and medium - diameter neurons . CONCLUSION : Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the P30874 receptor . In addition , we identified the P30872 receptor as a novel pharmacologic target for somatostatin - mediated peripheral analgesia in inflammatory pain .","Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .","Reliability and discriminant validity of P04626 gene quantification and chromosome 17 aneusomy analysis by real - time PCR in primary breast cancer . There is an increasing demand for the evaluation of P04626 status in breast cancer . In this study , sections from fixed tissues and triton extracts of tissue homogenates were obtained from 163 malignant breast tumors and analyzed in parallel using immunohistochemistry combined with fluorescence in situ hybridization , as gold standard tests , and an ELISA test ( c - erbB2 / c - neu Rapid Format ELISA , Oncogene Research Products , USA ) . Tumor DNA was employed to evaluate two quantitative PCR methods : the P04626 / neu DNA Quantification Kit ( Roche Diagnostics GmbH , Germany ) , which uses the gastrin chromosome 17 reference gene , and our recently developed Oncolab qPCR assay , where both a chromosome 17 gene ( somatostatin receptor type II ( P30874 ) ) and a non - chromosome 17 reference gene ( glyceraldehyde - 3 - phosphate deshydrogenase ( P04406 ) ) were used to detect an increase in P04626 gene copy number and to evaluate the aneusomy of chromosome 17 , respectively . By IHC / Q5TCZ1 and ELISA , P04626 was overexpressed in 27 ( 16 . 6 % ) and 24 ( 14 . 7 % ) samples , respectively . With the Roche and Oncolab qPCR assays , 29 ( 17 . 8 % ) samples showed a ratio of P04626 / gastrin > or = 2 . 0 and 26 ( 16 . 0 % ) showed a ratio of P04626 / P30874 > or = 2 . 0 , respectively . In samples presenting P04626 / P30874 < 2 . 0 and P04626 / P04406 > or = 2 . 0 , which was indicative of a chromosome 17 polysomy , we observed a modest increase in P04626 protein expression . Complete agreement between the four methods for P04626 status determination was obtained for 154 ( 94 . 5 % ) samples . Overall , these results demonstrate that quantitative PCR is a reliable method for analyzing P04626 status and chromosome 17 polysomy .","Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog DB06663 on hormone secretion in vitro and in ex vivo adrenal cells . BACKGROUND : Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion , cell proliferation , and apoptosis by 5 somatostatin receptors ( P30872 - 5 ) . The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and / or secretion of growth factors and growth - promoting hormones . AIM : Very little information is available on the effect of somatostatin analogs on adrenal tumors , so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog ( DB06663 ) on hormone secretion and cell viability in adrenal cells . MATERIAL / SUBJECTS AND METHODS : SSTR expression was analyzed by real - time PCR in 13 adrenocortical carcinomas ( ACC ) , 24 aldosterone - producing adenomas ( APA ) , 11 cortisol - producing adenomas ( P15085 ) , and 7 normal adrenals ( NA ) , and verified by immunohistochemistry ( IHC ) in 14 samples . The effect of DB06663 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay , and its effect on viability in H295R and SW13 using the MTT test . RESULTS : P30872 and P30874 mRNA was expressed in 100 % of adrenal tumors . Compared to NA , ACC revealed an increase in almost all SSTR , while only some APA over - expressed P32745 and P30872 . P15085 expressed SSTR similar to NA . IHC confirmed the mRNA expression data . At nanomolar concentrations , DB06663 inhibited hormone secretion in primary adrenal cultures and H295R cells , but had no evident effect on cell viability . CONCLUSIONS : The evidence of SSTR over - expression ( particularly in ACC ) and of hormone secretion being inhibited by DB06663 suggests a potential therapeutic role for this broad - spectrum somatostatin analog in adrenal tumors .","Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .","Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK74___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .","Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy . The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors ( GEP - NETs ) have increased in the past 20 years . GEP - NETs are heterogeneous tumors , in terms of clinical and biological features , that originate from the pancreas or the intestinal tract . Some GEP - NETs grow very slowly , some grow rapidly and do not cause symptoms , and others cause hormone hypersecretion and associated symptoms . Most GEP - NETs overexpress receptors for somatostatins . Somatostatins inhibit the release of many hormones and other secretory proteins ; their effects are mediated by G protein - coupled receptors that are expressed in a tissue - specific manner . Most GEP - NETs overexpress the somatostatin receptor P30874 ; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone - related symptoms and also have antitumor effects . Long - acting formulations of somatostatin analogues stabilize tumor growth over long periods . The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP - NETs . Peptide receptor radiotherapy has significant antitumor effects , increasing overall survival times of patients with tumors that express a high density of SSTRs , particularly P30874 and P35346 . The multi - receptor somatostatin analogue DB06663 ( pasireotide ) and chimeric molecules that bind P30874 and the dopamine receptor D2 are also being developed to treat patients with GEP - NETs . Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways , such as mammalian target of rapamycin ( P42345 ) and vascular endothelial growth factor , might be the most effective therapeutics for GEP - NETs .","[ Methylation profiling of human atherosclerotic plaques ] . Somatic mutation theory of atherogenesis proved by alterations at the DNA level such as \" loss of heterozygosity \" and microsatellite instability in atherosclerotic plaque is complemented by the date of epigenetic variability of genetic loci involved in the pathological process . However , only recently large - scale analysis of epigenetic modifications in the human genome became possible . For the first time quantitative microarray - based methylation profiling of 1505 CpG - sites across 807 genes was performed in atherosclerotic aorta and carotid artery wall lesions using the GoldenGate Methylation Cancer Panel I ( \" Illumina \" , USA ) . One hundred and three ( 7 % ) CpG - sites in 90 ( 11 % ) genes were differentially methylated between tissue samples . The most pronounced differences in DNA methylation levels were registered for a site which is located in CpG - island of imprinted gene H19 . By comparing 90 genes that were differentially methylated between tissue samples in our study , 10 genes ( P05362 , P09488 , P08833 , P01189 , P02647 , P18510 , P01308 , P01374 , P08254 , P35442 ) were overlapped with data in Human Genome Epidemiology Network ( HuGENet ) , in which they were identified as candidates for cardiovascular disease continuum .","Inhibitory effects of DB06663 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo . DB01285 ( DB01285 ) production by pituitary corticotroph adenomas is the main cause of Cushing ' s disease . A drug that targets pituitary DB01285 - secreting adenomas would aid treatment of Cushing ' s disease . DB00104 , a somatostatin receptor type 2 ( P30874 ) - preferring somatostatin analogue , has no effect on DB01285 secretion in patients with Cushing ' s disease . The multiligand DB06663 ( pasireotide ) displays a much higher affinity for P30872 and P35346 than octreotide and suppresses DB01285 secretion in cultures of human corticotroph tumors to a greater extent than octreotide . In the present in vitro and in vivo study , we determined the effect of DB06663 on DB01285 production and cell proliferation of AtT - 20 corticotroph tumor cells . DB06663 decreased proopiomelanocortin ( P01189 ) mRNA levels in AtT - 20 cells and DB01285 levels in the culture medium of these cells , suggesting that DB06663 suppresses DB01285 synthesis and secretion in corticotroph tumor cells . DB06663 also decreased cell proliferation and both cyclic adenosine monophosphate response element - binding protein and Akt phosphorylation in AtT - 20 cells . P35346 knockdown inhibited the DB06663 - induced decreases in cell proliferation . Fluorescence - activated cell sorting analyses revealed that DB06663 did not attenuate cell cycle progression . Tumor weight in mice xenografted with AtT - 20 cells and treated with DB06663 was significantly lower than in AtT - 20 - xenografted control mice . DB06663 also significantly decreased plasma DB01285 levels , and P01189 and pituitary tumor transforming gene mRNA levels in the tumor cells . Thus , DB06663 inhibits DB01285 production and corticotroph tumor cell proliferation in vitro and in vivo .","Chemical development of intracellular protein heterodimerizers . Cell activation initiated by receptor ligands or oncogenes triggers complex and convoluted intracellular signaling . Techniques initiating signals at defined starting points and cellular locations are attractive to elucidate the output of selected pathways . Here , we present the development and validation of a protein heterodimerization system based on small molecules cross - linking fusion proteins derived from HaloTags and P60880 - tags . Chemical dimerizers of HaloTag and P60880 - tag ( HaXS ) show excellent selectivity and have been optimized for intracellular reactivity . HaXS force protein - protein interactions and can translocate proteins to various cellular compartments . Due to the covalent nature of the HaloTag - HaXS - P60880 - tag complex , intracellular dimerization can be easily monitored . First applications include protein targeting to cytoskeleton , to the plasma membrane , to lysosomes , the initiation of the PI3K / P42345 pathway , and multiplexed protein complex formation in combination with the rapamycin dimerization system .","DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response ."],"string":"[\n \"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK49___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .\",\n \"Effects of chimeric somatostatin - dopamine molecules on human peripheral blood lymphocytes activation . O43521 23A761 , selective for somatostatin receptors subtypes 2 , 5 and the dopamine receptor subtype 2 , and O43521 23A757 with affinity for P30874 and DAR2 were studied on human PBL proliferation and activation . O43521 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen , while O43521 23A757 was more potent than specific P30874 and DAR2 agonists in suppressing antigen induced proliferation only . Both molecules displayed enhanced potency in suppressing IFNgamma and P05231 secretion compared with the SSTR and DAR2 analogs , while only O43521 23A761 was able to inhibit P60568 secretion and its effect is more potent than the control analogs . Furthermore O43521 23A761 inhibit cell progression into the S phase and then into the G2 / M , while O43521 23A757 inhibited bromodeoxyuridine incorporation only during the S phase . Both chimeric molecules resulted significantly more effective than the respective controls .\",\n \"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK93___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .\",\n \"Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( ___MASK26___ ) reduces hyperactive - impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate ___MASK26___ effects in P51689 , as in typically developing children with attention - deficit / hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to ___MASK26___ during a 1 - week safety / tolerability lead - in phase and 58 who went on to be randomized to placebo and three doses of ___MASK26___ during a 4 - week blinded , crossover study . Outcome measures included the Clinical Global Impression - Improvement ( CGI - I ) scale and the Aberrant Behavior Checklist ( ABC - hyperactivity index ) . A total of 14 subjects discontinued the study because of ___MASK26___ side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty - nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P = 0 . 006 ) , P08913 ( P < 0 . 02 ) , P21964 ( P < 0 . 04 ) , P35462 ( P < 0 . 05 ) , P21917 ( P < 0 . 05 ) , Q01959 ( P < 0 . 05 ) and P31645 ( P < 0 . 05 ) genotypes were found for responders versus non - responders . Variants in P14416 ( P < 0 . 001 ) and P35462 ( P < 0 . 04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first ___MASK26___ pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in ___MASK26___ ' s efficacy and tolerability .\",\n \"Modulation of expression of somatostatin receptor subtypes in Graves ' ophthalmopathy orbits : relevance to novel analogs . Apart from evaluating orbital inflammation in Graves ' ophthalmopathy ( GO ) , somatostatin ( P61278 ) analogs have been proposed as a therapy , but recent trials were disappointing . We aimed to measure somatostatin receptor ( SSTR ) expression in orbital tissues ex vivo and determine whether the new broad - affinity analog DB06663 might be of therapeutic use . Orbital adipose / connective tissues from 29 GO patients and 10 normal individuals were analyzed . Transcripts were quantified using SYBR Green and a light cycler . In vitro models were used to investigate whether thyrotropin receptor activation ( as occurs via thyroid stimulating antibodies ) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and DB06663 in their modulation . The expression of P30872 was significantly higher in GO patients than normal controls ( P = 0 . 024 ) . Although differences in the expression of P30874 were not significant , 39 % of GO samples had levels above the 97th percentile of the controls . P32745 , - 4 , and - 5 were at or below the limit of detection ( LOD ) . The lymphocyte contribution was minimal , since CD3alpha transcripts were at the LOD . DB00024 receptor activation did not modulate SSTR expression . An in vitro model of adipogenesis indicated upregulation of P30872 and P30874 during differentiation . DB06663 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide . Ex vivo analysis of orbital tissues reveals upregulation of P30872 and - 2 in a group of GO patients . Adipogenesis , a process occurring in GO orbits , provides one possible explanation for some of the observed increase .\",\n \"Filamin A in somatostatin and dopamine receptor regulation in pituitary and the role of DB02527 / PKA dependent phosphorylation . Molecular mechanisms underlying resistance of pituitary tumors to somatostatin ( SS ) and dopamine ( DA ) analogues treatment are not completely understood . Resistance has been associated with defective expression of functional somatostatin and dopamine receptors P30874 , P35346 , and P14416 , respectively . Recently , a role of cytoskeleton protein filamin A ( P21333 ) in P14416 and SSTR receptors expression and signaling in PRL - and GH - secreting tumors , respectively , has been demonstrated , first revealing a link between P21333 expression and responsiveness of pituitary tumors to pharmacological therapy . No molecular events underlying the reduction of P21333 levels in resistant tumors have been so far identified . P21333 can be phosphorylated by PKA on Ser2152 , with increased P21333 resistance to cleavage by calpain and conformational changes affecting P21333 regions involved in P30874 and P14416 binding and signal transduction . In this respect , the effect of DB02527 / PKA pathway in the regulation of P21333 stability and / or function by modulating its phosphorylation status could assume particular importance in pituitary , where DB02527 cascade plays a crucial role in pituitary cell functions and tumorigenesis . This review will discuss the role of P21333 in the regulation of the main GPCRs target of pharmacological treatment of pituitary tumors , that is , P30874 and P14416 , focusing on the effects of DB02527 / PKA - mediated P21333 phosphorylation on P21333 biological functions .\",\n \"Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK93___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .\",\n \"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK26___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK26___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK26___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK26___ among adults with ADHD .\",\n \"Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors . AIMS : To evaluate the frequency of somatostatin - receptor 5 ( SSTR 5 ) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies . MATERIAL AND METHOD : we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal ( clone UMB - 4 ) and polyclonal SSTR 5 - antibodies . Immunoreactive score ( P41252 ) and DAKO - score Her2 / neu were evaluated . RESULTS : Immunohistochemistry analysis demonstrated for the P41252 a significant higher staining of all specimen using the monoclonal antibodies ( P41252 P35346 poly vs P41252 SSTR 5 mono ; 20 . 0 % vs 30 . 3 % p < 0 . 001 ) by a correlation of 0 . 21 ; p = 0 . 04 . For the P04626 score there was also a significant higher staining in the monoclonal group ( Her2 SSTR 5 poly vs Her2 SSTR 5 mono ; 21 . 5 % vs 28 . 8 % p < 0 . 001 ) by a correlation of 0 . 20 ; p = 0 . 08 . CONCLUSION : Both antibodies are useful in staining of SSTR , although UMB - 4 demonstrated a 10 % higher SSTR 5 staining . Due to the previous underestimated expression rate of SSTR 5 , current standards in diagnostics and therapy should be reconsidered . The increasing usage of long - acting pansomatostatin receptor analogues will rise the adverse effects connected to P35346 binding .\",\n \"Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .\",\n \"P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .\",\n \"___MASK47___ induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase - 5 ( O76074 ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1 - 20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin - 1 ( P10599 - 1 ) , hemeoxygenase - 1 ( P09601 ) and P15692 . ___MASK47___ induced P15692 and angiopoietin specific receptors such as P35968 , Tie - 1 and Tie - 2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 enzyme activity . ___MASK47___ below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . ___MASK47___ along with SnPP inhibited both P15692 and Q15389 ( Ang - 1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro - angiogenic factor .\",\n \"Somatostatin activation of mitogen - activated protein kinase via somatostatin receptor 1 ( P30872 ) . Hormones and growth factors regulate cell growth via the mitogen - activated protein ( Q96HU1 ) kinase cascade . Here we examine the actions of the hormone somatostatin on the Q96HU1 kinase cascade through one of its two major receptor subtypes , the somatostatin receptor 1 ( P30872 ) stably expressed in CHO - P04264 cells . Somatostatin antagonizes the proliferative effects of fibroblast growth factor in CHO - P30872 cells via the P30872 receptor . However , in these cells , somatostatin robustly activates Q96HU1 kinase ( also called extracellular signal regulated kinase ; P29323 ) and augments fibroblast growth factor - stimulated P29323 activity . We show that the activation of P29323 via P30872 is pertussis toxin sensitive and requires the small G protein Ras , phosphatidylinositol 3 - kinase , the serine / threonine kinase P04049 , and the protein tyrosine phosphatase Q06124 . The activation of P29323 by P30872 increased the expression of the cyclin - dependent protein kinase inhibitor P38936 ( cip1 / P38936 ) . Previous studies have suggested that somatostatin - stimulated protein tyrosine phosphatase activity mediates the growth effects of somatostatin . Our data suggest that Q06124 stimulation by P30872 may mediate some of these effects through the activation of the Q96HU1 kinase cascade and the expression of P38936 ( cip1 / P38936 ) .\",\n \"___MASK49___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .\",\n \"___MASK94___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK94___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK94___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK94___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK94___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK94___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .\",\n \"Regeneration of insulin - producing pancreatic cells using a volatile bioactive compound and human teeth . Transplantation of insulin ( P01308 ) - secreting cells differentiated in vitro from stem cells promises a safer and easier treatment of severe diabetes mellitus . A volatile bioactive compound , hydrogen sulfide ( H2S ) , promotes cell differentiation ; human tooth - pulp stem cells undergo hepatic differentiation . The aim of this study is to develop a novel protocol using H2S to enhance pancreatic differentiation from the CD117 (+) cell fraction of human tooth pulp . During the differentiation , the cells were exposed to 0 . 1 ng ml (- 1 ) H2S . Immunocytochemistry , RT - PCR , determination of P01308 c - peptide content and flow cytometry of pancreatically related markers were carried out . Expression of WNT and the PI3K / AKT signaling pathway were also determined by PCR array . After differentiation , P01308 , glucagon ( P01275 ) , somatostatin ( P61278 ) and pancreatic polypeptide ( P01298 ) were positive when examined by immunofluorescence . P01308 and P01275 were also determined flow - cytometrically . Only the cells expressing P01308 increased after H2S exposure . The number of cells expressing P01275 was significantly decreased . Genes involved in canonical WNT and the WNT / calcium pathways were highly expressed after H2S exposure . H2S accelerated P01308 synthesis and secretion by regenerated P01308 - producing cells from human teeth . All signaling pathway functions of the PI3K - AKT pathway were extremely activated by H2S exposure . The matured P01308 - producing cells originating in human teeth were increased by H2S in order to control blood - glucose level .\",\n \"Somatostatin ameliorates lipopolysaccharide - induced tight junction damage via the P29323 - MAPK pathway in Caco2 cells . Dysfunction of the epithelial barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut . Somatostatin ( P61278 ) has been demonstrated to reduce local and systemic inflammation reactions and maintain the integrity of the blood - brain barrier ( BBB ) . To determine the beneficial effect of P61278 on lipopolysaccharide ( LPS ) - induced damage of the tight junction ( TJ ) and its mechanisms , Caco2 cells pretreated with P61278 ( 1nM ) or MEK inhibitor U0126 ( 10μM ) were exposed to LPS . LPS significantly reduced the expression of TJ proteins in a dose - dependent way . LPS ( 100μg / ml ) greatly induced Caco2 monolayer barrier dysfunction by decreasing transepithelial resistance and increasing epithelial permeability . Pretreatment with P61278 effectively improved the barrier dysfunction of Caco2 cells . P61278 significantly increased the expression of TJ proteins occludin and ZO - 1 and inhibited the redistribution of TJ proteins due to LPS stimulation . Furthermore , P61278 decreased the LPS - induced phosphorylation of P27361 / 2 , and a selective MEK inhibitor markedly protected the barrier function against LPS disturbance by blocking the activation of the P29323 - MAPK pathway in Caco2 cells . Besides , LPS significantly increased the mRNA level of P35346 , which was partly inhibited by pretreatment with P61278 . In conclusion , the present study indicates that P61278 protects the Caco2 monolayer barrier against LPS - induced tight junction breakdown by down - regulating the activation of the P29323 - MAPK pathway and suppression the activation of P35346 .\",\n \"ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .\",\n \"Corynoxine , a natural autophagy enhancer , promotes the clearance of alpha - synuclein via Akt / P42345 pathway . Parkinson ' s disease ( PD ) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates ( namely Lewy bodies ) in dopaminergic neurons in the substantia nigra region of the brain . P37840 ( α - syn ) is the major component of Lewy bodies in PD patients , and impairment of the autophagy - lysosomal system has been linked to its accumulation . In our previous study , we identified an oxindole alkaloid Corynoxine B ( Cory B ) , isolated from Uncaria rhynchophylla ( Miq . ) Jacks ( Gouteng in Chinese ) , as a Q14457 - dependent autophagy inducer . In this work , we show that Cory , an enantiomer of Cory B , also induces autophagy in different neuronal cell lines , including N2a and SHSY - 5Y cells , which is paralleled with increased lysosomal enzyme cathepsin D . In vivo , Cory promotes the formation of autophagosomes in the fat bodies of Drosophila . By inducing autophagy , Cory promotes the clearance of wild - type and A53T α - syn in inducible PC12 cells . Interestingly , different from its enantiomer Cory B , Cory induces autophagy through the Akt / P42345 pathway as evidenced by the reduction in the levels of phospho - Akt , phospho - P42345 and phospho - P08133 S6 Kinase . Collectively , our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine , which may have potential application in the prevention or treatment of PD .\",\n \"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK37___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK37___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK37___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .\",\n \"Inhibitory effect of somatostatin - 14 and some analogues on human natural killer cell activity . The effect of somatostatin - 14 ( P61278 ) and the P61278 analogues P52788 and RC160 on human natural killer ( NK ) activity mediated by large granular lymphocytes ( LGL ) , as well as on P60568 - and / or anti - CD16 monoclonal antibody ( mAb ) - induced activation of these cells , was investigated . The NK activity of LGL was studied by the release of 51Cr by the erythroleukemia - derived cell line K562 , whereas 51Cr release by the P815 murine mastocytoma - derived cell line , for which lysis was redirected by the use of an anti - CD16 mAb , was used to study the cytolytic potential of these cells . P60568 was used at the final concentration of 100 IU and was incubated overnight with LGL . P61278 and the analogues , added to these systems at final doses ranging from 10 (- 12 ) to 10 (- 5 ) M , were inhibitory of the NK cell activity to K562 , with a dose - response curve starting from 10 (- 8 ) M and reaching a significant level at 10 (- 6 ) M . On the contrary , no effect was observed on the redirected killing assay to P815 and on the P60568 - induced activation of NK cells . These results provide additional evidence for the immunomodulatory action of somatostatin .\",\n \"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \\\" inducible \\\" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \\\" constitutive \\\" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .\",\n \"DB06663 , a multiple somatostatin receptor subtypes ligand , reduces cell viability in non - functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion . Somatostatin ( SRIF ) analogs have been employed in medical therapy of non - functioning pituitary adenomas ( DB04552 ) , with contrasting results . Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor ( P15692 ) secretion and action , and that P15692 expression may be related to pituitary tumor growth . The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on P15692 secretion and cell proliferation in human DB04552 primary cultures . We assessed the expression of SRIF receptors ( P30872 - 5 ) , the in vitro effects on P15692 secretion , and on cell viability of SRIF and of the stable SRIF analog pasireotide ( DB06663 ) , which activates P30872 , 2 , 3 , and 5 . Twenty - five DB04552 were examined by RT - PCR for expression of alpha - subunit , SSTR , P15692 , and P15692 receptors 1 ( P15692 - Q96GN5 ) and 2 ( P15692 - R2 ) . Primary cultures were tested with SRIF and with pasireotide . All DB04552 samples expressed alpha - sub , P15692 and P17948 and 2 , while SSTR expression pattern was highly variable . Two different groups were identified according to P15692 secretion inhibition by SRIF . P15692 secretion and cell viability were reduced by SRIF and pasireotide in the ' responder ' group , but not in the ' non - responder ' group , including DB04552 expressing P35346 . SRIF and pasireotide completely blocked forskolin - induced P15692 secretion . In addition , SRIF and pasireotide completely abrogated the promoting effects of P15692 on DB04552 cell viability . Our data demonstrate that pasireotide can inhibit DB04552 cell viability by inhibiting P15692 secretion , and suggest that the multireceptor - SSTR agonist pasireotide might be useful in medical therapy of selected DB04552 .\",\n \"Effect of DB06663 ( pasireotide ) on corticotropic cells : action in dogs with Cushing ' s disease . DB06663 ( pasireotide ) is a multiligand somatostatin ( SRIF ) analog able to bind to somatostatin receptor ( SSTR ) subtypes 1 , 2 , 3 and 5 , and trigger antisecretory and antiproliferative signaling cascades . Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing ' s disease in a spontaneous manner , due to adrenocorticotropic hormone ( DB01285 ) - producing pituitary adenomas . Different levels of expression of P30874 and P35346 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells . The objective of this study was to evaluate whether DB06663 controls both tumor cell growth and hormone synthesis , therefore controlling the disease . DB06663 was tested in dogs suffering from Cushing ' s disease ( 10 animals were treated continuously during 6 months , and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2 - month rest period ) . A significant decrease in DB01285 , urinary cortisol creatinine ratio , adenoma size ( magnetic nuclear resonance ) and improvement of clinical signs were obtained , without side effects . AtT20 cells treated with DB06663 suppressed pro - opiomelanocortin ( P01189 ) promoter activity through P30874 , via the G ( i ) α - subunit , and reduced P22736 / Nurr1 transcriptional activity . We conclude that DB06663 , in addition to its well - described antisecretory effects , inhibits , as shown in AtT20 cells , DB01285 synthesis at the P01189 transcriptional level , an effect mediated mainly through P30874 , and limits tumor growth . The controlled Cushing ' s disease in the dogs that received the treatment indicates that DB06663 has a potential therapeutic use in humans suffering from Cushing ' s disease .\",\n \"Effect of chronic ___MASK47___ treatment on the prostate of C57Bl / 6 mice . ___MASK47___ is a potent and selective inhibitor of phosphodiesterase - 5 ( O76074 ) and is considered first - line therapy for erectile dysfunction . Nowadays , ___MASK47___ is used extensively throughout the world on patients with pulmonary hypertension . However , few studies have evaluated the possible side effects of chronic ___MASK47___ treatment on the male reproductive system , specifically in the prostate . In the present study , it was demonstrated via morphological and ultrastructural analysis that chronic treatment with ___MASK47___ induced an enhancement of the glandular activity of the prostate . In addition , mice treated with ___MASK47___ showed a significant increase in testosterone serum levels . However , no statistically significant differences were observed in nitric oxide serum levels , or in sGC , P29474 , PSA and TGF - β prostatic expression . In conclusion , the present study suggests that chronic use of ___MASK47___ does not cause evident prostatic damage , and therefore , can be used pharmacologically to treat a variety of disorders .\",\n \"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK54___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .\",\n \"[ New medical treatments in Cushing disease ] . The standard treatment of Cushing disease is surgery . Radiotherapy and steroïdogenesis inhibitors are second - line treatments . The new multi - ligand somatostatin analogs , such as DB06663 , having a much higher affinity with several receptors of somatostatin ( P30872 , 3 , and 5 ) than octreotid ( mostly a P30874 receptor ) have been synthetized . Some studies have shown that P35346 is predominantly expressed in corticotroph pituitary adenomas and that DB06663 has more efficacy than octreotid in the treatment of Cushing disease . It has been suggested that the thiazolinidinediones , P37231 agonists , might also be useful in the treatment of this disease , but studies are still limited and give conflicting results . In a recent study conducted on dogs , Castillo et al have shown that the retinoïds give encouraging results and might open a new pathway in the treatment of Cushing disease . But further studies , especially on humans , are necessary before conclusions can be reached . Labeur and his team have contributed a study on the use of gamma - interferon on murine pituitary cells and on human and murine corticotroph pituitary adenoma cells , and they have evidenced a 20 to 60 % decrease in the production of DB01285 in 5 cases out of 7 in the tumoral cells treated -- versus the non - treated ones . Eventually , Pivonello and his team have confirmed the D2 dopaminergic receptor expression in corticotroph pituitary cells , mainly in the intermediary zone . Thus they have suggested that the dopaminergic agonists -- such as cabergoline - could be used in corticotroph pituitary adenomas derivated from the intermediary zone .\",\n \"Brucine suppresses colon cancer cells growth via mediating P35968 signalling pathway . Angiogenesis plays an important role in colon cancer development . This study aimed to demonstrate the effect of brucine on tumour angiogenesis and its mechanism of action . The anti - angiogenic effect was evaluated on the chicken chorioallantoic membrane ( P62158 ) model and tube formation . The mechanism was demonstrated through detecting mRNA and protein expressions of P35968 ( P35968 ) , PKCα , PLCγ and Raf1 by reverse transcription - polymerase chain reaction ( RT - PCR ) and Western blot ( WB ) , as well as expressions of P15692 and PKCβ and P42345 by ELISA and WB . The results showed that brucine significantly reduced angiogenesis of P62158 and tube formation , inhibited the P15692 secretion and P42345 expression in LoVo cell and down - regulated the mRNA and phosphorylation protein expressions of P35968 , PKCα , PLCγ and Raf1 . In addition , the effects of brucine on P35968 kinase activity , viability of LoVo cell and gene knockdown cell were detected with the Lance ™ assay , WST - 1 assay and instantaneous siRNA . Compared to that of normal LoVo cells , the inhibition on proliferation of knockdown cells by brucine decreased significantly . These results suggest that brucine could inhibit angiogenesis and be a useful therapeutic candidate for colon cancer intervention .\",\n \"Distinct patterns of neuropeptide gene expression in the lateral hypothalamic area and arcuate nucleus are associated with dehydration - induced anorexia . We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration - associated anorexia . In situ hybridization and hormone analyses of anorexic and paired food - restricted rats revealed two distinct profiles . First , both groups had the characteristic gene expression and endocrine signatures usually associated with starvation : increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus ( Q5SW96 ) ; increased circulating glucocorticoid but reduced leptin and insulin . Dehydrated animals are strongly anorexic despite these attributes , showing that the output of leptin - and insulin - sensitive Q5SW96 neurons that ordinarily stimulate eating must be inhibited . The second pattern occurred only in anorexic animals and had two components : ( 1 ) reduced corticotropin - releasing hormone ( P06850 ) mRNA in the neuroendocrine paraventricular nucleus ( PVH ) and ( 2 ) increased P06850 and neurotensin mRNAs in the lateral hypothalamic ( LHA ) and retrochiasmatic areas . However , neither corticosterone nor suppressed PVH P06850 gene expression is required for anorexia after dehydration because PVH P06850 mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls . We also showed that LHA P06850 mRNA was strongly correlated with the intensity of anorexia , increased LHA P06850 gene expression preceded the onset of anorexia , and dehydrated adrenalectomized animals ( which also develop anorexia ) had elevated LHA P06850 gene expression with a distribution pattern similar to intact animals . Finally , we identified specific efferents from the P06850 - containing region of the LHA to the PVH , thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the Q5SW96 and the LHA . Together , these observations suggest that P06850 and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects .\",\n \"Effects of vasoactive intestinal peptide ( P01282 ) and somatostatin ( P61278 ) on lipoprotein receptor expression by A431 tumor cells . A variety of tumor cells have been shown to express lipoprotein receptors . Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells . We investigated the effects of vasoactive intestinal peptide ( P01282 ) and somatostatin - 14 ( P61278 - 14 ) on the binding of 111Indium - labeled lipoproteins [ ( 111 ) In - low density lipoprotein ( ( 111 ) In - LDL ) , ( 111 ) In - high density lipoprotein ( ( 111 ) In - HDL ) and ( 111 ) In - very low density lipoprotein ( ( 111 ) In - VLDL ) ] onto the epidermoid mammary carcinoma cell line A431 . Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL , HDL and VLDL expressed by A431 cells , respectively . P01282 increased significantly the binding capacity for ( 111 ) In - LDL on A431 cells . The P01282 - induced increase of ( 111 ) In - LDL binding sites was inhibited by P61278 - 14 . Furthermore , P61278 - 14 inhibited P01282 - induced 3H - thymidine incorporation and adenosine 3 '- 5 ' cyclic monophosphate ( DB02527 ) formation in A431 cells with IC50 values in the range of 5 - 7 nM . However , P61278 - 14 showed no effect on dibutyryl - DB02527 - induced increase of ( 111 ) In - LDL binding sites expressed on A431 cells . In contrast to ( 111 ) In - LDL binding , no effects of P01282 or P61278 - 14 on HDL or VLDL binding to A431 tumor cells were found . Our results suggest a direct effect of P01282 and P61278 - 14 on LDL - binding onto tumor cells . The complex interactions between P01282 and P61278 - 14 on P01130 expression of tumor cells may play a role in tumor cell lipid metabolism .\",\n \"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK94___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .\",\n \"___MASK37___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .\",\n \"P01308 - like growth factor pathway genes and blood concentrations , dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin - like growth factor 1 ( DB01277 ) . Several single nucleotide polymorphisms ( SNPs ) have been weakly associated with circulating concentrations of DB01277 and IGF binding protein 3 ( P17936 ) , but none of these SNPs was associated with risk of prostate cancer . We examined whether an association between 16 SNPs associated with circulating DB01277 or P17936 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5 , 253 cases and 4 , 963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . The BPC3 includes nested case - control studies within large North - American and European cohorts . Per - allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake , which was expressed as the percentage of energy derived from total , animal , dairy or plant protein sources , using conditional logistic regression models . Total , animal , dairy and plant protein intakes were significantly positively associated with blood DB01277 ( p < 0 . 01 ) , but not with P17936 concentrations ( p > 0 . 10 ) or with risk of prostate cancer ( p > 0 . 20 ) . After adjusting for multiple testing , the SNP - prostate cancer associations did not differ by intakes of protein , although two interactions by intake of plant protein were of marginal statistical significance [ P35346 ( somatostatin receptor 5 ) - rs197056 ( uncorrected p for interaction , 0 . 001 ) ; P35346 - rs197057 ( uncorrected p for interaction , 0 . 002 ) ] . We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein .\",\n \"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .\",\n \"Expression of somatostatin receptors in human melanoma cell lines : effect of two different somatostatin analogues , octreotide and DB06663 , on cell proliferation . Somatostatin analogues ( SAs ) are potential anticancer agents . This study was designed to investigate the expression of somatostatin receptors ( SSTRs ) in melanoma cells and the effect of two SAs on cell proliferation and viability . Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and DB06663 . Expression of P30872 , P30874 , P32745 and P35346 was assessed by real - time polymerase chain reaction . Proliferation , viability and cell death were assessed using standard assays . Inhibition was modelled by mixed - effect regression . Melanoma cells expressed one or more SSTR . Both SAs inhibited proliferation of most melanoma cell lines , but inhibition was < 50 % . Neither SA affected cell viability or induced cell death . The results suggest that melanoma cell lines express SSTRs . The SAs investigated , under the conditions used in this study , did not , however , significantly inhibit melanoma growth or induce cell death . Novel SAs , combination therapy with SAs and their anti - angiogenic properties should be further investigated .\",\n \"Modulation by cytokines of glucocorticoid action . Glucocorticoids ( GC ) are potent modulators of the inflammatory response . Their effects serve to down - regulate the inflammatory response and are mediated by genomic pathways that follow the interaction with specific receptors ( glucocorticoid receptors , GR ) . Interleukin ( IL ) - 1 , P60568 , and P05231 are able to increase GC secretion by enhancing synthesis and release of P06850 and DB01285 . Cytokine effects upon steroidogenesis also occur at the adrenal level . The role of cytokines as modulators of GR has received scarce attention . IL - 1 has been shown to up - regulate GR mRNA expression in hypothalamic P06850 secreting cells . On the other hand , macrophage migration inhibitory factor ( MIF ) , a T - cell product inducible by inflammatory substances including other cytokines , counterregulates GC action within the immune system . Besides immunocytes and neurons , bone cells are a sensitive target for GC and cytokines . We have found that P60568 and P05231 up - regulate remarkably the number of GR binding sites and the expression of GR mRNA in peripheral blood mononuclear cells and in osteoblast - like Saos - 2 cells . Available data suggest that inflammatory cytokines have both direct and indirect effects on GC action at the target level . Autocrine - induced transcription of GR in immunocytes and / or osteoblasts could be a mechanism that restrains excess cytokine production .\",\n \"Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK94___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .\",\n \"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .\",\n \"Ca2 + regulates hormone secretion and proopiomelanocortin gene expression in melanotrope cells via the calmodulin and the protein kinase C pathways . The mechanism by which Ca2 + regulates proopiomelanocortin ( P01189 ) - derived peptide secretion and P01189 mRNA levels was investigated in primary cultures of porcine intermediate lobe ( IL ) cells maintained in serum - free medium . P01189 gene expression was evaluated by the dot blot hybridization assay with a 32P - labeled DNA probe complementary to the full - length sequence of porcine P01189 mRNA . Treatment of IL cells for 24 h with the calmodulin ( P62158 ) antagonists W7 and W13 reduced P01189 mRNA levels by a maximum of 50 % in a dose - dependent manner ( ED50 approximately 10 (- 8 ) M ) . Accumulation of alpha - melanocyte - stimulating hormone ( alpha - MSH ) in the medium was also depressed by 50 % after 8 h of treatment . The role of protein kinase C ( PKC ) was investigated by depleting the IL cell PKC content with phorbol ester treatment . Phorbol 12 - myristate 13 - acetate ( PMA ) at 5 X 10 (- 8 ) M induced a rapid translocation of cytoplasmic PKC activity toward the membrane . After 12 h of PMA treatment , PKC activity was undetectable in either the cytoplasmic or the particulate fractions . The same dose of PMA induced a time - dependent decrease in P01189 mRNA levels ( 50 % inhibition after 24 h ) . The same effect was seen with the phorbol ester phorbol 12 , 13 - dibutyrate at 5 X 10 (- 8 ) M , whereas the inactive phorbol ester 4 alpha - phorbol at 5 X 10 (- 8 ) M was without effect after 24 h of treatment . PMA treatment had a biphasic effect on alpha - MSH secretion . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Fluvoxamine exerts anorexic effect in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m - chlorophenylpiperazine ( mCPP ) and fenfluramine . We previously reported that fluvoxamine , a selective serotonin reuptake inhibitor , together with pharmacological inactivation of P28335 receptors exert feeding suppression through activation of P28222 receptors in mice . Here , we report that fluvoxamine exerted anorexic effects in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene ( 2CREnd mice ) , whereas fluvoxamine had no effect on food intake in age - matched wild - type mice and P28335 receptor mutant mice , which are associated with decreases in hypothalamic proopiomelanocortin ( P01189 ) expression . mCPP suppressed food intake in P28335 receptor mutant mice , 2CREnd mice and age - matched wild - type mice . These results suggest that fluvoxamine - induced feeding suppression requires a perturbation of P28335 receptor and beta - endorphin signalling plus functional hypothalamic P01189 activity , whereas mCPP - induced feeding suppression does not always require functional P28335 receptor , beta - endorphin , and P01189 activity in mice .\",\n \"DB00428 - induced increase in cholesterol ester transfer protein ( P11597 ) and its reversal by insulin in transgenic mice expressing human P11597 . High plasma triacylglycerol and low high - density lipoprotein levels are risk factors for cardiovascular disease in diabetes . Plasma high - density lipoprotein levels are regulated by cholesterol ester transfer protein ( P11597 ) . The regulation of P11597 under diabetic conditions is not clear , and this is due to a lack of appropriate models . We used transgenic mice expressing human P11597 to study the regulation of this protein under type - 1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes . Mice expressing human P11597 under the control of its natural flanking region and age - matched littermates not expressing this protein were made diabetic by injecting streptozotocin , and the reversal of diabetes was assessed by injecting insulin . The plasma total cholesterol , low - density lipoprotein - cholesterol , and triacylglycerol concentrations were elevated , whereas high - density lipoprotein - cholesterol concentrations were reduced after the onset of diabetes . P01308 injection partially recovered this effect . The plasma cholesterol ester transfer activity , P11597 mass , and hepatic P11597 mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration . There was a strong correlation between high - density lipoprotein - cholesterol concentrations and cholesterol ester transfer activity . These results suggest that an increase in P11597 under diabetic conditions might be a major factor responsible for increased incidence of diabetes - induced atherosclerosis .\",\n \"P30872 and P35346 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors . The effectiveness of the long acting somatostatin analogues like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells . The immunohistochemical method performed on surgically removed tumors searches the expression of receptors at the level of receptor protein and gives us insight into receptor ' s cellular localization . The aim of study was to assess the presence of all the 5 subtypes of SSTR 1 - 5 ( including 2A and 2B SSTR isoforms ) in surgically treated human neuroendocrine tumors ( NETs ) to establish which receptor subtype is the dominant form of somatostatin receptor in particular tumor and thus to be able to predict which somatostatin analog will be effective in NETs treatment . 18 samples of neuroendocrine tumors ( surgically excised tumors or biopsies ) were immunostained with specific antibodies . Expression of SSTR was scored semiquantitatively . Only strong or moderate immunostaining was considered as positive reaction . The summarized expression pattern of SSTR in the investigated neuroendocrine tumors in our material was : SSTR 1 > SSTR 5 > SSTR 3 > SSTR 2A > SSTR 2B . The receptors were distributed mainly in the area of cells cytoplasm with a few specimens showing only membranous or mixed : membranous -- cytoplasmic localization . The observed pattern suggests that apart from octreotide and lanreotide , newly synthesized multiligand analogs such as DB06663 , KE 108 or SSTR 1 and SSTR 5 selective analogs could be effective in NETs treatment .\",\n \"___MASK47___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .\",\n \"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .\",\n \"Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin - dependent kinase ( CDK ) inhibitor . Cushing disease caused by adrenocorticotropin ( DB01285 ) - secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes , hypertension , osteoporosis , central obesity , cardiovascular morbidity , and increased mortality . There is no effective pituitary targeted pharmacotherapy for Cushing disease . Here , we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene ( O95997 / securin ) targeted to the adenohypophyseal proopiomelanocortin ( P01189 ) lineage , which recapitulated early features pathognomonic of corticotroph adenomas , including corticotroph expansion and partial glucocorticoid resistance . Adult Tg : Pomc - Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up - regulation , as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease . Early development of corticotroph pathologies in Tg : Pomc - Pttg embryos facilitated drug testing in vivo . We identified a pharmacologic P24941 / cyclin E inhibitor , R - roscovitine ( seliciclib ; CYC202 ) , which specifically reversed corticotroph expansion in live Tg : Pomc - Pttg embryos . We further validated that orally administered R - roscovitine suppresses DB01285 and corticosterone levels , and also restrained tumor growth in a mouse model of DB01285 - secreting pituitary adenomas . Molecular analyses in vitro and in vivo showed that R - roscovitine suppresses DB01285 expression , induces corticotroph tumor cell senescence and cell cycle exit by up - regulating p27 , P38936 and p57 , and downregulates cyclin E expression . The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion .\",\n \"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK74___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK78___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\",\n \"Inhibition of the tumour necrosis factor - alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs . Several autocrine soluble factors , including macrophage inflammatory protein - 1α and tumour necrosis factor - alpha ( P01375 - α ) , promote the survival and growth of multiple myeloma ( MM ) cells . We hypothesised that inhibition of the P01375 - α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines . In the present study , a P01375 - α - neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells . In addition , combination treatment with the P01375 - α - neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor κB ( NF - κB ) p65 nuclear translocation and mammalian target of rapamycin ( P42345 ) activation and upregulated the expression of Bax and Bim . Treatment of Q5SW96 - 77 cells with the NF - κB inhibitor dimethyl fumarate or the P42345 inhibitor rapamycin suppressed NF - κB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan . Furthermore , infliximab , a monoclonal antibody against P01375 - α , also enhanced the cytotoxic effect of anticancer drugs in Q5SW96 - 77 cells . These results indicated that P01375 - α - neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the P01375 receptor / P42345 / NF - κB pathways . The inhibition of P01375 - α may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients .\",\n \"Somatostatin modulates PI3K - Akt , P29474 and NHE activity in the ciliary epithelium . Somatostatin ( P61278 ) is a biologically active peptide produced in neuroendocrine cells . In the present study , we provide evidence of pro - P61278 and P61278 receptor ( P30872 and 2A ) mRNA expression in ocular ciliary epithelium ( CE ) . P61278 or P61278 - like immunoreactivity was detected by radioimmunoassay in tissue extract from ciliary processes and in aqueous humor . The distinct immunolabeling of CE with P61278 and proprotein convertases PC1 and P16519 antibodies suggested a tissue and cell - specific processing of pro - P61278 . P61278 ( 10 (- 8 ) to 10 (- 4 ) M ) added exogenously to the CE , elicited the following effects : ( i ) a dose - dependent attenuation of Na +/ H +- exchanger ( NHE ) activity ; ( ii ) up to a two - fold increase phosphorylation of p - Akt - Ser473 and of p - P29474 - Ser617 , and ( iii ) lack of response on intracellular cyclic GMP production . LY294002 , a PI3K - inhibitor , blocked P61278 - induced p - Akt - Ser473 and partially p - P29474 - Ser617 , however , it did not reverse P61278 - induced NHE attenuation . Collectively , these results suggested involvement of P61278 in multiple intracellular signaling pathways in the CE .\",\n \"Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune - mediated arthritis . OBJECTIVE : Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties . However , it is not known which of the 5 somatostatin receptor subtypes ( SSTRs 1 - 5 ) is involved in these actions . The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide ( DB06663 ) in a mouse model of antigen - induced arthritis ( AIA ) . METHODS : Studies were performed in P30874 - deficient mice ( P30874 (-/-) ) and their wild - type littermates ( P30874 (+/+) ) . The expression of P30872 , SSTR2A , P32745 , and P35346 in dorsal root ganglia was examined by immunohistochemistry . RESULTS : Untreated P30874 (-/-) mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in P30874 (+/+) mice . In wild - type mice , both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone . In P30874 (-/-) mice , the antiinflammatory effects of both octreotide and pasireotide were completely abrogated . Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions . In addition , both octreotide and pasireotide reduced inflammatory hyperalgesia . The antinociceptive actions of octreotide were abolished in P30874 (-/-) mice , but those of pasireotide were retained . In dorsal root ganglia of naive wild - type mice , only P30872 and SSTR2A , but not P32745 or P35346 , were detected in a subset of small - and medium - diameter neurons . CONCLUSION : Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the P30874 receptor . In addition , we identified the P30872 receptor as a novel pharmacologic target for somatostatin - mediated peripheral analgesia in inflammatory pain .\",\n \"Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .\",\n \"Reliability and discriminant validity of P04626 gene quantification and chromosome 17 aneusomy analysis by real - time PCR in primary breast cancer . There is an increasing demand for the evaluation of P04626 status in breast cancer . In this study , sections from fixed tissues and triton extracts of tissue homogenates were obtained from 163 malignant breast tumors and analyzed in parallel using immunohistochemistry combined with fluorescence in situ hybridization , as gold standard tests , and an ELISA test ( c - erbB2 / c - neu Rapid Format ELISA , Oncogene Research Products , USA ) . Tumor DNA was employed to evaluate two quantitative PCR methods : the P04626 / neu DNA Quantification Kit ( Roche Diagnostics GmbH , Germany ) , which uses the gastrin chromosome 17 reference gene , and our recently developed Oncolab qPCR assay , where both a chromosome 17 gene ( somatostatin receptor type II ( P30874 ) ) and a non - chromosome 17 reference gene ( glyceraldehyde - 3 - phosphate deshydrogenase ( P04406 ) ) were used to detect an increase in P04626 gene copy number and to evaluate the aneusomy of chromosome 17 , respectively . By IHC / Q5TCZ1 and ELISA , P04626 was overexpressed in 27 ( 16 . 6 % ) and 24 ( 14 . 7 % ) samples , respectively . With the Roche and Oncolab qPCR assays , 29 ( 17 . 8 % ) samples showed a ratio of P04626 / gastrin > or = 2 . 0 and 26 ( 16 . 0 % ) showed a ratio of P04626 / P30874 > or = 2 . 0 , respectively . In samples presenting P04626 / P30874 < 2 . 0 and P04626 / P04406 > or = 2 . 0 , which was indicative of a chromosome 17 polysomy , we observed a modest increase in P04626 protein expression . Complete agreement between the four methods for P04626 status determination was obtained for 154 ( 94 . 5 % ) samples . Overall , these results demonstrate that quantitative PCR is a reliable method for analyzing P04626 status and chromosome 17 polysomy .\",\n \"Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog DB06663 on hormone secretion in vitro and in ex vivo adrenal cells . BACKGROUND : Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion , cell proliferation , and apoptosis by 5 somatostatin receptors ( P30872 - 5 ) . The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and / or secretion of growth factors and growth - promoting hormones . AIM : Very little information is available on the effect of somatostatin analogs on adrenal tumors , so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog ( DB06663 ) on hormone secretion and cell viability in adrenal cells . MATERIAL / SUBJECTS AND METHODS : SSTR expression was analyzed by real - time PCR in 13 adrenocortical carcinomas ( ACC ) , 24 aldosterone - producing adenomas ( APA ) , 11 cortisol - producing adenomas ( P15085 ) , and 7 normal adrenals ( NA ) , and verified by immunohistochemistry ( IHC ) in 14 samples . The effect of DB06663 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay , and its effect on viability in H295R and SW13 using the MTT test . RESULTS : P30872 and P30874 mRNA was expressed in 100 % of adrenal tumors . Compared to NA , ACC revealed an increase in almost all SSTR , while only some APA over - expressed P32745 and P30872 . P15085 expressed SSTR similar to NA . IHC confirmed the mRNA expression data . At nanomolar concentrations , DB06663 inhibited hormone secretion in primary adrenal cultures and H295R cells , but had no evident effect on cell viability . CONCLUSIONS : The evidence of SSTR over - expression ( particularly in ACC ) and of hormone secretion being inhibited by DB06663 suggests a potential therapeutic role for this broad - spectrum somatostatin analog in adrenal tumors .\",\n \"Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .\",\n \"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK74___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .\",\n \"Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy . The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors ( GEP - NETs ) have increased in the past 20 years . GEP - NETs are heterogeneous tumors , in terms of clinical and biological features , that originate from the pancreas or the intestinal tract . Some GEP - NETs grow very slowly , some grow rapidly and do not cause symptoms , and others cause hormone hypersecretion and associated symptoms . Most GEP - NETs overexpress receptors for somatostatins . Somatostatins inhibit the release of many hormones and other secretory proteins ; their effects are mediated by G protein - coupled receptors that are expressed in a tissue - specific manner . Most GEP - NETs overexpress the somatostatin receptor P30874 ; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone - related symptoms and also have antitumor effects . Long - acting formulations of somatostatin analogues stabilize tumor growth over long periods . The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP - NETs . Peptide receptor radiotherapy has significant antitumor effects , increasing overall survival times of patients with tumors that express a high density of SSTRs , particularly P30874 and P35346 . The multi - receptor somatostatin analogue DB06663 ( pasireotide ) and chimeric molecules that bind P30874 and the dopamine receptor D2 are also being developed to treat patients with GEP - NETs . Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways , such as mammalian target of rapamycin ( P42345 ) and vascular endothelial growth factor , might be the most effective therapeutics for GEP - NETs .\",\n \"[ Methylation profiling of human atherosclerotic plaques ] . Somatic mutation theory of atherogenesis proved by alterations at the DNA level such as \\\" loss of heterozygosity \\\" and microsatellite instability in atherosclerotic plaque is complemented by the date of epigenetic variability of genetic loci involved in the pathological process . However , only recently large - scale analysis of epigenetic modifications in the human genome became possible . For the first time quantitative microarray - based methylation profiling of 1505 CpG - sites across 807 genes was performed in atherosclerotic aorta and carotid artery wall lesions using the GoldenGate Methylation Cancer Panel I ( \\\" Illumina \\\" , USA ) . One hundred and three ( 7 % ) CpG - sites in 90 ( 11 % ) genes were differentially methylated between tissue samples . The most pronounced differences in DNA methylation levels were registered for a site which is located in CpG - island of imprinted gene H19 . By comparing 90 genes that were differentially methylated between tissue samples in our study , 10 genes ( P05362 , P09488 , P08833 , P01189 , P02647 , P18510 , P01308 , P01374 , P08254 , P35442 ) were overlapped with data in Human Genome Epidemiology Network ( HuGENet ) , in which they were identified as candidates for cardiovascular disease continuum .\",\n \"Inhibitory effects of DB06663 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo . DB01285 ( DB01285 ) production by pituitary corticotroph adenomas is the main cause of Cushing ' s disease . A drug that targets pituitary DB01285 - secreting adenomas would aid treatment of Cushing ' s disease . DB00104 , a somatostatin receptor type 2 ( P30874 ) - preferring somatostatin analogue , has no effect on DB01285 secretion in patients with Cushing ' s disease . The multiligand DB06663 ( pasireotide ) displays a much higher affinity for P30872 and P35346 than octreotide and suppresses DB01285 secretion in cultures of human corticotroph tumors to a greater extent than octreotide . In the present in vitro and in vivo study , we determined the effect of DB06663 on DB01285 production and cell proliferation of AtT - 20 corticotroph tumor cells . DB06663 decreased proopiomelanocortin ( P01189 ) mRNA levels in AtT - 20 cells and DB01285 levels in the culture medium of these cells , suggesting that DB06663 suppresses DB01285 synthesis and secretion in corticotroph tumor cells . DB06663 also decreased cell proliferation and both cyclic adenosine monophosphate response element - binding protein and Akt phosphorylation in AtT - 20 cells . P35346 knockdown inhibited the DB06663 - induced decreases in cell proliferation . Fluorescence - activated cell sorting analyses revealed that DB06663 did not attenuate cell cycle progression . Tumor weight in mice xenografted with AtT - 20 cells and treated with DB06663 was significantly lower than in AtT - 20 - xenografted control mice . DB06663 also significantly decreased plasma DB01285 levels , and P01189 and pituitary tumor transforming gene mRNA levels in the tumor cells . Thus , DB06663 inhibits DB01285 production and corticotroph tumor cell proliferation in vitro and in vivo .\",\n \"Chemical development of intracellular protein heterodimerizers . Cell activation initiated by receptor ligands or oncogenes triggers complex and convoluted intracellular signaling . Techniques initiating signals at defined starting points and cellular locations are attractive to elucidate the output of selected pathways . Here , we present the development and validation of a protein heterodimerization system based on small molecules cross - linking fusion proteins derived from HaloTags and P60880 - tags . Chemical dimerizers of HaloTag and P60880 - tag ( HaXS ) show excellent selectivity and have been optimized for intracellular reactivity . HaXS force protein - protein interactions and can translocate proteins to various cellular compartments . Due to the covalent nature of the HaloTag - HaXS - P60880 - tag complex , intracellular dimerization can be easily monitored . First applications include protein targeting to cytoskeleton , to the plasma membrane , to lysosomes , the initiation of the PI3K / P42345 pathway , and multiplexed protein complex formation in combination with the rapamycin dimerization system .\",\n \"DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .\"\n]"},"candidates":{"kind":"list like","value":["___MASK26___","___MASK37___","___MASK47___","___MASK49___","___MASK54___","___MASK74___","___MASK78___","___MASK93___","___MASK94___"],"string":"[\n \"___MASK26___\",\n \"___MASK37___\",\n \"___MASK47___\",\n \"___MASK49___\",\n \"___MASK54___\",\n \"___MASK74___\",\n \"___MASK78___\",\n \"___MASK93___\",\n \"___MASK94___\"\n]"},"answer":{"kind":"string","value":"___MASK74___"},"id":{"kind":"string","value":"MH_train_388"}}},{"rowIdx":389,"cells":{"query":{"kind":"string","value":"interacts_with DB01248?"},"supports":{"kind":"list like","value":["Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing . Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer ( PCa ) . We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia ( BPH ) samples using the pyrosequencing ( PSQ ) method to identify genes with diagnostic and prognostic potential . P10826 , HIN1 , P10415 , P09211 , P30279 , Q86T13 , P25054 , RASSF1A , P08183 , P52952 , P55290 , Q14117 , P35354 , P24530 , MAL , P50479 , HLAa , P03372 and TIG1 were highly methylated in PCa compared to BPH ( p < 0 . 001 ) , while P36952 , CDH1 , Q15672 , P53355 , P10828 , P43121 , O94813 , CDKN2a and SFN were not . P10826 methylation above 21 % completely distinguished PCa Separation based on methylation level of SFN , O94813 and P36952 distinguished low and high Gleason score cancers , e . g . SFN and P36952 together correctly classified 81 % and 77 % of high and low Gleason score cancers respectively . Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study . Increasing age was positively associated with gene methylation ( p < 0 . 0001 ) . Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like P10826 , HIN1 , P10415 , P25054 and P09211 is warranted for diagnostic potential and SFN , O94813 and P36952 for prognostic potential .","P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . DB01248 dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .","The P10415 antagonist ABT - 199 triggers apoptosis , and augments ibrutinib and idelalisib mediated cytotoxicity in P61073 Wild - type and P61073 WHIM mutated Waldenstrom macroglobulinaemia cells .","chFRP5 - ZZ - PE38 , a large IgG - toxin immunoconjugate outperforms the corresponding smaller FRP5 ( Fv )- P25101 immunotoxin in eradicating ErbB2 - expressing tumor xenografts . As therapeutics , antibodies can be used \" un - armed \" or as immunoconjugates to direct cytotoxic moieties to tumor cells . Immunoconjugates are made by attaching chemotherapy drugs , radioisotopes or toxins to the antibody . Small recombinant antibody fragments fused to cytotoxic moieties , termed recombinant immunotoxins are also being developed as an additional approach for a targeted cancer therapy . Key parameters in determining the therapeutic potential of such targeted therapies are target specificity , affinity , stability and size . With regard to treating solid tumors , tumor penetration ( which is inversely proportional to size ) is currently regarded as the prime factor for efficacy , while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent . When comparing recombinant immunotoxins and antibody - toxin immunoconjugates that target ErbB2 / P04626 , here we found that a bivalent antibody - toxin immunoconjugate ( 200 kDa ) was superior to the corresponding recombinant monovalent immunotoxin ( 69 kDa ) in killing ErbB2 - expressing tumor cells in culture and as xenografts in nude mice , suggesting that higher avidity and longer residence time may outweigh tumor penetration . Our study suggests that the re - valuation of currently neglected , large IgG - effector molecule conjugates for anti - cancer therapy may be justified .","Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line , 1 . 1B4 . BACKGROUND : Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line , 1 . 1B4 , after exposure to proinflammatory cytokines - IL - 1β , IFN - γ , P01375 - α . METHODS : MTT assay , insulin radioimmunoassay , glucokinase assay , real time reverse transcription PCR , western blotting , nitrite assay , caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity . RESULTS : Viability of 1 . 1B4 cells decreased after 18h cytokine exposure . Cytokines significantly reduced cellular insulin content and impaired insulin secretion induced by glucose , alanine , DB00761 , elevated Ca ( 2 +) , P0C6A0 or forskolin . P35557 enzyme activity , regulation of intracellular Ca ( 2 +) and PDX1 protein expression were significantly reduced by cytokines . mRNA expression of genes involved in secretory function - P01308 , GCK , P16519 and P17302 was downregulated in cytokine treated 1 . 1B4 cells . Upregulation of transcription of genes involved in antioxidant defence - P04179 and P07203 was observed , suggesting involvement of oxidative stress . Cytokines also upregulated transcriptions of P19838 and P42224 , which was accompanied by a significant increase in NOS2 transcription and accumulation of nitrite in culture medium , implicating nitrosative stress . Oxidative and nitrosative stresses induced apoptosis was evident from increased % tail DNA , DNA fragmentation , caspase 3 / 7 activity , apoptotic cells and lower P10415 protein expression . CONCLUSIONS : This study delineates molecular mechanisms of cytokine toxicity in 1 . 1B4 cells , which agree with earlier observations using human islets and rodent beta cells . GENERAL SIGNIFICANCE : This study emphasizes the potential usefulness of this cell line as a human beta cell model for research investigating autoimmune destruction of pancreatic beta cells .","Q16696 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1 - induced DNA damage . Q16696 ( Q16696 ) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 ( AFB1 ) . Our previous study suggested that Q16696 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells ( BEAS - 2B ) . However , the role of Q16696 in AFB1 - induced DNA damage is unclear . Using BEAS - 2B cells that stably express Q16696 ( B - 2A13 ) , P05177 ( B - 1A2 ) , and P11509 ( B - 2A6 ) , we compared their effects in AFB1 - induced DNA adducts , DNA damage , and cell cycle changes . BEAS - 2B cells that were transfected with vector ( B - vector ) were used as a control . The results showed that AFB1 ( 5 - 80 nM ) dose - and time - dependently induced DNA damage in B - 2A13 cells . AFB1 at 10 and 80nM significantly augmented this effect in B - 2A13 and B - 1A2 cells , respectively . B - 2A6 cells showed no obvious DNA damage , similar to B - vector cells and the vehicle control . Similarly , compared with B - vector , B - 1A2 or B - 2A6 cells , B - 2A13 cells showed more sensitivity in AFB1 - induced γ P16104 expression , DNA adduct 8 - hydroxy - deoxyguanosine formation , and S - phase cell - cycle arrest . Furthermore , AFB1 activated the proteins related to DNA damage responses , such as Q13315 , ATR , Chk2 , p53 , P38398 , and P16104 , rather than the proteins related to DNA repair . These effects could be almost completely inhibited by 100 μM nicotine ( a substrate of Q16696 ) or 1 μM 8 - methoxypsoralen ( DB00553 ; an inhibitor of CYP enzyme ) . Collectively , these findings suggest that Q16696 plays an important role in low - concentration AFB1 - induced DNA damage , possibly linking environmental airborne AFB1 to genetic injury in human respiratory system .","Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell - cycle arrest during mitosis . DB01248 binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell - cycle activities . It has also been shown to promote apoptosis via P10415 phosphorylation . In hormone - refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .","Predictive factors for response to docetaxel in human breast cancers . DB01248 has come into wide use recently for the treatment of breast cancer in neoadjuvant , adjuvant and metastatic settings . DB01248 binds to beta - tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization , resulting in elevated levels of microtubule formation . During metaphase , defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest , culminating in apoptosis . However , docetaxel is not effective for all breast cancers . For example , in metastatic settings , the response rate to docetaxel reportedly ranges from 30 to 50 % . It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment . Currently it is impossible to identify , before the initiation of therapy , the patients for whom docetaxel will be effective . Various biological parameters have been studied clinically for their ability to predict response to docetaxel , such as parameters related to : ( 1 ) efflux ( p - glycoprotein ) and metabolism ( P08684 ) ; ( 2 ) beta - tubulin ( somatic mutation of beta - tubulin and changes in beta - tubulin isotypes levels ) ; ( 3 ) cell cycle ( P04626 , P38398 and Aurora - A ) ; and ( 4 ) apoptosis ( p53 , P10415 and thioredoxin ) . More recently , gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel . In the present paper , clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field .","MYC directs transcription of Q07820 and P06730 genes to control sensitivity of gastric cancer cells toward HDAC inhibitors . Histone deacetylases ( HDACs ) control fundamental physiological processes such as proliferation and differentiation . HDAC inhibitors ( HDACi ) induce cell cycle arrest and apoptosis of tumor cells . Therefore , they represent promising cancer therapeutics that appear particularly useful in combination therapies . Although HDACi are tested in current clinical trials , the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood . To gain insight into pathways that limit HDACi efficacy in gastric cancer , we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid ( DB02546 ) . We report that higher expression levels of the anti - apoptotic P10415 family members Q07820 and BCL ( XL ) were detectable in cells with high inhibitory concentration 50 ( IC ( 50 ) ) values for DB02546 . Using RNAi , we show that Q07820 and BCL ( XL ) lower the efficacy of DB02546 . To find strategies to interfere with Q07820 and BCL ( XL ) expression , we investigated molecular regulation of both proteins . We show that specific siRNAs against c - MYC as well as pharmacological inhibition of this cancer - relevant transcription factor reduced Q07820 and BCL ( XL ) expression . Subsequently , we observed an increase in DB02546 efficacy . Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors . Whereas c - MYC controls transcription of Q07820 directly , regulation of BCL ( XL ) was due to c - MYC ' s capability to regulate the P06730 gene , which encodes a rate - limiting factor of eukaryotic translation . Our data reveal a new molecular mechanism for how c - MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c - MYC in gastric cancer .","Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha - emitting radioisotope astatine - 211 conjugated to anti - P04626 / neu diabodies . PURPOSE : Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle . Small , engineered antitumor antibody fragments are capable of rapid , highly specific tumor targeting in immunodeficient mouse models . We hypothesized that the P13671 . 5 diabody , a noncovalent anti - P04626 single - chain Fv dimer , would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short - lived alpha - emitting radioisotope ( 211 ) At . EXPERIMENTAL DESIGN : Immunodeficient nude mice bearing established P04626 / neu - positive MDA - MB - 361 / DYT2 tumors treated with N - succinimidyl N -( 4 -[( 211 ) At ] astatophenethyl ) succinamate ( ( 211 ) At - O75563 ) - P13671 . 5 diabody . Additional cohorts of mice were treated with ( 211 ) At - O75563 T84 . 66 diabody targeting the carcinoembryonic antigen or ( 211 ) At - O75563 on a diabody specific for the Müllerian inhibiting substance type II receptor , which is minimally expressed on this tumor cell line . RESULTS : A single i . v . injection of ( 211 ) At - O75563 P13671 . 5 diabody led to a 30 - day delay in tumor growth when a 20 muCi dose was administered and a 57 - day delay in tumor growth ( 60 % tumor - free after 1 year ) when a 45 muCi dose was used . Treatment of mice bearing the same tumors with ( 211 ) At - O75563 T84 . 66 diabody at the same doses led to a delay in tumor growth , but no complete responses , likely due to substantially lower expression of this antigen on the MDA - MB - 361 / DYT2 tumors . In contrast , a dose of 20 muCi of ( 211 ) At - O75563 on the anti - Müllerian - inhibiting substance type II receptor diabody did not affect tumor growth rate , demonstrating specificity of the therapeutic effect . CONCLUSIONS : These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful , short - lived alpha - emitting radioisotopes .","P04626 interacts with P16070 to up - regulate P61073 via epigenetic silencing of microRNA - 139 in gastric cancer cells . BACKGROUND & AIMS : Human epidermal growth factor receptor 2 ( P04626 ) ( neu / P04626 ) is overexpressed on many types of cancer cells , including gastric cancer cells ; P04626 overexpression has been associated with metastasis and poor prognosis . We investigated the mechanisms by which P04626 regulates cell migration and invasion . METHODS : P04626 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody , trastuzumab . We identified proteins that interact with P04626 or microRNAs ( miRNAs ) involved in P04626 signaling . We used various software programs to identify miRNAs that regulate factors in the P04626 signaling pathway . We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients . RESULTS : We found that P16070 binds directly to P04626 , which up - regulates the expression of metastasis - associated protein - 1 , induces deacetylation of histone H3 lysine 9 , and suppresses transcription of microRNA139 ( miR - 139 ) to inhibit expression of its target gene , P61073 ( P61073 ) . Knockdown of P04626 and P16070 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice . Lymph node metastasis was associated with high levels of P04626 , P16070 , and P61073 , and reduced levels of miR - 139 in human metastatic gastric tumors . Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and / or DNA methyltransferase resulted in up - regulation of miR - 139 . CONCLUSIONS : P04626 interaction with P16070 up - regulates P61073 by inhibiting expression of miR - 139 , at the epigenetic level , in gastric cancer cells . These findings indicate how P04626 signaling might promote gastric tumor progression and metastasis .","P10242 suppresses differentiation and apoptosis of human breast cancer cells . INTRODUCTION : P10242 is highly expressed in estrogen receptor positive ( ER + ve ) breast tumours and tumour cell lines . We recently demonstrated that P10242 is essential for the proliferation of ER + ve breast cancer cells , and have now investigated its role in mammary epithelial differentiation . METHODS : MCF - 7 breast cancer cells were treated with sodium butyrate , vitamin E succinate or 12 - O - tetradecanoylphorbol - 13 - acetate to induce differentiation as measured by Nile Red staining of lipid droplets and β - casein expression . The non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 , was induced to differentiate with lactogenic hormones . P10242 levels were manipulated by inducible lentiviral shRNA - mediated knockdown and retroviral overexpression . RESULTS : We found that P10242 expression decreases following chemically - induced differentiation of the human breast cancer cell line MCF - 7 , and hormonally - induced differentiation of a non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 . We also found that shRNA - mediated P10242 knockdown initiated differentiation of breast cancer cells , and greatly sensitised them to the differentiative and pro - apoptotic effects of differentiation - inducing agents ( DIAs ) . Sensitisation to the pro - apoptotic effects DIAs is mediated by decreased expression of P10415 , which we show here is a direct P10242 target in breast cancer cells . Conversely , enforced expression of P10242 resulted in the cells remaining in an undifferentiated state , with concomitant suppression of apoptosis , in the presence of DIAs . CONCLUSIONS : Taken together , these data imply that P10242 function is critical in regulating the balance between proliferation , differentiation , and apoptosis in MECs . Moreover , our findings suggest P10242 may be a viable therapeutic target in breast cancer and suggest specific approaches for exploiting this possibility .","Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .","___MASK99___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK99___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .","Phase I trial of oral P42345 inhibitor everolimus in combination with trastuzumab and vinorelbine in pre - treated patients with P04626 - overexpressing metastatic breast cancer . To determine the feasible dose and schedule for everolimus , an oral P42345 inhibitor , combined with vinorelbine and trastuzumab for patients with P04626 - overexpressing metastatic breast cancer pretreated with trastuzumab . In this phase Ib multicenter , Bayesian dose - escalation study , 50 patients received everolimus 5 mg / day , 20 mg / week , or 30 mg / week plus vinorelbine ( 25 mg / m² on day 1 and 8 every 3 weeks ) and trastuzumab ( 2 mg / kg weekly ) . Endpoints included end - of - cycle - 1 dose - limiting toxicity ( DLT ) rate ( primary endpoint ) , safety , relative dose intensity , overall response rate ( ORR ) , and pharmacokinetics . Grade 3 / 4 neutropenia was the most common end - of - cycle - 1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg / day and 30 mg / week cohorts , respectively . Other end - of - cycle - 1 DLTs included single cases of febrile neutropenia , grade 3 stomatitis with concomitant fatigue , grade 2 stomatitis , grade 3 anorexia , and grade 2 acneiform dermatitis , all in the 5 - mg / day cohort . Based on the recorded DLTs and global safety , everolimus 5 mg / day and 30 mg / week were chosen as the optimal dose levels for the daily and weekly arms . Forty - seven patients were evaluable for efficacy . ORR was 19 . 1 % , with a disease control rate of 83 . 0 % and median progression - free survival of 30 . 7 weeks . No drug interaction was observed between everolimus and vinorelbine . ___MASK90___ combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with P04626 - overexpressing metastatic breast cancer that progressed on trastuzumab ( NCT00426530 ) .","P01308 - like growth factor - I controls P38398 gene expression through activation of transcription factor Sp1 . The insulin - like growth factors ( IGFs ) have a central role in mammary gland growth and differentiation as well as in breast cancer development . The P38398 gene encodes a pleiotropic protein that functions as a transcription factor . Germline P38398 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms . Several lines of evidence led us to hypothesize that there is a functional interaction between the P38398 and P05019 systems relevant to breast cancer biology . The present study tested the notion that P38398 gene expression is regulated by the P05019 signaling pathway . Results of Western immunoblotting and RT - PCR analyses show that P05019 stimulates P38398 protein and mRNA levels . Transient transfection experiments using P38398 promoter - luciferase reporter constructs reveal that P05019 enhances P38398 promoter activity , suggesting that the effect of P05019 is mediated at the transcriptional level . In addition , we provide evidence that the Sp1 zinc - finger protein is directly involved in P38398 gene transactivation . Combined , our data suggests that , at least part of the biological actions of P05019 in mammary gland cells may be mediated through P38398 . Dysregulated P38398 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis .","DB06809 and P27487 modulate mobilization , engraftment , and survival of hematopoietic stem and progenitor cells mediated by the P48061 / P48061 - P61073 axis . The chemokine stromal cell - derived factor - 1 ( P48061 / P48061 ) and its receptor , P61073 , are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem ( HSCs ) and progenitor ( HPCs ) cells . Modulation of this ligand - receptor interaction may be of clinical utility . We now report that : ( 1 ) the CC chemokine , macrophage inflammatory protein - 1alpha ( MIP - 1alpha / P10147 ) synergizes with DB06809 ( an antagonist of the binding of P48061 / P48061 to P61073 ) to rapidly mobilize HPCs to the blood of mice ; moreover , the combination of granulocyte colony - stimulating factor ( DB00099 ) with DB06809 and MIP - 1alpha / P10147 , given in a specific sequence , mobilizes the greatest number of HPCs compared to any combination of two of these mobilizing agents ; ( 2 ) pretreatment of recipient mice with Diprotin A , an inhibitor of P27487 / Dipeptidylpeptidase IV ( DPPIV ) , enhances the competitive HSCs repopulating capacity of untreated donor cells ; ( 3 ) the survival - enhancing effects of P48061 / P48061 on HPCs subjected in vitro to delayed addition of growth factors ( GFs ) are mediated in part through the cell cycle - related proteins P38936 ( cip1 / waf1 ) ( as assessed using P38936 ( cip1 / waf1 ) -/- and +/+ mice ) and Mad2 ( using Mad2 +/- and +/+ mice ) ; and ( 4 ) deletion of P27487 / DPPIV on mouse bone marrow cells increases the survival - enhancing effects of P48061 / P48061 on HPCs . These results demonstrate the means to increase the mobilization of HPCs , the engrafting capability of HSCs , and responsiveness of HPCs to the survival - enhancing activity of P48061 / P48061 , effects that may be of practical value .","Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom . The present study was aimed to investigate the cognitive enhancing and anti - oxidant activities of Inonotus obliquus ( Chaga ) against scopolamine - induced experimental amnesia . Methanolic extract of Chaga ( Q9NRJ3 ) at 50 and 100 mg kg (- 1 ) doses were administered orally for 7 days to amnesic mice . Learning and memory was assessed by passive avoidance task ( PAT ) and Morris water maze ( MWM ) test . Tacrine ( ___MASK18___ , 10 mg kg ( - 1 ) , orally ( p . o ) ) used as a reference drug . To elucidate the mechanism of the cognitive enhancing activity of Q9NRJ3 , the activities of acetylcholinesterase ( P22303 ) , anti - oxidant enzymes , the levels of acetylcholine ( ACh ) and nitrite of mice brain homogenates were evaluated . Q9NRJ3 treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms . Further , Q9NRJ3 significantly reduced the oxidative - nitritive stress , as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner . In addition , Q9NRJ3 treatment significantly decreased the P22303 activity in both the salt and detergent - soluble fraction of brain homogenates . Further , treatment with Q9NRJ3 restored the levels of ACh as did ___MASK18___ . Thus , the significant cognitive enhancement observed in mice after Q9NRJ3 administration is closely related to higher brain anti - oxidant properties and inhibition of P22303 activity . These findings stress the critical impact of Chaga , a medicinal mushroom , on the higher brain functions like learning and memory .","Combination therapy with anti - ErbB3 monoclonal antibodies and P00533 TKIs potently inhibits non - small cell lung cancer . Personalized therapy of advanced non - small cell lung cancer ( NSCLC ) has been improved by the introduction of P00533 tyrosine kinase inhibitors ( TKIs ) , gefitinib and erlotinib . P00533 TKIs induce dramatic objective responses and increase survival in patients bearing sensitizing mutations in the P00533 intracytoplasmic tyrosine kinase domain . However , virtually all patients develop resistance , and this is responsible for disease relapse . Hence several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable to sensitize resistant cells to P00533 TKIs . Recent studies have suggested that upregulation of another member of the P00533 receptor family , namely ErbB3 is involved in drug resistance , through increased phosphorylation of its intracytoplasmic domain and activation of PI3K / AKT signaling . In this paper we first show , by using a set of malignant pleural effusion derived cell cultures ( MPEDCC ) from patients with lung adenocarcinoma , that surface ErbB3 expression correlates with increased AKT phosphorylation . Antibodies against ErbB3 , namely A3 , which we previously demonstrated to induce receptor internalization and degradation , inhibit growth and induce apoptosis only in cells overexpressing surface ErbB3 . Furthermore , combination of anti - ErbB3 antibodies with P00533 TKIs synergistically affect cell proliferation in vitro , cause cell cycle arrest , up - regulate P38936 expression and inhibit tumor growth in mouse xenografts . Importantly , potentiation of gefitinib by anti - ErbB3 antibodies occurs both in de novo and in ab initio resistant cells . Anti - ErbB3 mAbs strongly synergize also with the dual P00533 and P04626 inhibitor lapatinib . Our results suggest that combination treatment with P00533 TKI and antibodies against ErbB3 should be a promising approach to pursue in the clinic .","Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK48___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK48___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK48___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK48___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK48___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK48___ increased the protein expression of hepatic P05181 and ___MASK48___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK48___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK48___ and RFP - induced hepatotoxicity .","Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK90___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .","Purinergic receptor - mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine - rich repeat phosphatase , calcineurin , protein phosphatase 2A , and P60484 phosphatases . Akt is an important oncoprotein , and data suggest a critical role for nuclear Akt in cancer development . We have previously described a rapid ( 3 - 5 min ) and Q99572 - dependent depletion of nuclear phosphorylated Akt ( pAkt ) and effects on downstream targets , and here we studied mechanisms behind the pAkt depletion . We show that cholesterol - lowering drugs , statins , or extracellular DB00171 , induced a complex and coordinated response in insulin - stimulated A549 cells leading to depletion of nuclear pAkt . It involved protein / lipid phosphatases P60484 , pleckstrin homology domain leucine - rich repeat phosphatase ( O60346 and - 2 ) , protein phosphatase 2A ( PP2A ) , and calcineurin . We employed immunocytology , immunoprecipitation , and proximity ligation assay techniques and show that O60346 and calcineurin translocated to the nucleus and formed complexes with Akt within 3 min . Also P60484 translocated to the nucleus and then co - localized with pAkt close to the nuclear membrane . An inhibitor of the scaffolding immunophilin FK506 - binding protein 51 ( FKBP51 ) and calcineurin , FK506 , prevented depletion of nuclear pAkt . Furthermore , okadaic acid , an inhibitor of PP2A , prevented the nuclear pAkt depletion . Chemical inhibition and siRNA indicated that O60346 , PP2A , and P60484 were required for a robust depletion of nuclear pAkt , and in prostate cancer cells lacking P60484 , transfection of P60484 restored the statin - induced pAkt depletion . The activation of protein and lipid phosphatases was paralleled by a rapid proliferating cell nuclear antigen ( P12004 ) translocation to the nucleus , a P12004 - P38936 ( cip1 ) complex formation , and cyclin D1 degradation . We conclude that these effects reflect a signaling pathway for rapid depletion of pAkt that may stop the cell cycle .","A multimarker model to predict outcome in tamoxifen - treated breast cancer patients . PURPOSE : This study was designed to produce a model to predict outcome in tamoxifen - treated breast cancer patients based on clinicopathologic features and multiple molecular markers . EXPERIMENTAL DESIGN : This was a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen for whom standard clinicopathologic data and tumor tissue microarrays were available . Nine molecular markers were studied by semiquantitative immunohistochemistry and / or fluorescence in situ hybridization . Cox proportional hazards analysis was used to determine the contributions of each variable to disease - specific and overall survival , and machine learning was used to produce a model to predict patient outcome . RESULTS : On a univariate basis , the following features were significantly associated with worse survival : high pathologic tumor or nodal class , histologic grade , epidermal growth factor receptor , P04626 , MYC , or P04637 ; absent estrogen receptor ( ER ) or progesterone receptor ; and low P10415 . P24385 and P46527 did not reach statistical significance . On a multivariate basis , nodal class , ER , and MYC were statistically significant as independent factors for survival . However , the benefit of ER - positive status was moderated by P10415 , P04626 , and progesterone receptor . P10415 and P04637 also interacted as an independent risk factor . A kernel partial least squares polynomial model was developed with an area under the receiver operating characteristic curve of 0 . 90 . CONCLUSIONS : Our data show the predictive value of P10415 , P04626 , MYC , and P04637 in addition to the standard hormone receptors and clinicopathologic features , and they show the importance of conditional interpretation of certain molecular markers . Our multimarker predictive model performed significantly better than standard guidelines .","Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK18___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK18___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK18___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK18___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK18___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .","___MASK90___ enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro - apoptotic and cell - cycle - progression regulatory proteins . DB06769 is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed / refractory multiple myeloma ( MM ) . ___MASK90___ , an mammalian target of rapamycin ( P42345 ) inhibitor , is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers . We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines ( RPMI8226 and MM1 . S ) and primary MM cells . Our results demonstrated a synergistic effect of these drugs , which was effective for both p53 - wild - type and p - 53 - deleted MM cells , but was minimal in mononuclear cells from a healthy donor . Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin - V / PI staining , caspase - 3 degradation , and PARP cleavage . Cell death was associated with the up - regulation of the pro - apoptotic protein Bax and the down - regulation of the anti - apoptotic proteins Mcl - 1 and survivin . The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the P42345 pathway , p70s6k , and 4EBP - 1 , as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1 . S cells . P38936 was also down - regulated upon treatment with the two drugs , suggesting a mechanism of sensitization through the release of cell cycle arrest . Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine , and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and P42345 inhibitors in future clinical practice .","Q9UBP4 maintains the PANC - 1 human pancreatic tumor cells in a dedifferentiated state . Pancreatic cancer ( PaCa ) is the fourth leading cause of cancer deaths in Western societies , with pancreatic ductal adenocarcinomas ( PDACs ) accounting for > 90 % of such cases . PDAC is a heterogeneous disease that includes a subset showing overexpression of the secreted glycoprotein Q9UBP4 ( Q9UBP4 ) , a protein shown to be downregulated in various cancers of different tissues . The biological function of Q9UBP4 in this subset was studied using the Q9UBP4 expressing PANC - 1 cell line as a model for PDACs . The influence of Q9UBP4 overexpression and knockdown on cellular differentiation and proliferation of PANC - 1 was investigated . Confocal microscopy showed that Q9UBP4 was expressed in a fraction of PANC - 1 cells . While lentiviral - mediated overexpression of Q9UBP4 did not alter cellular proliferation , knockdown of Q9UBP4 resulted in significant reduction of cellular proliferation and concomitant induction of cell cycle inhibitors P42772 ( p15INK4b ) , P38936 ( p21CIP1 ) and P46527 ( p27KIP1 ) . In parallel , pancreatic epithelial cell differentiation markers P04746 , Q9UNI1 , P17538 , P01275 , P16278 and P01308 were significantly upregulated . PANC - 1 cells differentiated using exendin - 4 showed analogous induction of cell cycle inhibitors and differentiation markers . Thus , we conclude that Q9UBP4 is required to maintain a highly dedifferentiated and consequently proliferative state in PANC - 1 , indicating a similar function in the Q9UBP4 overexpressing subset of PDACs . Therefore , Q9UBP4 represents a potential target for the treatment of Q9UBP4 - positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation .","Autocrine and paracrine roles of P15692 / P35968 and P49767 / P35916 signaling in angiosarcomas of the scalp and face . Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons . To clarify its characteristic features and cell cycle kinetics , we quantitatively evaluated the expression of cell cycle - related molecules and vascular endothelial growth factors using immunohistochemical staining , for comparison with 2 benign vascular tumors of the skin , the capillary hemangioma and the cavernous hemangioma . Cell proliferation , determined with reference to the Ki - 67 labeling index , was highest in angiosarcomas and lowest in cavernous hemangiomas ( angiosarcomas versus capillary hemangioma , P = . 014 ; capillary hemangioma versus cavernous hemangiomas , P = 1 . 4 x 10 (- 4 ) ) . Similar differences were also found in cyclin A , cyclin E , and P38936 ( Waf1 ) expression . Expressions of cyclin D1 and p16 ( INK4A ) were also significantly higher in angiosarcoma than in cavernous hemangioma . Expressions of these 5 proteins showed significant positive correlations with Ki - 67 labeling indices ( Spearman rho = 0 . 91 - 0 . 43 ) . Expression levels of vascular endothelial growth factor and its receptor , P35968 , were highest in angiosarcomas . P49767 expression in angiosarcomas was significantly higher than in cavernous hemangiomas , and its receptor P35916 expression was highest in angiosarcomas . Furthermore , significant positive correlations of these protein expression with Ki - 67 labeling indices were noted ( Spearman rho = 0 . 88 - 0 . 40 ) . Among them , P35916 showed the highest correlation coefficient . These results suggest that not only P35968 - mediated signal but also P35916 - mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors .","Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK20___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK20___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .","___MASK58___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK58___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .","___MASK26___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","Exome - level comparison of primary well - differentiated neuroendocrine tumors and their cell lines . Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors ( NET ) and have been instrumental in the design of clinical trials targeting the PI3K / AKT / P42345 pathways , P15692 inhibitors , and somatostatin analogues . It remains unknown , however , whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines . Four bronchopulmonary NET ( BP - NET ) - NCI - H720 , NCI - H727 , NCI - H835 , and UMC11 - and two pancreatic neuroendocrine tumors ( panNET ) - BON - 1 and QGP1 - were cultured . DNA was isolated , and exome sequencing was done . GATK and EXCAVATOR were used for bioinformatic analysis . We detected a total of 1 , 764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP - NET and 4 . 3 per Mb in panNET cell lines , including 52 mutated COSMIC cancer genes in these cell lines , such as P04637 , P38398 , P06400 , P49815 , P46531 , Q09472 , GNAS , P35968 , Q15831 , and P25054 but not P46100 , Q9UER7 , nor O00255 . Our data suggest that mutation rate , the pattern of copy number variations , and the mutational spectra in the BP - NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP - NET . Likewise , mutation rate and pattern including the absence of mutations in P46100 / Q9UER7 , O00255 , and P25490 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET . These results suggest that results from experiments with BP - NET and panNET cell lines need to be interpreted with caution .","Effects of maternal smoking on the placental expression of genes related to angiogenesis and apoptosis during the first trimester . OBJECTIVE : Maternal cigarette smoking is reportedly associated with miscarriage , fetal growth restriction and placental abruption , and is paradoxically associated with a decreased risk of developing preeclampsia . In the present study , we investigated the gene expression levels of villous tissues in early gestation . We compared the expression levels of the genes related to angiogenesis and apoptosis in the villous tissues obtained from smoking and non - smoking pregnant women . MATERIALS AND METHODS : We collected villous tissue samples from 57 women requesting surgical termination due to non - medical reasons at 6 - 8 weeks of gestation . The maternal cigarette smoking status was evaluated by the level of serum cotinine and patients were divided into active smokers and non - smokers by the serum cotinine level . The placental levels of P15692 , P49763 , P17948 , Q16665 , P04637 , Q07812 and P10415 mRNA were quantified by real time PCR . RESULTS : The gene expression level of P49763 and Q16665 in the active smoker group was significantly higher than that in the non - smoker group . We did not observe any significant differences in the P15692 or P17948 expression between the groups . In active smoker group , the gene expression levels of P04637 and Q07812 were significantly higher than those in the non - smoker group . The ratio of Q07812 / P10415 mRNA in the active smoker group was significantly higher than that in the non - smoker group . CONCLUSIONS : Our findings revealed that smoking might affect the placenta during early pregnancy . Maternal cigarette smoking in early pregnancy may be associated with villus hypoxia , which may influence angiogenesis and apoptosis .","[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK38___ GITS , Diaprel MR ) . One daily dose of ___MASK38___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .","Ubiquitin - dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen . We previously reported that acetaminophen ( DB00316 , 4 - hydroxyacetanilide ) caused apoptosis of P13671 glioma cells . Therefore , we hypothesized that the level of p53 , which usually stimulates apoptosis , might be increased after DB00316 exposure . However , DB00316 exposure for 24 h markedly decreased the p53 content and its downstream target P38936 in a concentration - dependent manner . Reduction of p53 was not accompanied by a decrease in p53 mRNA in P13671 glioma cells , suggesting that p53 was mainly affected at the protein level . Unexpectedly , DB00316 stimulated phosphorylation of p53 at Ser15 , Ser20 , and Ser37 , which usually elevates p53 content . However , phosphorylation of these residues did not prevent DB00316 - induced decrease in p53 . The p53 reduction was independent from the level of phospho - Akt , which is known to promote p53 degradation . Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 ( mdm2 ) and ubiquitin were bound to p53 during its degradation . Lactacystin and N - benzoyloxycarbonyl ( Z ) - DB00149 - DB00149 - leucinal ( MG132 ) , inhibitors of proteasomal proteolysis , prevented the decrease , supporting the proteasomal degradation of p53 upon DB00316 exposure . Pretreatment with chlormethiazole , an inhibitor of ethanol - inducible P05181 , significantly lowered the P05181 enzyme activity and the rate of DB00316 - induced cell death while it prevented the reduction of p53 and P38936 in P13671 glioma cells . A nontoxic analog of DB00316 , 3 - hydroxyacetanilde , did not reduce p53 and P38936 contents in P13671 glioma cells and LLC - P30613 porcine kidney cells . Taken together , our results show that DB00316 or its reactive metabolite ( s ) can directly reduce the p53 content through mdm2 - mediated ubiquitin conjugation , despite phosphorylation of p53 at its N terminus .","Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .","___MASK96___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy ."],"string":"[\n \"Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing . Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer ( PCa ) . We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia ( BPH ) samples using the pyrosequencing ( PSQ ) method to identify genes with diagnostic and prognostic potential . P10826 , HIN1 , P10415 , P09211 , P30279 , Q86T13 , P25054 , RASSF1A , P08183 , P52952 , P55290 , Q14117 , P35354 , P24530 , MAL , P50479 , HLAa , P03372 and TIG1 were highly methylated in PCa compared to BPH ( p < 0 . 001 ) , while P36952 , CDH1 , Q15672 , P53355 , P10828 , P43121 , O94813 , CDKN2a and SFN were not . P10826 methylation above 21 % completely distinguished PCa Separation based on methylation level of SFN , O94813 and P36952 distinguished low and high Gleason score cancers , e . g . SFN and P36952 together correctly classified 81 % and 77 % of high and low Gleason score cancers respectively . Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study . Increasing age was positively associated with gene methylation ( p < 0 . 0001 ) . Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like P10826 , HIN1 , P10415 , P25054 and P09211 is warranted for diagnostic potential and SFN , O94813 and P36952 for prognostic potential .\",\n \"P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . DB01248 dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .\",\n \"The P10415 antagonist ABT - 199 triggers apoptosis , and augments ibrutinib and idelalisib mediated cytotoxicity in P61073 Wild - type and P61073 WHIM mutated Waldenstrom macroglobulinaemia cells .\",\n \"chFRP5 - ZZ - PE38 , a large IgG - toxin immunoconjugate outperforms the corresponding smaller FRP5 ( Fv )- P25101 immunotoxin in eradicating ErbB2 - expressing tumor xenografts . As therapeutics , antibodies can be used \\\" un - armed \\\" or as immunoconjugates to direct cytotoxic moieties to tumor cells . Immunoconjugates are made by attaching chemotherapy drugs , radioisotopes or toxins to the antibody . Small recombinant antibody fragments fused to cytotoxic moieties , termed recombinant immunotoxins are also being developed as an additional approach for a targeted cancer therapy . Key parameters in determining the therapeutic potential of such targeted therapies are target specificity , affinity , stability and size . With regard to treating solid tumors , tumor penetration ( which is inversely proportional to size ) is currently regarded as the prime factor for efficacy , while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent . When comparing recombinant immunotoxins and antibody - toxin immunoconjugates that target ErbB2 / P04626 , here we found that a bivalent antibody - toxin immunoconjugate ( 200 kDa ) was superior to the corresponding recombinant monovalent immunotoxin ( 69 kDa ) in killing ErbB2 - expressing tumor cells in culture and as xenografts in nude mice , suggesting that higher avidity and longer residence time may outweigh tumor penetration . Our study suggests that the re - valuation of currently neglected , large IgG - effector molecule conjugates for anti - cancer therapy may be justified .\",\n \"Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line , 1 . 1B4 . BACKGROUND : Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line , 1 . 1B4 , after exposure to proinflammatory cytokines - IL - 1β , IFN - γ , P01375 - α . METHODS : MTT assay , insulin radioimmunoassay , glucokinase assay , real time reverse transcription PCR , western blotting , nitrite assay , caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity . RESULTS : Viability of 1 . 1B4 cells decreased after 18h cytokine exposure . Cytokines significantly reduced cellular insulin content and impaired insulin secretion induced by glucose , alanine , DB00761 , elevated Ca ( 2 +) , P0C6A0 or forskolin . P35557 enzyme activity , regulation of intracellular Ca ( 2 +) and PDX1 protein expression were significantly reduced by cytokines . mRNA expression of genes involved in secretory function - P01308 , GCK , P16519 and P17302 was downregulated in cytokine treated 1 . 1B4 cells . Upregulation of transcription of genes involved in antioxidant defence - P04179 and P07203 was observed , suggesting involvement of oxidative stress . Cytokines also upregulated transcriptions of P19838 and P42224 , which was accompanied by a significant increase in NOS2 transcription and accumulation of nitrite in culture medium , implicating nitrosative stress . Oxidative and nitrosative stresses induced apoptosis was evident from increased % tail DNA , DNA fragmentation , caspase 3 / 7 activity , apoptotic cells and lower P10415 protein expression . CONCLUSIONS : This study delineates molecular mechanisms of cytokine toxicity in 1 . 1B4 cells , which agree with earlier observations using human islets and rodent beta cells . GENERAL SIGNIFICANCE : This study emphasizes the potential usefulness of this cell line as a human beta cell model for research investigating autoimmune destruction of pancreatic beta cells .\",\n \"Q16696 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1 - induced DNA damage . Q16696 ( Q16696 ) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 ( AFB1 ) . Our previous study suggested that Q16696 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells ( BEAS - 2B ) . However , the role of Q16696 in AFB1 - induced DNA damage is unclear . Using BEAS - 2B cells that stably express Q16696 ( B - 2A13 ) , P05177 ( B - 1A2 ) , and P11509 ( B - 2A6 ) , we compared their effects in AFB1 - induced DNA adducts , DNA damage , and cell cycle changes . BEAS - 2B cells that were transfected with vector ( B - vector ) were used as a control . The results showed that AFB1 ( 5 - 80 nM ) dose - and time - dependently induced DNA damage in B - 2A13 cells . AFB1 at 10 and 80nM significantly augmented this effect in B - 2A13 and B - 1A2 cells , respectively . B - 2A6 cells showed no obvious DNA damage , similar to B - vector cells and the vehicle control . Similarly , compared with B - vector , B - 1A2 or B - 2A6 cells , B - 2A13 cells showed more sensitivity in AFB1 - induced γ P16104 expression , DNA adduct 8 - hydroxy - deoxyguanosine formation , and S - phase cell - cycle arrest . Furthermore , AFB1 activated the proteins related to DNA damage responses , such as Q13315 , ATR , Chk2 , p53 , P38398 , and P16104 , rather than the proteins related to DNA repair . These effects could be almost completely inhibited by 100 μM nicotine ( a substrate of Q16696 ) or 1 μM 8 - methoxypsoralen ( DB00553 ; an inhibitor of CYP enzyme ) . Collectively , these findings suggest that Q16696 plays an important role in low - concentration AFB1 - induced DNA damage , possibly linking environmental airborne AFB1 to genetic injury in human respiratory system .\",\n \"Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell - cycle arrest during mitosis . DB01248 binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell - cycle activities . It has also been shown to promote apoptosis via P10415 phosphorylation . In hormone - refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .\",\n \"Predictive factors for response to docetaxel in human breast cancers . DB01248 has come into wide use recently for the treatment of breast cancer in neoadjuvant , adjuvant and metastatic settings . DB01248 binds to beta - tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization , resulting in elevated levels of microtubule formation . During metaphase , defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest , culminating in apoptosis . However , docetaxel is not effective for all breast cancers . For example , in metastatic settings , the response rate to docetaxel reportedly ranges from 30 to 50 % . It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment . Currently it is impossible to identify , before the initiation of therapy , the patients for whom docetaxel will be effective . Various biological parameters have been studied clinically for their ability to predict response to docetaxel , such as parameters related to : ( 1 ) efflux ( p - glycoprotein ) and metabolism ( P08684 ) ; ( 2 ) beta - tubulin ( somatic mutation of beta - tubulin and changes in beta - tubulin isotypes levels ) ; ( 3 ) cell cycle ( P04626 , P38398 and Aurora - A ) ; and ( 4 ) apoptosis ( p53 , P10415 and thioredoxin ) . More recently , gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel . In the present paper , clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field .\",\n \"MYC directs transcription of Q07820 and P06730 genes to control sensitivity of gastric cancer cells toward HDAC inhibitors . Histone deacetylases ( HDACs ) control fundamental physiological processes such as proliferation and differentiation . HDAC inhibitors ( HDACi ) induce cell cycle arrest and apoptosis of tumor cells . Therefore , they represent promising cancer therapeutics that appear particularly useful in combination therapies . Although HDACi are tested in current clinical trials , the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood . To gain insight into pathways that limit HDACi efficacy in gastric cancer , we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid ( DB02546 ) . We report that higher expression levels of the anti - apoptotic P10415 family members Q07820 and BCL ( XL ) were detectable in cells with high inhibitory concentration 50 ( IC ( 50 ) ) values for DB02546 . Using RNAi , we show that Q07820 and BCL ( XL ) lower the efficacy of DB02546 . To find strategies to interfere with Q07820 and BCL ( XL ) expression , we investigated molecular regulation of both proteins . We show that specific siRNAs against c - MYC as well as pharmacological inhibition of this cancer - relevant transcription factor reduced Q07820 and BCL ( XL ) expression . Subsequently , we observed an increase in DB02546 efficacy . Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors . Whereas c - MYC controls transcription of Q07820 directly , regulation of BCL ( XL ) was due to c - MYC ' s capability to regulate the P06730 gene , which encodes a rate - limiting factor of eukaryotic translation . Our data reveal a new molecular mechanism for how c - MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c - MYC in gastric cancer .\",\n \"Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha - emitting radioisotope astatine - 211 conjugated to anti - P04626 / neu diabodies . PURPOSE : Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle . Small , engineered antitumor antibody fragments are capable of rapid , highly specific tumor targeting in immunodeficient mouse models . We hypothesized that the P13671 . 5 diabody , a noncovalent anti - P04626 single - chain Fv dimer , would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short - lived alpha - emitting radioisotope ( 211 ) At . EXPERIMENTAL DESIGN : Immunodeficient nude mice bearing established P04626 / neu - positive MDA - MB - 361 / DYT2 tumors treated with N - succinimidyl N -( 4 -[( 211 ) At ] astatophenethyl ) succinamate ( ( 211 ) At - O75563 ) - P13671 . 5 diabody . Additional cohorts of mice were treated with ( 211 ) At - O75563 T84 . 66 diabody targeting the carcinoembryonic antigen or ( 211 ) At - O75563 on a diabody specific for the Müllerian inhibiting substance type II receptor , which is minimally expressed on this tumor cell line . RESULTS : A single i . v . injection of ( 211 ) At - O75563 P13671 . 5 diabody led to a 30 - day delay in tumor growth when a 20 muCi dose was administered and a 57 - day delay in tumor growth ( 60 % tumor - free after 1 year ) when a 45 muCi dose was used . Treatment of mice bearing the same tumors with ( 211 ) At - O75563 T84 . 66 diabody at the same doses led to a delay in tumor growth , but no complete responses , likely due to substantially lower expression of this antigen on the MDA - MB - 361 / DYT2 tumors . In contrast , a dose of 20 muCi of ( 211 ) At - O75563 on the anti - Müllerian - inhibiting substance type II receptor diabody did not affect tumor growth rate , demonstrating specificity of the therapeutic effect . CONCLUSIONS : These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful , short - lived alpha - emitting radioisotopes .\",\n \"P04626 interacts with P16070 to up - regulate P61073 via epigenetic silencing of microRNA - 139 in gastric cancer cells . BACKGROUND & AIMS : Human epidermal growth factor receptor 2 ( P04626 ) ( neu / P04626 ) is overexpressed on many types of cancer cells , including gastric cancer cells ; P04626 overexpression has been associated with metastasis and poor prognosis . We investigated the mechanisms by which P04626 regulates cell migration and invasion . METHODS : P04626 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody , trastuzumab . We identified proteins that interact with P04626 or microRNAs ( miRNAs ) involved in P04626 signaling . We used various software programs to identify miRNAs that regulate factors in the P04626 signaling pathway . We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients . RESULTS : We found that P16070 binds directly to P04626 , which up - regulates the expression of metastasis - associated protein - 1 , induces deacetylation of histone H3 lysine 9 , and suppresses transcription of microRNA139 ( miR - 139 ) to inhibit expression of its target gene , P61073 ( P61073 ) . Knockdown of P04626 and P16070 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice . Lymph node metastasis was associated with high levels of P04626 , P16070 , and P61073 , and reduced levels of miR - 139 in human metastatic gastric tumors . Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and / or DNA methyltransferase resulted in up - regulation of miR - 139 . CONCLUSIONS : P04626 interaction with P16070 up - regulates P61073 by inhibiting expression of miR - 139 , at the epigenetic level , in gastric cancer cells . These findings indicate how P04626 signaling might promote gastric tumor progression and metastasis .\",\n \"P10242 suppresses differentiation and apoptosis of human breast cancer cells . INTRODUCTION : P10242 is highly expressed in estrogen receptor positive ( ER + ve ) breast tumours and tumour cell lines . We recently demonstrated that P10242 is essential for the proliferation of ER + ve breast cancer cells , and have now investigated its role in mammary epithelial differentiation . METHODS : MCF - 7 breast cancer cells were treated with sodium butyrate , vitamin E succinate or 12 - O - tetradecanoylphorbol - 13 - acetate to induce differentiation as measured by Nile Red staining of lipid droplets and β - casein expression . The non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 , was induced to differentiate with lactogenic hormones . P10242 levels were manipulated by inducible lentiviral shRNA - mediated knockdown and retroviral overexpression . RESULTS : We found that P10242 expression decreases following chemically - induced differentiation of the human breast cancer cell line MCF - 7 , and hormonally - induced differentiation of a non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 . We also found that shRNA - mediated P10242 knockdown initiated differentiation of breast cancer cells , and greatly sensitised them to the differentiative and pro - apoptotic effects of differentiation - inducing agents ( DIAs ) . Sensitisation to the pro - apoptotic effects DIAs is mediated by decreased expression of P10415 , which we show here is a direct P10242 target in breast cancer cells . Conversely , enforced expression of P10242 resulted in the cells remaining in an undifferentiated state , with concomitant suppression of apoptosis , in the presence of DIAs . CONCLUSIONS : Taken together , these data imply that P10242 function is critical in regulating the balance between proliferation , differentiation , and apoptosis in MECs . Moreover , our findings suggest P10242 may be a viable therapeutic target in breast cancer and suggest specific approaches for exploiting this possibility .\",\n \"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .\",\n \"___MASK99___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK99___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .\",\n \"Phase I trial of oral P42345 inhibitor everolimus in combination with trastuzumab and vinorelbine in pre - treated patients with P04626 - overexpressing metastatic breast cancer . To determine the feasible dose and schedule for everolimus , an oral P42345 inhibitor , combined with vinorelbine and trastuzumab for patients with P04626 - overexpressing metastatic breast cancer pretreated with trastuzumab . In this phase Ib multicenter , Bayesian dose - escalation study , 50 patients received everolimus 5 mg / day , 20 mg / week , or 30 mg / week plus vinorelbine ( 25 mg / m² on day 1 and 8 every 3 weeks ) and trastuzumab ( 2 mg / kg weekly ) . Endpoints included end - of - cycle - 1 dose - limiting toxicity ( DLT ) rate ( primary endpoint ) , safety , relative dose intensity , overall response rate ( ORR ) , and pharmacokinetics . Grade 3 / 4 neutropenia was the most common end - of - cycle - 1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg / day and 30 mg / week cohorts , respectively . Other end - of - cycle - 1 DLTs included single cases of febrile neutropenia , grade 3 stomatitis with concomitant fatigue , grade 2 stomatitis , grade 3 anorexia , and grade 2 acneiform dermatitis , all in the 5 - mg / day cohort . Based on the recorded DLTs and global safety , everolimus 5 mg / day and 30 mg / week were chosen as the optimal dose levels for the daily and weekly arms . Forty - seven patients were evaluable for efficacy . ORR was 19 . 1 % , with a disease control rate of 83 . 0 % and median progression - free survival of 30 . 7 weeks . No drug interaction was observed between everolimus and vinorelbine . ___MASK90___ combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with P04626 - overexpressing metastatic breast cancer that progressed on trastuzumab ( NCT00426530 ) .\",\n \"P01308 - like growth factor - I controls P38398 gene expression through activation of transcription factor Sp1 . The insulin - like growth factors ( IGFs ) have a central role in mammary gland growth and differentiation as well as in breast cancer development . The P38398 gene encodes a pleiotropic protein that functions as a transcription factor . Germline P38398 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms . Several lines of evidence led us to hypothesize that there is a functional interaction between the P38398 and P05019 systems relevant to breast cancer biology . The present study tested the notion that P38398 gene expression is regulated by the P05019 signaling pathway . Results of Western immunoblotting and RT - PCR analyses show that P05019 stimulates P38398 protein and mRNA levels . Transient transfection experiments using P38398 promoter - luciferase reporter constructs reveal that P05019 enhances P38398 promoter activity , suggesting that the effect of P05019 is mediated at the transcriptional level . In addition , we provide evidence that the Sp1 zinc - finger protein is directly involved in P38398 gene transactivation . Combined , our data suggests that , at least part of the biological actions of P05019 in mammary gland cells may be mediated through P38398 . Dysregulated P38398 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis .\",\n \"DB06809 and P27487 modulate mobilization , engraftment , and survival of hematopoietic stem and progenitor cells mediated by the P48061 / P48061 - P61073 axis . The chemokine stromal cell - derived factor - 1 ( P48061 / P48061 ) and its receptor , P61073 , are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem ( HSCs ) and progenitor ( HPCs ) cells . Modulation of this ligand - receptor interaction may be of clinical utility . We now report that : ( 1 ) the CC chemokine , macrophage inflammatory protein - 1alpha ( MIP - 1alpha / P10147 ) synergizes with DB06809 ( an antagonist of the binding of P48061 / P48061 to P61073 ) to rapidly mobilize HPCs to the blood of mice ; moreover , the combination of granulocyte colony - stimulating factor ( DB00099 ) with DB06809 and MIP - 1alpha / P10147 , given in a specific sequence , mobilizes the greatest number of HPCs compared to any combination of two of these mobilizing agents ; ( 2 ) pretreatment of recipient mice with Diprotin A , an inhibitor of P27487 / Dipeptidylpeptidase IV ( DPPIV ) , enhances the competitive HSCs repopulating capacity of untreated donor cells ; ( 3 ) the survival - enhancing effects of P48061 / P48061 on HPCs subjected in vitro to delayed addition of growth factors ( GFs ) are mediated in part through the cell cycle - related proteins P38936 ( cip1 / waf1 ) ( as assessed using P38936 ( cip1 / waf1 ) -/- and +/+ mice ) and Mad2 ( using Mad2 +/- and +/+ mice ) ; and ( 4 ) deletion of P27487 / DPPIV on mouse bone marrow cells increases the survival - enhancing effects of P48061 / P48061 on HPCs . These results demonstrate the means to increase the mobilization of HPCs , the engrafting capability of HSCs , and responsiveness of HPCs to the survival - enhancing activity of P48061 / P48061 , effects that may be of practical value .\",\n \"Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom . The present study was aimed to investigate the cognitive enhancing and anti - oxidant activities of Inonotus obliquus ( Chaga ) against scopolamine - induced experimental amnesia . Methanolic extract of Chaga ( Q9NRJ3 ) at 50 and 100 mg kg (- 1 ) doses were administered orally for 7 days to amnesic mice . Learning and memory was assessed by passive avoidance task ( PAT ) and Morris water maze ( MWM ) test . Tacrine ( ___MASK18___ , 10 mg kg ( - 1 ) , orally ( p . o ) ) used as a reference drug . To elucidate the mechanism of the cognitive enhancing activity of Q9NRJ3 , the activities of acetylcholinesterase ( P22303 ) , anti - oxidant enzymes , the levels of acetylcholine ( ACh ) and nitrite of mice brain homogenates were evaluated . Q9NRJ3 treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms . Further , Q9NRJ3 significantly reduced the oxidative - nitritive stress , as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner . In addition , Q9NRJ3 treatment significantly decreased the P22303 activity in both the salt and detergent - soluble fraction of brain homogenates . Further , treatment with Q9NRJ3 restored the levels of ACh as did ___MASK18___ . Thus , the significant cognitive enhancement observed in mice after Q9NRJ3 administration is closely related to higher brain anti - oxidant properties and inhibition of P22303 activity . These findings stress the critical impact of Chaga , a medicinal mushroom , on the higher brain functions like learning and memory .\",\n \"Combination therapy with anti - ErbB3 monoclonal antibodies and P00533 TKIs potently inhibits non - small cell lung cancer . Personalized therapy of advanced non - small cell lung cancer ( NSCLC ) has been improved by the introduction of P00533 tyrosine kinase inhibitors ( TKIs ) , gefitinib and erlotinib . P00533 TKIs induce dramatic objective responses and increase survival in patients bearing sensitizing mutations in the P00533 intracytoplasmic tyrosine kinase domain . However , virtually all patients develop resistance , and this is responsible for disease relapse . Hence several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable to sensitize resistant cells to P00533 TKIs . Recent studies have suggested that upregulation of another member of the P00533 receptor family , namely ErbB3 is involved in drug resistance , through increased phosphorylation of its intracytoplasmic domain and activation of PI3K / AKT signaling . In this paper we first show , by using a set of malignant pleural effusion derived cell cultures ( MPEDCC ) from patients with lung adenocarcinoma , that surface ErbB3 expression correlates with increased AKT phosphorylation . Antibodies against ErbB3 , namely A3 , which we previously demonstrated to induce receptor internalization and degradation , inhibit growth and induce apoptosis only in cells overexpressing surface ErbB3 . Furthermore , combination of anti - ErbB3 antibodies with P00533 TKIs synergistically affect cell proliferation in vitro , cause cell cycle arrest , up - regulate P38936 expression and inhibit tumor growth in mouse xenografts . Importantly , potentiation of gefitinib by anti - ErbB3 antibodies occurs both in de novo and in ab initio resistant cells . Anti - ErbB3 mAbs strongly synergize also with the dual P00533 and P04626 inhibitor lapatinib . Our results suggest that combination treatment with P00533 TKI and antibodies against ErbB3 should be a promising approach to pursue in the clinic .\",\n \"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK48___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK48___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK48___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK48___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK48___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK48___ increased the protein expression of hepatic P05181 and ___MASK48___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK48___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK48___ and RFP - induced hepatotoxicity .\",\n \"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK90___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .\",\n \"Purinergic receptor - mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine - rich repeat phosphatase , calcineurin , protein phosphatase 2A , and P60484 phosphatases . Akt is an important oncoprotein , and data suggest a critical role for nuclear Akt in cancer development . We have previously described a rapid ( 3 - 5 min ) and Q99572 - dependent depletion of nuclear phosphorylated Akt ( pAkt ) and effects on downstream targets , and here we studied mechanisms behind the pAkt depletion . We show that cholesterol - lowering drugs , statins , or extracellular DB00171 , induced a complex and coordinated response in insulin - stimulated A549 cells leading to depletion of nuclear pAkt . It involved protein / lipid phosphatases P60484 , pleckstrin homology domain leucine - rich repeat phosphatase ( O60346 and - 2 ) , protein phosphatase 2A ( PP2A ) , and calcineurin . We employed immunocytology , immunoprecipitation , and proximity ligation assay techniques and show that O60346 and calcineurin translocated to the nucleus and formed complexes with Akt within 3 min . Also P60484 translocated to the nucleus and then co - localized with pAkt close to the nuclear membrane . An inhibitor of the scaffolding immunophilin FK506 - binding protein 51 ( FKBP51 ) and calcineurin , FK506 , prevented depletion of nuclear pAkt . Furthermore , okadaic acid , an inhibitor of PP2A , prevented the nuclear pAkt depletion . Chemical inhibition and siRNA indicated that O60346 , PP2A , and P60484 were required for a robust depletion of nuclear pAkt , and in prostate cancer cells lacking P60484 , transfection of P60484 restored the statin - induced pAkt depletion . The activation of protein and lipid phosphatases was paralleled by a rapid proliferating cell nuclear antigen ( P12004 ) translocation to the nucleus , a P12004 - P38936 ( cip1 ) complex formation , and cyclin D1 degradation . We conclude that these effects reflect a signaling pathway for rapid depletion of pAkt that may stop the cell cycle .\",\n \"A multimarker model to predict outcome in tamoxifen - treated breast cancer patients . PURPOSE : This study was designed to produce a model to predict outcome in tamoxifen - treated breast cancer patients based on clinicopathologic features and multiple molecular markers . EXPERIMENTAL DESIGN : This was a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen for whom standard clinicopathologic data and tumor tissue microarrays were available . Nine molecular markers were studied by semiquantitative immunohistochemistry and / or fluorescence in situ hybridization . Cox proportional hazards analysis was used to determine the contributions of each variable to disease - specific and overall survival , and machine learning was used to produce a model to predict patient outcome . RESULTS : On a univariate basis , the following features were significantly associated with worse survival : high pathologic tumor or nodal class , histologic grade , epidermal growth factor receptor , P04626 , MYC , or P04637 ; absent estrogen receptor ( ER ) or progesterone receptor ; and low P10415 . P24385 and P46527 did not reach statistical significance . On a multivariate basis , nodal class , ER , and MYC were statistically significant as independent factors for survival . However , the benefit of ER - positive status was moderated by P10415 , P04626 , and progesterone receptor . P10415 and P04637 also interacted as an independent risk factor . A kernel partial least squares polynomial model was developed with an area under the receiver operating characteristic curve of 0 . 90 . CONCLUSIONS : Our data show the predictive value of P10415 , P04626 , MYC , and P04637 in addition to the standard hormone receptors and clinicopathologic features , and they show the importance of conditional interpretation of certain molecular markers . Our multimarker predictive model performed significantly better than standard guidelines .\",\n \"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK18___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK18___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK18___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK18___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK18___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .\",\n \"___MASK90___ enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro - apoptotic and cell - cycle - progression regulatory proteins . DB06769 is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed / refractory multiple myeloma ( MM ) . ___MASK90___ , an mammalian target of rapamycin ( P42345 ) inhibitor , is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers . We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines ( RPMI8226 and MM1 . S ) and primary MM cells . Our results demonstrated a synergistic effect of these drugs , which was effective for both p53 - wild - type and p - 53 - deleted MM cells , but was minimal in mononuclear cells from a healthy donor . Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin - V / PI staining , caspase - 3 degradation , and PARP cleavage . Cell death was associated with the up - regulation of the pro - apoptotic protein Bax and the down - regulation of the anti - apoptotic proteins Mcl - 1 and survivin . The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the P42345 pathway , p70s6k , and 4EBP - 1 , as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1 . S cells . P38936 was also down - regulated upon treatment with the two drugs , suggesting a mechanism of sensitization through the release of cell cycle arrest . Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine , and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and P42345 inhibitors in future clinical practice .\",\n \"Q9UBP4 maintains the PANC - 1 human pancreatic tumor cells in a dedifferentiated state . Pancreatic cancer ( PaCa ) is the fourth leading cause of cancer deaths in Western societies , with pancreatic ductal adenocarcinomas ( PDACs ) accounting for > 90 % of such cases . PDAC is a heterogeneous disease that includes a subset showing overexpression of the secreted glycoprotein Q9UBP4 ( Q9UBP4 ) , a protein shown to be downregulated in various cancers of different tissues . The biological function of Q9UBP4 in this subset was studied using the Q9UBP4 expressing PANC - 1 cell line as a model for PDACs . The influence of Q9UBP4 overexpression and knockdown on cellular differentiation and proliferation of PANC - 1 was investigated . Confocal microscopy showed that Q9UBP4 was expressed in a fraction of PANC - 1 cells . While lentiviral - mediated overexpression of Q9UBP4 did not alter cellular proliferation , knockdown of Q9UBP4 resulted in significant reduction of cellular proliferation and concomitant induction of cell cycle inhibitors P42772 ( p15INK4b ) , P38936 ( p21CIP1 ) and P46527 ( p27KIP1 ) . In parallel , pancreatic epithelial cell differentiation markers P04746 , Q9UNI1 , P17538 , P01275 , P16278 and P01308 were significantly upregulated . PANC - 1 cells differentiated using exendin - 4 showed analogous induction of cell cycle inhibitors and differentiation markers . Thus , we conclude that Q9UBP4 is required to maintain a highly dedifferentiated and consequently proliferative state in PANC - 1 , indicating a similar function in the Q9UBP4 overexpressing subset of PDACs . Therefore , Q9UBP4 represents a potential target for the treatment of Q9UBP4 - positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation .\",\n \"Autocrine and paracrine roles of P15692 / P35968 and P49767 / P35916 signaling in angiosarcomas of the scalp and face . Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons . To clarify its characteristic features and cell cycle kinetics , we quantitatively evaluated the expression of cell cycle - related molecules and vascular endothelial growth factors using immunohistochemical staining , for comparison with 2 benign vascular tumors of the skin , the capillary hemangioma and the cavernous hemangioma . Cell proliferation , determined with reference to the Ki - 67 labeling index , was highest in angiosarcomas and lowest in cavernous hemangiomas ( angiosarcomas versus capillary hemangioma , P = . 014 ; capillary hemangioma versus cavernous hemangiomas , P = 1 . 4 x 10 (- 4 ) ) . Similar differences were also found in cyclin A , cyclin E , and P38936 ( Waf1 ) expression . Expressions of cyclin D1 and p16 ( INK4A ) were also significantly higher in angiosarcoma than in cavernous hemangioma . Expressions of these 5 proteins showed significant positive correlations with Ki - 67 labeling indices ( Spearman rho = 0 . 91 - 0 . 43 ) . Expression levels of vascular endothelial growth factor and its receptor , P35968 , were highest in angiosarcomas . P49767 expression in angiosarcomas was significantly higher than in cavernous hemangiomas , and its receptor P35916 expression was highest in angiosarcomas . Furthermore , significant positive correlations of these protein expression with Ki - 67 labeling indices were noted ( Spearman rho = 0 . 88 - 0 . 40 ) . Among them , P35916 showed the highest correlation coefficient . These results suggest that not only P35968 - mediated signal but also P35916 - mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors .\",\n \"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK20___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK20___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .\",\n \"___MASK58___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK58___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .\",\n \"___MASK26___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"Exome - level comparison of primary well - differentiated neuroendocrine tumors and their cell lines . Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors ( NET ) and have been instrumental in the design of clinical trials targeting the PI3K / AKT / P42345 pathways , P15692 inhibitors , and somatostatin analogues . It remains unknown , however , whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines . Four bronchopulmonary NET ( BP - NET ) - NCI - H720 , NCI - H727 , NCI - H835 , and UMC11 - and two pancreatic neuroendocrine tumors ( panNET ) - BON - 1 and QGP1 - were cultured . DNA was isolated , and exome sequencing was done . GATK and EXCAVATOR were used for bioinformatic analysis . We detected a total of 1 , 764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP - NET and 4 . 3 per Mb in panNET cell lines , including 52 mutated COSMIC cancer genes in these cell lines , such as P04637 , P38398 , P06400 , P49815 , P46531 , Q09472 , GNAS , P35968 , Q15831 , and P25054 but not P46100 , Q9UER7 , nor O00255 . Our data suggest that mutation rate , the pattern of copy number variations , and the mutational spectra in the BP - NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP - NET . Likewise , mutation rate and pattern including the absence of mutations in P46100 / Q9UER7 , O00255 , and P25490 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET . These results suggest that results from experiments with BP - NET and panNET cell lines need to be interpreted with caution .\",\n \"Effects of maternal smoking on the placental expression of genes related to angiogenesis and apoptosis during the first trimester . OBJECTIVE : Maternal cigarette smoking is reportedly associated with miscarriage , fetal growth restriction and placental abruption , and is paradoxically associated with a decreased risk of developing preeclampsia . In the present study , we investigated the gene expression levels of villous tissues in early gestation . We compared the expression levels of the genes related to angiogenesis and apoptosis in the villous tissues obtained from smoking and non - smoking pregnant women . MATERIALS AND METHODS : We collected villous tissue samples from 57 women requesting surgical termination due to non - medical reasons at 6 - 8 weeks of gestation . The maternal cigarette smoking status was evaluated by the level of serum cotinine and patients were divided into active smokers and non - smokers by the serum cotinine level . The placental levels of P15692 , P49763 , P17948 , Q16665 , P04637 , Q07812 and P10415 mRNA were quantified by real time PCR . RESULTS : The gene expression level of P49763 and Q16665 in the active smoker group was significantly higher than that in the non - smoker group . We did not observe any significant differences in the P15692 or P17948 expression between the groups . In active smoker group , the gene expression levels of P04637 and Q07812 were significantly higher than those in the non - smoker group . The ratio of Q07812 / P10415 mRNA in the active smoker group was significantly higher than that in the non - smoker group . CONCLUSIONS : Our findings revealed that smoking might affect the placenta during early pregnancy . Maternal cigarette smoking in early pregnancy may be associated with villus hypoxia , which may influence angiogenesis and apoptosis .\",\n \"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK38___ GITS , Diaprel MR ) . One daily dose of ___MASK38___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .\",\n \"Ubiquitin - dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen . We previously reported that acetaminophen ( DB00316 , 4 - hydroxyacetanilide ) caused apoptosis of P13671 glioma cells . Therefore , we hypothesized that the level of p53 , which usually stimulates apoptosis , might be increased after DB00316 exposure . However , DB00316 exposure for 24 h markedly decreased the p53 content and its downstream target P38936 in a concentration - dependent manner . Reduction of p53 was not accompanied by a decrease in p53 mRNA in P13671 glioma cells , suggesting that p53 was mainly affected at the protein level . Unexpectedly , DB00316 stimulated phosphorylation of p53 at Ser15 , Ser20 , and Ser37 , which usually elevates p53 content . However , phosphorylation of these residues did not prevent DB00316 - induced decrease in p53 . The p53 reduction was independent from the level of phospho - Akt , which is known to promote p53 degradation . Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 ( mdm2 ) and ubiquitin were bound to p53 during its degradation . Lactacystin and N - benzoyloxycarbonyl ( Z ) - DB00149 - DB00149 - leucinal ( MG132 ) , inhibitors of proteasomal proteolysis , prevented the decrease , supporting the proteasomal degradation of p53 upon DB00316 exposure . Pretreatment with chlormethiazole , an inhibitor of ethanol - inducible P05181 , significantly lowered the P05181 enzyme activity and the rate of DB00316 - induced cell death while it prevented the reduction of p53 and P38936 in P13671 glioma cells . A nontoxic analog of DB00316 , 3 - hydroxyacetanilde , did not reduce p53 and P38936 contents in P13671 glioma cells and LLC - P30613 porcine kidney cells . Taken together , our results show that DB00316 or its reactive metabolite ( s ) can directly reduce the p53 content through mdm2 - mediated ubiquitin conjugation , despite phosphorylation of p53 at its N terminus .\",\n \"Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .\",\n \"___MASK96___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .\"\n]"},"candidates":{"kind":"list like","value":["___MASK18___","___MASK20___","___MASK26___","___MASK38___","___MASK48___","___MASK58___","___MASK90___","___MASK96___","___MASK99___"],"string":"[\n \"___MASK18___\",\n \"___MASK20___\",\n \"___MASK26___\",\n \"___MASK38___\",\n \"___MASK48___\",\n \"___MASK58___\",\n \"___MASK90___\",\n \"___MASK96___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK20___"},"id":{"kind":"string","value":"MH_train_389"}}},{"rowIdx":390,"cells":{"query":{"kind":"string","value":"interacts_with DB00918?"},"supports":{"kind":"list like","value":["___MASK77___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .","Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK85___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .","Dose finding , placebo - controlled study of oral almotriptan in the acute treatment of migraine . OBJECTIVE : To assess the efficacy and tolerability of oral almotriptan , a selective serotonin receptor ( P28222 / 1D ) agonist , when used at different doses in the treatment of acute migraine . METHODS : This was a placebo controlled , double - blind , parallel - group , dose - finding study . Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2 , 6 . 25 , 12 . 5 , or 25 mg at the onset of moderate or severe pain . Patients graded pain intensity on a 4 - point verbal scale from 0 ( no pain ) to 3 ( severe pain ) and recorded adverse events . The primary efficacy variable was headache response at 2 hours . Data were analyzed on an intent - to - treat basis . RESULTS : Nine hundred and three patients were randomized , and 742 were included in the evaluation of the efficacy and tolerability . Headache response at 2 hours was 32 . 5 % with placebo , and 30 % , 56 . 3 % , 58 . 5 % , and 66 . 5 % with almotriptan 2 , 6 . 25 , 12 . 5 , and 25 mg doses ( p < 0 . 05 for 6 . 25 , 12 . 5 , and 25 mg vs placebo ) . A dose - dependent decrease in the incidence of migraine - associated symptoms and the need for escape medication was observed . The incidence of adverse events with the almotriptan 2 - mg , 6 . 25 - mg , and 12 . 5 - mg groups was comparable to that with the placebo group . CONCLUSION : DB00918 12 . 5 mg demonstrated the most favorable ratio between efficacy and tolerability , offering equivalent efficacy and better tolerability compared with the 25 mg dose . The minimum effective dose of almotriptan was 6 . 25 mg .","Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .","Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .","P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .","Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .","DB00918 : a novel P28222 / D agonist for the symptomatic treatment of migraine . Currently available oral triptans are not ideal , at least for 20 - 30 % of migraine patients , due to either response failure or adverse events . DB00918 is a novel selective P28222 / D receptor agonist exhibiting the highest bioavailability among triptans , both outside and within a migraine attack . The tolerability of the therapeutic oral dose of almotriptan , 12 . 5 mg , is similar to that of placebo , with a remarkably low incidence of chest symptoms . At this dose , efficacy parameters remain comparable to those of sumatriptan 100 mg , while the recurrence rate is in the lower range . This balanced profile makes almotriptan 12 . 5 mg a good choice for the symptomatic treatment of the typical migraine patient .","[ ___MASK53___ sodium ( Photofrin - II ) ] . ___MASK53___ sodium ( ___MASK53___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK53___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .","Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK35___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .","Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK36___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .","Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .","DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .","The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .","Safety profile of almotriptan , a new antimigraine agent . Effects on central nervous system , renal function and respiratory dynamics . DB00918 ( 3 - [ 2 -( dimethylamino ) ethyl ] - 5 -( pyrrolidin - 1 - ylsulfonylmethyl )- 1H - indole , CAS 154323 - 57 - 6 ) is a new P28222 / 1D agonist whose clinical efficacy has been demonstrated in Phase III clinical trials . This study aimed to evaluate the safety of almotriptan with respect to the central nervous system , renal function and respiratory dynamics using preclinical animal models . The results indicate that almotriptan does not cross the blood - brain barrier , since no effects on / interaction with spontaneous locomotor activity , hexobarbital - induced sleeping time , caffeine - induced increase of spontaneous locomotor activity , or hypothermia ( caused by stimulation of central P28221 receptors ) was observed following treatment . DB00918 had a mild antiemetic effect and a slight , transient diuretic effect in dogs , although the latter effect is probably of no clinical relevance . In addition , no effect on the respiratory system of conscious guinea pigs was observed following almotriptan treatment . These results indicate that almotriptan has a favourable safety profile with respect to the central nervous , renal and respiratory systems .","Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 / 1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69 . 1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first - pass metabolism ( 18 . 7 - 79 . 6 % ) . The elimination half - life was short and ranged between 0 . 7 and 3 h . The main route of elimination of almotriptan was urine with 75 . 6 % and 80 . 4 % of the dose recovered over a 168 - h period in rats and dogs , respectively . The gamma - aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N - oxide metabolite were the main metabolites in dog .","[ 5 - hydroxytryptamine ( serotonin ) receptors -- nomenclature and classification of types and subtypes ] . 5 - HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes . At present 15 receptor subtypes of three groups has been recognized . The 5 - HT1 subfamily of receptors contains subtypes P08908 , P28222 , P28221 , P28566 , and P30939 ; activation of all of them results in the inhibition of adenylylcyclase . The subfamily of 5 - HT2 contains subtypes 5 - Q13049 , P41595 , and P28335 ; their activation leads to the stimulation of P98160 . Finally , subfamily of miscellaneous 5 - HT receptors contains subtypes 5 - Q9H205 , Q13639 , 5 - HT5 , P50406 , and P34969 ; some of them has been cloned , however , our knowledge on their function is still minimal . 5 - HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease . 5 - HT plays an important role in depression ; to cure this disease , drugs which increase levels of this neurotransmitter are used . A new drug group called Selective Serotonin Reuptake Inhibitors ( SSRI ) has been recently discovered . These drugs block the reuptake of 5 - HT into nerve endings . There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential .","DB00918 is an effective and well - tolerated treatment for migraine pain : results of a randomized , double - blind , placebo - controlled clinical trial . DB00918 is a novel and specific serotonin P28222 / 1D agonist for the acute treatment of migraine . This randomized , single - dose , double - blind , multicentre , study assessed the efficacy and safety of oral almotriptan ( 12 . 5 mg and 25 mg ) in patients with migraine , and compared it with the standard treatment ( sumatriptan 100 mg ) and placebo . A total of 668 patients treated one migraine attack of moderate or severe intensity with study medication . The primary efficacy assessment was migraine pain relief , improvement from severe or moderate pain to mild or no pain , at 2 h after treatment . Response rates , stratified for variation in baseline pain levels , for both almotriptan doses were equivalent to sumatriptan and significantly better than placebo . Other efficacy assessments confirmed the equivalence of the almotriptan groups with the sumatriptan group . DB00918 12 . 5 mg was as well tolerated as placebo ( P = 0 . 493 ) and significantly better tolerated than sumatriptan ( P < 0 . 001 ) , in terms of the overall incidence of adverse events . There was no statistically significant difference in the incidence of adverse events between almotriptan 25 mg and sumatriptan 100 mg ( P = 0 . 376 ) . The results from this large clinical study indicate that the new , specific P28222 / 1D agonist , almotriptan , is an effective and well - tolerated treatment for migraine pain .","Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK91___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .","Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .","___MASK91___ binding to human and rat dopamine and 5 - HT receptors . ___MASK91___ ( ___MASK91___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK91___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK91___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK91___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .","Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers . OBJECTIVE : To assess the interaction between almotriptan , a P28222 / 1D - receptor agonist used to treat migraine , and verapamil , an agent for migraine prophylaxis . METHODS : Twelve healthy volunteers received the following treatments in a crossover design : ( 1 ) 120 - mg sustained - release verapamil tablet twice daily for 7 days and one 12 . 5 - mg almotriptan tablet on day 7 and ( 2 ) one 12 . 5 - mg almotriptan tablet alone on day 7 . Serial plasma and urine samples were obtained on day 7 . DB00918 plasma concentrations were determined by liquid chromatography - tandem mass spectrometry ; urine samples were analyzed by ultraviolet HPLC . Safety measures included blood pressure and pulse measurements , electrocardiography , and adverse event monitoring . Statistical comparisons of pharmacokinetic parameters and vital sign data were made by Q9UNW9 . RESULTS : Mean almotriptan peak concentration and area under the plasma concentration - time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone . The magnitudes of these differences were approximately 20 % . Renal clearance was unaffected by verapamil coadministration . No significant effects of treatment on blood pressure or pulse were detected , with the exception of sitting systolic blood pressure at 2 hours after administration . However , the difference in mean change from baseline at this time point was only 8 mm Hg . CONCLUSIONS : Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of P08684 to almotriptan metabolism . This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted .","Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK80___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .","How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .","[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK28___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .","Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .","Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .","Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK60___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice ."],"string":"[\n \"___MASK77___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .\",\n \"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK85___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .\",\n \"Dose finding , placebo - controlled study of oral almotriptan in the acute treatment of migraine . OBJECTIVE : To assess the efficacy and tolerability of oral almotriptan , a selective serotonin receptor ( P28222 / 1D ) agonist , when used at different doses in the treatment of acute migraine . METHODS : This was a placebo controlled , double - blind , parallel - group , dose - finding study . Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2 , 6 . 25 , 12 . 5 , or 25 mg at the onset of moderate or severe pain . Patients graded pain intensity on a 4 - point verbal scale from 0 ( no pain ) to 3 ( severe pain ) and recorded adverse events . The primary efficacy variable was headache response at 2 hours . Data were analyzed on an intent - to - treat basis . RESULTS : Nine hundred and three patients were randomized , and 742 were included in the evaluation of the efficacy and tolerability . Headache response at 2 hours was 32 . 5 % with placebo , and 30 % , 56 . 3 % , 58 . 5 % , and 66 . 5 % with almotriptan 2 , 6 . 25 , 12 . 5 , and 25 mg doses ( p < 0 . 05 for 6 . 25 , 12 . 5 , and 25 mg vs placebo ) . A dose - dependent decrease in the incidence of migraine - associated symptoms and the need for escape medication was observed . The incidence of adverse events with the almotriptan 2 - mg , 6 . 25 - mg , and 12 . 5 - mg groups was comparable to that with the placebo group . CONCLUSION : DB00918 12 . 5 mg demonstrated the most favorable ratio between efficacy and tolerability , offering equivalent efficacy and better tolerability compared with the 25 mg dose . The minimum effective dose of almotriptan was 6 . 25 mg .\",\n \"Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .\",\n \"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .\",\n \"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .\",\n \"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .\",\n \"DB00918 : a novel P28222 / D agonist for the symptomatic treatment of migraine . Currently available oral triptans are not ideal , at least for 20 - 30 % of migraine patients , due to either response failure or adverse events . DB00918 is a novel selective P28222 / D receptor agonist exhibiting the highest bioavailability among triptans , both outside and within a migraine attack . The tolerability of the therapeutic oral dose of almotriptan , 12 . 5 mg , is similar to that of placebo , with a remarkably low incidence of chest symptoms . At this dose , efficacy parameters remain comparable to those of sumatriptan 100 mg , while the recurrence rate is in the lower range . This balanced profile makes almotriptan 12 . 5 mg a good choice for the symptomatic treatment of the typical migraine patient .\",\n \"[ ___MASK53___ sodium ( Photofrin - II ) ] . ___MASK53___ sodium ( ___MASK53___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK53___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .\",\n \"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK35___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .\",\n \"Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK36___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .\",\n \"Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .\",\n \"DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .\",\n \"The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .\",\n \"Safety profile of almotriptan , a new antimigraine agent . Effects on central nervous system , renal function and respiratory dynamics . DB00918 ( 3 - [ 2 -( dimethylamino ) ethyl ] - 5 -( pyrrolidin - 1 - ylsulfonylmethyl )- 1H - indole , CAS 154323 - 57 - 6 ) is a new P28222 / 1D agonist whose clinical efficacy has been demonstrated in Phase III clinical trials . This study aimed to evaluate the safety of almotriptan with respect to the central nervous system , renal function and respiratory dynamics using preclinical animal models . The results indicate that almotriptan does not cross the blood - brain barrier , since no effects on / interaction with spontaneous locomotor activity , hexobarbital - induced sleeping time , caffeine - induced increase of spontaneous locomotor activity , or hypothermia ( caused by stimulation of central P28221 receptors ) was observed following treatment . DB00918 had a mild antiemetic effect and a slight , transient diuretic effect in dogs , although the latter effect is probably of no clinical relevance . In addition , no effect on the respiratory system of conscious guinea pigs was observed following almotriptan treatment . These results indicate that almotriptan has a favourable safety profile with respect to the central nervous , renal and respiratory systems .\",\n \"Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 / 1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69 . 1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first - pass metabolism ( 18 . 7 - 79 . 6 % ) . The elimination half - life was short and ranged between 0 . 7 and 3 h . The main route of elimination of almotriptan was urine with 75 . 6 % and 80 . 4 % of the dose recovered over a 168 - h period in rats and dogs , respectively . The gamma - aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N - oxide metabolite were the main metabolites in dog .\",\n \"[ 5 - hydroxytryptamine ( serotonin ) receptors -- nomenclature and classification of types and subtypes ] . 5 - HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes . At present 15 receptor subtypes of three groups has been recognized . The 5 - HT1 subfamily of receptors contains subtypes P08908 , P28222 , P28221 , P28566 , and P30939 ; activation of all of them results in the inhibition of adenylylcyclase . The subfamily of 5 - HT2 contains subtypes 5 - Q13049 , P41595 , and P28335 ; their activation leads to the stimulation of P98160 . Finally , subfamily of miscellaneous 5 - HT receptors contains subtypes 5 - Q9H205 , Q13639 , 5 - HT5 , P50406 , and P34969 ; some of them has been cloned , however , our knowledge on their function is still minimal . 5 - HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease . 5 - HT plays an important role in depression ; to cure this disease , drugs which increase levels of this neurotransmitter are used . A new drug group called Selective Serotonin Reuptake Inhibitors ( SSRI ) has been recently discovered . These drugs block the reuptake of 5 - HT into nerve endings . There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential .\",\n \"DB00918 is an effective and well - tolerated treatment for migraine pain : results of a randomized , double - blind , placebo - controlled clinical trial . DB00918 is a novel and specific serotonin P28222 / 1D agonist for the acute treatment of migraine . This randomized , single - dose , double - blind , multicentre , study assessed the efficacy and safety of oral almotriptan ( 12 . 5 mg and 25 mg ) in patients with migraine , and compared it with the standard treatment ( sumatriptan 100 mg ) and placebo . A total of 668 patients treated one migraine attack of moderate or severe intensity with study medication . The primary efficacy assessment was migraine pain relief , improvement from severe or moderate pain to mild or no pain , at 2 h after treatment . Response rates , stratified for variation in baseline pain levels , for both almotriptan doses were equivalent to sumatriptan and significantly better than placebo . Other efficacy assessments confirmed the equivalence of the almotriptan groups with the sumatriptan group . DB00918 12 . 5 mg was as well tolerated as placebo ( P = 0 . 493 ) and significantly better tolerated than sumatriptan ( P < 0 . 001 ) , in terms of the overall incidence of adverse events . There was no statistically significant difference in the incidence of adverse events between almotriptan 25 mg and sumatriptan 100 mg ( P = 0 . 376 ) . The results from this large clinical study indicate that the new , specific P28222 / 1D agonist , almotriptan , is an effective and well - tolerated treatment for migraine pain .\",\n \"Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK91___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .\",\n \"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .\",\n \"___MASK91___ binding to human and rat dopamine and 5 - HT receptors . ___MASK91___ ( ___MASK91___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK91___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK91___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK91___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .\",\n \"Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers . OBJECTIVE : To assess the interaction between almotriptan , a P28222 / 1D - receptor agonist used to treat migraine , and verapamil , an agent for migraine prophylaxis . METHODS : Twelve healthy volunteers received the following treatments in a crossover design : ( 1 ) 120 - mg sustained - release verapamil tablet twice daily for 7 days and one 12 . 5 - mg almotriptan tablet on day 7 and ( 2 ) one 12 . 5 - mg almotriptan tablet alone on day 7 . Serial plasma and urine samples were obtained on day 7 . DB00918 plasma concentrations were determined by liquid chromatography - tandem mass spectrometry ; urine samples were analyzed by ultraviolet HPLC . Safety measures included blood pressure and pulse measurements , electrocardiography , and adverse event monitoring . Statistical comparisons of pharmacokinetic parameters and vital sign data were made by Q9UNW9 . RESULTS : Mean almotriptan peak concentration and area under the plasma concentration - time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone . The magnitudes of these differences were approximately 20 % . Renal clearance was unaffected by verapamil coadministration . No significant effects of treatment on blood pressure or pulse were detected , with the exception of sitting systolic blood pressure at 2 hours after administration . However , the difference in mean change from baseline at this time point was only 8 mm Hg . CONCLUSIONS : Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of P08684 to almotriptan metabolism . This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted .\",\n \"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK80___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .\",\n \"How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK28___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .\",\n \"Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .\",\n \"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK60___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .\"\n]"},"candidates":{"kind":"list like","value":["___MASK28___","___MASK35___","___MASK36___","___MASK53___","___MASK60___","___MASK77___","___MASK80___","___MASK85___","___MASK91___"],"string":"[\n \"___MASK28___\",\n \"___MASK35___\",\n \"___MASK36___\",\n \"___MASK53___\",\n \"___MASK60___\",\n \"___MASK77___\",\n \"___MASK80___\",\n \"___MASK85___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK85___"},"id":{"kind":"string","value":"MH_train_390"}}},{"rowIdx":391,"cells":{"query":{"kind":"string","value":"interacts_with DB02701?"},"supports":{"kind":"list like","value":["DB02701 inhibits alkylating agent - induced apoptotic neurodegeneration in the developing rat brain . BACKGROUND : Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system ( CNS ) . Administration of single dose of thiotepa in 7 - d postnatal ( Q0GE19 ) rat triggers activation of apoptotic cascade and widespread neuronal death . The present study was aimed to elucidate whether nicotinamide may prevent thiotepa - induced neurodegeneration in the developing rat brain . METHODOLOGY / PRINCIPAL FINDINGS : Neuronal cell death induced by thiotepa was associated with the induction of Bax , release of cytochrome - c from mitochondria into the cytosol , activation of caspase - 3 and cleavage of poly ( ADP - ribose ) polymerase ( P09874 ) . Post - treatment of developing rats with nicotinamide suppressed thiotepa - induced upregulation of Bax , reduced cytochrome - c release into the cytosol and reduced expression of activated caspase - 3 and cleavage of P09874 . Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus ; post - treatment with nicotinamide reduced the number of dead cells in these brain regions . Terminal deoxynucleotidyl transferase ( TdT ) - mediated dUTP nick end - labeling ( TUNEL ) and immunohistochemical analysis of caspase - 3 show that thiotepa - induced cell death is apoptotic and that it is inhibited by nicotinamide treatment . CONCLUSION : DB02701 ( Nic ) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat . These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants .","N - methyl - 2 - pyridone - 5 - carboxamide : a novel uremic toxin ? BACKGROUND : N - methyl - 2 - pyridone - 5 - carboxamide ( 2PY ) is one of the end products of nicotinamide - adenine dinucleotide ( NAD ) degradation . We recently found that serum 2PY concentrations in chronic renal failure ( CRF ) patients were enhanced to the values , which are potentially toxic . The aim of this study was to determine whether 2PY is an inhibitor of poly ( ADP - ribose ) polymerase , the nuclear enzyme that is highly involved in variety of physiologic events , including regulation of DNA replication and DNA repair . METHODS : High - performance liquid chromatography ( HPLC ) was used to determine 2PY and other NAD catabolite concentrations in serum of : nondialyzed patients ; patients chronically hemodialyzed ; patients after kidney transplantation ; and healthy individuals ( control group ) . Moreover , the effect of nicotinamide and 2PY on poly ( ADP - ribose ) polymerase ( P09874 ) in vitro was studied . RESULTS : The serum nicotinamide , 2PY , and 4PY ( N - methyl - 4 - pyridone - 3 - carboxamide ) concentrations are many times elevated in nondialyzed CRF patients when compared with controls . The direct correlations were found between serum 2PY ( as well as 4PY and nicotinamide ) concentrations and serum creatinine concentration , and negative correlations between serum concentrations of these compounds and creatinine clearance . The concentration of 2PY decreases considerably after hemodialysis ( HD ) session , but elevates back 48 hours later . It permanently declines after kidney transplantation . DB02701 and 2PY significantly inhibit P09874 activity in vitro . CONCLUSIONS : Increased serum 2PY concentration , along with a deterioration of kidney function and its toxic properties ( significant inhibition of P09874 by 2PY ) , suggest that it could be a novel uremic toxin .","P09874 ( P09874 ) activation and NAD (+) in DNA repair and cell death . DB02701 adenine dinucleotide , NAD (+) , is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis , the tricarboxylic acid cycle ( TCA ) and mitochondrial respiration . These processes consume and produce both oxidative and reduced forms of NAD ( NAD (+) and DB00157 ) . NAD (+) is also important for ADP ( ribosyl ) ation reactions mediated by the ADP - ribosyltransferase enzymes ( ARTDs ) or deacetylation reactions catalyzed by the sirtuins ( SIRTs ) which use NAD (+) as a substrate . In this review , we highlight the significance of NAD (+) catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs . We summarize the current findings on the involvement of P09874 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by P09874 activation and energy depletion . By sharing the same substrate , the activities of ARTDs and SIRTs are tightly linked , are dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology , inflammatory diseases and ischaemia / reperfusion .","Role of nicotinamide in DNA damage , mutagenesis , and DNA repair . DB02701 is a water - soluble amide form of niacin ( nicotinic acid or vitamin B3 ) . Both niacin and nicotinamide are widely available in plant and animal foods , and niacin can also be endogenously synthesized in the liver from dietary tryptophan . DB02701 is also commercially available in vitamin supplements and in a range of cosmetic , hair , and skin preparations . DB02701 is the primary precursor of nicotinamide adenine dinucleotide ( NAD (+) ) , an essential coenzyme in DB00171 production and the sole substrate of the nuclear enzyme poly - ADP - ribose polymerase - 1 ( P09874 ) . Numerous in vitro and in vivo studies have clearly shown that P09874 and NAD (+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation . This paper will examine the role of nicotinamide in the protection from carcinogenesis , DNA repair , and maintenance of genomic stability .","Preventing NAD (+) depletion protects neurons against excitotoxicity : bioenergetic effects of mild mitochondrial uncoupling and caloric restriction . Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity , which involves energy depletion . By examining bioenergetic changes induced by glutamate , we found that the cellular nicotinamide adenine dinucleotide ( NAD (+) ) level is a critical determinant of neuronal survival . The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain . 2 , 4 - dinitrophenol ( DNP ) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons , which accelerates oxidation of NAD ( P ) H to NAD (+) in mitochondria . The NAD (+)- dependent histone deacetylase sirtulin 1 ( Q96EB6 ) and glucose transporter 1 ( P11166 ) mRNA are upregulated mouse brain under caloric restriction . To examine whether NAD (+) mediates neuroprotective effects , nicotinamide , a precursor of NAD (+) and inhibitor of Q96EB6 and poly ( ADP - ribose ) polymerase 1 ( P09874 ) ( two NAD (+)- dependent enzymes ) , was employed . DB02701 attenuated excitotoxic death and preserved cellular NAD (+) levels to support Q96EB6 and PARP 1 activities . Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress .","DB02701 deficiency in human lymphocytes prevents the [ 3H ] thymidine - induced adaptive response for the repair of X - ray - induced chromosomal damage . Human lymphocytes treated with [ 3H ] thymidine ( [ 3H ] dThd ) become refractory to the induction of chromosomal aberrations by subsequent doses of X rays . This adaptive response to [ 3H ] dThd does not occur in the presence of 3 - aminobenzamide ( 3AB ) . 3AB inhibits the synthesis of poly ( ADP - ribose ) by the enzyme adenosine diphosphate ribosyl transferase ( P09874 ) , which requires NAD as a substrate . 3AB also prevents chromosomal repair , as measured in X - ray dose - fractionation studies . Because 3AB might interfere with metabolic reactions other than those mediated by P09874 , experiments were carried out to see if the adaptive response was also inhibited in nicotinamide - free medium , which prevents poly ( ADP - ribosyl ) ation by depleting cellular NAD . The experiments show that the incorporation of [ 3H ] dThd has no effect on the induction of chromosomal aberrations by subsequent doses of X rays if the cells are cultured in nicotinamide - free medium . DB02701 deficiency mimics the effects of 3AB on both the adaptive response and chromosome repair . The results indicate that P09874 activity itself , and not other metabolic processes affected by inhibitors of this enzyme , plays an essential role in the adaptive response .","Endothelial sirtuin 1 deficiency perpetrates nephrosclerosis through downregulation of matrix metalloproteinase - 14 : relevance to fibrosis of vascular senescence . Sirtuin 1 ( Q96EB6 ) depletion in vascular endothelial cells mediates endothelial dysfunction and premature senescence in diverse cardiovascular and renal diseases . However , the molecular mechanisms underlying these pathologic effects remain unclear . Here , we examined the phenotype of a mouse model of vascular senescence created by genetically ablating exon 4 of Sirt1 in endothelial cells ( Sirt1 ( endo -/-) ) . Under basal conditions , Sirt1 ( endo -/-) mice showed impaired endothelium - dependent vasorelaxation and angiogenesis , and fibrosis occurred spontaneously at low levels at an early age . In contrast , induction of nephrotoxic stress ( acute and chronic folic acid - induced nephropathy ) in Sirt1 ( endo -/-) mice resulted in robust acute renal functional deterioration followed by an exaggerated fibrotic response compared with control animals . Additional studies identified matrix metalloproteinase - 14 ( P50281 ) as a target of Q96EB6 . In the kidneys of Sirt1 ( endo -/-) mice , impaired angiogenesis , reduced matrilytic activity , and retention of the profibrotic cleavage substrates tissue transglutaminase and endoglin accompanied P50281 suppression . Furthermore , restoration of P50281 expression in Q96EB6 - depeleted mice improved angiogenic and matrilytic functions of the endothelium , prevented renal dysfunction , and attenuated nephrosclerosis . Our findings establish a novel mechanistic molecular link between endothelial Q96EB6 depletion , downregulation of P50281 , and the development of nephrosclerosis .","Presence of functionally active protease - activated receptors 1 and 2 in myenteric glia . Protease - activated receptors ( PARs ) belong to the family of membrane receptors coupled to G - proteins ; their presence is reported in a wide variety of cells . The object of this study was to demonstrate the presence of P25116 and P55085 in myenteric glia of the guinea pig , and to elucidate the cellular mechanisms that are triggered upon receptor activation . Thrombin and P25116 agonist peptide ( P09874 ) activate P25116 with a maximum mean +/- SEM change in intracellular calcium concentration with respect to basal level ( Delta [ Ca2 +] i ) of 183 +/- 18 nm and 169 +/- 6 nm , respectively . Trypsin and P55085 agonist peptide ( Q9UGN5 ) activate P55085 with a maximum Delta [ Ca2 +] i of 364 +/- 28 nm and 239 +/- 19 nm , respectively . Inhibition of phospholipase C by U73312 ( 1 microm ) decreased the Delta [ Ca2 +] i due to P25116 activation from 167 +/- 10 nm to 87 +/- 6 nm . The P55085 - mediated Delta [ Ca2 +] i decreased from 193 +/- 10 nm to 124 +/- 8 nm when phospholipase C activity was inhibited . Blockade of sphingosine kinase with dimethylsphingosine ( 1 microm ) decreased the Delta [ Ca2 +] i due to P55085 activation from 149 +/- 19 nm to 67 +/- 1 nm , but did not influence the P25116 - mediated Delta [ Ca2 +] i . P25116 and P55085 were localized in myenteric glia by immunolabeling . Our results indicate that P25116 and P55085 are present in myenteric glia of the guinea pig , and their activation leads to increases in intracellular calcium via different signal transduction mechanisms that involve activation of phospholipase C and sphingosine kinase .","MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in P01308 - 1 pancreatic beta - cells . DB02701 has been reported to induce differentiation of precursor / stem cells toward a beta - cell phenotype , increase islet regeneration , and enhance insulin biosynthesis . Exposure of P01308 - 1 beta - cells to elevated glucose leads to reduced insulin gene transcription , and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 ( P52945 ) and mammalian homologue of avian MafA / l - Maf ( MafA ) . DB02701 and other low - potency poly ( ADP - ribose ) polymerase ( PARP ) inhibitors were thus tested for their ability to restore insulin promoter activity . The low - potency PARP inhibitors nicotinamide , 3 - aminobenzamide , or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose . In contrast , the potent P09874 inhibitors PJ34 or DB04335 - 1001 had no effect on promoter activity . Antioxidants , including DB06151 , lipoic acid , or quercetin , only minimally induced the insulin promoter . Site - directed mutations of the human insulin promoter mapped the low - potency PARP inhibitor response to the C1 element , which serves as a MafA binding site . P01308 - 1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels . Low - potency PARP inhibitors restored MafA mRNA and protein levels , but they had no affect on P52945 protein levels or binding activity . Increased MafA expression by low - potency PARP inhibitors was independent of increased MafA protein or mRNA stability . These data suggest that low - potency PARP inhibitors increase insulin biosynthesis , in part , through a mechanism involving increased MafA gene transcription .","P43490 regulates cell survival through autophagy in cardiomyocytes . DB02701 adenine dinucleotide ( NAD (+) ) acts as a transfer molecule for electrons , thereby acting as a key cofactor for energy production . NAD (+) also serves as a substrate for cellular enzymes , including poly ( ADPribose ) polymerase ( PARP ) - 1 and Sirt1 . Activation of P09874 by DNA damage depletes the cellular pool of NAD (+) , leading to necrotic cell death . NAD (+) in the nucleus enhances the activity of Sirt1 , thereby modulating transcription . NAD (+) is either synthesized de novo from amino acids , namely tryptophan and aspartic acid , or resynthesized from NAD (+) metabolites , such as nicotinamide ( NAM ) , through the salvage pathway . NAM phosphoribosyltransferase ( P43490 ) is a rate - limiting enzyme in the NAD (+) salvage pathway . We have recently demonstrated that P43490 is an important regulator of NAD (+) and autophagy in cardiomyocytes . Here we discuss the role of P43490 in regulating autophagy and potential mechanisms by which NAD (+) regulates autophagy in the heart .","Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .","Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK57___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .","Accumulation of poly ( ADP - ribose ) polymerase inhibitors in children with chronic renal failure . DB02701 , N - methyl - 2 - pyridone - 5 - carboxamide ( Met2PY ) and N - methyl - 4 - pyridone - 3 - carboxamide ( Met4PY ) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide ( NAD ) that can potentially inhibit poly ( ADP - ribose ) polymerase 1 ( P09874 ; DNA repair enzyme ) . Our research was aimed at establishing whether chronic renal failure ( CRF ) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit P09874 activity . DB02701 , Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children . The effect of these NAD metabolites on P09874 activity was studied in vitro . We found that plasma concentration of all NAD metabolites ( nicotinamide , Met2PY , Met4PY ) in children with CRF could reach the concentration of 2 , 30 and 10 microM as compared to 0 . 2 , 1 and 0 . 5 microM , respectively , in healthy children . The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF . We found that Met2PY , Met4PY and nicotinamide inhibited in vitro P09874 activity with IC50 values of 2 . 1 , 0 . 18 and 0 . 12 mM , respectively . Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of P09874 activity . NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults .","DB02701 uncouples hormone - dependent chromatin remodeling from transcription complex assembly . Sirtuins , homologs of the yeast SIR2 family , are protein deacetylases that require nicotinamide adenosine dinucleotide as cofactor . To determine whether the sirtuin family of deacetylases is involved in progesterone receptor ( PR ) - mediated transcription , the effect of sirtuin inhibitor , nicotinamide ( NAM ) , was monitored in T47D breast cancer cells . NAM suppressed hormone - dependent activation of PR - regulated genes in a dose - dependent manner . Surprisingly , NAM - mediated inhibition of PR - mediated transcription occurs independently of Q96EB6 and P09874 . Chromatin immunoprecipitation experiments did not show that PR binding nor that of the coactivators CBP and SRC3 was compromised . Consistent with the recruitment of the P51532 chromatin remodeling complex , promoter chromatin remodeling still occurs despite NAM inhibition of PR transactivation . Rather , we show that this inhibition of transcription is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter . These results show that NAM uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital NAM - regulated steps required for promoter chromatin remodeling and basal transcription complex communication .","Genome - wide methylation profiling of schizophrenia . Schizophrenia is one of the major psychiatric disorders . It is a disorder of complex inheritance , involving both heritable and environmental factors . DNA methylation is an inheritable epigenetic modification that stably alters gene expression . We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution . We have performed 26 high - resolution genome - wide methylation array analyses to determine the methylation status of 27 , 627 CpG islands and compared the data between patients and healthy controls . Methylation profiles of DNAs were analyzed in six pools : 220 schizophrenia patients ; 220 age - matched healthy controls ; 110 female schizophrenia patients ; 110 age - matched healthy females ; 110 male schizophrenia patients ; 110 age - matched healthy males . We also investigated the methylation status of 20 individual patient DNA samples ( eight females and 12 males . We found significant differences in the methylation profile between schizophrenia and control DNA pools . We found new candidate genes that principally participate in apoptosis , synaptic transmission and nervous system development ( P47869 , Q9HAP6 , P42574 ) . Methylation profiles differed between the genders . In females , the most important genes participate in apoptosis and synaptic transmission ( P98170 , O14764 , P01178 , P08729 ) , whereas in the males , the implicated genes in the molecular pathology of the disease were Q8IY37 , P36507 , Q9H6D8 and O14908 . Data from the individual methylation analyses confirmed , the gender - specific pools results . Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients . The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis .","___MASK51___ attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells . BACKGROUND & AIMS : Activation of hepatic stellate cells ( P19526 ) and transdifferentiation to myofibroblasts following liver injury is the main culprit for hepatic fibrosis . Myofibroblasts show increased proliferation , migration , contraction , and production of extracellular matrix ( Q13201 ) . In vitro , P04035 inhibitors ( statins ) inhibit proliferation and induce apoptosis of myofibroblastic P19526 . To investigate the antifibrotic effects of atorvastatin in vivo we used bile duct ligated rats ( BDL ) . METHODS : BDL rats were treated with atorvastatin ( 15 mg / kg / d ) immediately after ligation ( prophylactically ) or in on - going fibrosis ( therapeutically ) . Fibrosis was assessed by hydroxyproline content and Sirius - red staining . The activation of P19526 was investigated by analysis of alphaSMA expression . mRNA levels of cytokines and procollagen were analyzed by RT - PCR , and P08253 activity by zymography . Proliferation was assessed by expression of cathepsins ( B and D ) , proliferating cell nuclear antigen ( P12004 ) , and Ki67 - staining . Apoptosis was characterized by caspase - 3 activity , cleavage of P09874 , and TUNEL assay . Hepatic inflammation was investigated by serum parameters and liver histology . RESULTS : Prophylactic and early therapy with atorvastatin significantly attenuated fibrosis and P19526 activation . Later therapy lacked significant effects on fibrosis but reduced profibrotic cytokine expression and led to a more quiescent state of P19526 with less proliferation and apoptosis , while hepatic inflammation did not change . CONCLUSIONS : This study shows that very early atorvastatin treatment inhibits P19526 activation and fibrosis in the BDL model in vivo , while late treatment reduces P19526 turnover and activity . Our findings underline that long - term studies in humans are warranted .","Poly ( ADP - ribose ) metabolism in X - irradiated Chinese hamster cells : its relation to repair of potentially lethal damage . DB02701 - adenine dinucleotide ( NAD + ) is the substrate used by cells in poly ( ADP - ribose ) synthesis . X - irradiation of log - phase Chinese hamster cells caused a rapid decrease in NAD + levels which was linearly dependent on radiation dose . The activity of ADP - ribosyl transferase ( P09874 ) also increased linearly with radiation dose . The decrease of NAD + was slower , and the increase in P09874 activity was less pronounced , in a radiation sensitive line , V79 - AL162 / S - 10 . An inhibitor of P09874 , m - aminobenzamide , largely prevented the depletion of cellular NAD + and reduced the rate at which P09874 activity disappeared during post - irradiation incubation . Post - irradiation treatment with hypertonic buffer or with medium containing D2O -- which inhibit repair of radiation - induced potentially lethal damage -- enhanced the depletion of NAD + and prevented the reduction in P09874 activity following irradiation . The characteristics of the effects of treatment with hypertonic buffer on NAD + metabolism were qualitatively similar to the effects that such treatment has on radiation - induced cell killing . These results suggest that poly ( ADP - ribose ) synthesis after irradiation plays a role in the repair of potentially lethal damage .","DBC1 / Q8N163 and Q8IX12 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor . Deleted in breast cancer 1 ( DBC1 , Q8N163 , Q8N163 ) is a large , predominantly nuclear , multidomain protein that modulates gene expression by inhibiting several epigenetic modifiers , including the deacetylases Q96EB6 and O15379 , and the methyltransferase O43463 . DBC1 shares many highly conserved protein domains with its paralog cell cycle and apoptosis regulator 1 ( Q8IX12 , CARP - 1 ) . In this study , we examined the full - length sequential and structural properties of DBC1 and Q8IX12 from multiple species and correlated these properties with evolution . Our data shows that the conserved domains shared between DBC1 and Q8IX12 have similar domain structures , as well as similar patterns of predicted disorder in less - conserved intrinsically disordered regions . Our analysis indicates similarities between DBC1 , Q8IX12 , and the nematode protein lateral signaling target 3 ( G3V0H7 ) , suggesting that DBC1 and Q8IX12 may have evolved from G3V0H7 . Our data also suggests that DBC1 emerged later in evolution than Q8IX12 . DBC1 contains regions that show less conservation across species as compared to the same regions in Q8IX12 , suggesting a continuously evolving scenario for DBC1 . Overall , this study provides insight into the structure and evolution of DBC1 and Q8IX12 , which may impact future studies on the biological functions of these proteins .","Radiosensitizing effects of nicotinamide on a C3H mouse mammary adenocarcinoma . A study on per os drug administration . DB02701 is an inhibitor of adenosine diphosphate ribosyl transferase ( P09874 ) which is involved in the mechanism of DNA repair after high doses of ionizing radiation . C3H mice with transplanted mammary adenocarcinomas were treated with low doses of nicotinamide , 10 mg / kg , 5 days a week , and in combination with ionizing radiation , 30 Gy , using different drug dose schedules . Mice given nicotinamide in combination with irradiation took a longer time to reach a tumor volume of 1 , 000 mm3 and a higher complete response rate ( i . e . defined as total disappearance of the tumor for at least 7 days ) than those given radiation alone . This was true whether nicotinamide was given daily from one week before tumor transplantation until the animal was killed or from transplantation day until day of irradiation . In addition , nicotinamide given per os at a dose between the recommended maximum daily allowance for human subjects ( 20 mg / 70 kg ) , and the therapeutic allowance ( 1 g - 12 g daily ) 5 days a week for 9 weeks , showed a radiosensitizing effect without any histologically detectable damage to the normal tissues of the mouse , including bone marrow , intestine and the liver .","___MASK49___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK49___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK49___ is a promising pharmacological tool in the treatment of renal edema .","DB02701 pre - treatment ameliorates NAD ( H ) hyperoxidation and improves neuronal function after severe hypoxia . Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling ( between NAD (+) and DB00157 ) immediately after reoxygenation , resulting in DB00157 hyperoxidation . We test whether the addition of nicotinamide ( to enhance NAD (+) levels ) or P09874 inhibition ( to prevent consumption of NAD (+) ) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices . After severe , prolonged hypoxia ( maintained for 3min after spreading depression ) there was hyperoxidation of DB00157 following reoxygenation , an increased soluble NAD (+)/ DB00157 ratio , loss of neuronal field excitatory post - synaptic potential ( fEPSP ) and decreased DB00171 content . DB02701 incubation ( 5mM ) 2h prior to hypoxia significantly increased total NAD ( H ) content , improved neuronal recovery , enhanced DB00171 content , and prevented DB00157 hyperoxidation . The nicotinamide - induced increase in total soluble NAD ( H ) was more significant in the cytosolic compartment than within mitochondria . Prolonged incubation with PJ - 34 ( > 1h ) led to enhanced baseline DB00157 fluorescence prior to hypoxia , as well as improved neuronal recovery , DB00157 hyperoxidation and DB00171 content on recovery from severe hypoxia and reoxygenation . In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ - 34 prior to hypoxia improved recovery of neuronal function , enhanced DB00157 reduction and DB00171 content , but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation .","DB02701 treatment reduces the levels of histone H3K4 trimethylation in the promoter of the mper1 circadian clock gene and blocks the ability of dexamethasone to induce the acute response . Circadian rhythms , which measure time on a scale of 24h , are generated by one of the most ubiquitous endogenous mechanisms , the circadian clock . Q96EB6 , a class III histone deacetylase , and P09874 , a poly ( ADP - ribose ) polymerase , are two NAD (+)- dependent enzymes that have been shown to be involved in the regulation of the clock . Here we present evidence that the metabolite nicotinamide , an inhibitor of Q96EB6 , P09874 and mono ( ADP - ribosyl ) transferases , blocks the ability of dexamethasone to induce the acute response of the circadian clock gene , mper1 , while it concomitantly reduces the levels of histone H3 trimethylation of lysine 4 ( H3K4me3 ) in the mper1 promoter . Moreover , application of alternative inhibitors of Q96EB6 and ADP - ribosylation did not lead to similar results . Therefore , inhibition of these enzymes does not seem to be the mode by which NAM exerts these effects . These results suggest the presence of a novel mechanism , not previously documented , by which NAM can alter gene expression levels via changes in the histone H3K4 trimethylation state .","Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .","DB02701 rescues human embryonic stem cell - derived neuroectoderm from parthanatic cell death . Abundant cell death is observed when human embryonic stem cells ( hESCs ) undergo neuralization , a critical first step for future cell - based therapies addressing neurodegeneration . Using hESC neuralization as an in vitro model of human development , we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death . We found that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) / apoptosis - inducing factor ( O95831 ) - mediated cell death ( parthanatos ) is a dominant mechanism responsible for cell loss during hESC neuralization . The demise of neural progenitor cells , at least in part , is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions . Under such conditions , P09874 overactivation triggered cell death through the mitochondrial - nuclear translocation of O95831 . Blocking P09874 activity with small hairpin RNA interference or nicotinamide dramatically enhanced hESC neuralization , providing optimal survival of the developing neuroepithelium . Because nicotinamide is a physiological metabolite , our results raise the possibility that neural stem / progenitor cell survival in vivo requires a metabolic niche . We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine .","O60603 and poly ( ADP - ribose ) polymerase 1 promote central nervous system neuroinflammation in progressive EAE . Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing - remitting disease ( RRMS ) and is followed by a progressive phase ( SPMS ) . The progressive phase causes the greatest disability and has no effective therapy , but the processes that drive SPMS are mostly unknown . Here we found higher serum concentrations of 15alpha - hydroxicholestene ( 15 - HC ) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis ( EAE ) but not in patients with RRMS . In mice , 15 - HC activated microglia , macrophages and astrocytes through a pathway involving O60603 ( O60603 ) and poly ( ADP - ribose ) polymerase 1 ( P09874 ) . P09874 activity was higher in monocytes of patients with SPMS , and P09874 inhibition suppressed the progression of EAE . Thus , the O60603 - P09874 pathway is a potential new therapeutic target in SPMS .","DB02701 sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors enhance the effect of DNA alkylating agents on BRCA1 ‑ and P51587 - deficient cell lines . The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide ( NAM ) on breast cancer cells with different P38398 expression or function , such as BRCA1 ‑ deficient MDA - MB - 436 cells , low expression P38398 MCF - 7 cells , and the P38398 wild ‑ type MDA - MB - 231 cells , to demonstrate its effects as a chemo ‑ or radiosensitizing agent . PARP activity was analyzed in MDA - MB - 436 , MCF - 7 and MDA - MB - 231 breast cancer cells subjected or not to NAM . Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence . Crystal violet assays were used to test growth inhibition and the chemo ‑ and radiosensitization effects of NAM were investigated using clonogenic assays . Significant differences among data sets were determined using two - tailed Q9UNW9 and Bonferroni tests . We demonstrated that NAM reduces PARP activity in vitro , and in cells subjected or not to DNA damage , it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA - MB - 436 and MCF - 7 cells . Downregulation of P09874 with siRNA led to modest growth inhibition , which was further increased by cisplatin . DB02701 also induced radiosensitization in MDA - MB - 436 and MDA - MB - 231 cells . In conclusion , NAM may be used as a chemo ‑ or radiosensitizing agent regardless of the P38398 status in breast cancer .","DB00853 : mechanisms of action , repair and resistance . Glioblastoma multiforme is the most common aggressive adult primary tumour of the central nervous system . Treatment includes surgery , radiotherapy and adjuvant temozolomide ( DB00853 ) chemotherapy . DB00853 is an alkylating agent prodrug , delivering a methyl group to purine bases of DNA ( O6 - guanine ; N7 - guanine and N3 - adenine ) . The primary cytotoxic lesion , O6 - methylguanine ( O6 - MeG ) can be removed by methylguanine methyltransferase ( P16455 ; direct repair ) in tumours expressing this protein , or tolerated in mismatch repair - deficient ( P22897 - ) tumours . Thus P16455 or P22897 deficiency confers resistance to DB00853 . Inherent - and acquired resistance to DB00853 present major obstacles to successful treatment . Strategies devised to thwart resistance and enhance response to DB00853 , including inhibition of DNA repair mechanisms which contribute to DB00853 resistance , are under clinical evaluation . Depletion of P16455 prior to alkylating agent chemotherapy prevents O6 - MeG repair ; thus , P16455 pseudosubstrates O6 - benzylguanine and lomeguatrib are able to sensitise tumours to DB00853 . Disruption of base excision repair ( BER ) results in persistence of potentially lethal N7 - and N3 - purine lesions contributing significantly to DB00853 cytoxicity particularly when O6 - MeG adducts are repaired or tolerated . Several small molecule inhibitors of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , a critical BER protein are yielding promising results clinically , both in combination with DB00853 and as single agent chemotherapy in patients whose tumours possess homologous recombination DNA repair defects . Another validated , but as yet preclinical protein target , mandatory to BER is abasic ( AP ) endonuclease - 1 ( P27695 ) ; in preclinical tests , P27695 inhibition potentiates DB00853 activity . An alternative strategy is synthesis of a molecule , evoking an irrepairable cytotoxic O6 - G lesion . Preliminary efforts to achieve this goal are described .","Regulation of rat haptoglobin gene expression is coordinated by the nuclear matrix . Using computer stress - induced duplex destabilization ( SIDD ) analysis and binding experiments , we identified a S / MAR element ( - 599 /- 200 bp ) ( Hp - S / MAR ) adjacent to the cis - element ( - 165 /- 56 bp ) in the rat haptoglobin gene . We examined its functional interactions with the lamins and lamin - associated proteins in the basal state and during acute - phase ( AP ) response - induced increased transcription . Colocalization , electrophoretic mobility shift assay ( EMSA ) , and re - electrophoresis of nucleoprotein complexes , South - Western and Western blot analysis and coimmunoprecipitation experiments revealed that the lamins , P09874 , P17676 , and Hp - S / MAR assembled higher order complexes through direct lamin - Hp - S / MAR and probably P09874 - Hp - S / MAR interactions although P17676 did not bind to the Hp - S / MAR but established direct interaction with P09874 . The transition from constitutive to increased haptoglobin gene transcription during the AP response was associated with quantitative and qualitative changes in Hp - S / MAR - protein interactions , respectively , observed as increased association of the lamin ( s ) with the Hp - S / MAR and as the appearance of a 90 kDa Hp - S / MAR - binding protein . Also , during the AP response the contact between P17676 and P09874 established in the basal state was lost . DNA chromatography with the haptoglobin cis - element and Western blot analysis suggests that P09874 was a coactivator during constitutive and elevated transcription . The results show that the lamin components of the nuclear matrix form a network of functional , dynamic protein - protein and protein - Hp - S / MAR associations with multiple partners , and underline the involvement of P09874 in the regulation of haptoglobin gene transcription . We concluded that the interplay of these interactions fine tunes haptoglobin gene expression to meet the changing requirements of liver cells .","A nuclear poly ( ADP - ribose )- dependent signalosome confers DNA damage - induced O15111 activation . Upon genotoxic stresses , cells activate IkappaB kinases ( IKKs ) and the transcription factor NF - kappaB to modulate apoptotic responses . The P63165 ligase Q8N2W9 and the kinase ataxia talengiectasia mutated ( Q13315 ) have been implicated to SUMOylate and phosphorylate nuclear IKKgamma ( Q9Y6K9 ) in a consecutive mode of action , which in turn results in activation of cytoplasmic IKK holocomplexes . However , the nuclear signals and scaffold structures that initiate IKKgamma recruitment and activation are unknown . Here , we show that poly ( ADP - ribose )- polymerase - 1 ( P09874 ) is the DNA proximal regulator , which senses DNA strand breaks and , through poly ( ADP - ribose ) ( PAR ) synthesis , assembles IKKgamma , Q8N2W9 , and Q13315 in a dynamic manner . Signalosome formation involves direct protein - protein interactions and binding to ADP - ribose polymers through PAR binding motifs ( PARBM ) . Activated P09874 and a PARBM in Q8N2W9 are required to trigger IKKgamma SUMOylation , which in turn permits IKK and NF - kappaB activation , as well as NF - kappaB - regulated resistance to apoptosis .","Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .","Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects . Neural tube defects ( NTDs ) are a common cause of disability or death of new - borns , but the aetiology and genetic background of this disease are still poorly understood . Therefore , it was decided to determine the conditions for the identification of several polymorphisms and to perform a preliminary study on Polish NTD patients and their parents . According to the results of this study , the genetic predisposition to NTD can be correlated with the 677TT genotype in the P42898 gene , 677CT / 1298AC haplotype ( the P42898 gene ) , 2756G allele in the Q99707 gene , 66AG variant and minisatellite sequence with 5 or 10 repeats in intron 6 of the Q9UBK8 gene . The 530GG and TIVS7 - 2 / TIVS7 - 2 genotypes in the T gene could also be considered as a risk factor for NTD . The analysis also revealed no correlation between neurulation disturbances and A4956G and A1186G mutations in the P38398 gene and the 844ins68bp in P35520 gene . Although a correlation was found of some molecular markers with NTD , an additional examination should be conducted on more numerous groups to obtain statistically significant results .","Perinatal asphyxia : CNS development and deficits with delayed onset . Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted . The primary insult relates to the duration of the period lacking oxygenation , leading to death if not re - established . Re - oxygenation leads to a secondary insult , related to a cascade of biochemical events required for restoring proper function . Perinatal asphyxia interferes with neonatal development , resulting in long - term deficits associated to mental and neurological diseases with delayed clinical onset , by mechanisms not yet clarified . In the experimental scenario , the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy . Asphyxia induces transcriptional activation of pro - inflammatory factors , in tandem with P09874 overactivation , and pharmacologically induced P09874 inhibition also down - regulates the expression of proinflammatory cytokines . DB02701 has been proposed as a suitable P09874 inhibitor . Its effect has been studied in an experimental model of global hypoxia in rats . In that model , the insult is induced by immersing rat fetus into a water bath for various periods of time . Following asphyxia , the pups are delivered , treated , and nursed by surrogate dams , pending further experiments . DB02701 rapidly distributes into the brain following systemic administration , reaching steady state concentrations sufficient to inhibit P09874 activity for several hours , preventing several of the long - term consequences of perinatal asphyxia , supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles .","Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .","Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK63___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK63___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .","Effects of hyperthermia and nicotinamide on DNA repair synthesis , ADP - ribosyl transferase activity , NAD + and DB00171 pools , and cytotoxicity in gamma - irradiated human mononuclear leukocytes . Effects of hyperthermia and nicotinamide on ADP - ribosyl transferase activity ( P09874 ) , unscheduled DNA synthesis ( UDS ) , NAD +- and DB00171 - pools and cytotoxicity were investigated in gamma - irradiated human mononuclear leukocytes . A significant decrease in radiation - induced UDS after heat treatment for 45 min was found . DB02701 increased the UDS levels in irradiated cells , but no effect of hyperthermia on these increased UDS values was observed . In the presence of 2 mM nicotinamide radiation - induced P09874 activity was reduced to about 50 per cent . However , hyperthermia for 45 min was found to have no effect on the enzyme activity for temperatures below 46 degrees C . DB02701 increased the NAD + pool in unirradiated cells . Damaging the cells with gamma - radiation leads to a severe depletion of the NAD + pool . The NAD + pool is restored , however , if the cells repair for 5 h at 37 degrees C . When radiation - damaged cells were treated with hyperthermia , exogenously supplied nicotinamide could not be converted to NAD + in sufficient amounts to prevent NAD + depletion . These data indicate that the radiosensitizing effect of heat and nicotinamide could both be explained by effects on the enzyme P09874 , i . e . nicotinamide by directly blocking the enzyme and hyperthermia by limiting the co - substrate ( NAD + ) .","[ Treatment of type 1 diabetes mellitus revealed below 7 years of age in the Diabetes Center of Silesia , Poland ] . INTRODUCTION : Frequency of type 1 diabetes mellitus diagnosis in young children increases . Within this group , such factors as limited cooperation , little acceptance of multiple injections and other typical patterns of behavior can strongly influence the insulin management outcome . AIM OF THE STUDY : The objective of the study was to provide information regarding metabolic control in young diabetes patients . MATERIAL AND METHODS : Charts of 58 children with T1DM , all subjects under control of our Department , that were aged at onset ( 1998 - 2003 ) below 7 years ( mean 4 . 05 +/- 1 . 6 ) were studied retrospectively . HbA1c , total , bolus and basal daily insulin requirement ( P30518 ) , weight , height , severe hypoglycaemia and diabetic ketoacidosis ( DKA ) were analyzed till April 2006 in 2 - year intervals . P01308 therapy model was also taken into consideration . RESULTS : Mean HbA1c was 7 . 2 +/- 1 . 2 % for all children for the whole studied period and did not alter significantly between analyzed intervals . Most common treatment model at diabetes onset was the therapy with premixed insulin ( Mix ) ( 67 % ) and after 4 and 6 years - continuous subcutaneous insulin infusion ( CSII ) ( 50 % and 75 % respectively ) . A tendency for a better metabolic control was observed at multiple daily injections and CSII than at Mix . Change of the weight or height percentile channel was not revealed . Bolus and basal P30518 increased in the first observation interval . Afterwards they stabilized respectively at 0 . 35 - 0 . 42 U / kg / 24 h and 0 . 35 - 0 . 39 U / kg / 24 h . Severe hypoglycaemia occurred 6 . 72 / 100 patient - years . CONCLUSION : P01308 therapy aimed at maintaining long - term good metabolic control is possible to achieve and is safe in young diabetic children .","P01308 resistance and angiotensin converting enzyme polymorphism in Japanese hypertensive subjects . P00797 - angiotensin system activity has been shown to affect insulin sensitivity . However , the relationship between I / D polymorphism and insulin resistance is controversial . Therefore , we examined the relationship between the P12821 genotype and insulin sensitivity in 51 Japanese hypertensive patients using the glucose clamp technique . The P12821 genotype distribution in the hypertensive subjects was : 7 subjects with DD , 20 subjects with ID , and 24 subjects with II . P01308 sensitivity in terms of the glucose disposal rate was not significantly different among the three P12821 genotypes , although there was a tendency for insulin sensitivity to decrease in the order of II , ID and DD , DD being the lowest . These findings are contrary to previous reports that insulin sensitivity was increased in normotensive subjects with the DD genotype who were Caucasian or African - American . There might be a difference due to race and whether the subjects are hypertensive or obese . We concluded that insulin sensitivity was not different among the P12821 genotypes in the Japanese hypertensive subjects , supporting a previous report on the Chinese population . To date , insulin sensitivity has not been found to differ with P12821 genotypes in the oriental population .","Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .","Plasticity of the central nervous system ( CNS ) following perinatal asphyxia : does nicotinamide provide neuroprotection ? We have investigated the idea that nicotinamide , a non - selective inhibitor of the sentinel enzyme Poly ( ADP - ribose ) polymerase - I ( P09874 ) , provides neuroprotection against the long - term neurological changes induced by perinatal asphyxia . Perinatal asphyxia was induced in vivo by immersing foetuses - containing uterine horns removed from ready - to - deliver rats into a water bath for 20 min . Sibling caesarean - delivered pups were used as controls . The effect of perinatal asphyxia on neurocircuitry development was studied in vitro with organotypic cultures from substantia nigra , neostriatum and neocortex , platted on a coverslip 3 days after birth . After approximately one month in vitro ( DIV 25 ) , the cultures were treated for immunocytochemistry to characterise neuronal phenotype with markers against the N - methyl - D - aspartate receptor subunit 1 ( Q9UHB4 ) , the dopamine pacemaker enzyme tyrosine hydroxylase ( TH ) , and nitric oxide synthase ( NOS ) , the enzyme regulating the bioavailability of NO . DB02701 ( 0 . 8 mmol / kg , i . p . ) or saline was administered to asphyctic and caesarean - delivered pups 24 , 48 and 72 h after birth . It was found that nicotinamide treatment prevented the effect of perinatal asphyxia on several neuronal parameters , including TH - and NOS - positive neurite atrophy and NOS - positive neuronal loss ; supporting the idea that nicotinamide constitutes a therapeutic alternative for the effects produced by sustained energy - failure conditions , as occurring during perinatal asphyxia .","DB02701 : a potential addition to the anti - psoriatic weaponry . Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern . Increased expression of adhesion molecules , prominent neutrophil accumulation , and increased production of nitric oxide are characteristics of this disorder . Moreover , histamine and proteases are supposed to participate in the pathogenesis of psoriasis . DB02701 is an inhibitor of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) that , through enhancement of nuclear kappa B - mediated transcription , plays a pivotal role in the expression of inflammatory cytokines , chemokines , adhesion molecules , and inflammatory mediators . Through interaction with P28907 and inhibition of IL - 1 , IL - 12 , and P01375 production , nicotinamide produces a mild TH2 bias . DB02701 is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release . It inhibits nitric oxide synthase mRNA induction and suppresses antigen - induced lymphocyte transformation . DB02701 increases the biosynthesis of ceramides , which upon degradation produce sphingosine . DB03203 inhibits protein kinase C ( PKC ) and decreases basal cell proliferation dependent on PKC . Taken together , it can be reasoned that nicotinamide could be a useful addition to anti - psoriatic armamentarium . The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen - induced arthritis . DB02701 decreased the methotrexate - induced hepatotoxicity . The above combinations may prove to have a powerful anti - psoriatic effect as well . As PARP inhibitors could exert anti - retroviral effect , nicotinamide could also be of special value in the treatment of HIV - infected psoriatics .","Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .","Protective effect of nicotinamide against poly ( ADP - ribose ) polymerase - 1 - mediated astrocyte death depends on its transporter - mediated uptake . AIM : Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a DNA repair enzyme , and its excessive activation , following ischemia , trauma , etc . , depletes cellular nicotinamide adenine dinucleotide ( NAD (+) ) as a substrate and eventually leads to brain cell death . DB02701 , an NAD (+) precursor and a P09874 inhibitor , is known to prevent P09874 - triggered cell death , but there is no available information on the mechanisms involved in its transport . Here we clarified the transport characteristics of nicotinamide in primary cultured mouse astrocytes . MAIN METHODS : Uptake characteristics of [( 14 ) C ] nicotinamide were assessed by a conventional method with primary cultured mouse astrocytes . Cell viability and P09874 activity were determined with intracellular LDH activity and immunocytochemical detection of PAR accumulation , respectively . KEY FINDINGS : P09874 activation was induced by treatment of astrocytes with N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) , an alkylating agent . MNNG - triggered astrocyte death and PAR accumulation were completely inhibited by treatment with nicotinamide as with DPQ ( 3 , 4 - dihydro - 5 -( 4 -( 1 - piperidinyl ) butoxy )- 1 ( 2H )- isoquinolinone ) , a second generation PARP inhibitor . The uptake of [( 14 ) C ] nicotinamide was time - , temperature - , concentration - and pH - dependent , and was inhibited and stimulated by co - and pre - treatment with N - methylnicotinamide , a representative substrate of an organic cation transport system , respectively . Co - treatment of astrocytes with nicotinamide and N - methylnicotinamide resulted in a decrease in PAR accumulation and absolute prevention of cell death . SIGNIFICANCE : These findings suggest that nicotinamide has a protective effect against P09874 - induced astrocyte death and that its transporter - mediated uptake , which is extracellular pH - sensitive and common to N - methylnicotinamide , is critical for prevention of P09874 - triggered cell death .","Establishment of an immortalized P09874 -/- murine endothelial cell line : a new tool to study P09874 mediated endothelial cell dysfunction . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays a critical role in endothelial cell dysfunction associated with various pathophysiological conditions . To elucidate P09874 pathways involved in endothelial cell dysfunction , it is essential to establish \" in vitro \" experimental models using isolated endothelial cells . So far , two approaches have been used : primary endothelial cells from P09874 -/- mice which have a limited life - span , being a major handicap if large quantities of cells are required ; and pharmacological inhibition of PARP in P09874 +/+ endothelial cell lines , which is not specific for P09874 and would have biological effects different that genetic inhibition . To overcome these limitations , we have established an immortalized P09874 -/- endothelial cell line ( HYKO6 ) by transfection of primary cells with a plasmid containing the SV40 genome and selected on the basis of morphological and phenotypical features . The HYKO6 cell line exhibited endothelial characteristics , such as constitutive expression of CD105 , CD31 , P13598 , P19320 , and P04275 and formation of capillary - like structures ( CLS ) on Matrigel surface . However , expression of P05362 antigen is lost in the HYKO6 cells . After P01375 treatment , HYKO6 cells exhibited increased expression of P16581 and P19320 . Likewise , NF - kappaB - dependent transcriptional activation was increased in the HYKO6 cell line in response to P01375 at a level similar to that found for primary P09874 -/- cells . This cell line should provide , for the first time , a valuable tool to study P09874 pathways in endothelial cell dysfunction .","P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .","p53 - , Q96EB6 - , and P09874 - independent downregulation of p21WAF1 expression in nicotinamide - treated cells . DB02701 at mM concentration is a potent inhibitor of certain key molecules involved in cell survival , such as Q96EB6 and P09874 , and affects cell survival in various conditions in vivo and in vitro . However , the effect of an acute treatment of nicotinamide on gene expression has rarely been closely examined . In our study , the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 - negative or Q96EB6 - knockdown cells indicating gene regulation not mediated by p53 or Q96EB6 . Meanwhile , in the nicotinamide - treated cells , Sp1 activity and protein level was substantially reduced due to increased proteasome - mediated degradation . Our results indicate that nicotinamide treatment attenuates p21WAF1 expression through Sp1 downregulation , and suggest a possible involvement of nicotinamide metabolism in cellular gene expression .","Changes in the response of the Q9HBH0 - 1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP - ribosyl transferase . The effect of inhibitors of nuclear ADP - ribosyl transferase ( P09874 ) on the cytotoxicity of melphalan ( DB01042 ) in the Q9HBH0 - 1 tumour in vivo was investigated . A large single dose of nicotinamide ( 1000 mg kg - 1 ) enhanced the tumour cell killing by DB01042 as measured by tumour cell survival . This enhancement was maximum when nicotinamide was administered within 1 h before injecting the DB01042 . When given at this time , the nicotinamide had a dose - modifying effect on all DB01042 doses tested , giving rise to a mean enhancement ratio ( ER ) of 2 . 2 . DB02701 did not appear to inhibit the recovery from DB01042 induced potentially lethal damage . DB01042 ( 6 mg kg - 1 ) produced a transient drop in mouse body temperature . This effect was both increased and prolonged by nicotinamide . In addition the inhibitor also delayed the clearance of DB01042 from the plasma of C3H mice , such that the half - life of the chemotherapeutic agent was extended from 41 min to 143 min . The effect of combining DB01042 with nicotinamide doses below 1000 mg kg - 1 was also investigated . The results showed that as the nicotinamide dose was decreased , the enhancement of the effects on body temperature , pharmacokinetics and white blood cell counts were reduced . However , a concomitant loss in the enhancement of tumour cell killing was also observed . Similar results were obtained using 3 - aminobenzamide , a more efficient inhibitor of P09874 .","Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK59___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .","Activation of the P47900 receptor induces apoptosis and inhibits proliferation of prostate cancer cells . G protein - coupled receptors , the largest cell surface receptor family , have emerged as critical players in cell death and survival . High gene expression level of the G ( q )- coupled P2Y ( 1 ) nucleotide receptor in PC - 3 prostate cancer cells was demonstrated using real - time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy . A selective P2Y ( 1 ) receptor agonist , the ADP analogue MRS2365 , concentration - dependently induced intracellular calcium mobilization ( EC ( 50 ) 5 . 28nM ) , which was diminished by P2Y ( 1 ) receptor - selective antagonist MRS2500 . P2Y ( 1 ) receptor activation by MRS2365 induced apoptosis in assays of P42574 , LDH release , and annexin - V staining . The pro - apoptotic effect of MRS2365 was blocked by MRS2500 , P2Y ( 1 ) siRNA , and an inhibitor of the Q96HU1 kinase pathway PD98059 . MRS2365 significantly inhibited the proliferation of PC - 3 cells , examined using a MTT assay . Thus , activation of the P2Y ( 1 ) receptor induced cell death and inhibited growth of human prostatic carcinoma PC - 3 cells . Activation of the P2Y ( 1 ) receptor should be a novel and promising therapeutic strategy for prostate cancer .","Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK80___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .","Poly ( ADP - ribose ) polymerase - 1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22 - 28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD + ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 overactivation may ensue , depleting cells of NAD + and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 expression and that administration of a P09874 inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty - four percent of control pups developed high - grade NEC ( grades 3 - 4 ) , whereas only 7 % of pups receiving nicotinamide developed high - grade NEC . DB02701 treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 overactivation in NEC may drive mucosal cell death in this disease and that P09874 may be a novel therapeutic target in NEC .","Further studies on the hypothesis of P09874 inhibition as a strategy for lessening the long - term effects produced by perinatal asphyxia : effects of nicotinamide and theophylline on P09874 activity in brain and peripheral tissue : nicotinamide and theophylline on P09874 activity . DB09140 interruption leads to death when re - oxygenation is not promptly re - established . Re - oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis . The effects observed long after perinatal asphyxia ( PA ) have been explained by over - expression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a therapeutic strategy . We studied the effects of nicotinamide and theophylline on P09874 activity assayed in brain and peripheral ( heart ) rat tissue 1 - 24 h after birth , as well as on changes in behaviour and monoamine neurotransmission in adult rats . PA was induced by immersing rat foetuses into a water bath for 0 or 21 min . After resuscitation , the pups were treated with nicotinamide ( 0 . 8 mmol / kg , i . p . ) , theophylline ( 0 . 14 mmol / kg , i . p . ) or saline ( 0 . 9 % NaCl ) and nurtured by surrogate dams , pending behavioural and microdialysis experiments , or euthanised after birth for assaying P09874 activity . To estimate the in vivo distribution of a single dose of nicotinamide or theophylline into brain and peripheral compartment , a series of animals were implanted with microdialysis probes , one into the brain and other subcutaneously , 1 h after birth , assaying the drugs with a HPLC - UV system . DB02701 , but not theophylline prevented the long - term effects induced by PA . Only nicotinamide produced a consistent decrease in P09874 activity in brain and heart , whether assayed in control or asphyxia - exposed pups . The present results support the idea that the long - term effects induced by PA imply P09874 over - activation .","Genetic polymorphisms associated with ___MASK1___ - induced neurotoxicity . BACKGROUND : Encephalopathy is a rare drug toxicity of fluorouracil therapy . Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes , thymidylate synthase and dihydropyrimidine dehydrogenase . METHODS : Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5 - fluorouracil - based chemotherapy presented with acute mental change and hyperammonemia . To evaluate the genetic background of the fluorouracil - associated hyperammonemic encephalopathy , analysis of the polymorphisms of the P04818 , Q12882 and P42898 genes was performed . RESULTS : The patients revealed to be P04818 suppressors showing homogenous deletion of 6 bp in the 3 '- UTR and 3RC / 3RC genotype in the promoter enhancer region ( TSER ) , respectively . CONCLUSION : Genetic polymorphisms of the P04818 gene would contribute to the 5 - fluorouracil - associated hyperammonemic encephalopathy . The prospective validation of the clinical implication of P04818 gene polymorphisms is warranted .","NAD + and nicotinamide : sex differences in cerebral ischemia . BACKGROUND : Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes . While caspase - dependent mechanisms predominate in the female brain , caspase - independent cell death induced by the activation of poly ( ADP - ribose ) polymerase ( PARP ) predominates in the male brain . P09874 gene deletion decreases infarction volume in the male brain , but paradoxically increases damage in P09874 knockout females . PURPOSE : This study examined stroke - induced changes in NAD + , a key energy molecule involved in P09874 activation in both sexes . METHODS : Mice were subjected to middle cerebral artery occlusion and NAD + levels were assessed . P42574 activity and nuclear translocation were assessed 6h after ischemia . In additional cohorts , DB02701 ( 500 mg / kg i . p . ) a precursor of NAD + or vehicle was administered and infarction volume was measured 24h after ischemia . RESULTS : Males have higher baseline NAD + levels than females . Significant stroke - induced NAD + depletion occurred in males and ovariectomized females but not in intact females . P09874 deletion prevented the stroke - induced loss in NAD + in males , but worsened NAD + loss in P09874 deficient females . Preventing NAD + loss with nicotinamide reduced infarct in wild - type males and P09874 knockout mice of both sexes , with no effect in WT females . P42574 activity was significantly increased in P09874 knockout females compared to males and wild - type females , this was reversed with nicotinamide . CONCLUSIONS : Sex differences exist in baseline and stroke - induced NAD + levels . DB02701 protected males and PARP knockout mice , but had minimal effects in the wild - type female brain . This may be secondary to differences in energy metabolism between the sexes .","Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK68___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK80___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .","P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK25___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .","Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK57___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .","Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK1___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK1___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK1___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .","Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .","Crosslinked electrospun P32926 nanofibrous membranes : elucidation of their physicochemical , physicomechanical and molecular disposition . The effects of modifying electrospun poly ( vinyl alcohol ) ( P32926 ) nanofibers through crosslinking using glutaraldehyde ( GA ) are explored in this paper . Various concentrations of P32926 solutions containing model drugs rifampicin ( Q9HBH0 ) and isoniazid ( DB00951 ) were electrospun and thereafter crosslinked using GA vapors . P32926 nanofibers demonstrated high drug entrapment efficiency of 98 . 77 % ± 1 . 384 % and 95 . 07 % ± 1 . 988 % for the DB00951 - and Q9HBH0 - loaded P32926 nanofibers , respectively . The surface morphology , molecular vibrational transitions , tensile attributes and in vitro drug release were characterized and supported by in silico molecular mechanics simulations . Results indicated that crosslinking caused a significant reduction in the rate of drug release where 81 . 11 % ± 2 . 35 % of DB00951 and 59 . 31 % ± 2 . 57 % of Q9HBH0 were released after 12 h . Tensile properties such as the ultimate strength and Young ' s modulus increased after crosslinking , caused by crosslinks forming between P32926 nanofibers as was revealed through scanning electron microscopy analysis . Fourier Transform infrared analysis was conducted to further support the mode of crosslinking . Additionally , image processing analysis was carried out to quantify the effect of formulation variables on the morphology of nanofibers . Furthermore , the effect of GA - induced crosslinking and addition of drugs on the performance of electrospun fibers was further elucidated and conceptualized using a molecular mechanics assisted model building and energy refinement approach via molecular mechanics energy relationships by exploring the spatial disposition of energy - minimized molecular structures of the polymer , crosslinker and the drugs .","P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK25___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK25___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis ."],"string":"[\n \"DB02701 inhibits alkylating agent - induced apoptotic neurodegeneration in the developing rat brain . BACKGROUND : Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system ( CNS ) . Administration of single dose of thiotepa in 7 - d postnatal ( Q0GE19 ) rat triggers activation of apoptotic cascade and widespread neuronal death . The present study was aimed to elucidate whether nicotinamide may prevent thiotepa - induced neurodegeneration in the developing rat brain . METHODOLOGY / PRINCIPAL FINDINGS : Neuronal cell death induced by thiotepa was associated with the induction of Bax , release of cytochrome - c from mitochondria into the cytosol , activation of caspase - 3 and cleavage of poly ( ADP - ribose ) polymerase ( P09874 ) . Post - treatment of developing rats with nicotinamide suppressed thiotepa - induced upregulation of Bax , reduced cytochrome - c release into the cytosol and reduced expression of activated caspase - 3 and cleavage of P09874 . Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus ; post - treatment with nicotinamide reduced the number of dead cells in these brain regions . Terminal deoxynucleotidyl transferase ( TdT ) - mediated dUTP nick end - labeling ( TUNEL ) and immunohistochemical analysis of caspase - 3 show that thiotepa - induced cell death is apoptotic and that it is inhibited by nicotinamide treatment . CONCLUSION : DB02701 ( Nic ) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat . These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants .\",\n \"N - methyl - 2 - pyridone - 5 - carboxamide : a novel uremic toxin ? BACKGROUND : N - methyl - 2 - pyridone - 5 - carboxamide ( 2PY ) is one of the end products of nicotinamide - adenine dinucleotide ( NAD ) degradation . We recently found that serum 2PY concentrations in chronic renal failure ( CRF ) patients were enhanced to the values , which are potentially toxic . The aim of this study was to determine whether 2PY is an inhibitor of poly ( ADP - ribose ) polymerase , the nuclear enzyme that is highly involved in variety of physiologic events , including regulation of DNA replication and DNA repair . METHODS : High - performance liquid chromatography ( HPLC ) was used to determine 2PY and other NAD catabolite concentrations in serum of : nondialyzed patients ; patients chronically hemodialyzed ; patients after kidney transplantation ; and healthy individuals ( control group ) . Moreover , the effect of nicotinamide and 2PY on poly ( ADP - ribose ) polymerase ( P09874 ) in vitro was studied . RESULTS : The serum nicotinamide , 2PY , and 4PY ( N - methyl - 4 - pyridone - 3 - carboxamide ) concentrations are many times elevated in nondialyzed CRF patients when compared with controls . The direct correlations were found between serum 2PY ( as well as 4PY and nicotinamide ) concentrations and serum creatinine concentration , and negative correlations between serum concentrations of these compounds and creatinine clearance . The concentration of 2PY decreases considerably after hemodialysis ( HD ) session , but elevates back 48 hours later . It permanently declines after kidney transplantation . DB02701 and 2PY significantly inhibit P09874 activity in vitro . CONCLUSIONS : Increased serum 2PY concentration , along with a deterioration of kidney function and its toxic properties ( significant inhibition of P09874 by 2PY ) , suggest that it could be a novel uremic toxin .\",\n \"P09874 ( P09874 ) activation and NAD (+) in DNA repair and cell death . DB02701 adenine dinucleotide , NAD (+) , is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis , the tricarboxylic acid cycle ( TCA ) and mitochondrial respiration . These processes consume and produce both oxidative and reduced forms of NAD ( NAD (+) and DB00157 ) . NAD (+) is also important for ADP ( ribosyl ) ation reactions mediated by the ADP - ribosyltransferase enzymes ( ARTDs ) or deacetylation reactions catalyzed by the sirtuins ( SIRTs ) which use NAD (+) as a substrate . In this review , we highlight the significance of NAD (+) catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs . We summarize the current findings on the involvement of P09874 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by P09874 activation and energy depletion . By sharing the same substrate , the activities of ARTDs and SIRTs are tightly linked , are dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology , inflammatory diseases and ischaemia / reperfusion .\",\n \"Role of nicotinamide in DNA damage , mutagenesis , and DNA repair . DB02701 is a water - soluble amide form of niacin ( nicotinic acid or vitamin B3 ) . Both niacin and nicotinamide are widely available in plant and animal foods , and niacin can also be endogenously synthesized in the liver from dietary tryptophan . DB02701 is also commercially available in vitamin supplements and in a range of cosmetic , hair , and skin preparations . DB02701 is the primary precursor of nicotinamide adenine dinucleotide ( NAD (+) ) , an essential coenzyme in DB00171 production and the sole substrate of the nuclear enzyme poly - ADP - ribose polymerase - 1 ( P09874 ) . Numerous in vitro and in vivo studies have clearly shown that P09874 and NAD (+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation . This paper will examine the role of nicotinamide in the protection from carcinogenesis , DNA repair , and maintenance of genomic stability .\",\n \"Preventing NAD (+) depletion protects neurons against excitotoxicity : bioenergetic effects of mild mitochondrial uncoupling and caloric restriction . Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity , which involves energy depletion . By examining bioenergetic changes induced by glutamate , we found that the cellular nicotinamide adenine dinucleotide ( NAD (+) ) level is a critical determinant of neuronal survival . The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain . 2 , 4 - dinitrophenol ( DNP ) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons , which accelerates oxidation of NAD ( P ) H to NAD (+) in mitochondria . The NAD (+)- dependent histone deacetylase sirtulin 1 ( Q96EB6 ) and glucose transporter 1 ( P11166 ) mRNA are upregulated mouse brain under caloric restriction . To examine whether NAD (+) mediates neuroprotective effects , nicotinamide , a precursor of NAD (+) and inhibitor of Q96EB6 and poly ( ADP - ribose ) polymerase 1 ( P09874 ) ( two NAD (+)- dependent enzymes ) , was employed . DB02701 attenuated excitotoxic death and preserved cellular NAD (+) levels to support Q96EB6 and PARP 1 activities . Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress .\",\n \"DB02701 deficiency in human lymphocytes prevents the [ 3H ] thymidine - induced adaptive response for the repair of X - ray - induced chromosomal damage . Human lymphocytes treated with [ 3H ] thymidine ( [ 3H ] dThd ) become refractory to the induction of chromosomal aberrations by subsequent doses of X rays . This adaptive response to [ 3H ] dThd does not occur in the presence of 3 - aminobenzamide ( 3AB ) . 3AB inhibits the synthesis of poly ( ADP - ribose ) by the enzyme adenosine diphosphate ribosyl transferase ( P09874 ) , which requires NAD as a substrate . 3AB also prevents chromosomal repair , as measured in X - ray dose - fractionation studies . Because 3AB might interfere with metabolic reactions other than those mediated by P09874 , experiments were carried out to see if the adaptive response was also inhibited in nicotinamide - free medium , which prevents poly ( ADP - ribosyl ) ation by depleting cellular NAD . The experiments show that the incorporation of [ 3H ] dThd has no effect on the induction of chromosomal aberrations by subsequent doses of X rays if the cells are cultured in nicotinamide - free medium . DB02701 deficiency mimics the effects of 3AB on both the adaptive response and chromosome repair . The results indicate that P09874 activity itself , and not other metabolic processes affected by inhibitors of this enzyme , plays an essential role in the adaptive response .\",\n \"Endothelial sirtuin 1 deficiency perpetrates nephrosclerosis through downregulation of matrix metalloproteinase - 14 : relevance to fibrosis of vascular senescence . Sirtuin 1 ( Q96EB6 ) depletion in vascular endothelial cells mediates endothelial dysfunction and premature senescence in diverse cardiovascular and renal diseases . However , the molecular mechanisms underlying these pathologic effects remain unclear . Here , we examined the phenotype of a mouse model of vascular senescence created by genetically ablating exon 4 of Sirt1 in endothelial cells ( Sirt1 ( endo -/-) ) . Under basal conditions , Sirt1 ( endo -/-) mice showed impaired endothelium - dependent vasorelaxation and angiogenesis , and fibrosis occurred spontaneously at low levels at an early age . In contrast , induction of nephrotoxic stress ( acute and chronic folic acid - induced nephropathy ) in Sirt1 ( endo -/-) mice resulted in robust acute renal functional deterioration followed by an exaggerated fibrotic response compared with control animals . Additional studies identified matrix metalloproteinase - 14 ( P50281 ) as a target of Q96EB6 . In the kidneys of Sirt1 ( endo -/-) mice , impaired angiogenesis , reduced matrilytic activity , and retention of the profibrotic cleavage substrates tissue transglutaminase and endoglin accompanied P50281 suppression . Furthermore , restoration of P50281 expression in Q96EB6 - depeleted mice improved angiogenic and matrilytic functions of the endothelium , prevented renal dysfunction , and attenuated nephrosclerosis . Our findings establish a novel mechanistic molecular link between endothelial Q96EB6 depletion , downregulation of P50281 , and the development of nephrosclerosis .\",\n \"Presence of functionally active protease - activated receptors 1 and 2 in myenteric glia . Protease - activated receptors ( PARs ) belong to the family of membrane receptors coupled to G - proteins ; their presence is reported in a wide variety of cells . The object of this study was to demonstrate the presence of P25116 and P55085 in myenteric glia of the guinea pig , and to elucidate the cellular mechanisms that are triggered upon receptor activation . Thrombin and P25116 agonist peptide ( P09874 ) activate P25116 with a maximum mean +/- SEM change in intracellular calcium concentration with respect to basal level ( Delta [ Ca2 +] i ) of 183 +/- 18 nm and 169 +/- 6 nm , respectively . Trypsin and P55085 agonist peptide ( Q9UGN5 ) activate P55085 with a maximum Delta [ Ca2 +] i of 364 +/- 28 nm and 239 +/- 19 nm , respectively . Inhibition of phospholipase C by U73312 ( 1 microm ) decreased the Delta [ Ca2 +] i due to P25116 activation from 167 +/- 10 nm to 87 +/- 6 nm . The P55085 - mediated Delta [ Ca2 +] i decreased from 193 +/- 10 nm to 124 +/- 8 nm when phospholipase C activity was inhibited . Blockade of sphingosine kinase with dimethylsphingosine ( 1 microm ) decreased the Delta [ Ca2 +] i due to P55085 activation from 149 +/- 19 nm to 67 +/- 1 nm , but did not influence the P25116 - mediated Delta [ Ca2 +] i . P25116 and P55085 were localized in myenteric glia by immunolabeling . Our results indicate that P25116 and P55085 are present in myenteric glia of the guinea pig , and their activation leads to increases in intracellular calcium via different signal transduction mechanisms that involve activation of phospholipase C and sphingosine kinase .\",\n \"MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in P01308 - 1 pancreatic beta - cells . DB02701 has been reported to induce differentiation of precursor / stem cells toward a beta - cell phenotype , increase islet regeneration , and enhance insulin biosynthesis . Exposure of P01308 - 1 beta - cells to elevated glucose leads to reduced insulin gene transcription , and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 ( P52945 ) and mammalian homologue of avian MafA / l - Maf ( MafA ) . DB02701 and other low - potency poly ( ADP - ribose ) polymerase ( PARP ) inhibitors were thus tested for their ability to restore insulin promoter activity . The low - potency PARP inhibitors nicotinamide , 3 - aminobenzamide , or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose . In contrast , the potent P09874 inhibitors PJ34 or DB04335 - 1001 had no effect on promoter activity . Antioxidants , including DB06151 , lipoic acid , or quercetin , only minimally induced the insulin promoter . Site - directed mutations of the human insulin promoter mapped the low - potency PARP inhibitor response to the C1 element , which serves as a MafA binding site . P01308 - 1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels . Low - potency PARP inhibitors restored MafA mRNA and protein levels , but they had no affect on P52945 protein levels or binding activity . Increased MafA expression by low - potency PARP inhibitors was independent of increased MafA protein or mRNA stability . These data suggest that low - potency PARP inhibitors increase insulin biosynthesis , in part , through a mechanism involving increased MafA gene transcription .\",\n \"P43490 regulates cell survival through autophagy in cardiomyocytes . DB02701 adenine dinucleotide ( NAD (+) ) acts as a transfer molecule for electrons , thereby acting as a key cofactor for energy production . NAD (+) also serves as a substrate for cellular enzymes , including poly ( ADPribose ) polymerase ( PARP ) - 1 and Sirt1 . Activation of P09874 by DNA damage depletes the cellular pool of NAD (+) , leading to necrotic cell death . NAD (+) in the nucleus enhances the activity of Sirt1 , thereby modulating transcription . NAD (+) is either synthesized de novo from amino acids , namely tryptophan and aspartic acid , or resynthesized from NAD (+) metabolites , such as nicotinamide ( NAM ) , through the salvage pathway . NAM phosphoribosyltransferase ( P43490 ) is a rate - limiting enzyme in the NAD (+) salvage pathway . We have recently demonstrated that P43490 is an important regulator of NAD (+) and autophagy in cardiomyocytes . Here we discuss the role of P43490 in regulating autophagy and potential mechanisms by which NAD (+) regulates autophagy in the heart .\",\n \"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \\\" febrile episode \\\" cases may also result from the dysfunction of serotonin transmission .\",\n \"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK57___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .\",\n \"Accumulation of poly ( ADP - ribose ) polymerase inhibitors in children with chronic renal failure . DB02701 , N - methyl - 2 - pyridone - 5 - carboxamide ( Met2PY ) and N - methyl - 4 - pyridone - 3 - carboxamide ( Met4PY ) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide ( NAD ) that can potentially inhibit poly ( ADP - ribose ) polymerase 1 ( P09874 ; DNA repair enzyme ) . Our research was aimed at establishing whether chronic renal failure ( CRF ) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit P09874 activity . DB02701 , Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children . The effect of these NAD metabolites on P09874 activity was studied in vitro . We found that plasma concentration of all NAD metabolites ( nicotinamide , Met2PY , Met4PY ) in children with CRF could reach the concentration of 2 , 30 and 10 microM as compared to 0 . 2 , 1 and 0 . 5 microM , respectively , in healthy children . The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF . We found that Met2PY , Met4PY and nicotinamide inhibited in vitro P09874 activity with IC50 values of 2 . 1 , 0 . 18 and 0 . 12 mM , respectively . Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of P09874 activity . NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults .\",\n \"DB02701 uncouples hormone - dependent chromatin remodeling from transcription complex assembly . Sirtuins , homologs of the yeast SIR2 family , are protein deacetylases that require nicotinamide adenosine dinucleotide as cofactor . To determine whether the sirtuin family of deacetylases is involved in progesterone receptor ( PR ) - mediated transcription , the effect of sirtuin inhibitor , nicotinamide ( NAM ) , was monitored in T47D breast cancer cells . NAM suppressed hormone - dependent activation of PR - regulated genes in a dose - dependent manner . Surprisingly , NAM - mediated inhibition of PR - mediated transcription occurs independently of Q96EB6 and P09874 . Chromatin immunoprecipitation experiments did not show that PR binding nor that of the coactivators CBP and SRC3 was compromised . Consistent with the recruitment of the P51532 chromatin remodeling complex , promoter chromatin remodeling still occurs despite NAM inhibition of PR transactivation . Rather , we show that this inhibition of transcription is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter . These results show that NAM uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital NAM - regulated steps required for promoter chromatin remodeling and basal transcription complex communication .\",\n \"Genome - wide methylation profiling of schizophrenia . Schizophrenia is one of the major psychiatric disorders . It is a disorder of complex inheritance , involving both heritable and environmental factors . DNA methylation is an inheritable epigenetic modification that stably alters gene expression . We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution . We have performed 26 high - resolution genome - wide methylation array analyses to determine the methylation status of 27 , 627 CpG islands and compared the data between patients and healthy controls . Methylation profiles of DNAs were analyzed in six pools : 220 schizophrenia patients ; 220 age - matched healthy controls ; 110 female schizophrenia patients ; 110 age - matched healthy females ; 110 male schizophrenia patients ; 110 age - matched healthy males . We also investigated the methylation status of 20 individual patient DNA samples ( eight females and 12 males . We found significant differences in the methylation profile between schizophrenia and control DNA pools . We found new candidate genes that principally participate in apoptosis , synaptic transmission and nervous system development ( P47869 , Q9HAP6 , P42574 ) . Methylation profiles differed between the genders . In females , the most important genes participate in apoptosis and synaptic transmission ( P98170 , O14764 , P01178 , P08729 ) , whereas in the males , the implicated genes in the molecular pathology of the disease were Q8IY37 , P36507 , Q9H6D8 and O14908 . Data from the individual methylation analyses confirmed , the gender - specific pools results . Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients . The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis .\",\n \"___MASK51___ attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells . BACKGROUND & AIMS : Activation of hepatic stellate cells ( P19526 ) and transdifferentiation to myofibroblasts following liver injury is the main culprit for hepatic fibrosis . Myofibroblasts show increased proliferation , migration , contraction , and production of extracellular matrix ( Q13201 ) . In vitro , P04035 inhibitors ( statins ) inhibit proliferation and induce apoptosis of myofibroblastic P19526 . To investigate the antifibrotic effects of atorvastatin in vivo we used bile duct ligated rats ( BDL ) . METHODS : BDL rats were treated with atorvastatin ( 15 mg / kg / d ) immediately after ligation ( prophylactically ) or in on - going fibrosis ( therapeutically ) . Fibrosis was assessed by hydroxyproline content and Sirius - red staining . The activation of P19526 was investigated by analysis of alphaSMA expression . mRNA levels of cytokines and procollagen were analyzed by RT - PCR , and P08253 activity by zymography . Proliferation was assessed by expression of cathepsins ( B and D ) , proliferating cell nuclear antigen ( P12004 ) , and Ki67 - staining . Apoptosis was characterized by caspase - 3 activity , cleavage of P09874 , and TUNEL assay . Hepatic inflammation was investigated by serum parameters and liver histology . RESULTS : Prophylactic and early therapy with atorvastatin significantly attenuated fibrosis and P19526 activation . Later therapy lacked significant effects on fibrosis but reduced profibrotic cytokine expression and led to a more quiescent state of P19526 with less proliferation and apoptosis , while hepatic inflammation did not change . CONCLUSIONS : This study shows that very early atorvastatin treatment inhibits P19526 activation and fibrosis in the BDL model in vivo , while late treatment reduces P19526 turnover and activity . Our findings underline that long - term studies in humans are warranted .\",\n \"Poly ( ADP - ribose ) metabolism in X - irradiated Chinese hamster cells : its relation to repair of potentially lethal damage . DB02701 - adenine dinucleotide ( NAD + ) is the substrate used by cells in poly ( ADP - ribose ) synthesis . X - irradiation of log - phase Chinese hamster cells caused a rapid decrease in NAD + levels which was linearly dependent on radiation dose . The activity of ADP - ribosyl transferase ( P09874 ) also increased linearly with radiation dose . The decrease of NAD + was slower , and the increase in P09874 activity was less pronounced , in a radiation sensitive line , V79 - AL162 / S - 10 . An inhibitor of P09874 , m - aminobenzamide , largely prevented the depletion of cellular NAD + and reduced the rate at which P09874 activity disappeared during post - irradiation incubation . Post - irradiation treatment with hypertonic buffer or with medium containing D2O -- which inhibit repair of radiation - induced potentially lethal damage -- enhanced the depletion of NAD + and prevented the reduction in P09874 activity following irradiation . The characteristics of the effects of treatment with hypertonic buffer on NAD + metabolism were qualitatively similar to the effects that such treatment has on radiation - induced cell killing . These results suggest that poly ( ADP - ribose ) synthesis after irradiation plays a role in the repair of potentially lethal damage .\",\n \"DBC1 / Q8N163 and Q8IX12 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor . Deleted in breast cancer 1 ( DBC1 , Q8N163 , Q8N163 ) is a large , predominantly nuclear , multidomain protein that modulates gene expression by inhibiting several epigenetic modifiers , including the deacetylases Q96EB6 and O15379 , and the methyltransferase O43463 . DBC1 shares many highly conserved protein domains with its paralog cell cycle and apoptosis regulator 1 ( Q8IX12 , CARP - 1 ) . In this study , we examined the full - length sequential and structural properties of DBC1 and Q8IX12 from multiple species and correlated these properties with evolution . Our data shows that the conserved domains shared between DBC1 and Q8IX12 have similar domain structures , as well as similar patterns of predicted disorder in less - conserved intrinsically disordered regions . Our analysis indicates similarities between DBC1 , Q8IX12 , and the nematode protein lateral signaling target 3 ( G3V0H7 ) , suggesting that DBC1 and Q8IX12 may have evolved from G3V0H7 . Our data also suggests that DBC1 emerged later in evolution than Q8IX12 . DBC1 contains regions that show less conservation across species as compared to the same regions in Q8IX12 , suggesting a continuously evolving scenario for DBC1 . Overall , this study provides insight into the structure and evolution of DBC1 and Q8IX12 , which may impact future studies on the biological functions of these proteins .\",\n \"Radiosensitizing effects of nicotinamide on a C3H mouse mammary adenocarcinoma . A study on per os drug administration . DB02701 is an inhibitor of adenosine diphosphate ribosyl transferase ( P09874 ) which is involved in the mechanism of DNA repair after high doses of ionizing radiation . C3H mice with transplanted mammary adenocarcinomas were treated with low doses of nicotinamide , 10 mg / kg , 5 days a week , and in combination with ionizing radiation , 30 Gy , using different drug dose schedules . Mice given nicotinamide in combination with irradiation took a longer time to reach a tumor volume of 1 , 000 mm3 and a higher complete response rate ( i . e . defined as total disappearance of the tumor for at least 7 days ) than those given radiation alone . This was true whether nicotinamide was given daily from one week before tumor transplantation until the animal was killed or from transplantation day until day of irradiation . In addition , nicotinamide given per os at a dose between the recommended maximum daily allowance for human subjects ( 20 mg / 70 kg ) , and the therapeutic allowance ( 1 g - 12 g daily ) 5 days a week for 9 weeks , showed a radiosensitizing effect without any histologically detectable damage to the normal tissues of the mouse , including bone marrow , intestine and the liver .\",\n \"___MASK49___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK49___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK49___ is a promising pharmacological tool in the treatment of renal edema .\",\n \"DB02701 pre - treatment ameliorates NAD ( H ) hyperoxidation and improves neuronal function after severe hypoxia . Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling ( between NAD (+) and DB00157 ) immediately after reoxygenation , resulting in DB00157 hyperoxidation . We test whether the addition of nicotinamide ( to enhance NAD (+) levels ) or P09874 inhibition ( to prevent consumption of NAD (+) ) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices . After severe , prolonged hypoxia ( maintained for 3min after spreading depression ) there was hyperoxidation of DB00157 following reoxygenation , an increased soluble NAD (+)/ DB00157 ratio , loss of neuronal field excitatory post - synaptic potential ( fEPSP ) and decreased DB00171 content . DB02701 incubation ( 5mM ) 2h prior to hypoxia significantly increased total NAD ( H ) content , improved neuronal recovery , enhanced DB00171 content , and prevented DB00157 hyperoxidation . The nicotinamide - induced increase in total soluble NAD ( H ) was more significant in the cytosolic compartment than within mitochondria . Prolonged incubation with PJ - 34 ( > 1h ) led to enhanced baseline DB00157 fluorescence prior to hypoxia , as well as improved neuronal recovery , DB00157 hyperoxidation and DB00171 content on recovery from severe hypoxia and reoxygenation . In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ - 34 prior to hypoxia improved recovery of neuronal function , enhanced DB00157 reduction and DB00171 content , but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation .\",\n \"DB02701 treatment reduces the levels of histone H3K4 trimethylation in the promoter of the mper1 circadian clock gene and blocks the ability of dexamethasone to induce the acute response . Circadian rhythms , which measure time on a scale of 24h , are generated by one of the most ubiquitous endogenous mechanisms , the circadian clock . Q96EB6 , a class III histone deacetylase , and P09874 , a poly ( ADP - ribose ) polymerase , are two NAD (+)- dependent enzymes that have been shown to be involved in the regulation of the clock . Here we present evidence that the metabolite nicotinamide , an inhibitor of Q96EB6 , P09874 and mono ( ADP - ribosyl ) transferases , blocks the ability of dexamethasone to induce the acute response of the circadian clock gene , mper1 , while it concomitantly reduces the levels of histone H3 trimethylation of lysine 4 ( H3K4me3 ) in the mper1 promoter . Moreover , application of alternative inhibitors of Q96EB6 and ADP - ribosylation did not lead to similar results . Therefore , inhibition of these enzymes does not seem to be the mode by which NAM exerts these effects . These results suggest the presence of a novel mechanism , not previously documented , by which NAM can alter gene expression levels via changes in the histone H3K4 trimethylation state .\",\n \"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .\",\n \"DB02701 rescues human embryonic stem cell - derived neuroectoderm from parthanatic cell death . Abundant cell death is observed when human embryonic stem cells ( hESCs ) undergo neuralization , a critical first step for future cell - based therapies addressing neurodegeneration . Using hESC neuralization as an in vitro model of human development , we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death . We found that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) / apoptosis - inducing factor ( O95831 ) - mediated cell death ( parthanatos ) is a dominant mechanism responsible for cell loss during hESC neuralization . The demise of neural progenitor cells , at least in part , is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions . Under such conditions , P09874 overactivation triggered cell death through the mitochondrial - nuclear translocation of O95831 . Blocking P09874 activity with small hairpin RNA interference or nicotinamide dramatically enhanced hESC neuralization , providing optimal survival of the developing neuroepithelium . Because nicotinamide is a physiological metabolite , our results raise the possibility that neural stem / progenitor cell survival in vivo requires a metabolic niche . We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine .\",\n \"O60603 and poly ( ADP - ribose ) polymerase 1 promote central nervous system neuroinflammation in progressive EAE . Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing - remitting disease ( RRMS ) and is followed by a progressive phase ( SPMS ) . The progressive phase causes the greatest disability and has no effective therapy , but the processes that drive SPMS are mostly unknown . Here we found higher serum concentrations of 15alpha - hydroxicholestene ( 15 - HC ) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis ( EAE ) but not in patients with RRMS . In mice , 15 - HC activated microglia , macrophages and astrocytes through a pathway involving O60603 ( O60603 ) and poly ( ADP - ribose ) polymerase 1 ( P09874 ) . P09874 activity was higher in monocytes of patients with SPMS , and P09874 inhibition suppressed the progression of EAE . Thus , the O60603 - P09874 pathway is a potential new therapeutic target in SPMS .\",\n \"DB02701 sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors enhance the effect of DNA alkylating agents on BRCA1 ‑ and P51587 - deficient cell lines . The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide ( NAM ) on breast cancer cells with different P38398 expression or function , such as BRCA1 ‑ deficient MDA - MB - 436 cells , low expression P38398 MCF - 7 cells , and the P38398 wild ‑ type MDA - MB - 231 cells , to demonstrate its effects as a chemo ‑ or radiosensitizing agent . PARP activity was analyzed in MDA - MB - 436 , MCF - 7 and MDA - MB - 231 breast cancer cells subjected or not to NAM . Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence . Crystal violet assays were used to test growth inhibition and the chemo ‑ and radiosensitization effects of NAM were investigated using clonogenic assays . Significant differences among data sets were determined using two - tailed Q9UNW9 and Bonferroni tests . We demonstrated that NAM reduces PARP activity in vitro , and in cells subjected or not to DNA damage , it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA - MB - 436 and MCF - 7 cells . Downregulation of P09874 with siRNA led to modest growth inhibition , which was further increased by cisplatin . DB02701 also induced radiosensitization in MDA - MB - 436 and MDA - MB - 231 cells . In conclusion , NAM may be used as a chemo ‑ or radiosensitizing agent regardless of the P38398 status in breast cancer .\",\n \"DB00853 : mechanisms of action , repair and resistance . Glioblastoma multiforme is the most common aggressive adult primary tumour of the central nervous system . Treatment includes surgery , radiotherapy and adjuvant temozolomide ( DB00853 ) chemotherapy . DB00853 is an alkylating agent prodrug , delivering a methyl group to purine bases of DNA ( O6 - guanine ; N7 - guanine and N3 - adenine ) . The primary cytotoxic lesion , O6 - methylguanine ( O6 - MeG ) can be removed by methylguanine methyltransferase ( P16455 ; direct repair ) in tumours expressing this protein , or tolerated in mismatch repair - deficient ( P22897 - ) tumours . Thus P16455 or P22897 deficiency confers resistance to DB00853 . Inherent - and acquired resistance to DB00853 present major obstacles to successful treatment . Strategies devised to thwart resistance and enhance response to DB00853 , including inhibition of DNA repair mechanisms which contribute to DB00853 resistance , are under clinical evaluation . Depletion of P16455 prior to alkylating agent chemotherapy prevents O6 - MeG repair ; thus , P16455 pseudosubstrates O6 - benzylguanine and lomeguatrib are able to sensitise tumours to DB00853 . Disruption of base excision repair ( BER ) results in persistence of potentially lethal N7 - and N3 - purine lesions contributing significantly to DB00853 cytoxicity particularly when O6 - MeG adducts are repaired or tolerated . Several small molecule inhibitors of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , a critical BER protein are yielding promising results clinically , both in combination with DB00853 and as single agent chemotherapy in patients whose tumours possess homologous recombination DNA repair defects . Another validated , but as yet preclinical protein target , mandatory to BER is abasic ( AP ) endonuclease - 1 ( P27695 ) ; in preclinical tests , P27695 inhibition potentiates DB00853 activity . An alternative strategy is synthesis of a molecule , evoking an irrepairable cytotoxic O6 - G lesion . Preliminary efforts to achieve this goal are described .\",\n \"Regulation of rat haptoglobin gene expression is coordinated by the nuclear matrix . Using computer stress - induced duplex destabilization ( SIDD ) analysis and binding experiments , we identified a S / MAR element ( - 599 /- 200 bp ) ( Hp - S / MAR ) adjacent to the cis - element ( - 165 /- 56 bp ) in the rat haptoglobin gene . We examined its functional interactions with the lamins and lamin - associated proteins in the basal state and during acute - phase ( AP ) response - induced increased transcription . Colocalization , electrophoretic mobility shift assay ( EMSA ) , and re - electrophoresis of nucleoprotein complexes , South - Western and Western blot analysis and coimmunoprecipitation experiments revealed that the lamins , P09874 , P17676 , and Hp - S / MAR assembled higher order complexes through direct lamin - Hp - S / MAR and probably P09874 - Hp - S / MAR interactions although P17676 did not bind to the Hp - S / MAR but established direct interaction with P09874 . The transition from constitutive to increased haptoglobin gene transcription during the AP response was associated with quantitative and qualitative changes in Hp - S / MAR - protein interactions , respectively , observed as increased association of the lamin ( s ) with the Hp - S / MAR and as the appearance of a 90 kDa Hp - S / MAR - binding protein . Also , during the AP response the contact between P17676 and P09874 established in the basal state was lost . DNA chromatography with the haptoglobin cis - element and Western blot analysis suggests that P09874 was a coactivator during constitutive and elevated transcription . The results show that the lamin components of the nuclear matrix form a network of functional , dynamic protein - protein and protein - Hp - S / MAR associations with multiple partners , and underline the involvement of P09874 in the regulation of haptoglobin gene transcription . We concluded that the interplay of these interactions fine tunes haptoglobin gene expression to meet the changing requirements of liver cells .\",\n \"A nuclear poly ( ADP - ribose )- dependent signalosome confers DNA damage - induced O15111 activation . Upon genotoxic stresses , cells activate IkappaB kinases ( IKKs ) and the transcription factor NF - kappaB to modulate apoptotic responses . The P63165 ligase Q8N2W9 and the kinase ataxia talengiectasia mutated ( Q13315 ) have been implicated to SUMOylate and phosphorylate nuclear IKKgamma ( Q9Y6K9 ) in a consecutive mode of action , which in turn results in activation of cytoplasmic IKK holocomplexes . However , the nuclear signals and scaffold structures that initiate IKKgamma recruitment and activation are unknown . Here , we show that poly ( ADP - ribose )- polymerase - 1 ( P09874 ) is the DNA proximal regulator , which senses DNA strand breaks and , through poly ( ADP - ribose ) ( PAR ) synthesis , assembles IKKgamma , Q8N2W9 , and Q13315 in a dynamic manner . Signalosome formation involves direct protein - protein interactions and binding to ADP - ribose polymers through PAR binding motifs ( PARBM ) . Activated P09874 and a PARBM in Q8N2W9 are required to trigger IKKgamma SUMOylation , which in turn permits IKK and NF - kappaB activation , as well as NF - kappaB - regulated resistance to apoptosis .\",\n \"Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .\",\n \"Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects . Neural tube defects ( NTDs ) are a common cause of disability or death of new - borns , but the aetiology and genetic background of this disease are still poorly understood . Therefore , it was decided to determine the conditions for the identification of several polymorphisms and to perform a preliminary study on Polish NTD patients and their parents . According to the results of this study , the genetic predisposition to NTD can be correlated with the 677TT genotype in the P42898 gene , 677CT / 1298AC haplotype ( the P42898 gene ) , 2756G allele in the Q99707 gene , 66AG variant and minisatellite sequence with 5 or 10 repeats in intron 6 of the Q9UBK8 gene . The 530GG and TIVS7 - 2 / TIVS7 - 2 genotypes in the T gene could also be considered as a risk factor for NTD . The analysis also revealed no correlation between neurulation disturbances and A4956G and A1186G mutations in the P38398 gene and the 844ins68bp in P35520 gene . Although a correlation was found of some molecular markers with NTD , an additional examination should be conducted on more numerous groups to obtain statistically significant results .\",\n \"Perinatal asphyxia : CNS development and deficits with delayed onset . Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted . The primary insult relates to the duration of the period lacking oxygenation , leading to death if not re - established . Re - oxygenation leads to a secondary insult , related to a cascade of biochemical events required for restoring proper function . Perinatal asphyxia interferes with neonatal development , resulting in long - term deficits associated to mental and neurological diseases with delayed clinical onset , by mechanisms not yet clarified . In the experimental scenario , the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy . Asphyxia induces transcriptional activation of pro - inflammatory factors , in tandem with P09874 overactivation , and pharmacologically induced P09874 inhibition also down - regulates the expression of proinflammatory cytokines . DB02701 has been proposed as a suitable P09874 inhibitor . Its effect has been studied in an experimental model of global hypoxia in rats . In that model , the insult is induced by immersing rat fetus into a water bath for various periods of time . Following asphyxia , the pups are delivered , treated , and nursed by surrogate dams , pending further experiments . DB02701 rapidly distributes into the brain following systemic administration , reaching steady state concentrations sufficient to inhibit P09874 activity for several hours , preventing several of the long - term consequences of perinatal asphyxia , supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles .\",\n \"Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .\",\n \"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK63___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK63___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .\",\n \"Effects of hyperthermia and nicotinamide on DNA repair synthesis , ADP - ribosyl transferase activity , NAD + and DB00171 pools , and cytotoxicity in gamma - irradiated human mononuclear leukocytes . Effects of hyperthermia and nicotinamide on ADP - ribosyl transferase activity ( P09874 ) , unscheduled DNA synthesis ( UDS ) , NAD +- and DB00171 - pools and cytotoxicity were investigated in gamma - irradiated human mononuclear leukocytes . A significant decrease in radiation - induced UDS after heat treatment for 45 min was found . DB02701 increased the UDS levels in irradiated cells , but no effect of hyperthermia on these increased UDS values was observed . In the presence of 2 mM nicotinamide radiation - induced P09874 activity was reduced to about 50 per cent . However , hyperthermia for 45 min was found to have no effect on the enzyme activity for temperatures below 46 degrees C . DB02701 increased the NAD + pool in unirradiated cells . Damaging the cells with gamma - radiation leads to a severe depletion of the NAD + pool . The NAD + pool is restored , however , if the cells repair for 5 h at 37 degrees C . When radiation - damaged cells were treated with hyperthermia , exogenously supplied nicotinamide could not be converted to NAD + in sufficient amounts to prevent NAD + depletion . These data indicate that the radiosensitizing effect of heat and nicotinamide could both be explained by effects on the enzyme P09874 , i . e . nicotinamide by directly blocking the enzyme and hyperthermia by limiting the co - substrate ( NAD + ) .\",\n \"[ Treatment of type 1 diabetes mellitus revealed below 7 years of age in the Diabetes Center of Silesia , Poland ] . INTRODUCTION : Frequency of type 1 diabetes mellitus diagnosis in young children increases . Within this group , such factors as limited cooperation , little acceptance of multiple injections and other typical patterns of behavior can strongly influence the insulin management outcome . AIM OF THE STUDY : The objective of the study was to provide information regarding metabolic control in young diabetes patients . MATERIAL AND METHODS : Charts of 58 children with T1DM , all subjects under control of our Department , that were aged at onset ( 1998 - 2003 ) below 7 years ( mean 4 . 05 +/- 1 . 6 ) were studied retrospectively . HbA1c , total , bolus and basal daily insulin requirement ( P30518 ) , weight , height , severe hypoglycaemia and diabetic ketoacidosis ( DKA ) were analyzed till April 2006 in 2 - year intervals . P01308 therapy model was also taken into consideration . RESULTS : Mean HbA1c was 7 . 2 +/- 1 . 2 % for all children for the whole studied period and did not alter significantly between analyzed intervals . Most common treatment model at diabetes onset was the therapy with premixed insulin ( Mix ) ( 67 % ) and after 4 and 6 years - continuous subcutaneous insulin infusion ( CSII ) ( 50 % and 75 % respectively ) . A tendency for a better metabolic control was observed at multiple daily injections and CSII than at Mix . Change of the weight or height percentile channel was not revealed . Bolus and basal P30518 increased in the first observation interval . Afterwards they stabilized respectively at 0 . 35 - 0 . 42 U / kg / 24 h and 0 . 35 - 0 . 39 U / kg / 24 h . Severe hypoglycaemia occurred 6 . 72 / 100 patient - years . CONCLUSION : P01308 therapy aimed at maintaining long - term good metabolic control is possible to achieve and is safe in young diabetic children .\",\n \"P01308 resistance and angiotensin converting enzyme polymorphism in Japanese hypertensive subjects . P00797 - angiotensin system activity has been shown to affect insulin sensitivity . However , the relationship between I / D polymorphism and insulin resistance is controversial . Therefore , we examined the relationship between the P12821 genotype and insulin sensitivity in 51 Japanese hypertensive patients using the glucose clamp technique . The P12821 genotype distribution in the hypertensive subjects was : 7 subjects with DD , 20 subjects with ID , and 24 subjects with II . P01308 sensitivity in terms of the glucose disposal rate was not significantly different among the three P12821 genotypes , although there was a tendency for insulin sensitivity to decrease in the order of II , ID and DD , DD being the lowest . These findings are contrary to previous reports that insulin sensitivity was increased in normotensive subjects with the DD genotype who were Caucasian or African - American . There might be a difference due to race and whether the subjects are hypertensive or obese . We concluded that insulin sensitivity was not different among the P12821 genotypes in the Japanese hypertensive subjects , supporting a previous report on the Chinese population . To date , insulin sensitivity has not been found to differ with P12821 genotypes in the oriental population .\",\n \"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .\",\n \"Plasticity of the central nervous system ( CNS ) following perinatal asphyxia : does nicotinamide provide neuroprotection ? We have investigated the idea that nicotinamide , a non - selective inhibitor of the sentinel enzyme Poly ( ADP - ribose ) polymerase - I ( P09874 ) , provides neuroprotection against the long - term neurological changes induced by perinatal asphyxia . Perinatal asphyxia was induced in vivo by immersing foetuses - containing uterine horns removed from ready - to - deliver rats into a water bath for 20 min . Sibling caesarean - delivered pups were used as controls . The effect of perinatal asphyxia on neurocircuitry development was studied in vitro with organotypic cultures from substantia nigra , neostriatum and neocortex , platted on a coverslip 3 days after birth . After approximately one month in vitro ( DIV 25 ) , the cultures were treated for immunocytochemistry to characterise neuronal phenotype with markers against the N - methyl - D - aspartate receptor subunit 1 ( Q9UHB4 ) , the dopamine pacemaker enzyme tyrosine hydroxylase ( TH ) , and nitric oxide synthase ( NOS ) , the enzyme regulating the bioavailability of NO . DB02701 ( 0 . 8 mmol / kg , i . p . ) or saline was administered to asphyctic and caesarean - delivered pups 24 , 48 and 72 h after birth . It was found that nicotinamide treatment prevented the effect of perinatal asphyxia on several neuronal parameters , including TH - and NOS - positive neurite atrophy and NOS - positive neuronal loss ; supporting the idea that nicotinamide constitutes a therapeutic alternative for the effects produced by sustained energy - failure conditions , as occurring during perinatal asphyxia .\",\n \"DB02701 : a potential addition to the anti - psoriatic weaponry . Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern . Increased expression of adhesion molecules , prominent neutrophil accumulation , and increased production of nitric oxide are characteristics of this disorder . Moreover , histamine and proteases are supposed to participate in the pathogenesis of psoriasis . DB02701 is an inhibitor of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) that , through enhancement of nuclear kappa B - mediated transcription , plays a pivotal role in the expression of inflammatory cytokines , chemokines , adhesion molecules , and inflammatory mediators . Through interaction with P28907 and inhibition of IL - 1 , IL - 12 , and P01375 production , nicotinamide produces a mild TH2 bias . DB02701 is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release . It inhibits nitric oxide synthase mRNA induction and suppresses antigen - induced lymphocyte transformation . DB02701 increases the biosynthesis of ceramides , which upon degradation produce sphingosine . DB03203 inhibits protein kinase C ( PKC ) and decreases basal cell proliferation dependent on PKC . Taken together , it can be reasoned that nicotinamide could be a useful addition to anti - psoriatic armamentarium . The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen - induced arthritis . DB02701 decreased the methotrexate - induced hepatotoxicity . The above combinations may prove to have a powerful anti - psoriatic effect as well . As PARP inhibitors could exert anti - retroviral effect , nicotinamide could also be of special value in the treatment of HIV - infected psoriatics .\",\n \"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .\",\n \"Protective effect of nicotinamide against poly ( ADP - ribose ) polymerase - 1 - mediated astrocyte death depends on its transporter - mediated uptake . AIM : Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a DNA repair enzyme , and its excessive activation , following ischemia , trauma , etc . , depletes cellular nicotinamide adenine dinucleotide ( NAD (+) ) as a substrate and eventually leads to brain cell death . DB02701 , an NAD (+) precursor and a P09874 inhibitor , is known to prevent P09874 - triggered cell death , but there is no available information on the mechanisms involved in its transport . Here we clarified the transport characteristics of nicotinamide in primary cultured mouse astrocytes . MAIN METHODS : Uptake characteristics of [( 14 ) C ] nicotinamide were assessed by a conventional method with primary cultured mouse astrocytes . Cell viability and P09874 activity were determined with intracellular LDH activity and immunocytochemical detection of PAR accumulation , respectively . KEY FINDINGS : P09874 activation was induced by treatment of astrocytes with N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) , an alkylating agent . MNNG - triggered astrocyte death and PAR accumulation were completely inhibited by treatment with nicotinamide as with DPQ ( 3 , 4 - dihydro - 5 -( 4 -( 1 - piperidinyl ) butoxy )- 1 ( 2H )- isoquinolinone ) , a second generation PARP inhibitor . The uptake of [( 14 ) C ] nicotinamide was time - , temperature - , concentration - and pH - dependent , and was inhibited and stimulated by co - and pre - treatment with N - methylnicotinamide , a representative substrate of an organic cation transport system , respectively . Co - treatment of astrocytes with nicotinamide and N - methylnicotinamide resulted in a decrease in PAR accumulation and absolute prevention of cell death . SIGNIFICANCE : These findings suggest that nicotinamide has a protective effect against P09874 - induced astrocyte death and that its transporter - mediated uptake , which is extracellular pH - sensitive and common to N - methylnicotinamide , is critical for prevention of P09874 - triggered cell death .\",\n \"Establishment of an immortalized P09874 -/- murine endothelial cell line : a new tool to study P09874 mediated endothelial cell dysfunction . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays a critical role in endothelial cell dysfunction associated with various pathophysiological conditions . To elucidate P09874 pathways involved in endothelial cell dysfunction , it is essential to establish \\\" in vitro \\\" experimental models using isolated endothelial cells . So far , two approaches have been used : primary endothelial cells from P09874 -/- mice which have a limited life - span , being a major handicap if large quantities of cells are required ; and pharmacological inhibition of PARP in P09874 +/+ endothelial cell lines , which is not specific for P09874 and would have biological effects different that genetic inhibition . To overcome these limitations , we have established an immortalized P09874 -/- endothelial cell line ( HYKO6 ) by transfection of primary cells with a plasmid containing the SV40 genome and selected on the basis of morphological and phenotypical features . The HYKO6 cell line exhibited endothelial characteristics , such as constitutive expression of CD105 , CD31 , P13598 , P19320 , and P04275 and formation of capillary - like structures ( CLS ) on Matrigel surface . However , expression of P05362 antigen is lost in the HYKO6 cells . After P01375 treatment , HYKO6 cells exhibited increased expression of P16581 and P19320 . Likewise , NF - kappaB - dependent transcriptional activation was increased in the HYKO6 cell line in response to P01375 at a level similar to that found for primary P09874 -/- cells . This cell line should provide , for the first time , a valuable tool to study P09874 pathways in endothelial cell dysfunction .\",\n \"P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .\",\n \"p53 - , Q96EB6 - , and P09874 - independent downregulation of p21WAF1 expression in nicotinamide - treated cells . DB02701 at mM concentration is a potent inhibitor of certain key molecules involved in cell survival , such as Q96EB6 and P09874 , and affects cell survival in various conditions in vivo and in vitro . However , the effect of an acute treatment of nicotinamide on gene expression has rarely been closely examined . In our study , the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 - negative or Q96EB6 - knockdown cells indicating gene regulation not mediated by p53 or Q96EB6 . Meanwhile , in the nicotinamide - treated cells , Sp1 activity and protein level was substantially reduced due to increased proteasome - mediated degradation . Our results indicate that nicotinamide treatment attenuates p21WAF1 expression through Sp1 downregulation , and suggest a possible involvement of nicotinamide metabolism in cellular gene expression .\",\n \"Changes in the response of the Q9HBH0 - 1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP - ribosyl transferase . The effect of inhibitors of nuclear ADP - ribosyl transferase ( P09874 ) on the cytotoxicity of melphalan ( DB01042 ) in the Q9HBH0 - 1 tumour in vivo was investigated . A large single dose of nicotinamide ( 1000 mg kg - 1 ) enhanced the tumour cell killing by DB01042 as measured by tumour cell survival . This enhancement was maximum when nicotinamide was administered within 1 h before injecting the DB01042 . When given at this time , the nicotinamide had a dose - modifying effect on all DB01042 doses tested , giving rise to a mean enhancement ratio ( ER ) of 2 . 2 . DB02701 did not appear to inhibit the recovery from DB01042 induced potentially lethal damage . DB01042 ( 6 mg kg - 1 ) produced a transient drop in mouse body temperature . This effect was both increased and prolonged by nicotinamide . In addition the inhibitor also delayed the clearance of DB01042 from the plasma of C3H mice , such that the half - life of the chemotherapeutic agent was extended from 41 min to 143 min . The effect of combining DB01042 with nicotinamide doses below 1000 mg kg - 1 was also investigated . The results showed that as the nicotinamide dose was decreased , the enhancement of the effects on body temperature , pharmacokinetics and white blood cell counts were reduced . However , a concomitant loss in the enhancement of tumour cell killing was also observed . Similar results were obtained using 3 - aminobenzamide , a more efficient inhibitor of P09874 .\",\n \"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK59___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .\",\n \"Activation of the P47900 receptor induces apoptosis and inhibits proliferation of prostate cancer cells . G protein - coupled receptors , the largest cell surface receptor family , have emerged as critical players in cell death and survival . High gene expression level of the G ( q )- coupled P2Y ( 1 ) nucleotide receptor in PC - 3 prostate cancer cells was demonstrated using real - time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy . A selective P2Y ( 1 ) receptor agonist , the ADP analogue MRS2365 , concentration - dependently induced intracellular calcium mobilization ( EC ( 50 ) 5 . 28nM ) , which was diminished by P2Y ( 1 ) receptor - selective antagonist MRS2500 . P2Y ( 1 ) receptor activation by MRS2365 induced apoptosis in assays of P42574 , LDH release , and annexin - V staining . The pro - apoptotic effect of MRS2365 was blocked by MRS2500 , P2Y ( 1 ) siRNA , and an inhibitor of the Q96HU1 kinase pathway PD98059 . MRS2365 significantly inhibited the proliferation of PC - 3 cells , examined using a MTT assay . Thus , activation of the P2Y ( 1 ) receptor induced cell death and inhibited growth of human prostatic carcinoma PC - 3 cells . Activation of the P2Y ( 1 ) receptor should be a novel and promising therapeutic strategy for prostate cancer .\",\n \"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK80___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .\",\n \"Poly ( ADP - ribose ) polymerase - 1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22 - 28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD + ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 overactivation may ensue , depleting cells of NAD + and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 expression and that administration of a P09874 inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty - four percent of control pups developed high - grade NEC ( grades 3 - 4 ) , whereas only 7 % of pups receiving nicotinamide developed high - grade NEC . DB02701 treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 overactivation in NEC may drive mucosal cell death in this disease and that P09874 may be a novel therapeutic target in NEC .\",\n \"Further studies on the hypothesis of P09874 inhibition as a strategy for lessening the long - term effects produced by perinatal asphyxia : effects of nicotinamide and theophylline on P09874 activity in brain and peripheral tissue : nicotinamide and theophylline on P09874 activity . DB09140 interruption leads to death when re - oxygenation is not promptly re - established . Re - oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis . The effects observed long after perinatal asphyxia ( PA ) have been explained by over - expression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a therapeutic strategy . We studied the effects of nicotinamide and theophylline on P09874 activity assayed in brain and peripheral ( heart ) rat tissue 1 - 24 h after birth , as well as on changes in behaviour and monoamine neurotransmission in adult rats . PA was induced by immersing rat foetuses into a water bath for 0 or 21 min . After resuscitation , the pups were treated with nicotinamide ( 0 . 8 mmol / kg , i . p . ) , theophylline ( 0 . 14 mmol / kg , i . p . ) or saline ( 0 . 9 % NaCl ) and nurtured by surrogate dams , pending behavioural and microdialysis experiments , or euthanised after birth for assaying P09874 activity . To estimate the in vivo distribution of a single dose of nicotinamide or theophylline into brain and peripheral compartment , a series of animals were implanted with microdialysis probes , one into the brain and other subcutaneously , 1 h after birth , assaying the drugs with a HPLC - UV system . DB02701 , but not theophylline prevented the long - term effects induced by PA . Only nicotinamide produced a consistent decrease in P09874 activity in brain and heart , whether assayed in control or asphyxia - exposed pups . The present results support the idea that the long - term effects induced by PA imply P09874 over - activation .\",\n \"Genetic polymorphisms associated with ___MASK1___ - induced neurotoxicity . BACKGROUND : Encephalopathy is a rare drug toxicity of fluorouracil therapy . Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes , thymidylate synthase and dihydropyrimidine dehydrogenase . METHODS : Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5 - fluorouracil - based chemotherapy presented with acute mental change and hyperammonemia . To evaluate the genetic background of the fluorouracil - associated hyperammonemic encephalopathy , analysis of the polymorphisms of the P04818 , Q12882 and P42898 genes was performed . RESULTS : The patients revealed to be P04818 suppressors showing homogenous deletion of 6 bp in the 3 '- UTR and 3RC / 3RC genotype in the promoter enhancer region ( TSER ) , respectively . CONCLUSION : Genetic polymorphisms of the P04818 gene would contribute to the 5 - fluorouracil - associated hyperammonemic encephalopathy . The prospective validation of the clinical implication of P04818 gene polymorphisms is warranted .\",\n \"NAD + and nicotinamide : sex differences in cerebral ischemia . BACKGROUND : Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes . While caspase - dependent mechanisms predominate in the female brain , caspase - independent cell death induced by the activation of poly ( ADP - ribose ) polymerase ( PARP ) predominates in the male brain . P09874 gene deletion decreases infarction volume in the male brain , but paradoxically increases damage in P09874 knockout females . PURPOSE : This study examined stroke - induced changes in NAD + , a key energy molecule involved in P09874 activation in both sexes . METHODS : Mice were subjected to middle cerebral artery occlusion and NAD + levels were assessed . P42574 activity and nuclear translocation were assessed 6h after ischemia . In additional cohorts , DB02701 ( 500 mg / kg i . p . ) a precursor of NAD + or vehicle was administered and infarction volume was measured 24h after ischemia . RESULTS : Males have higher baseline NAD + levels than females . Significant stroke - induced NAD + depletion occurred in males and ovariectomized females but not in intact females . P09874 deletion prevented the stroke - induced loss in NAD + in males , but worsened NAD + loss in P09874 deficient females . Preventing NAD + loss with nicotinamide reduced infarct in wild - type males and P09874 knockout mice of both sexes , with no effect in WT females . P42574 activity was significantly increased in P09874 knockout females compared to males and wild - type females , this was reversed with nicotinamide . CONCLUSIONS : Sex differences exist in baseline and stroke - induced NAD + levels . DB02701 protected males and PARP knockout mice , but had minimal effects in the wild - type female brain . This may be secondary to differences in energy metabolism between the sexes .\",\n \"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK68___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK80___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .\",\n \"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK25___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .\",\n \"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK57___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .\",\n \"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK1___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK1___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK1___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .\",\n \"Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .\",\n \"Crosslinked electrospun P32926 nanofibrous membranes : elucidation of their physicochemical , physicomechanical and molecular disposition . The effects of modifying electrospun poly ( vinyl alcohol ) ( P32926 ) nanofibers through crosslinking using glutaraldehyde ( GA ) are explored in this paper . Various concentrations of P32926 solutions containing model drugs rifampicin ( Q9HBH0 ) and isoniazid ( DB00951 ) were electrospun and thereafter crosslinked using GA vapors . P32926 nanofibers demonstrated high drug entrapment efficiency of 98 . 77 % ± 1 . 384 % and 95 . 07 % ± 1 . 988 % for the DB00951 - and Q9HBH0 - loaded P32926 nanofibers , respectively . The surface morphology , molecular vibrational transitions , tensile attributes and in vitro drug release were characterized and supported by in silico molecular mechanics simulations . Results indicated that crosslinking caused a significant reduction in the rate of drug release where 81 . 11 % ± 2 . 35 % of DB00951 and 59 . 31 % ± 2 . 57 % of Q9HBH0 were released after 12 h . Tensile properties such as the ultimate strength and Young ' s modulus increased after crosslinking , caused by crosslinks forming between P32926 nanofibers as was revealed through scanning electron microscopy analysis . Fourier Transform infrared analysis was conducted to further support the mode of crosslinking . Additionally , image processing analysis was carried out to quantify the effect of formulation variables on the morphology of nanofibers . Furthermore , the effect of GA - induced crosslinking and addition of drugs on the performance of electrospun fibers was further elucidated and conceptualized using a molecular mechanics assisted model building and energy refinement approach via molecular mechanics energy relationships by exploring the spatial disposition of energy - minimized molecular structures of the polymer , crosslinker and the drugs .\",\n \"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK25___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK25___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .\"\n]"},"candidates":{"kind":"list like","value":["___MASK1___","___MASK25___","___MASK49___","___MASK51___","___MASK57___","___MASK59___","___MASK63___","___MASK68___","___MASK80___"],"string":"[\n \"___MASK1___\",\n \"___MASK25___\",\n \"___MASK49___\",\n \"___MASK51___\",\n \"___MASK57___\",\n \"___MASK59___\",\n \"___MASK63___\",\n \"___MASK68___\",\n \"___MASK80___\"\n]"},"answer":{"kind":"string","value":"___MASK51___"},"id":{"kind":"string","value":"MH_train_391"}}},{"rowIdx":392,"cells":{"query":{"kind":"string","value":"interacts_with DB04835?"},"supports":{"kind":"list like","value":["DB04835 , a P51681 coreceptor antagonist that blocks entry of human immunodeficiency virus type 1 . Inhibition of the human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor is an encouraging new approach to pharmacotherapy against HIV . The HIV - 1 strain makes use of either the P51681 or the P61073 coreceptor to gain access into host P01730 + cells . DB04835 , the first HIV - 1 P51681 coreceptor antagonist , blocks entry of HIV - 1 . This recently approved drug has demonstrated clinically significant decreases in plasma concentrations of HIV - 1 RNA and increases in P01730 + cell counts ; however , it is indicated only for use as salvage therapy . Drug resistance is a concern , as is selective pressure on viral coreceptor use , because viral coreceptor targets may switch as disease progresses . In addition , before maraviroc therapy can be started , costly assays are required to determine the host ' s viral coreceptor tropism . Emerging therapies targeting P61073 , the other HIV coreceptor , have shown promise in decreasing plasma concentrations of HIV - 1 RNA . Long - term studies with both targets are required to explore the critical issues of efficacy and immunologic safety , as the function of these coreceptors is linked to host chemokine pathways .","What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation ___MASK45___ ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .","DB04835 . DB04835 , first in a new pharmacological class of antiretroviral agents known as P51681 antagonists , has been approved by the U . S . Food and Drug Administration for the treatment of HIV - infected adult patients who are infected with only P51681 - tropic HIV - 1 virus and who have HIV - 1 strains resistant to multiple antiretroviral agents . DB04835 has demonstrated in vitro activity against a wide range of P51681 tropic clinical isolates , including those resistant to the four currently existing drug classes of antiretroviral agents . In the two pivotal phase III studies , MOTIVATE - 1 and - 2 , maraviroc , in combination with optimized background therapy ( OBT ) , demonstrated superior virologic and immunologic treatment outcomes than OBT alone in treatment - experienced patients infected with P51681 - tropic HIV - 1 . In these studies , maraviroc also demonstrated acceptable safety and tolerability profiles with adverse events and discontinuation rates in general comparable to those noted in the placebo arms .","Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK75___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK75___ .","A novel bivalent HIV - 1 entry inhibitor reveals fundamental differences in P51681 - μ - opioid receptor interactions between human astroglia and microglia . OBJECTIVE : We explored whether the opiate , morphine , affects the actions of maraviroc , as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist , naltrexone , on HIV - 1 entry in primary human glia . METHODS : HIV - 1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV - 1 transactivator protein Tat . The effect of maraviroc and the bivalent ligand with or without morphine on P51681 surface expression and cytokine release was also explored . RESULTS : DB04835 inhibits HIV - 1 entry into glial cells , whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry . We also demonstrate that the maraviroc - containing bivalent ligand better inhibits R5 - tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine . Importantly , the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine . Exposure to maraviroc decreased the release of pro - inflammatory cytokines and restricted HIV - 1 - dependent increases in P51681 expression in both astrocytes and microglia , whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia . The P51681 - μ - opioid receptor ( MOR ) stoichiometric ratio varied among the two cell types with P51681 expressed at much higher levels than MOR in microglia , which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia . CONCLUSION : A novel bivalent compound reveals fundamental differences in P51681 - MOR interactions and HIV - 1 infectivity among glia , and has unique therapeutic potential in opiate abuse - HIV interactive comorbidity .","In vitro phenotypic susceptibility of HIV - 2 clinical isolates to P51681 inhibitors . HIV - 2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors , to a fusion inhibitor , and to some of the protease inhibitors . DB04835 is the first drug of the new anti - P51681 drug class and is effective only on P51681 - tropic ( R5 ) HIV - 1 . No previous studies concerning HIV - 2 susceptibility to maraviroc have been reported yet . We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell ( PBMC ) model . We analyzed the maraviroc susceptibility of 13 R5 HIV - 2 , 2 X4R5 ( dual ) HIV - 2 , and 2 P61073 - tropic ( X4 ) HIV - 2 clinical isolates . We also tested , with the same protocol , 1 X4 HIV - 1 and 4 R5 HIV - 1 clinical isolates . For the R5 HIV - 2 clinical isolates , the 50 % effective concentration ( EC ( 50 ) ) for maraviroc was 0 . 80 nM ( interquartile range [ IQR ] , 0 . 48 to 1 . 39 nM ) , similar to that observed for the R5 HIV - 1 isolates . The median maximum percentage of inhibition in the R5 HIV - 2 isolates was 93 % ( IQR , 84 to 98 % ) , similar to that observed in the R5 HIV - 1 isolates . As expected , both X4 HIV - 1 and HIV - 2 were highly resistant to maraviroc . Our study showed for the first time that maraviroc is active in vitro against R5 HIV - 2 . The new tools we developed will allow identification of HIV - 2 - infected patients eligible for P51681 inhibitor use and management of virological failure when receiving a maraviroc - based regimen .","The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .","Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK20___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .","Granulocyte - macrophage colony stimulating factor up - regulates P32246 in human neutrophils . Neutrophils ( polymorphonuclear leukocytes ; PMN ) are phagocytic cells instrumental in the clearance of infectious pathogens . Human PMN are commonly thought to respond primarily to chemokines from the CXC family . However , recent findings suggest that under specific cytokine activation conditions , PMN can also respond to some CC chemokines . In this study , the effect of GM - P04141 , a well - characterized PMN priming and maturation factor , on CC - chemokine receptor ( CCR ) expression in PMN was investigated . Constitutive expression of P32246 and P51677 mRNA in PMN was detected by ribonuclease protection assay . Following incubation of PMN with GM - P04141 ( 0 . 01 - 10 ng / ml ; 6 h ) P32246 mRNA expression was rapidly ( approximately 1 h ) up - regulated . In contrast , no significant induction of P41597 , P51677 , CCR4 , or P51681 mRNA was observed . P32246 protein was also up - regulated by GM - P04141 stimulation . GM - P04141 - induced up - regulation of P32246 showed functional consequences because GM - P04141 - treated PMN , but not control cells , responded to the CC chemokines macrophage inflammatory protein - 1alpha , monocyte chemoattractant protein - 3 , and RANTES in assays of chemotactic migration and intracellular calcium mobilization . These results suggest that PMN activated by the proinflammatory cytokine GM - P04141 can change their receptor expression pattern and become responsive to CC chemokines .","Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV - 1 ) is the predominant mode of infection world - wide . To better understand sexual transmission of HIV - 1 in women we have analysed virus co - receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA - DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV - 1 infection . P61073 was expressed at marginally higher levels than P51681 on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV - 1 following sexual contact can not be explained solely on the expression of chemokine co - receptors by T lymphocyte subsets .","Structure and dynamics of the gp120 V3 loop that confers noncompetitive resistance in R5 HIV - 1 ( JR - FL ) to maraviroc . DB04835 , an ( HIV - 1 ) entry inhibitor , binds to P51681 and efficiently prevents R5 human immunodeficiency virus type 1 ( HIV - 1 ) from using P51681 as a coreceptor for entry into P01730 (+) cells . However , HIV - 1 can elude maraviroc by using the drug - bound form of P51681 as a coreceptor . This property is known as noncompetitive resistance . HIV - 1 ( V3 - M5 ) derived from HIV - 1 ( JR - FLan ) is a noncompetitive - resistant virus that contains five mutations ( I304V / F312W / T314A / E317D / I318V ) in the gp120 V3 loop alone . To obtain genetic and structural insights into maraviroc resistance in HIV - 1 , we performed here mutagenesis and computer - assisted structural study . A series of site - directed mutagenesis experiments demonstrated that combinations of V3 mutations are required for HIV - 1 ( JR - FLan ) to replicate in the presence of 1 µM maraviroc , and that a T199K mutation in the P06681 region increases viral fitness in combination with V3 mutations . Molecular dynamic ( MD ) simulations of the gp120 outer domain V3 loop with or without the five mutations showed that the V3 mutations induced ( i ) changes in V3 configuration on the gp120 outer domain , ( ii ) reduction of an anti - parallel β - sheet in the V3 stem region , ( iii ) reduction in fluctuations of the V3 tip and stem regions , and ( iv ) a shift of the fluctuation site at the V3 base region . These results suggest that the HIV - 1 gp120 V3 mutations that confer maraviroc resistance alter structure and dynamics of the V3 loop on the gp120 outer domain , and enable interactions between gp120 and the drug - bound form of P51681 .","Host factors mediating HIV - 1 replication . Human immunodeficiency virus type 1 ( HIV - 1 ) infection is the leading cause of death worldwide in adults attributable to infectious diseases . Although the majority of infections are in sub - Saharan Africa and Southeast Asia , HIV - 1 is also a major health concern in most countries throughout the globe . While current antiretroviral treatments are generally effective , particularly in combination therapy , limitations exist due to drug resistance occurring among the drug classes . Traditionally , HIV - 1 drugs have targeted viral proteins , which are mutable targets . As cellular genes mutate relatively infrequently , host proteins may prove to be more durable targets than viral proteins . HIV - 1 replication is dependent upon cellular proteins that perform essential roles during the viral life cycle . DB04835 is the first FDA - approved antiretroviral drug to target a cellular factor , HIV - 1 coreceptor P51681 , and serves to intercept viral - host protein - protein interactions mediating entry . Recent large - scale siRNA and shRNA screens have revealed over 1000 candidate host factors that potentially support HIV - 1 replication , and have implicated new pathways in the viral life cycle . These host proteins and cellular pathways may represent important targets for future therapeutic discoveries . This review discusses critical cellular factors that facilitate the successive steps in HIV - 1 replication .","Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .","P51681 antibodies HGS004 and HGS101 preferentially inhibit drug - bound P51681 infection and restore drug sensitivity of DB04835 - resistant HIV - 1 in primary cells . R5 HIV - 1 strains resistant to the P51681 antagonist DB04835 ( MVC ) can use drug - bound P51681 . We demonstrate that MVC - resistant HIV - 1 exhibits delayed kinetics of coreceptor engagement and fusion during drug - bound versus free P51681 infection of cell lines . Antibodies directed against the second extracellular loop ( ECL2 ) of P51681 had greater antiviral activity against MVC - bound compared to MVC - free P51681 infection . However , in PBMCs , only ECL2 P51681 antibodies HGS004 and HGS101 , but not 2D7 , inhibited infection by MVC resistant HIV - 1 more potently with MVC - bound than with free P51681 . In addition , HGS004 and HGS101 , but not 2D7 , restored the antiviral activity of MVC against resistant virus in PBMCs . In flow cytometric studies , P51681 binding by the O14964 mAbs , but not by 2D7 , was increased when PBMCs were treated with MVC , suggesting MVC increases exposure of the relevant epitope . Thus , HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance .","Multipotent stem / progenitor cells in human biliary tree give rise to hepatocytes , cholangiocytes , and pancreatic islets . Multipotent stem / progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato - pancreatic common duct , cystic duct , and hilum . They express endodermal transcription factors ( e . g . , Sox9 , Q9H6I2 , Q9Y261 , PDX1 , HES1 , Q9Y4Z2 , Q92786 ) intranuclearly , stem / progenitor surface markers ( EpCAM , P13591 , CD133 , P61073 ) , and sometimes weakly adult liver , bile duct , and pancreatic genes ( albumin , cystic fibrosis transmembrane conductance regulator [ P13569 ] , and insulin ) . They clonogenically expand on plastic and in serum - free medium , tailored for endodermal progenitors , remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈ 36 hours and slowing to one every 2 - 3 days . Transfer into distinct culture conditions , each comprised of a specific mix of hormones and matrix components , yields either cords of hepatocytes ( express albumin , P08684 , and transferrin ) , branching ducts of cholangiocytes ( expressing anion exchanger - 2 - P04920 and P13569 ) , or regulatable C - peptide secreting neoislet - like clusters ( expressing glucagon , insulin ) and accompanied by changes in gene expression correlating with the adult fate . Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes , whereas if into fat pads of streptozocin - induced diabetic mice , results in functional islets secreting glucose - regulatable human C - peptide . CONCLUSION : The phenotypes and availability from all age donors suggest that these stem / progenitors have considerable potential for regenerative therapies of liver , bile duct , and pancreatic diseases including diabetes .","Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice . Guidelines state that the P51681 - inhibitor DB04835 should be prescribed to patients infected with R5 - tropic HIV - 1 only . Therefore , viral tropism needs to be assessed phenotypically or genotypically . Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4 - tropic variants . Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co - receptor usage in routine clinical practice . Samples from therapy - naive and therapy - experienced patients were collected for routine tropism testing at three European clinical centres . Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells . Q14624 - V3 was amplified in a triplicate nested RT - PCR procedure and sequenced . Co - receptor usage was predicted using the Geno2Pheno ( [ coreceptor ] ) algorithm and analysed with a false - positive rate ( P21462 ) of 5 . 75 % , 10 % , or an P21462 of 20 % and according to the current European guidelines on the clinical management of HIV - 1 tropism testing . A total of 266 sequences were obtained from 101 patient samples . Discordance in tropism prediction for the triplicates was observed in ten samples using an P21462 of 10 % . Triplicate testing resulted in a 16 . 7 % increase in X4 - predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for DB04835 treatment . In conclusion , triplicate genotypic tropism testing increases X4 tropism detection in individual cases , which may prove to be pivotal when P51681 - inhibitor therapy is applied .","Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .","Discordance rates between Trofile test and short - term virological response to maraviroc . Enhanced sensitivity Trofile ( ES - Trofile ) is the most frequently used technique to assay HIV tropism . A clinical approach to predict P51681 - antagonists efficacy , based on the virological response to a short - term maraviroc exposure ( DB04835 Clinical Test , Q8IVS2 ) , has been recently reported . We compared the results of ES - Trofile with Q8IVS2 in 47 HIV - infected patients , and a global discordance around 15 % was observed between the phenotypic method and the clinical approach . Discordance results were mainly found in patients with an ES - Trofile reported as dual / mixed . These provocative results might have important clinical implications and should be considered in order to accurately prescribe treatment with P51681 antagonists .","___MASK17___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK17___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .","Regulation of cell cycle proteins by chemokine receptors : A novel pathway in human immunodeficiency virus neuropathogenesis ? In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus ( HIV ) , the authors have been studying the effect of chemokines on the CDK / P06400 / Q01094 pathway -- which is involved in neuronal apoptosis and differentiation . First , they have asked whether P61073 , the specific receptor for the chemokine P48061 and X4 - using gp120s , can regulate P06400 and Q01094 activity in cultures of differentiated rat neurons . Although P51677 and P51681 are known to mediate infection of microglia by HIV - 1 , recent evidence indicate that P61073 also play important roles in HIV - induced neuronal injury , and dual - tropic isolates that use P61073 to infect macrophages have recently been reported . The authors have focused on two specific brain areas in which P61073 is physiologically relevant , i . e . , the cerebellum and the hippocampus . So far , the data indicate that changes in the nuclear and cytosolic levels of P06400 , which result in the functional loss of this protein , are associated with apoptosis in these neurons , and that SDF - 1alpha and gp120IIIB affect this pathway . A summary of the findings are presented .","___MASK95___ : kinetic and dynamic profile in the treatment of pain . ___MASK95___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK95___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK95___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK95___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .","Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced P22301 expression . Biomaterial scaffolds are central to many tissue engineering strategies as they create a space for tissue growth and provide a support for cell adhesion and migration . However , biomaterial implantation results in unavoidable injury resulting in an inflammatory response , which can impair integration with the host and tissue regeneration . Toward the goal of reducing inflammation , we investigated the hypothesis that a lentiviral gene therapy - based approach to localized and sustained P22301 expression at a scaffold could modulate the number , relative proportions , and cytokine production of infiltrating leukocyte populations . Flow cytometry was used to quantify infiltration of six leukocyte populations for 21 days following implantation of P00747 scaffolds into intraperitoneal fat . Leukocytes with innate immune functions ( i . e . , macrophages , dendritic cells , neutrophils ) were most prevalent at early time points , while T lymphocytes became prevalent by day 14 . Reporter gene delivery indicated that transgene expression persisted at the scaffold for up to 28 days and macrophages were the most common leukocyte transduced , while transduced dendritic cells expressed the greatest levels of transgene . P22301 delivery decreased leukocyte infiltration by 50 % relative to controls , increased macrophage P22301 expression , and decreased macrophage , dendritic cell , and P01730 T cell IFN - γ expression . Thus , P22301 gene delivery significantly decreased inflammation following scaffold implant into the intraperitoneal fat , in part by modulating cytokine expression of infiltrating leukocytes .","Two - year safety and virologic efficacy of maraviroc in treatment - experienced patients with P51681 - tropic HIV - 1 infection : 96 - week combined analysis of MOTIVATE 1 and 2 . BACKGROUND : DB04835 , the first approved P51681 antagonist , demonstrated 48 - week safety and virologic efficacy in P51681 - tropic HIV - infected , treatment - experienced patients ; however , critical longer - term safety and durability of responses are unknown . METHODS : Two - year follow - up of 2 prospective , randomized , blinded studies of maraviroc once daily or twice daily , or placebo in treatment - experienced patients with R5 - tropic HIV - 1 receiving an optimized background regimen . Unblinding occurred after the week - 48 visit of the last enrolled patient . Safety and virologic parameters were assessed through week 96 . RESULTS : One thousand forty - nine patients were randomized and received study drugs . HIV - 1 RNA was < 50 copies per milliliter at week 96 in 39 % and 41 % of patients receiving maraviroc every day or twice a day , respectively . Among patients with HIV - 1 RNA < 50 copies per milliliter at week 48 , 81 % and 87 % of patients receiving maraviroc every day or twice a day , respectively , maintained this response at week 96 . At week 96 , median P01730 + T - cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day , respectively . Exposure - adjusted rates of adverse events were similar with maraviroc or placebo . No new or unexpected events were observed after week 48 . CONCLUSIONS : DB04835 - containing antiretroviral regimens maintained durable responses in treatment - experienced patients with R5 HIV - 1 through 96 weeks of treatment with a safety profile similar to placebo .","Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis - infected mice is modulated by interferon - gamma . Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions . Here , we evaluated the expression of chemokines and chemokine receptors and their regulation by P01579 in the course of Paracoccidioides brasiliensis ( Pb ) infection in mice . We found an association between KC and MIP - 1alpha ( P10147 ) production and neutrophil infiltration in the lungs of Pb - infected mice during the early acute phase of infection . High levels of RANTES / P13501 , P13500 / P13500 , P02778 / P02778 , and Mig / Q07325 simultaneously with mononuclear cell infiltration in the lungs was found . In the absence of P01579 ( GKO mice ) we observed increased production of KC and MIP - 1alpha and chronic neutrophilia . Moreover , we found a change in the chemokine receptor profiles expressed by wild - type ( WT ) versus GKO animals . Increased expression of P49682 and P51681 , and low levels of P51677 and CCR4 were observed in the lungs of Pb - infected WT mice , whereas the opposite effect was observed in the lungs of GKO mice . Consistent with these results , infected cells from WT mice preferentially migrated in response to P02778 ( P49682 ligand ) , while those from GKO mice migrated in response to eotaxin / P51671 ( P51677 ligand ) . These results suggest that P01579 modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb - infected mice .","The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK45___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .","[ At what time and with which combinations should maraviroc be indicated in the new antiretroviral treatment scenario ? ] . DB04835 is a selective and slowly reversible antagonist of the P51681 co - receptor which has shown to have powerful antiviral activity , in vitro , against a wide range of HIV clinical isolates , including strains multi - resistant to 4 classes of pre - existing antiretroviral drugs . DB04835 is active against HIV populations that only use the P51681 coreceptor to enter the cell and has not demonstrated significant activity in the treatment of viral populations that use the P61073 co - receptor . The mechanism of action of maraviroc , non - competitive with other antiretroviral drugs , and the absence of crossed resistance with the rest of their families , has led to DB04835 being a drug available for use in rescue antiretroviral treatment . However , the excellent tolerance of maraviroc compared to the placebo in phase III clinical trials , its safety and its favourable pharmacological interactions profile with other drugs commonly used in HIV infected patients with comorbidity brings to light other scenarios in which DB04835 could be useful .","Reviews of anti - infective agents : maraviroc : the first of a new class of antiretroviral agents . DB04835 is the first US Food and Drug Administration - approved drug from a new class of antiretroviral agents that targets a host protein , the chemokine receptor P51681 , rather than a viral target . Binding of maraviroc to this cell - surface protein results in blocking human immunodeficiency virus type 1 ( HIV - 1 ) attachment to the coreceptor and prevents the virus from entering P01730 + cells . In this review , we include the details of the discoveries that led to the development of this drug . The drug ' s pharmacology , including pharmacokinetics and drug interactions , is discussed , as are the clinical efficacy studies that led to licensure . HIV - 1 mechanisms of resistance to maraviroc , assays to determine viral coreceptor use ( tropism ) , drug safety , and clinical use of maraviroc are discussed at length .","The use of intraallelic variability for testing neutrality and estimating population growth rate . To better understand the forces affecting individual alleles , we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci ( the intraallelic variability ) . We model three types of intraallelic variability : ( a ) the number of nonrecombinants at a linked biallelic marker locus , ( b ) the length of a conserved haplotype , and ( c ) the number of mutations at a linked marker locus . If the population growth rate is known , the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency . If the population growth rate is unknown but neutrality can be assumed , the joint distribution provides the likelihood of the growth rate and leads to a maximum - likelihood estimate . We apply the method to data from published data sets for four loci in humans . We conclude that the Delta32 allele at P51681 and a disease - associated allele at P40692 arose recently and have been subject to strong selection . Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0 . 027 per generation with a support interval of ( 0 . 017 - 0 . 037 ) . Four of the relatively common alleles at P13569 also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers .","Allosteric model of maraviroc binding to CC chemokine receptor 5 ( P51681 ) . DB04835 is a nonpeptidic small molecule human immunodeficiency virus type 1 ( HIV - 1 ) entry inhibitor that has just entered the therapeutic arsenal for the treatment of patients . We recently demonstrated that maraviroc binding to the HIV - 1 coreceptor , CC chemokine receptor 5 ( P51681 ) , prevents it from binding the chemokine P10147 and the viral envelope glycoprotein gp120 by an allosteric mechanism . However , incomplete knowledge of ligand - binding sites and the lack of P51681 crystal structures have hampered an in - depth molecular understanding of how the inhibitor works . Here , we addressed these issues by combining site - directed mutagenesis ( SDM ) with homology modeling and docking . Six crystal structures of G - protein - coupled receptors were compared for their suitability for P51681 modeling . All P51681 models had equally good geometry , but that built from the recently reported dimeric structure of the other HIV - 1 coreceptor P61073 bound to the peptide CVX15 ( Protein Data Bank code 3OE0 ) best agreed with the SDM data and discriminated P51681 from non - P51681 binders in a virtual screening approach . SDM and automated docking predicted that maraviroc inserts deeply in P51681 transmembrane cavity where it can occupy three different binding sites , whereas P10147 and gp120 lie on distinct yet overlapped regions of the P51681 extracellular loop 2 . Data suggesting that the transmembrane cavity remains accessible for maraviroc in P10147 - bound and gp120 - bound P51681 help explain our previous observation that the inhibitor enhances dissociation of preformed ligand - P51681 complexes . Finally , we identified residues in the predicted P51681 dimer interface that are mandatory for gp120 binding , suggesting that receptor dimerization might represent a target for new P51681 entry inhibitors .","Hepatic safety and tolerability in the maraviroc clinical development program . DB04835 is the first P51681 antagonist to be approved for the treatment of HIV - 1 infection . It is generally well tolerated , with a similar side - effect profile to placebo in controlled studies . Many agents used to treat HIV disease are associated with the potential for hepatotoxicity . The hepatic effects of maraviroc were analyzed across all Pfizer - sponsored maraviroc clinical trials , in which 2350 volunteers received maraviroc . Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1 / 2a studies of up to 28 - day duration , they demonstrated no dose relationship or association with hyperbilirubinemia . In the four phase 2b / 3 studies in antiretroviral - naive and antiretroviral - experienced patients , there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96 . The findings were similar in patients coinfected with hepatitis B and / or C virus , although the number of coinfected patients was small . No patient met the strict definition for Hy ' s Law . Two participants reported severe hepatotoxicity and although other potential causes were present , the contribution of maraviroc to these events could not be excluded . This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied .","[ Methods for determining viral tropism : genotype and phenotype tests ] . The recent approval of the first P51681 antagonist , DB04835 ( MVC , Celsentri ) , with specific antiviral activity against R5 - tropic virus variants has generated the need for studies to determine the viral tropism in all those patient candidates for starting treatment with this new drug . Although genotyping methods appear to be the most useful tool due to its speed and simplicity , in the case of viral tropism , phenotyping techniques are currently considered the most reliable . In the last few years , different phenotyping assays have been developed to determine the use of the co - receptor . However , the Trofile phenotype assay is currently the one most used for the determination of tropism , since it is the only one that has been clinically validated . Given that the presence of X4 - tropic variants in the viral population has been associated with virological failure to MVC , the main challenge of both genotyping and phenotyping tools is to optimise their sensitivity for detecting X4 - tropic variants present in a minority of the viral population . At the same time , the correlation between genotyping / phenotyping methods is being evaluated to determine whether genotyping tools can be useful to make therapeutic decisions .","Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK75___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK75___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .","Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK44___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .","Essential role for retinoic acid in the promotion of P01730 (+) T cell effector responses via retinoic acid receptor alpha . DB00162 and its metabolite , retinoic acid ( RA ) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells . Here we showed RA was also required to elicit proinflammatory P01730 (+) helper T cell responses to infection and mucosal vaccination . P10276 ( RARα ) was the critical mediator of these effects . Antagonism of RAR signaling and deficiency in RARα ( Rara (-/-) ) resulted in a cell - autonomous P01730 (+) T cell activation defect , which impaired intermediate signaling events , including calcium mobilization . Altogether , these findings reveal a fundamental role for the RA - RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses .","DB04835 . DB04835 is a specific , slowly reversible , noncompetitive , small - molecule antagonist of the P51681 chemokine receptor , which also serves as an HIV - 1 coreceptor . By acting as an antagonist at the P51681 coreceptor , maraviroc inhibits HIV - 1 from entering host cells . Clinical data for maraviroc are available from two large , well designed , ongoing phase IIb / III trials ( MOTIVATE - 1 and MOTIVATE - 2 ) conducted in patients infected with R5 - tropic HIV - 1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and / or were triple - class resistant . According to 24 - week interim results of the MOTIVATE - 1 and - 2 trials , a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg ( depending on optimised background therapy [ OBT ] ) twice daily plus OBT compared with placebo plus OBT . This significant difference was maintained at 48 weeks in MOTIVATE - 1 . In the MOTIVATE - 1 and - 2 trials , a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV - 1 RNA level < 400 and < 50 copies / mL compared with those receiving placebo plus OBT . In addition , the P01730 + cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT . The 48 - week results of MOTIVATE - 1 also report a significant difference in favour of maraviroc for all these endpoints . In general , maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment - experienced patients infected with R5 - tropic HIV - 1 .","Deep sequencing to infer HIV - 1 co - receptor usage : application to three clinical trials of maraviroc in treatment - experienced patients . BACKGROUND : The DB04835 versus Optimized Therapy in Viremic Antiretroviral Treatment - Experienced Patients ( MOTIVATE ) studies compared maraviroc versus placebo in treatment - experienced patients with P51681 - using ( R5 ) human immunodeficiency virus type 1 ( HIV - 1 ) , screened using the original Trofile assay . A subset with non - R5 HIV infection entered the A4001029 trial . We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials . METHODS : V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche / 454 GS - FLX to a depth of > 3000 sequences / sample . Samples were considered non - R5 if ≥ 2 % of their viral population scored greater than or equal to - 4 . 75 or ≤ 3 . 5 using the PSSM ( x4 / R5 ) or geno2pheno algorithms , respectively . RESULTS : Deep sequencing identified more than twice as many maraviroc recipients as having non - R5 HIV , compared with the original Trofile . With use of genotyping , we determined that 49 % of maraviroc recipients with R5 HIV at screening had a week 48 viral load < 50 copies / mL versus 26 % of recipients with non - R5 . Corresponding percentages were 46 % and 23 % with screening by Trofile . In cases in which screening assays differed , median week 8 log₁₀ copies / mL viral load decrease favored 454 . Other parameters predicted by genotyping included likelihood of changing to non - R5 tropism . CONCLUSIONS : This large study establishes deep V3 sequencing as a promising tool for identifying treatment - experienced individuals who could benefit from P51681 - antagonist - containing regimens .","[ Pharmacokinetics , interactions and mechanism of action of maraviroc ] . DB04835 ( MVC , Celsentri ) is an allosteric and reversible inhibitor of the P51681 chemokine coreceptor . MVC is the first marketed P51681 antagonist and the only oral entry inhibitor approved so far for the treatment of HIV infection . It has been approved for adults with previous antiretroviral exposure . MVC exclusively inhibits the replication of R5 - tropic HIV - 1 variants after binding to the transmembrane P51681 receptor cavity . MVC is rapidly absorbed following oral administration , and plasma T ( max ) is achieved within 0 . 5 - 4 hours after a 300 mg dose . Renal clearance is approximately 10 - 12 L / h . MVC is a substrate of the cytochrome P450 isoenzyme 3A4 ; therefore dose adjustments are required when co - administrated with other drugs that induce or inhibit P08684 . In addition , MVC dose adjustments are advised in patients with renal failure ( CLcr < 80 ml / min ) only if they receive P08684 inhibitors .","A microsimulation of the cost - effectiveness of maraviroc for antiretroviral treatment - experienced HIV - infected individuals . PURPOSE : DB04835 ( MVC ) is the first approved P51681 antagonist . The aim of this study was to explore the cost - effectiveness of MVC in treatment - experienced or treatment - resistant HIV - infected adults . METHODS : The validated HIV microsimulation model ARAMIS was used to predict clinical and economic outcomes of treating patients with optimized background therapy ( OBT ) alone , as compared to a strategy of testing for the patient ' s viral tropism and treating with OBT with or without ( +/- ) MVC in a cohort corresponding to the MOTIVATE screening cohort . RESULTS : Compared to treatment with OBT alone , a treatment strategy of OBT +/- MVC ( twice daily ) according to tropism test result was predicted to increase P01730 + cell count after 5 years ( from mean 249 to 360 cells / microL ) , undiscounted life expectancy ( 7 . 6 to 8 . 9 years ) , and quality - adjusted life years ( QALYs ; from 4 . 99 to 5 . 71 ) for an additional $ 40 , 500 , giving an incremental cost - effectiveness ratio of $ 56 , 400 per QALY gained . The result was relatively insensitive to alternative clinical and cost assumptions within reasonable ranges , but for individuals with HIV susceptible to only two or fewer components of OBT , the Q03060 decreased to $ 52 , 000 per QALY gained . CONCLUSION : MVC is cost - effective , especially among individuals with few remaining options for active antiretroviral therapy .","Development and application of a simple LC - MS method for the determination of plasma maraviroc concentrations . DB04835 is an orally available antagonist of the P51681 chemokine receptor , which acts as a human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor . Binding of maraviroc to this receptor blocks HIV - 1 attachment to the coreceptor and prevents HIV - 1 from entering host cells . DB04835 does not require intracellular processing to exert this activity . Drug interaction studies have shown changes in maraviroc exposure when given with other anti - HIV medications , and thus quantification of maraviroc in human plasma is important to manage drug interactions and to evaluate the relationship between plasma concentrations and treatment response . We developed a conventional LC - MS method for determining plasma maraviroc concentrations , validated by estimating precision and accuracy for inter - and intraday analysis in the concentration range of 0 . 011 - 2 . 188 µg / ml . The calibration curve was linear within this range . The average accuracy ranged from 92 . 7 % to 99 . 7 % , while the relative standard deviations of both inter - and intraday assays were less than 7 . 1 % . Recovery of maraviroc exceeded 86 . 7 % . Our LC - MS method provides a conventional , accurate and precise way to determine the maraviroc concentration in human plasma . This method enables dose adjustment based on monitoring plasma maraviroc concentrations and permits management of drug interactions and toxicity .","DB04835 is able to inhibit dual - R5 viruses in a dual / mixed HIV - 1 - infected patient . OBJECTIVES : DB04835 is the first licensed chemokine co - receptor 5 ( P51681 ) co - receptor antagonist in clinical practice . It is currently being used in patients harbouring exclusively P51681 - tropic virus . The objective of the study was to investigate the impact of maraviroc on viruses with different co - receptor preferences in a patient with a dual / mixed ( D / M ) infection . METHODS : We present a case report of an HIV - 1 patient infected with a D / M virus population . Co - receptor tropism was determined by phenotypic and genotypic tests . Biological clones from pre - and post - maraviroc therapy were generated . Tropism of these infectious clones was investigated in U373 - MAGI cells expressing P01730 + P51681 + or P01730 + P61073 + . DB04835 susceptibility and viral replication were determined using donor peripheral blood mononuclear cells ( PBMCs ) . RESULTS : In - depth clonal genotypic analysis revealed the presence of both R5 - tropic variants and X4 - tropic viruses before the start of maraviroc . During maraviroc therapy all R5 - predicted viruses were suppressed . Phenotypic analyses revealed that all biological clones before maraviroc therapy could infect both P51681 - and P61073 - bearing U373 - MAGI cells , demonstrating dual tropism . The baseline biological clones preferentially infected the P51681 cell line and were fully susceptible to maraviroc in PBMCs ( dual - R5 ) . In contrast , during maraviroc therapy the dual - R5 - tropic viruses were replaced by more X4 - tropic viruses ( dual - X4 ) , which could not be inhibited by maraviroc . CONCLUSIONS : This case report demonstrates that dual - tropic viruses , capable of using both co - receptors in phenotypic assays , can be inhibited by maraviroc if they have a P51681 co - receptor preference in vivo .","Safety profile of maraviroc in patients coinfected with HIV - 1 and hepatitis B or C included in the maraviroc expanded access program . OBJECTIVE : To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV - 1 coinfected with hepatitis B virus ( HBV ) or hepatitis C virus ( HCV ) . METHODS : This was a multicenter , noncomparative , open - label , expanded access program ( EAP ) initiated in February 2007 . Patients with P51681 - tropic HIV - 1 and HIV - 1 RNA ≥ 1000 copies / mL on their current treatment received maraviroc 300 mg ( 150 mg with protease inhibitors ) twice daily with optimized background therapy ( OBT ) , which could include the newer agents raltegravir , etravirine , and darunavir . The adverse event ( AE ) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2 , where the OBT did not include these agents . RESULTS : A total of 1 , 032 patients were enrolled : 51 HIV / HBV coinfected ; 149 HIV / HCV coinfected , 9 HIV / HBV / HCV coinfected , and 823 HIV - 1 monoinfected . Most ( 76 % ) received at least 1 newer agent . Overall AE frequency was comparable across coinfection groups ( 63 % - 72 % ) . Hepatobiliary events were more common in HIV / HCV coinfection than in HIV monoinfection or HIV / HBV coinfection ( 10 . 0 , 4 . 8 , and 3 . 1 per 100 patient - years , respectively ) . Across all coinfection groups , there was a trend toward lower exposure - adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies . Grade 3 / 4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm . CONCLUSION : DB04835 plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV - 1 - infected patients coinfected with HBV or HCV .","Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .","Maternal - fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques . Single - dose nevirapine ( DB00238 ) is effective in reducing mother - to - child transmission ( MTCT ) of HIV ; however , the subsequent development of drug resistance is problematic . The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to DB00238 in a single - dose strategy . Four pregnant macaques received an oral dose of maraviroc 2 h before delivery , and both infant and maternal plasma maraviroc concentrations and P51681 receptor occupancy on P01730 (+) lymphocytes were measured over time . Maximum plasma maraviroc concentrations were found at delivery ( 2 - h - postintrapartum dose ) in both the mothers and infants , with median concentrations of 974 ng / ml ( range , 86 to 2 , 830 ng / ml ) and 22 ng / ml ( range , 4 to 99 ng / ml ) , respectively . DB04835 was detected in the plasma of mothers up to 48 h after dosing but only as long as 3 . 5 h in the infants . The median fetal - maternal area under the concentration - time curve ( AUC ) ratio was 0 . 009 ( range , 0 . 000 to 0 . 015 ) . DB04835 receptor occupancy data showed evidence of unprotected P51681 receptors on P01730 (+) cells in the mothers 24 to 48 h after dosing . Extremely low P51681 expression on P01730 (+) cells of newborn macaques prevented determination of receptor occupancy in the infants . In rhesus macaques , maraviroc was poorly transferred across the placenta and was quickly cleared from the infants ' blood . The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV .","HIV - 1 resistance to maraviroc conferred by a P01730 binding site mutation in the envelope glycoprotein gp120 . DB04835 ( MVC ) is a P51681 antagonist that inhibits HIV - 1 entry by binding to the coreceptor and inducing structural alterations in the extracellular loops . In this study , we isolated MVC - resistant variants from an HIV - 1 primary isolate that arose after 21 weeks of tissue culture passage in the presence of inhibitor . gp120 sequences from passage control and MVC - resistant cultures were cloned into NL4 - 3 via yeast - based recombination followed by sequencing and drug susceptibility testing . Using 140 clones , three mutations were linked to MVC resistance , but none appeared in the V3 loop as was the case with previous HIV - 1 strains resistant to P51681 antagonists . Rather , resistance was dependent upon a single mutation in the C4 region of gp120 . Chimeric clones bearing this N425K mutation replicated at high MVC concentrations and displayed significant shifts in 50 % inhibitory concentrations ( IC ( 50 ) s ) , characteristic of resistance to all other antiretroviral drugs but not typical of MVC resistance . Previous reports on MVC resistance describe an ability to use a drug - bound form of the receptor , leading to reduction in maximal drug inhibition . In contrast , our structural models on K425 gp120 suggest that this resistant mutation impacts P01730 interactions and highlights a novel pathway for MVC resistance .","P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .","Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .","DB04835 versus efavirenz , both in combination with zidovudine - lamivudine , for the treatment of antiretroviral - naive subjects with P51681 - tropic HIV - 1 infection . BACKGROUND : The MERIT ( DB04835 versus Efavirenz in Treatment - Naive Patients ) study compared maraviroc and efavirenz , both with zidovudine - lamivudine , in antiretroviral - naive patients with R5 human immunodeficiency virus type 1 ( HIV - 1 ) infection . METHODS : Patients screened for R5 HIV - 1 were randomized to receive efavirenz ( 600 mg once daily ) or maraviroc ( 300 mg once or twice daily ) with zidovudine - lamivudine . Coprimary end points were proportions of patients with a viral load < 400 and < 50 copies / mL at week 48 ; the noninferiority of maraviroc was assessed . RESULTS : The once - daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria . In the primary 48 - week analysis ( n = 721 ) , maraviroc was noninferior for < 400 copies / mL ( 70 . 6 % for maraviroc vs 73 . 1 % for efavirenz ) but not for < 50 copies / mL ( 65 . 3 % vs 69 . 3 % ) at a threshold of - 10 % . More maraviroc patients discontinued for lack of efficacy ( 11 . 9 % vs 4 . 2 % ) , but fewer discontinued for adverse events ( 4 . 2 % vs 13 . 6 % ) . In a post hoc reanalysis excluding 107 patients ( 15 % ) with non - R5 screening virus by the current , more sensitive tropism assay , the lower bound of the 1 - sided 97 . 5 % confidence interval for the difference between treatment groups was above - 10 % for each end point . CONCLUSIONS : Twice - daily maraviroc was not noninferior to efavirenz at < 50 copies / mL in the primary analysis . However , 15 % of patients would have been ineligible for inclusion by a more sensitive screening assay . Their retrospective exclusion resulted in similar response rates in both arms Trial registration . ClinicalTrials . gov identifier : ( NCT00098293 ) .","Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK87___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .","Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc , an inhibitor of HIV - 1 entry via the P51681 co - receptor . An effective vaginal microbicide could reduce human immunodeficiency virus type 1 ( HIV - 1 ) transmission to women . Among microbicide candidates in clinical development is DB04835 ( MVC ) , a small - molecule drug that binds the P51681 co - receptor and impedes HIV - 1 entry into cells . Delivered systemically , MVC reduces viral load in HIV - 1 - infected individuals , but its ability to prevent transmission is untested . We have now evaluated MVC as a vaginal microbicide with use of a stringent model that involves challenge of rhesus macaques with a high - dose of a P51681 - using virus , SHIV - 162P3 . Gel - formulated , prescription - grade MVC provided dose - dependent protection , half - maximally at 0 . 5 mM ( 0 . 25 mg / mL ) . The duration of protection was transient ; the longer the delay between MVC application and virus challenge , the less protection ( half life of approximately 4 h ) . As expected , MVC neither protected against challenge with a P61073 - using virus , SHIV - KU1 , nor exacerbated postinfection viremia . These findings validate MVC development as a vaginal microbicide for women and should guide clinical programs .","Inhibition of thrombin activity by prothrombin activation fragment 1 . 2 . P00734 is the precursor of thrombin , the central enzyme in coagulation . P00734 is activated in vivo by the prothrombinase complex to form fragment 1 . 2 and thrombin . Fragment 1 . 2 has an amino - terminal gla domain and two kringle domains . The second kringle domain ( kringle 2 ) binds to the exosite II on thrombin . Nascent thrombin generated on platelet surface remains non - covalently bound to fragment 1 . 2 by kringle 2 - exosite II interaction . To determine whether this interaction can modulate coagulant activity of thrombin , we labeled thrombin at the active site with fluorescein - DB00120 - Pro - DB00125 chloromethylketone and monitored the fluorescence changes upon ligand binding . Anionic phospholipid - bound fragment 1 . 2 and fragment 2 bound to P21462 - thrombin and induced changes in the active site with half maximal effects at 7 . 2 microM and 8 . 8 microM , respectively . We also tested the effect of anionic phospholipid - bound fragment 1 . 2 ( 0 - 10 microM ) on thrombin clotting activity . Phospholipid - bound fragment 1 . 2 inhibited fibrinogen clotting in a concentration - dependent manner but had no significant effect on amidolytic activity towards S2238 , suggesting a competitive inhibition of the fibrinogen binding site . Furthermore , fragment 1 . 2 inhibited P21462 - thrombin binding to platelet . Consistent with these findings fragment 1 . 2 inhibited thrombin - induced aggregation of gel filtered platelets in a concentration - dependant manner . These results suggest that the membrane - bound prothrombin fragment 1 . 2 may play a role in hemostasis by down regulating the procoagulant activity of newly formed thrombin .","[ Clinical pharmacokinetic of maraviroc ] . DB04835 ( MVC , UK - 427 , 857 ) is the first member of a new class , the P51681 antagonists . By an original mechanism of action , maraviroc binds to the P51681 receptor in order to prevent HIV from binding and entering human cells . DB04835 ( Celsentri ) is an orally administered drug available as 150 and 300 mg film - coated tablets . The current approved daily dosage of maraviroc is 300 mg bid in combination with other antiretroviral medications . DB04835 plasma exposure is not dose proportional . After a rapid ( but moderate ) intestinal absorption , several inactive oxidized metabolites are produced via cytochrome P450 3A4 pathway . According to this liver metabolism , dosage adjustments are required when maraviroc is administered in combination with cytochrome P450 inhibitors or inducers . The potential for drug - drug interactions and the well - defined relationship between plasma concentrations and virological response suggest the usefulness of Therapeutic Drug Monitoring of maraviroc in HIV - infected patients .","[ Mechanisms of resistance and failure of treatment with maraviroc ] . DB04835 ( MVC ) is a new antagonist of the P51681 coreceptor and is the first antiviral compound available that has a cell factor essential for HIV entry as a target . The information available from clinical studies with MVC suggests that the main cause of therapeutic failure is , more than the tropism change , the rapid selection of pre - existing strains with an affinity for P61073 , not detected by the reference test . A recently developed tropism test with an improved sensitivity will help to detect the minority , but clinically significant , presence of strains that use P61073 . Evidence of resistance to MVC has been shown in vivo in some patients . The mechanism of this resistance appears to be related to changes in gp120 and mainly in the V3 region which enables the virus to recognise the P51681 - co - receptor bound to the MVC molecule . From a practical point of view , standardised tests are currently unavailable to assess susceptibility to MVC , although in dose - response phenotype tests a maximum percentage inhibition ( MPI ) < 95 % would be indicative of resistance to the compound . Similarly , although some mutations associated with resistance in V3 , and other zones of gp120 , have been described , this preliminary information suggests different resistance patterns and at the moment , we do not know the canonical mutations to be able to establish genotyping algorithms .","Multifaceted mechanisms of HIV inhibition and resistance to P51681 inhibitors PSC - RANTES and DB04835 . Small - molecule P51681 antagonists , such as maraviroc ( MVC ) , likely block HIV - 1 through an allosteric , noncompetitive inhibition mechanism , whereas inhibition by agonists such as PSC - RANTES is less defined and may involve receptor removal by cell surface downregulation , competitive inhibition by occluding the HIV - 1 envelope binding , and / or allosteric effects by altering P51681 conformation . We explored the inhibitory mechanisms of maraviroc and PSC - RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors . Intrinsic PSC - RANTES - resistant virus ( YA versus RT ) or those selected in PSC - RANTES treated macaques ( M584 versus P09131 - 4 ) only displayed resistance in multiple - cycle assays or with a P51681 mutant that can not be downregulated . In single - cycle assays , these HIV - 1 clones displayed equal sensitivity to PSC - RANTES inhibition , suggesting effective receptor downregulation . Prolonged PSC - RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration ( substrate ) could saturate the receptors and overcome PSC - RANTES inhibition . In contrast , resistance to MVC was observed with the MVC - resistant HIV - 1 ( R3 versus S2 ) in both multiple - and single - cycle assays and with altered virus concentrations , which is indicative of allosteric inhibition . MVC could also mediate inhibition and possibly resistance through competitive mechanisms .","P10275 negatively influences the expression of chemokine receptors ( P61073 , P32246 ) and ligand - mediated migration in prostate cancer DU - 145 . We previously reported that androgen receptor ( AR ) plays a role in the regulation of adhesion to the extracellular matrix and invasion of human prostate cancer cells by influencing the expression of specific integrin subunits . It is now considered that chemokines play a significant role in organ - selective cancer metastasis . In this study , we hypothesized that AR may influence the expression of these chemokine receptors and cell function . The mRNA expression of chemokine receptors in human prostate cancer cell line DU - 145 and DU - 145 cells expressing AR ( DU - 145 / AR ) was investigated by RT - PCR . DU - 145 cells selectively expressed P61073 and P32246 mRNA at high levels compared with DU - 145 / AR cells . DU - 145 showed vigorous migratory responses to its ligand P48061 ( also called stromal - derived factor - 1alpha , SDF - 1alpha ) and P10147 ( also called macrophage inflammatory protein - 1 , MIP - 1alpha ) . In contrast , neither P48061 nor P10147 affected the migration of DU - 145 / AR cells . These results indicate that expression of AR down - regulates the migratory responses of human prostate cancer cells via chemokine and its receptor systems .","Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK57___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .","Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .","[ Secondary effects of treatment with maraviroc and other P51681 antagonists . Potential impact of the P51681 blocker ] . DB04835 is the first inhibitor of P51681 co - receptors to be marketed as an antiretroviral . The pre - clinical studies and phase III trials have shown that it has a very favourable safety profile . No characteristic adverse effect of maraviroc has been identified . Unlike with aplaviroc , where its clinical development was stopped due to serious hepatoxicity , no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co - infected by hepatotropic virus . Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients treated with maraviroc . In a study on naive patients , maraviroc produced nonsignificant changes in total cholesterol , LDL , HDL and triglycerides . Although P51681 co - receptors play a role in the immune response of the body , it has not been shown whether individuals homozygote for its deletion ( delta - 32 mutation ) have an increased risk of serious infections , with the possible exception of encephalitis due to the West Nile virus . However , long - term follow up is required on patients treated with to be able to rule out any increased susceptibility to infections or neoplasms .","Investigating hypothetical products from noncoding frames ( HyPNoFs ) . Hypothetical Products from Noncoding Frames ( i . e . , HyPNoFs ) are hypothetical , not - coded proteins , translated from alternate reading frames ( i . e . , coding + 1 and coding + 2 ) of cDNAs . HyPNoFs of P01730 , PKC , oncostatin , bcl - 2 proto - oncogene , tumor suppressor p53 , cystic fibrosis transmembrane regulator ( P13569 ) , and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS - Q99884 data bank . Homology searchers carried out revealed that hypothetical products ( i . e . , HyPNoFs ) may share high similarity with real protein products actually coded . Sequence similarity of hypothetical products to real proteins is sometimes very high , suggesting common conformational features , according to the Sander and Schneider cutoff value . This finding supports the hypothesis that eukaryotic DNA , currently considered to be monocistronic , might occasionally have polycistronic regions , carrying different protein messages on overlapping frames . As yet , polycistronic genes have been observed in viral genomes only . The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy , rather than a present feature of the genome in eukaryotes . These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes ' evolution and to investigate structure - function relationships of protein and DNA sequences ."],"string":"[\n \"DB04835 , a P51681 coreceptor antagonist that blocks entry of human immunodeficiency virus type 1 . Inhibition of the human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor is an encouraging new approach to pharmacotherapy against HIV . The HIV - 1 strain makes use of either the P51681 or the P61073 coreceptor to gain access into host P01730 + cells . DB04835 , the first HIV - 1 P51681 coreceptor antagonist , blocks entry of HIV - 1 . This recently approved drug has demonstrated clinically significant decreases in plasma concentrations of HIV - 1 RNA and increases in P01730 + cell counts ; however , it is indicated only for use as salvage therapy . Drug resistance is a concern , as is selective pressure on viral coreceptor use , because viral coreceptor targets may switch as disease progresses . In addition , before maraviroc therapy can be started , costly assays are required to determine the host ' s viral coreceptor tropism . Emerging therapies targeting P61073 , the other HIV coreceptor , have shown promise in decreasing plasma concentrations of HIV - 1 RNA . Long - term studies with both targets are required to explore the critical issues of efficacy and immunologic safety , as the function of these coreceptors is linked to host chemokine pathways .\",\n \"What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation ___MASK45___ ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .\",\n \"DB04835 . DB04835 , first in a new pharmacological class of antiretroviral agents known as P51681 antagonists , has been approved by the U . S . Food and Drug Administration for the treatment of HIV - infected adult patients who are infected with only P51681 - tropic HIV - 1 virus and who have HIV - 1 strains resistant to multiple antiretroviral agents . DB04835 has demonstrated in vitro activity against a wide range of P51681 tropic clinical isolates , including those resistant to the four currently existing drug classes of antiretroviral agents . In the two pivotal phase III studies , MOTIVATE - 1 and - 2 , maraviroc , in combination with optimized background therapy ( OBT ) , demonstrated superior virologic and immunologic treatment outcomes than OBT alone in treatment - experienced patients infected with P51681 - tropic HIV - 1 . In these studies , maraviroc also demonstrated acceptable safety and tolerability profiles with adverse events and discontinuation rates in general comparable to those noted in the placebo arms .\",\n \"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK75___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK75___ .\",\n \"A novel bivalent HIV - 1 entry inhibitor reveals fundamental differences in P51681 - μ - opioid receptor interactions between human astroglia and microglia . OBJECTIVE : We explored whether the opiate , morphine , affects the actions of maraviroc , as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist , naltrexone , on HIV - 1 entry in primary human glia . METHODS : HIV - 1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV - 1 transactivator protein Tat . The effect of maraviroc and the bivalent ligand with or without morphine on P51681 surface expression and cytokine release was also explored . RESULTS : DB04835 inhibits HIV - 1 entry into glial cells , whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry . We also demonstrate that the maraviroc - containing bivalent ligand better inhibits R5 - tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine . Importantly , the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine . Exposure to maraviroc decreased the release of pro - inflammatory cytokines and restricted HIV - 1 - dependent increases in P51681 expression in both astrocytes and microglia , whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia . The P51681 - μ - opioid receptor ( MOR ) stoichiometric ratio varied among the two cell types with P51681 expressed at much higher levels than MOR in microglia , which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia . CONCLUSION : A novel bivalent compound reveals fundamental differences in P51681 - MOR interactions and HIV - 1 infectivity among glia , and has unique therapeutic potential in opiate abuse - HIV interactive comorbidity .\",\n \"In vitro phenotypic susceptibility of HIV - 2 clinical isolates to P51681 inhibitors . HIV - 2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors , to a fusion inhibitor , and to some of the protease inhibitors . DB04835 is the first drug of the new anti - P51681 drug class and is effective only on P51681 - tropic ( R5 ) HIV - 1 . No previous studies concerning HIV - 2 susceptibility to maraviroc have been reported yet . We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell ( PBMC ) model . We analyzed the maraviroc susceptibility of 13 R5 HIV - 2 , 2 X4R5 ( dual ) HIV - 2 , and 2 P61073 - tropic ( X4 ) HIV - 2 clinical isolates . We also tested , with the same protocol , 1 X4 HIV - 1 and 4 R5 HIV - 1 clinical isolates . For the R5 HIV - 2 clinical isolates , the 50 % effective concentration ( EC ( 50 ) ) for maraviroc was 0 . 80 nM ( interquartile range [ IQR ] , 0 . 48 to 1 . 39 nM ) , similar to that observed for the R5 HIV - 1 isolates . The median maximum percentage of inhibition in the R5 HIV - 2 isolates was 93 % ( IQR , 84 to 98 % ) , similar to that observed in the R5 HIV - 1 isolates . As expected , both X4 HIV - 1 and HIV - 2 were highly resistant to maraviroc . Our study showed for the first time that maraviroc is active in vitro against R5 HIV - 2 . The new tools we developed will allow identification of HIV - 2 - infected patients eligible for P51681 inhibitor use and management of virological failure when receiving a maraviroc - based regimen .\",\n \"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .\",\n \"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \\\" correctors \\\" such as ___MASK20___ ( VX - 809 ) that improve P13569 maturation and trafficking and \\\" potentiators \\\" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .\",\n \"Granulocyte - macrophage colony stimulating factor up - regulates P32246 in human neutrophils . Neutrophils ( polymorphonuclear leukocytes ; PMN ) are phagocytic cells instrumental in the clearance of infectious pathogens . Human PMN are commonly thought to respond primarily to chemokines from the CXC family . However , recent findings suggest that under specific cytokine activation conditions , PMN can also respond to some CC chemokines . In this study , the effect of GM - P04141 , a well - characterized PMN priming and maturation factor , on CC - chemokine receptor ( CCR ) expression in PMN was investigated . Constitutive expression of P32246 and P51677 mRNA in PMN was detected by ribonuclease protection assay . Following incubation of PMN with GM - P04141 ( 0 . 01 - 10 ng / ml ; 6 h ) P32246 mRNA expression was rapidly ( approximately 1 h ) up - regulated . In contrast , no significant induction of P41597 , P51677 , CCR4 , or P51681 mRNA was observed . P32246 protein was also up - regulated by GM - P04141 stimulation . GM - P04141 - induced up - regulation of P32246 showed functional consequences because GM - P04141 - treated PMN , but not control cells , responded to the CC chemokines macrophage inflammatory protein - 1alpha , monocyte chemoattractant protein - 3 , and RANTES in assays of chemotactic migration and intracellular calcium mobilization . These results suggest that PMN activated by the proinflammatory cytokine GM - P04141 can change their receptor expression pattern and become responsive to CC chemokines .\",\n \"Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV - 1 ) is the predominant mode of infection world - wide . To better understand sexual transmission of HIV - 1 in women we have analysed virus co - receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA - DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV - 1 infection . P61073 was expressed at marginally higher levels than P51681 on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV - 1 following sexual contact can not be explained solely on the expression of chemokine co - receptors by T lymphocyte subsets .\",\n \"Structure and dynamics of the gp120 V3 loop that confers noncompetitive resistance in R5 HIV - 1 ( JR - FL ) to maraviroc . DB04835 , an ( HIV - 1 ) entry inhibitor , binds to P51681 and efficiently prevents R5 human immunodeficiency virus type 1 ( HIV - 1 ) from using P51681 as a coreceptor for entry into P01730 (+) cells . However , HIV - 1 can elude maraviroc by using the drug - bound form of P51681 as a coreceptor . This property is known as noncompetitive resistance . HIV - 1 ( V3 - M5 ) derived from HIV - 1 ( JR - FLan ) is a noncompetitive - resistant virus that contains five mutations ( I304V / F312W / T314A / E317D / I318V ) in the gp120 V3 loop alone . To obtain genetic and structural insights into maraviroc resistance in HIV - 1 , we performed here mutagenesis and computer - assisted structural study . A series of site - directed mutagenesis experiments demonstrated that combinations of V3 mutations are required for HIV - 1 ( JR - FLan ) to replicate in the presence of 1 µM maraviroc , and that a T199K mutation in the P06681 region increases viral fitness in combination with V3 mutations . Molecular dynamic ( MD ) simulations of the gp120 outer domain V3 loop with or without the five mutations showed that the V3 mutations induced ( i ) changes in V3 configuration on the gp120 outer domain , ( ii ) reduction of an anti - parallel β - sheet in the V3 stem region , ( iii ) reduction in fluctuations of the V3 tip and stem regions , and ( iv ) a shift of the fluctuation site at the V3 base region . These results suggest that the HIV - 1 gp120 V3 mutations that confer maraviroc resistance alter structure and dynamics of the V3 loop on the gp120 outer domain , and enable interactions between gp120 and the drug - bound form of P51681 .\",\n \"Host factors mediating HIV - 1 replication . Human immunodeficiency virus type 1 ( HIV - 1 ) infection is the leading cause of death worldwide in adults attributable to infectious diseases . Although the majority of infections are in sub - Saharan Africa and Southeast Asia , HIV - 1 is also a major health concern in most countries throughout the globe . While current antiretroviral treatments are generally effective , particularly in combination therapy , limitations exist due to drug resistance occurring among the drug classes . Traditionally , HIV - 1 drugs have targeted viral proteins , which are mutable targets . As cellular genes mutate relatively infrequently , host proteins may prove to be more durable targets than viral proteins . HIV - 1 replication is dependent upon cellular proteins that perform essential roles during the viral life cycle . DB04835 is the first FDA - approved antiretroviral drug to target a cellular factor , HIV - 1 coreceptor P51681 , and serves to intercept viral - host protein - protein interactions mediating entry . Recent large - scale siRNA and shRNA screens have revealed over 1000 candidate host factors that potentially support HIV - 1 replication , and have implicated new pathways in the viral life cycle . These host proteins and cellular pathways may represent important targets for future therapeutic discoveries . This review discusses critical cellular factors that facilitate the successive steps in HIV - 1 replication .\",\n \"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .\",\n \"P51681 antibodies HGS004 and HGS101 preferentially inhibit drug - bound P51681 infection and restore drug sensitivity of DB04835 - resistant HIV - 1 in primary cells . R5 HIV - 1 strains resistant to the P51681 antagonist DB04835 ( MVC ) can use drug - bound P51681 . We demonstrate that MVC - resistant HIV - 1 exhibits delayed kinetics of coreceptor engagement and fusion during drug - bound versus free P51681 infection of cell lines . Antibodies directed against the second extracellular loop ( ECL2 ) of P51681 had greater antiviral activity against MVC - bound compared to MVC - free P51681 infection . However , in PBMCs , only ECL2 P51681 antibodies HGS004 and HGS101 , but not 2D7 , inhibited infection by MVC resistant HIV - 1 more potently with MVC - bound than with free P51681 . In addition , HGS004 and HGS101 , but not 2D7 , restored the antiviral activity of MVC against resistant virus in PBMCs . In flow cytometric studies , P51681 binding by the O14964 mAbs , but not by 2D7 , was increased when PBMCs were treated with MVC , suggesting MVC increases exposure of the relevant epitope . Thus , HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance .\",\n \"Multipotent stem / progenitor cells in human biliary tree give rise to hepatocytes , cholangiocytes , and pancreatic islets . Multipotent stem / progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato - pancreatic common duct , cystic duct , and hilum . They express endodermal transcription factors ( e . g . , Sox9 , Q9H6I2 , Q9Y261 , PDX1 , HES1 , Q9Y4Z2 , Q92786 ) intranuclearly , stem / progenitor surface markers ( EpCAM , P13591 , CD133 , P61073 ) , and sometimes weakly adult liver , bile duct , and pancreatic genes ( albumin , cystic fibrosis transmembrane conductance regulator [ P13569 ] , and insulin ) . They clonogenically expand on plastic and in serum - free medium , tailored for endodermal progenitors , remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈ 36 hours and slowing to one every 2 - 3 days . Transfer into distinct culture conditions , each comprised of a specific mix of hormones and matrix components , yields either cords of hepatocytes ( express albumin , P08684 , and transferrin ) , branching ducts of cholangiocytes ( expressing anion exchanger - 2 - P04920 and P13569 ) , or regulatable C - peptide secreting neoislet - like clusters ( expressing glucagon , insulin ) and accompanied by changes in gene expression correlating with the adult fate . Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes , whereas if into fat pads of streptozocin - induced diabetic mice , results in functional islets secreting glucose - regulatable human C - peptide . CONCLUSION : The phenotypes and availability from all age donors suggest that these stem / progenitors have considerable potential for regenerative therapies of liver , bile duct , and pancreatic diseases including diabetes .\",\n \"Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice . Guidelines state that the P51681 - inhibitor DB04835 should be prescribed to patients infected with R5 - tropic HIV - 1 only . Therefore , viral tropism needs to be assessed phenotypically or genotypically . Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4 - tropic variants . Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co - receptor usage in routine clinical practice . Samples from therapy - naive and therapy - experienced patients were collected for routine tropism testing at three European clinical centres . Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells . Q14624 - V3 was amplified in a triplicate nested RT - PCR procedure and sequenced . Co - receptor usage was predicted using the Geno2Pheno ( [ coreceptor ] ) algorithm and analysed with a false - positive rate ( P21462 ) of 5 . 75 % , 10 % , or an P21462 of 20 % and according to the current European guidelines on the clinical management of HIV - 1 tropism testing . A total of 266 sequences were obtained from 101 patient samples . Discordance in tropism prediction for the triplicates was observed in ten samples using an P21462 of 10 % . Triplicate testing resulted in a 16 . 7 % increase in X4 - predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for DB04835 treatment . In conclusion , triplicate genotypic tropism testing increases X4 tropism detection in individual cases , which may prove to be pivotal when P51681 - inhibitor therapy is applied .\",\n \"Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .\",\n \"Discordance rates between Trofile test and short - term virological response to maraviroc . Enhanced sensitivity Trofile ( ES - Trofile ) is the most frequently used technique to assay HIV tropism . A clinical approach to predict P51681 - antagonists efficacy , based on the virological response to a short - term maraviroc exposure ( DB04835 Clinical Test , Q8IVS2 ) , has been recently reported . We compared the results of ES - Trofile with Q8IVS2 in 47 HIV - infected patients , and a global discordance around 15 % was observed between the phenotypic method and the clinical approach . Discordance results were mainly found in patients with an ES - Trofile reported as dual / mixed . These provocative results might have important clinical implications and should be considered in order to accurately prescribe treatment with P51681 antagonists .\",\n \"___MASK17___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK17___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .\",\n \"Regulation of cell cycle proteins by chemokine receptors : A novel pathway in human immunodeficiency virus neuropathogenesis ? In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus ( HIV ) , the authors have been studying the effect of chemokines on the CDK / P06400 / Q01094 pathway -- which is involved in neuronal apoptosis and differentiation . First , they have asked whether P61073 , the specific receptor for the chemokine P48061 and X4 - using gp120s , can regulate P06400 and Q01094 activity in cultures of differentiated rat neurons . Although P51677 and P51681 are known to mediate infection of microglia by HIV - 1 , recent evidence indicate that P61073 also play important roles in HIV - induced neuronal injury , and dual - tropic isolates that use P61073 to infect macrophages have recently been reported . The authors have focused on two specific brain areas in which P61073 is physiologically relevant , i . e . , the cerebellum and the hippocampus . So far , the data indicate that changes in the nuclear and cytosolic levels of P06400 , which result in the functional loss of this protein , are associated with apoptosis in these neurons , and that SDF - 1alpha and gp120IIIB affect this pathway . A summary of the findings are presented .\",\n \"___MASK95___ : kinetic and dynamic profile in the treatment of pain . ___MASK95___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK95___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK95___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK95___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .\",\n \"Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced P22301 expression . Biomaterial scaffolds are central to many tissue engineering strategies as they create a space for tissue growth and provide a support for cell adhesion and migration . However , biomaterial implantation results in unavoidable injury resulting in an inflammatory response , which can impair integration with the host and tissue regeneration . Toward the goal of reducing inflammation , we investigated the hypothesis that a lentiviral gene therapy - based approach to localized and sustained P22301 expression at a scaffold could modulate the number , relative proportions , and cytokine production of infiltrating leukocyte populations . Flow cytometry was used to quantify infiltration of six leukocyte populations for 21 days following implantation of P00747 scaffolds into intraperitoneal fat . Leukocytes with innate immune functions ( i . e . , macrophages , dendritic cells , neutrophils ) were most prevalent at early time points , while T lymphocytes became prevalent by day 14 . Reporter gene delivery indicated that transgene expression persisted at the scaffold for up to 28 days and macrophages were the most common leukocyte transduced , while transduced dendritic cells expressed the greatest levels of transgene . P22301 delivery decreased leukocyte infiltration by 50 % relative to controls , increased macrophage P22301 expression , and decreased macrophage , dendritic cell , and P01730 T cell IFN - γ expression . Thus , P22301 gene delivery significantly decreased inflammation following scaffold implant into the intraperitoneal fat , in part by modulating cytokine expression of infiltrating leukocytes .\",\n \"Two - year safety and virologic efficacy of maraviroc in treatment - experienced patients with P51681 - tropic HIV - 1 infection : 96 - week combined analysis of MOTIVATE 1 and 2 . BACKGROUND : DB04835 , the first approved P51681 antagonist , demonstrated 48 - week safety and virologic efficacy in P51681 - tropic HIV - infected , treatment - experienced patients ; however , critical longer - term safety and durability of responses are unknown . METHODS : Two - year follow - up of 2 prospective , randomized , blinded studies of maraviroc once daily or twice daily , or placebo in treatment - experienced patients with R5 - tropic HIV - 1 receiving an optimized background regimen . Unblinding occurred after the week - 48 visit of the last enrolled patient . Safety and virologic parameters were assessed through week 96 . RESULTS : One thousand forty - nine patients were randomized and received study drugs . HIV - 1 RNA was < 50 copies per milliliter at week 96 in 39 % and 41 % of patients receiving maraviroc every day or twice a day , respectively . Among patients with HIV - 1 RNA < 50 copies per milliliter at week 48 , 81 % and 87 % of patients receiving maraviroc every day or twice a day , respectively , maintained this response at week 96 . At week 96 , median P01730 + T - cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day , respectively . Exposure - adjusted rates of adverse events were similar with maraviroc or placebo . No new or unexpected events were observed after week 48 . CONCLUSIONS : DB04835 - containing antiretroviral regimens maintained durable responses in treatment - experienced patients with R5 HIV - 1 through 96 weeks of treatment with a safety profile similar to placebo .\",\n \"Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis - infected mice is modulated by interferon - gamma . Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions . Here , we evaluated the expression of chemokines and chemokine receptors and their regulation by P01579 in the course of Paracoccidioides brasiliensis ( Pb ) infection in mice . We found an association between KC and MIP - 1alpha ( P10147 ) production and neutrophil infiltration in the lungs of Pb - infected mice during the early acute phase of infection . High levels of RANTES / P13501 , P13500 / P13500 , P02778 / P02778 , and Mig / Q07325 simultaneously with mononuclear cell infiltration in the lungs was found . In the absence of P01579 ( GKO mice ) we observed increased production of KC and MIP - 1alpha and chronic neutrophilia . Moreover , we found a change in the chemokine receptor profiles expressed by wild - type ( WT ) versus GKO animals . Increased expression of P49682 and P51681 , and low levels of P51677 and CCR4 were observed in the lungs of Pb - infected WT mice , whereas the opposite effect was observed in the lungs of GKO mice . Consistent with these results , infected cells from WT mice preferentially migrated in response to P02778 ( P49682 ligand ) , while those from GKO mice migrated in response to eotaxin / P51671 ( P51677 ligand ) . These results suggest that P01579 modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb - infected mice .\",\n \"The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK45___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .\",\n \"[ At what time and with which combinations should maraviroc be indicated in the new antiretroviral treatment scenario ? ] . DB04835 is a selective and slowly reversible antagonist of the P51681 co - receptor which has shown to have powerful antiviral activity , in vitro , against a wide range of HIV clinical isolates , including strains multi - resistant to 4 classes of pre - existing antiretroviral drugs . DB04835 is active against HIV populations that only use the P51681 coreceptor to enter the cell and has not demonstrated significant activity in the treatment of viral populations that use the P61073 co - receptor . The mechanism of action of maraviroc , non - competitive with other antiretroviral drugs , and the absence of crossed resistance with the rest of their families , has led to DB04835 being a drug available for use in rescue antiretroviral treatment . However , the excellent tolerance of maraviroc compared to the placebo in phase III clinical trials , its safety and its favourable pharmacological interactions profile with other drugs commonly used in HIV infected patients with comorbidity brings to light other scenarios in which DB04835 could be useful .\",\n \"Reviews of anti - infective agents : maraviroc : the first of a new class of antiretroviral agents . DB04835 is the first US Food and Drug Administration - approved drug from a new class of antiretroviral agents that targets a host protein , the chemokine receptor P51681 , rather than a viral target . Binding of maraviroc to this cell - surface protein results in blocking human immunodeficiency virus type 1 ( HIV - 1 ) attachment to the coreceptor and prevents the virus from entering P01730 + cells . In this review , we include the details of the discoveries that led to the development of this drug . The drug ' s pharmacology , including pharmacokinetics and drug interactions , is discussed , as are the clinical efficacy studies that led to licensure . HIV - 1 mechanisms of resistance to maraviroc , assays to determine viral coreceptor use ( tropism ) , drug safety , and clinical use of maraviroc are discussed at length .\",\n \"The use of intraallelic variability for testing neutrality and estimating population growth rate . To better understand the forces affecting individual alleles , we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci ( the intraallelic variability ) . We model three types of intraallelic variability : ( a ) the number of nonrecombinants at a linked biallelic marker locus , ( b ) the length of a conserved haplotype , and ( c ) the number of mutations at a linked marker locus . If the population growth rate is known , the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency . If the population growth rate is unknown but neutrality can be assumed , the joint distribution provides the likelihood of the growth rate and leads to a maximum - likelihood estimate . We apply the method to data from published data sets for four loci in humans . We conclude that the Delta32 allele at P51681 and a disease - associated allele at P40692 arose recently and have been subject to strong selection . Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0 . 027 per generation with a support interval of ( 0 . 017 - 0 . 037 ) . Four of the relatively common alleles at P13569 also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers .\",\n \"Allosteric model of maraviroc binding to CC chemokine receptor 5 ( P51681 ) . DB04835 is a nonpeptidic small molecule human immunodeficiency virus type 1 ( HIV - 1 ) entry inhibitor that has just entered the therapeutic arsenal for the treatment of patients . We recently demonstrated that maraviroc binding to the HIV - 1 coreceptor , CC chemokine receptor 5 ( P51681 ) , prevents it from binding the chemokine P10147 and the viral envelope glycoprotein gp120 by an allosteric mechanism . However , incomplete knowledge of ligand - binding sites and the lack of P51681 crystal structures have hampered an in - depth molecular understanding of how the inhibitor works . Here , we addressed these issues by combining site - directed mutagenesis ( SDM ) with homology modeling and docking . Six crystal structures of G - protein - coupled receptors were compared for their suitability for P51681 modeling . All P51681 models had equally good geometry , but that built from the recently reported dimeric structure of the other HIV - 1 coreceptor P61073 bound to the peptide CVX15 ( Protein Data Bank code 3OE0 ) best agreed with the SDM data and discriminated P51681 from non - P51681 binders in a virtual screening approach . SDM and automated docking predicted that maraviroc inserts deeply in P51681 transmembrane cavity where it can occupy three different binding sites , whereas P10147 and gp120 lie on distinct yet overlapped regions of the P51681 extracellular loop 2 . Data suggesting that the transmembrane cavity remains accessible for maraviroc in P10147 - bound and gp120 - bound P51681 help explain our previous observation that the inhibitor enhances dissociation of preformed ligand - P51681 complexes . Finally , we identified residues in the predicted P51681 dimer interface that are mandatory for gp120 binding , suggesting that receptor dimerization might represent a target for new P51681 entry inhibitors .\",\n \"Hepatic safety and tolerability in the maraviroc clinical development program . DB04835 is the first P51681 antagonist to be approved for the treatment of HIV - 1 infection . It is generally well tolerated , with a similar side - effect profile to placebo in controlled studies . Many agents used to treat HIV disease are associated with the potential for hepatotoxicity . The hepatic effects of maraviroc were analyzed across all Pfizer - sponsored maraviroc clinical trials , in which 2350 volunteers received maraviroc . Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1 / 2a studies of up to 28 - day duration , they demonstrated no dose relationship or association with hyperbilirubinemia . In the four phase 2b / 3 studies in antiretroviral - naive and antiretroviral - experienced patients , there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96 . The findings were similar in patients coinfected with hepatitis B and / or C virus , although the number of coinfected patients was small . No patient met the strict definition for Hy ' s Law . Two participants reported severe hepatotoxicity and although other potential causes were present , the contribution of maraviroc to these events could not be excluded . This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied .\",\n \"[ Methods for determining viral tropism : genotype and phenotype tests ] . The recent approval of the first P51681 antagonist , DB04835 ( MVC , Celsentri ) , with specific antiviral activity against R5 - tropic virus variants has generated the need for studies to determine the viral tropism in all those patient candidates for starting treatment with this new drug . Although genotyping methods appear to be the most useful tool due to its speed and simplicity , in the case of viral tropism , phenotyping techniques are currently considered the most reliable . In the last few years , different phenotyping assays have been developed to determine the use of the co - receptor . However , the Trofile phenotype assay is currently the one most used for the determination of tropism , since it is the only one that has been clinically validated . Given that the presence of X4 - tropic variants in the viral population has been associated with virological failure to MVC , the main challenge of both genotyping and phenotyping tools is to optimise their sensitivity for detecting X4 - tropic variants present in a minority of the viral population . At the same time , the correlation between genotyping / phenotyping methods is being evaluated to determine whether genotyping tools can be useful to make therapeutic decisions .\",\n \"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK75___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK75___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .\",\n \"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK44___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .\",\n \"Essential role for retinoic acid in the promotion of P01730 (+) T cell effector responses via retinoic acid receptor alpha . DB00162 and its metabolite , retinoic acid ( RA ) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells . Here we showed RA was also required to elicit proinflammatory P01730 (+) helper T cell responses to infection and mucosal vaccination . P10276 ( RARα ) was the critical mediator of these effects . Antagonism of RAR signaling and deficiency in RARα ( Rara (-/-) ) resulted in a cell - autonomous P01730 (+) T cell activation defect , which impaired intermediate signaling events , including calcium mobilization . Altogether , these findings reveal a fundamental role for the RA - RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses .\",\n \"DB04835 . DB04835 is a specific , slowly reversible , noncompetitive , small - molecule antagonist of the P51681 chemokine receptor , which also serves as an HIV - 1 coreceptor . By acting as an antagonist at the P51681 coreceptor , maraviroc inhibits HIV - 1 from entering host cells . Clinical data for maraviroc are available from two large , well designed , ongoing phase IIb / III trials ( MOTIVATE - 1 and MOTIVATE - 2 ) conducted in patients infected with R5 - tropic HIV - 1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and / or were triple - class resistant . According to 24 - week interim results of the MOTIVATE - 1 and - 2 trials , a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg ( depending on optimised background therapy [ OBT ] ) twice daily plus OBT compared with placebo plus OBT . This significant difference was maintained at 48 weeks in MOTIVATE - 1 . In the MOTIVATE - 1 and - 2 trials , a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV - 1 RNA level < 400 and < 50 copies / mL compared with those receiving placebo plus OBT . In addition , the P01730 + cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT . The 48 - week results of MOTIVATE - 1 also report a significant difference in favour of maraviroc for all these endpoints . In general , maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment - experienced patients infected with R5 - tropic HIV - 1 .\",\n \"Deep sequencing to infer HIV - 1 co - receptor usage : application to three clinical trials of maraviroc in treatment - experienced patients . BACKGROUND : The DB04835 versus Optimized Therapy in Viremic Antiretroviral Treatment - Experienced Patients ( MOTIVATE ) studies compared maraviroc versus placebo in treatment - experienced patients with P51681 - using ( R5 ) human immunodeficiency virus type 1 ( HIV - 1 ) , screened using the original Trofile assay . A subset with non - R5 HIV infection entered the A4001029 trial . We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials . METHODS : V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche / 454 GS - FLX to a depth of > 3000 sequences / sample . Samples were considered non - R5 if ≥ 2 % of their viral population scored greater than or equal to - 4 . 75 or ≤ 3 . 5 using the PSSM ( x4 / R5 ) or geno2pheno algorithms , respectively . RESULTS : Deep sequencing identified more than twice as many maraviroc recipients as having non - R5 HIV , compared with the original Trofile . With use of genotyping , we determined that 49 % of maraviroc recipients with R5 HIV at screening had a week 48 viral load < 50 copies / mL versus 26 % of recipients with non - R5 . Corresponding percentages were 46 % and 23 % with screening by Trofile . In cases in which screening assays differed , median week 8 log₁₀ copies / mL viral load decrease favored 454 . Other parameters predicted by genotyping included likelihood of changing to non - R5 tropism . CONCLUSIONS : This large study establishes deep V3 sequencing as a promising tool for identifying treatment - experienced individuals who could benefit from P51681 - antagonist - containing regimens .\",\n \"[ Pharmacokinetics , interactions and mechanism of action of maraviroc ] . DB04835 ( MVC , Celsentri ) is an allosteric and reversible inhibitor of the P51681 chemokine coreceptor . MVC is the first marketed P51681 antagonist and the only oral entry inhibitor approved so far for the treatment of HIV infection . It has been approved for adults with previous antiretroviral exposure . MVC exclusively inhibits the replication of R5 - tropic HIV - 1 variants after binding to the transmembrane P51681 receptor cavity . MVC is rapidly absorbed following oral administration , and plasma T ( max ) is achieved within 0 . 5 - 4 hours after a 300 mg dose . Renal clearance is approximately 10 - 12 L / h . MVC is a substrate of the cytochrome P450 isoenzyme 3A4 ; therefore dose adjustments are required when co - administrated with other drugs that induce or inhibit P08684 . In addition , MVC dose adjustments are advised in patients with renal failure ( CLcr < 80 ml / min ) only if they receive P08684 inhibitors .\",\n \"A microsimulation of the cost - effectiveness of maraviroc for antiretroviral treatment - experienced HIV - infected individuals . PURPOSE : DB04835 ( MVC ) is the first approved P51681 antagonist . The aim of this study was to explore the cost - effectiveness of MVC in treatment - experienced or treatment - resistant HIV - infected adults . METHODS : The validated HIV microsimulation model ARAMIS was used to predict clinical and economic outcomes of treating patients with optimized background therapy ( OBT ) alone , as compared to a strategy of testing for the patient ' s viral tropism and treating with OBT with or without ( +/- ) MVC in a cohort corresponding to the MOTIVATE screening cohort . RESULTS : Compared to treatment with OBT alone , a treatment strategy of OBT +/- MVC ( twice daily ) according to tropism test result was predicted to increase P01730 + cell count after 5 years ( from mean 249 to 360 cells / microL ) , undiscounted life expectancy ( 7 . 6 to 8 . 9 years ) , and quality - adjusted life years ( QALYs ; from 4 . 99 to 5 . 71 ) for an additional $ 40 , 500 , giving an incremental cost - effectiveness ratio of $ 56 , 400 per QALY gained . The result was relatively insensitive to alternative clinical and cost assumptions within reasonable ranges , but for individuals with HIV susceptible to only two or fewer components of OBT , the Q03060 decreased to $ 52 , 000 per QALY gained . CONCLUSION : MVC is cost - effective , especially among individuals with few remaining options for active antiretroviral therapy .\",\n \"Development and application of a simple LC - MS method for the determination of plasma maraviroc concentrations . DB04835 is an orally available antagonist of the P51681 chemokine receptor , which acts as a human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor . Binding of maraviroc to this receptor blocks HIV - 1 attachment to the coreceptor and prevents HIV - 1 from entering host cells . DB04835 does not require intracellular processing to exert this activity . Drug interaction studies have shown changes in maraviroc exposure when given with other anti - HIV medications , and thus quantification of maraviroc in human plasma is important to manage drug interactions and to evaluate the relationship between plasma concentrations and treatment response . We developed a conventional LC - MS method for determining plasma maraviroc concentrations , validated by estimating precision and accuracy for inter - and intraday analysis in the concentration range of 0 . 011 - 2 . 188 µg / ml . The calibration curve was linear within this range . The average accuracy ranged from 92 . 7 % to 99 . 7 % , while the relative standard deviations of both inter - and intraday assays were less than 7 . 1 % . Recovery of maraviroc exceeded 86 . 7 % . Our LC - MS method provides a conventional , accurate and precise way to determine the maraviroc concentration in human plasma . This method enables dose adjustment based on monitoring plasma maraviroc concentrations and permits management of drug interactions and toxicity .\",\n \"DB04835 is able to inhibit dual - R5 viruses in a dual / mixed HIV - 1 - infected patient . OBJECTIVES : DB04835 is the first licensed chemokine co - receptor 5 ( P51681 ) co - receptor antagonist in clinical practice . It is currently being used in patients harbouring exclusively P51681 - tropic virus . The objective of the study was to investigate the impact of maraviroc on viruses with different co - receptor preferences in a patient with a dual / mixed ( D / M ) infection . METHODS : We present a case report of an HIV - 1 patient infected with a D / M virus population . Co - receptor tropism was determined by phenotypic and genotypic tests . Biological clones from pre - and post - maraviroc therapy were generated . Tropism of these infectious clones was investigated in U373 - MAGI cells expressing P01730 + P51681 + or P01730 + P61073 + . DB04835 susceptibility and viral replication were determined using donor peripheral blood mononuclear cells ( PBMCs ) . RESULTS : In - depth clonal genotypic analysis revealed the presence of both R5 - tropic variants and X4 - tropic viruses before the start of maraviroc . During maraviroc therapy all R5 - predicted viruses were suppressed . Phenotypic analyses revealed that all biological clones before maraviroc therapy could infect both P51681 - and P61073 - bearing U373 - MAGI cells , demonstrating dual tropism . The baseline biological clones preferentially infected the P51681 cell line and were fully susceptible to maraviroc in PBMCs ( dual - R5 ) . In contrast , during maraviroc therapy the dual - R5 - tropic viruses were replaced by more X4 - tropic viruses ( dual - X4 ) , which could not be inhibited by maraviroc . CONCLUSIONS : This case report demonstrates that dual - tropic viruses , capable of using both co - receptors in phenotypic assays , can be inhibited by maraviroc if they have a P51681 co - receptor preference in vivo .\",\n \"Safety profile of maraviroc in patients coinfected with HIV - 1 and hepatitis B or C included in the maraviroc expanded access program . OBJECTIVE : To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV - 1 coinfected with hepatitis B virus ( HBV ) or hepatitis C virus ( HCV ) . METHODS : This was a multicenter , noncomparative , open - label , expanded access program ( EAP ) initiated in February 2007 . Patients with P51681 - tropic HIV - 1 and HIV - 1 RNA ≥ 1000 copies / mL on their current treatment received maraviroc 300 mg ( 150 mg with protease inhibitors ) twice daily with optimized background therapy ( OBT ) , which could include the newer agents raltegravir , etravirine , and darunavir . The adverse event ( AE ) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2 , where the OBT did not include these agents . RESULTS : A total of 1 , 032 patients were enrolled : 51 HIV / HBV coinfected ; 149 HIV / HCV coinfected , 9 HIV / HBV / HCV coinfected , and 823 HIV - 1 monoinfected . Most ( 76 % ) received at least 1 newer agent . Overall AE frequency was comparable across coinfection groups ( 63 % - 72 % ) . Hepatobiliary events were more common in HIV / HCV coinfection than in HIV monoinfection or HIV / HBV coinfection ( 10 . 0 , 4 . 8 , and 3 . 1 per 100 patient - years , respectively ) . Across all coinfection groups , there was a trend toward lower exposure - adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies . Grade 3 / 4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm . CONCLUSION : DB04835 plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV - 1 - infected patients coinfected with HBV or HCV .\",\n \"Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .\",\n \"Maternal - fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques . Single - dose nevirapine ( DB00238 ) is effective in reducing mother - to - child transmission ( MTCT ) of HIV ; however , the subsequent development of drug resistance is problematic . The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to DB00238 in a single - dose strategy . Four pregnant macaques received an oral dose of maraviroc 2 h before delivery , and both infant and maternal plasma maraviroc concentrations and P51681 receptor occupancy on P01730 (+) lymphocytes were measured over time . Maximum plasma maraviroc concentrations were found at delivery ( 2 - h - postintrapartum dose ) in both the mothers and infants , with median concentrations of 974 ng / ml ( range , 86 to 2 , 830 ng / ml ) and 22 ng / ml ( range , 4 to 99 ng / ml ) , respectively . DB04835 was detected in the plasma of mothers up to 48 h after dosing but only as long as 3 . 5 h in the infants . The median fetal - maternal area under the concentration - time curve ( AUC ) ratio was 0 . 009 ( range , 0 . 000 to 0 . 015 ) . DB04835 receptor occupancy data showed evidence of unprotected P51681 receptors on P01730 (+) cells in the mothers 24 to 48 h after dosing . Extremely low P51681 expression on P01730 (+) cells of newborn macaques prevented determination of receptor occupancy in the infants . In rhesus macaques , maraviroc was poorly transferred across the placenta and was quickly cleared from the infants ' blood . The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV .\",\n \"HIV - 1 resistance to maraviroc conferred by a P01730 binding site mutation in the envelope glycoprotein gp120 . DB04835 ( MVC ) is a P51681 antagonist that inhibits HIV - 1 entry by binding to the coreceptor and inducing structural alterations in the extracellular loops . In this study , we isolated MVC - resistant variants from an HIV - 1 primary isolate that arose after 21 weeks of tissue culture passage in the presence of inhibitor . gp120 sequences from passage control and MVC - resistant cultures were cloned into NL4 - 3 via yeast - based recombination followed by sequencing and drug susceptibility testing . Using 140 clones , three mutations were linked to MVC resistance , but none appeared in the V3 loop as was the case with previous HIV - 1 strains resistant to P51681 antagonists . Rather , resistance was dependent upon a single mutation in the C4 region of gp120 . Chimeric clones bearing this N425K mutation replicated at high MVC concentrations and displayed significant shifts in 50 % inhibitory concentrations ( IC ( 50 ) s ) , characteristic of resistance to all other antiretroviral drugs but not typical of MVC resistance . Previous reports on MVC resistance describe an ability to use a drug - bound form of the receptor , leading to reduction in maximal drug inhibition . In contrast , our structural models on K425 gp120 suggest that this resistant mutation impacts P01730 interactions and highlights a novel pathway for MVC resistance .\",\n \"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \\\" normal \\\" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .\",\n \"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .\",\n \"DB04835 versus efavirenz , both in combination with zidovudine - lamivudine , for the treatment of antiretroviral - naive subjects with P51681 - tropic HIV - 1 infection . BACKGROUND : The MERIT ( DB04835 versus Efavirenz in Treatment - Naive Patients ) study compared maraviroc and efavirenz , both with zidovudine - lamivudine , in antiretroviral - naive patients with R5 human immunodeficiency virus type 1 ( HIV - 1 ) infection . METHODS : Patients screened for R5 HIV - 1 were randomized to receive efavirenz ( 600 mg once daily ) or maraviroc ( 300 mg once or twice daily ) with zidovudine - lamivudine . Coprimary end points were proportions of patients with a viral load < 400 and < 50 copies / mL at week 48 ; the noninferiority of maraviroc was assessed . RESULTS : The once - daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria . In the primary 48 - week analysis ( n = 721 ) , maraviroc was noninferior for < 400 copies / mL ( 70 . 6 % for maraviroc vs 73 . 1 % for efavirenz ) but not for < 50 copies / mL ( 65 . 3 % vs 69 . 3 % ) at a threshold of - 10 % . More maraviroc patients discontinued for lack of efficacy ( 11 . 9 % vs 4 . 2 % ) , but fewer discontinued for adverse events ( 4 . 2 % vs 13 . 6 % ) . In a post hoc reanalysis excluding 107 patients ( 15 % ) with non - R5 screening virus by the current , more sensitive tropism assay , the lower bound of the 1 - sided 97 . 5 % confidence interval for the difference between treatment groups was above - 10 % for each end point . CONCLUSIONS : Twice - daily maraviroc was not noninferior to efavirenz at < 50 copies / mL in the primary analysis . However , 15 % of patients would have been ineligible for inclusion by a more sensitive screening assay . Their retrospective exclusion resulted in similar response rates in both arms Trial registration . ClinicalTrials . gov identifier : ( NCT00098293 ) .\",\n \"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK87___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \\\" neurological dose \\\" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .\",\n \"Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc , an inhibitor of HIV - 1 entry via the P51681 co - receptor . An effective vaginal microbicide could reduce human immunodeficiency virus type 1 ( HIV - 1 ) transmission to women . Among microbicide candidates in clinical development is DB04835 ( MVC ) , a small - molecule drug that binds the P51681 co - receptor and impedes HIV - 1 entry into cells . Delivered systemically , MVC reduces viral load in HIV - 1 - infected individuals , but its ability to prevent transmission is untested . We have now evaluated MVC as a vaginal microbicide with use of a stringent model that involves challenge of rhesus macaques with a high - dose of a P51681 - using virus , SHIV - 162P3 . Gel - formulated , prescription - grade MVC provided dose - dependent protection , half - maximally at 0 . 5 mM ( 0 . 25 mg / mL ) . The duration of protection was transient ; the longer the delay between MVC application and virus challenge , the less protection ( half life of approximately 4 h ) . As expected , MVC neither protected against challenge with a P61073 - using virus , SHIV - KU1 , nor exacerbated postinfection viremia . These findings validate MVC development as a vaginal microbicide for women and should guide clinical programs .\",\n \"Inhibition of thrombin activity by prothrombin activation fragment 1 . 2 . P00734 is the precursor of thrombin , the central enzyme in coagulation . P00734 is activated in vivo by the prothrombinase complex to form fragment 1 . 2 and thrombin . Fragment 1 . 2 has an amino - terminal gla domain and two kringle domains . The second kringle domain ( kringle 2 ) binds to the exosite II on thrombin . Nascent thrombin generated on platelet surface remains non - covalently bound to fragment 1 . 2 by kringle 2 - exosite II interaction . To determine whether this interaction can modulate coagulant activity of thrombin , we labeled thrombin at the active site with fluorescein - DB00120 - Pro - DB00125 chloromethylketone and monitored the fluorescence changes upon ligand binding . Anionic phospholipid - bound fragment 1 . 2 and fragment 2 bound to P21462 - thrombin and induced changes in the active site with half maximal effects at 7 . 2 microM and 8 . 8 microM , respectively . We also tested the effect of anionic phospholipid - bound fragment 1 . 2 ( 0 - 10 microM ) on thrombin clotting activity . Phospholipid - bound fragment 1 . 2 inhibited fibrinogen clotting in a concentration - dependent manner but had no significant effect on amidolytic activity towards S2238 , suggesting a competitive inhibition of the fibrinogen binding site . Furthermore , fragment 1 . 2 inhibited P21462 - thrombin binding to platelet . Consistent with these findings fragment 1 . 2 inhibited thrombin - induced aggregation of gel filtered platelets in a concentration - dependant manner . These results suggest that the membrane - bound prothrombin fragment 1 . 2 may play a role in hemostasis by down regulating the procoagulant activity of newly formed thrombin .\",\n \"[ Clinical pharmacokinetic of maraviroc ] . DB04835 ( MVC , UK - 427 , 857 ) is the first member of a new class , the P51681 antagonists . By an original mechanism of action , maraviroc binds to the P51681 receptor in order to prevent HIV from binding and entering human cells . DB04835 ( Celsentri ) is an orally administered drug available as 150 and 300 mg film - coated tablets . The current approved daily dosage of maraviroc is 300 mg bid in combination with other antiretroviral medications . DB04835 plasma exposure is not dose proportional . After a rapid ( but moderate ) intestinal absorption , several inactive oxidized metabolites are produced via cytochrome P450 3A4 pathway . According to this liver metabolism , dosage adjustments are required when maraviroc is administered in combination with cytochrome P450 inhibitors or inducers . The potential for drug - drug interactions and the well - defined relationship between plasma concentrations and virological response suggest the usefulness of Therapeutic Drug Monitoring of maraviroc in HIV - infected patients .\",\n \"[ Mechanisms of resistance and failure of treatment with maraviroc ] . DB04835 ( MVC ) is a new antagonist of the P51681 coreceptor and is the first antiviral compound available that has a cell factor essential for HIV entry as a target . The information available from clinical studies with MVC suggests that the main cause of therapeutic failure is , more than the tropism change , the rapid selection of pre - existing strains with an affinity for P61073 , not detected by the reference test . A recently developed tropism test with an improved sensitivity will help to detect the minority , but clinically significant , presence of strains that use P61073 . Evidence of resistance to MVC has been shown in vivo in some patients . The mechanism of this resistance appears to be related to changes in gp120 and mainly in the V3 region which enables the virus to recognise the P51681 - co - receptor bound to the MVC molecule . From a practical point of view , standardised tests are currently unavailable to assess susceptibility to MVC , although in dose - response phenotype tests a maximum percentage inhibition ( MPI ) < 95 % would be indicative of resistance to the compound . Similarly , although some mutations associated with resistance in V3 , and other zones of gp120 , have been described , this preliminary information suggests different resistance patterns and at the moment , we do not know the canonical mutations to be able to establish genotyping algorithms .\",\n \"Multifaceted mechanisms of HIV inhibition and resistance to P51681 inhibitors PSC - RANTES and DB04835 . Small - molecule P51681 antagonists , such as maraviroc ( MVC ) , likely block HIV - 1 through an allosteric , noncompetitive inhibition mechanism , whereas inhibition by agonists such as PSC - RANTES is less defined and may involve receptor removal by cell surface downregulation , competitive inhibition by occluding the HIV - 1 envelope binding , and / or allosteric effects by altering P51681 conformation . We explored the inhibitory mechanisms of maraviroc and PSC - RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors . Intrinsic PSC - RANTES - resistant virus ( YA versus RT ) or those selected in PSC - RANTES treated macaques ( M584 versus P09131 - 4 ) only displayed resistance in multiple - cycle assays or with a P51681 mutant that can not be downregulated . In single - cycle assays , these HIV - 1 clones displayed equal sensitivity to PSC - RANTES inhibition , suggesting effective receptor downregulation . Prolonged PSC - RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration ( substrate ) could saturate the receptors and overcome PSC - RANTES inhibition . In contrast , resistance to MVC was observed with the MVC - resistant HIV - 1 ( R3 versus S2 ) in both multiple - and single - cycle assays and with altered virus concentrations , which is indicative of allosteric inhibition . MVC could also mediate inhibition and possibly resistance through competitive mechanisms .\",\n \"P10275 negatively influences the expression of chemokine receptors ( P61073 , P32246 ) and ligand - mediated migration in prostate cancer DU - 145 . We previously reported that androgen receptor ( AR ) plays a role in the regulation of adhesion to the extracellular matrix and invasion of human prostate cancer cells by influencing the expression of specific integrin subunits . It is now considered that chemokines play a significant role in organ - selective cancer metastasis . In this study , we hypothesized that AR may influence the expression of these chemokine receptors and cell function . The mRNA expression of chemokine receptors in human prostate cancer cell line DU - 145 and DU - 145 cells expressing AR ( DU - 145 / AR ) was investigated by RT - PCR . DU - 145 cells selectively expressed P61073 and P32246 mRNA at high levels compared with DU - 145 / AR cells . DU - 145 showed vigorous migratory responses to its ligand P48061 ( also called stromal - derived factor - 1alpha , SDF - 1alpha ) and P10147 ( also called macrophage inflammatory protein - 1 , MIP - 1alpha ) . In contrast , neither P48061 nor P10147 affected the migration of DU - 145 / AR cells . These results indicate that expression of AR down - regulates the migratory responses of human prostate cancer cells via chemokine and its receptor systems .\",\n \"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK57___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .\",\n \"Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .\",\n \"[ Secondary effects of treatment with maraviroc and other P51681 antagonists . Potential impact of the P51681 blocker ] . DB04835 is the first inhibitor of P51681 co - receptors to be marketed as an antiretroviral . The pre - clinical studies and phase III trials have shown that it has a very favourable safety profile . No characteristic adverse effect of maraviroc has been identified . Unlike with aplaviroc , where its clinical development was stopped due to serious hepatoxicity , no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co - infected by hepatotropic virus . Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients treated with maraviroc . In a study on naive patients , maraviroc produced nonsignificant changes in total cholesterol , LDL , HDL and triglycerides . Although P51681 co - receptors play a role in the immune response of the body , it has not been shown whether individuals homozygote for its deletion ( delta - 32 mutation ) have an increased risk of serious infections , with the possible exception of encephalitis due to the West Nile virus . However , long - term follow up is required on patients treated with to be able to rule out any increased susceptibility to infections or neoplasms .\",\n \"Investigating hypothetical products from noncoding frames ( HyPNoFs ) . Hypothetical Products from Noncoding Frames ( i . e . , HyPNoFs ) are hypothetical , not - coded proteins , translated from alternate reading frames ( i . e . , coding + 1 and coding + 2 ) of cDNAs . HyPNoFs of P01730 , PKC , oncostatin , bcl - 2 proto - oncogene , tumor suppressor p53 , cystic fibrosis transmembrane regulator ( P13569 ) , and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS - Q99884 data bank . Homology searchers carried out revealed that hypothetical products ( i . e . , HyPNoFs ) may share high similarity with real protein products actually coded . Sequence similarity of hypothetical products to real proteins is sometimes very high , suggesting common conformational features , according to the Sander and Schneider cutoff value . This finding supports the hypothesis that eukaryotic DNA , currently considered to be monocistronic , might occasionally have polycistronic regions , carrying different protein messages on overlapping frames . As yet , polycistronic genes have been observed in viral genomes only . The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy , rather than a present feature of the genome in eukaryotes . These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes ' evolution and to investigate structure - function relationships of protein and DNA sequences .\"\n]"},"candidates":{"kind":"list like","value":["___MASK17___","___MASK20___","___MASK44___","___MASK45___","___MASK57___","___MASK75___","___MASK82___","___MASK87___","___MASK95___"],"string":"[\n \"___MASK17___\",\n \"___MASK20___\",\n \"___MASK44___\",\n \"___MASK45___\",\n \"___MASK57___\",\n \"___MASK75___\",\n \"___MASK82___\",\n \"___MASK87___\",\n \"___MASK95___\"\n]"},"answer":{"kind":"string","value":"___MASK57___"},"id":{"kind":"string","value":"MH_train_392"}}},{"rowIdx":393,"cells":{"query":{"kind":"string","value":"interacts_with DB06695?"},"supports":{"kind":"list like","value":["Pharmacogenetics and future strategies in treating hyperglycaemia in diabetes . This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes : metformin , sulphonylureas and thiazolidinediones . Currently , metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in O75051 transporters might affect metformin response . An aetiological approach has identified monogenic patients with diabetes due to TCF1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas , and Q14654 or Q09428 mutations in which sulphonylureas can be used in place of insulin treatment . In Type 2 diabetes sulphonylurea response has been shown to be associated with variants Q9NQB0 associated with type 2 diabetes risk . For thiazolidinediones , focus has been on PPARgamma variants although with no consistent result . Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies . Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required . Establishing such cohorts is a priority in diabetes pharmacogenetics research .","An antibody from a patient with ranitidine - induced thrombocytopenia recognizes a site on glycoprotein IX that is a favored target for drug - induced antibodies . Although thrombocytopenia associated with the use of histamine H2 receptor ( P25021 ) antagonists has been described , a drug - dependent , platelet - reactive antibody has not previously been identified in such cases . We studied serum from a patient who developed acute , severe thrombocytopenia after exposure to the H2 receptor antagonist , ranitidine , and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations . In flow cytometric and immunoprecipitation studies , the antibody was shown to be specific for the glycoprotein Ib / IX complex ( GPIb / IX ) . From the pattern of monoclonal antibody ( MoAb ) inhibition and the reactions of antibody with Chinese hamster ovary ( CHO ) cells transfected with P14770 and GPIbbeta , we found that the patient ' s antibody is specific for an epitope on P14770 close to , or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine , drugs structurally unrelated to ranitidine . These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on P14770 may be a common target for drug - induced antibodies . Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism ( s ) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity .","The role of genetics in the risk of thromboembolism : prothrombin 20210A and oral contraceptive therapy . PURPOSE : To provide an overview of the prothrombin 20210A mutation , its effects on the incidence of venous thromboembolism ( VTE ) in users of oral contraceptive therapy ( O75051 ) , and screening recommendations for the primary care practice setting . DATA SOURCES : Several databases , including MEDLINE , EMBASE , BIOSIS , Cochrane Library , and SciSearch , were searched for articles published between 1996 and 2003 . An integrative review of studies addressing prothrombin 20210A was done using available case - series and case - control studies . No randomized controlled trials on prothrombin 20210A were available in the literature from the years searched . CONCLUSIONS : P00734 20210A increases the risk of developing a VTE for those who carry the genetic mutation . The presence of either concomitant circumstantial factors ( e . g . , surgery or immobilization ) or a combination of genetic factors ( e . g . , factor V Leiden and prothrombin 20210A ) raises the frequency of VTEs to an even greater extent . The risk increases exponentially in users of O75051 . Screening guidelines for the use of O75051 in prothrombin 20210A carriers remain unclear due to the paucity of empirical evidence related to the topic . IMPLICATIONS Q9NZC7 PRACTICE : Practitioners caring for a prothrombin 20210A carrier should maintain a high degree of suspicion with even vague signs or symptoms of a possible VTE . Practitioners should consider completing a full diagnostic workup for VTE on that patient , particularly if that patient is taking O75051 . Until evidence becomes available as to the best anticoagulation practice after an initial or recurrent VTE in a prothrombin 20210A carrier , standard treatment guidelines for anticoagulation should be followed .","NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .","Interpretation of point - of - care INR results in patients treated with dabigatran . BACKGROUND : Point - of - care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . DB06695 , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point - of - care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature + point - of - care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2 - to 4 - fold with the point - of - care device compared with laboratory measures across the plasma dabigatran concentration range 50 - 1400 ng / mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60 - 275 ng / mL ) , whole blood point - of - care INR values increased from 1 . 7 to 4 . 0 , versus 1 . 1 to 1 . 5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr . point - of - care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran .","Effect of zymogen domains and active site occupation on activation of prothrombin by P04275 - binding protein . P00734 is conformationally activated by P04275 - binding protein ( vWbp ) from Staphylococcus aureus through insertion of the NH ( 2 )- terminal residues of vWbp into the prothrombin catalytic domain . The rate of prothrombin activation by vWbp ( 1 - 263 ) is controlled by a hysteretic kinetic mechanism initiated by substrate binding . The present study evaluates activation of prothrombin by full - length vWbp ( 1 - 474 ) through activity progress curve analysis . Additional interactions from the COOH - terminal half of vWbp ( 1 - 474 ) strengthened the initial binding of vWbp to prothrombin , resulting in higher activity and an ∼ 100 - fold enhancement in affinity . The affinities of vWbp ( 1 - 263 ) or vWbp ( 1 - 474 ) were compared by equilibrium binding to the prothrombin derivatives prethrombin 1 , prethrombin 2 , thrombin , meizothrombin , and meizothrombin ( des - fragment 1 ) and their corresponding active site - blocked analogs . Loss of fragment 1 in prethrombin 1 enhanced affinity for both vWbp ( 1 - 263 ) and vWbp ( 1 - 474 ) , with a 30 - 45 % increase in Gibbs free energy , implicating a regulatory role for fragment 1 in the activation mechanism . Active site labeling of all prothrombin derivatives with D - DB00120 - Pro - DB00125 - chloromethyl ketone , analogous to irreversible binding of a substrate , decreased their K ( D ) values for vWbp into the subnanomolar range , reflecting the dependence of the activating conformational change on substrate binding . The results suggest a role for prothrombin domains in the pathophysiological activation of prothrombin by vWbp , and may reveal a function for autocatalysis of the vWbp · prothrombin complexes during initiation of blood coagulation .","Bernard - Soulier syndrome ( hemorrhagiparous thrombocytic dystrophy ) . Bernard - Soulier syndrome ( BSS ) , also known as Hemorrhagiparous thrombocytic dystrophy , is a hereditary bleeding disorder affecting the megakaryocyte / platelet lineage and characterized by bleeding tendency , giant blood platelets and low platelet counts . This syndrome is extremely rare as only approximately 100 cases have been reported in the literature . Clinical manifestations usually include purpura , epistaxis , menorrhagia , gingival and gastrointestinal bleeding . The syndrome is transmitted as an autosomal recessive trait . The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb - V - IX complex , a platelet - restricted multisubunit receptor required for normal primary hemostasis . The GPIb - V - IX complex binds P04275 , allowing platelet adhesion and platelet plug formation at sites of vascular injury . Genes coding for the four subunits of the receptor , GPIBA , GPIBB , P40197 and P14770 , map to chromosomes 17p12 , 22q11 . 2 , 3q29 , and 3q21 , respectively . Defects have been identified in GPIBA , GPIBB , and P14770 but not in P40197 . Diagnosis is based on a prolonged skin bleeding time , the presence of a small number of very large platelets ( macrothrombocytopenia ) , defective ristocetin - induced platelet agglutination and low or absent expression of the GPIb - V - IX complex . P00734 consumption is markedly reduced . The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses , trauma and surgical procedures . Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion .","Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .","Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK84___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK84___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK6___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","Inhibition of prothrombin kringle - 2 - induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo . P00734 kringle - 2 ( pKr - 2 ) , a domain of prothrombin , can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation . However , the chemical products that inhibit pKr - 2 - induced inflammatory activities in the brain are still not well known . The present study investigated whether minocycline , a semisynthetic tetracycline derivative , could inhibit pKr - 2 - induced microglial activation and prevent the loss of nigral dopaminergic ( DA ) neurons in vivo . To address this question , rats were administered a unilateral injection of pKr - 2 in the substantia nigra in the presence or absence of minocycline . Our results show that pKr - 2 induces the production of proinflammatory cytokines , such as tumor necrosis factor - α ( P01375 - α ) and interleukin - 1β ( IL - 1β ) , and inducible nitric oxide synthase from the activated microglia . In parallel , 7 days after pKr - 2 injection , tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons . This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor - α , interleukin - 1β , and nitric oxide synthase . These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr - 2 - induced microglial activation .","Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK50___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK50___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK50___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK50___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK50___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .","Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK31___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .","Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .","Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .","Cellular mechanisms of the hemostatic effects of desmopressin ( ___MASK49___ ) . The synthetic analog of vasopressin desmopressin ( ___MASK49___ ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . ___MASK49___ induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of ___MASK49___ on FVIII plasma levels remains to be elucidated . The hemostatic effect of ___MASK49___ likely involves additional cellular effects that remain to be discovered .","Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK96___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .","Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .","DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK3___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .","___MASK33___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .","___MASK17___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .","Integrin alpha5 - induced P00533 activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway . We have previously shown that prothrombin , a blood coagulation factor , can cause an inhibition of DNA synthesis in normal rat hepatocytes . To explore the mechanisms of this prothrombin action , we examined its effects on the activation of fibronectin receptor integrin alpha5 , since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures . We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor ( P00533 ) , leading to P00533 tyrosine phosphorylation at tyrosine residues DB00135 - 845 and DB00135 - 1173 . P00533 tyrosine phosphorylation triggered phosphorylation of its down - stream target Shc and the activation of the c - Jun N - terminal kinase ( JNK ) pathway . P00734 also induced hepatocyte apoptosis , a change in cell shape and activation of caspase 3 pathway . The JNK pathway is most likely involved in prothrombin - induced hepatocyte apoptosis , because pre - treatment of hepatocytes with JNK kinase inhibitor II ( SP600125 ) antagonized these prothrombin actions . The data suggest that integrin - related P00533 activation by prothrombin can induce cell growth inhibition and apoptosis via an P00533 - JNK signaling pathway .","Effects of G - P04141 on systemic inflammation , coagulation and platelet activation in patients with acute myocardial infarction . INTRODUCTION : In the prospective , randomised , double - blind , placebo - controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells ( REVIVAL ) - 2 trial patients with acute myocardial infarction ( AMI ) and successful mechanical reperfusion received granulocyte - colony stimulating factor ( DB00099 , 10 μg / kg KG s . c . ) or placebo for 5 days . Aim of this substudy was to assess the impact of G - P04141 on systemic inflammatory and procoagulant responses and platelet activation . METHODS AND RESULTS : Before and five days after DB00099 ( n = 56 ) or placebo ( n = 58 ) circulating cytokine concentrations of interleukin ( IL ) - 1ß , P05231 , P10145 , P22301 , IL - 12 and Tumor - Necrosis Factor - α ( P01375 - α were measured . P00734 fragment F1 + 2 and Tissue Factor activity served as a measure for activated coagulation . Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor ( O95456 ) , P16109 and P29965 by flow cytometry . Administration of G - P04141 was associated with elevated P01375 - α and CRP concentrations compared to the placebo group after 5 days . Other cytokines ( IL - 1ß , P05231 , P10145 , P22301 , IL - 12 ) were comparable after treatment with G - P21583 or placebo . Similarly , circulating prothrombin fragments F1 + 2 , TF activity and platelet activation did not differ in both groups . CONCLUSION : Treatment with G - P04141 in patients with AMI was associated with enhanced proinflammatory P01375 - α and CRP levels but no activation of coagulation ."],"string":"[\n \"Pharmacogenetics and future strategies in treating hyperglycaemia in diabetes . This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes : metformin , sulphonylureas and thiazolidinediones . Currently , metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in O75051 transporters might affect metformin response . An aetiological approach has identified monogenic patients with diabetes due to TCF1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas , and Q14654 or Q09428 mutations in which sulphonylureas can be used in place of insulin treatment . In Type 2 diabetes sulphonylurea response has been shown to be associated with variants Q9NQB0 associated with type 2 diabetes risk . For thiazolidinediones , focus has been on PPARgamma variants although with no consistent result . Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies . Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required . Establishing such cohorts is a priority in diabetes pharmacogenetics research .\",\n \"An antibody from a patient with ranitidine - induced thrombocytopenia recognizes a site on glycoprotein IX that is a favored target for drug - induced antibodies . Although thrombocytopenia associated with the use of histamine H2 receptor ( P25021 ) antagonists has been described , a drug - dependent , platelet - reactive antibody has not previously been identified in such cases . We studied serum from a patient who developed acute , severe thrombocytopenia after exposure to the H2 receptor antagonist , ranitidine , and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations . In flow cytometric and immunoprecipitation studies , the antibody was shown to be specific for the glycoprotein Ib / IX complex ( GPIb / IX ) . From the pattern of monoclonal antibody ( MoAb ) inhibition and the reactions of antibody with Chinese hamster ovary ( CHO ) cells transfected with P14770 and GPIbbeta , we found that the patient ' s antibody is specific for an epitope on P14770 close to , or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine , drugs structurally unrelated to ranitidine . These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on P14770 may be a common target for drug - induced antibodies . Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism ( s ) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity .\",\n \"The role of genetics in the risk of thromboembolism : prothrombin 20210A and oral contraceptive therapy . PURPOSE : To provide an overview of the prothrombin 20210A mutation , its effects on the incidence of venous thromboembolism ( VTE ) in users of oral contraceptive therapy ( O75051 ) , and screening recommendations for the primary care practice setting . DATA SOURCES : Several databases , including MEDLINE , EMBASE , BIOSIS , Cochrane Library , and SciSearch , were searched for articles published between 1996 and 2003 . An integrative review of studies addressing prothrombin 20210A was done using available case - series and case - control studies . No randomized controlled trials on prothrombin 20210A were available in the literature from the years searched . CONCLUSIONS : P00734 20210A increases the risk of developing a VTE for those who carry the genetic mutation . The presence of either concomitant circumstantial factors ( e . g . , surgery or immobilization ) or a combination of genetic factors ( e . g . , factor V Leiden and prothrombin 20210A ) raises the frequency of VTEs to an even greater extent . The risk increases exponentially in users of O75051 . Screening guidelines for the use of O75051 in prothrombin 20210A carriers remain unclear due to the paucity of empirical evidence related to the topic . IMPLICATIONS Q9NZC7 PRACTICE : Practitioners caring for a prothrombin 20210A carrier should maintain a high degree of suspicion with even vague signs or symptoms of a possible VTE . Practitioners should consider completing a full diagnostic workup for VTE on that patient , particularly if that patient is taking O75051 . Until evidence becomes available as to the best anticoagulation practice after an initial or recurrent VTE in a prothrombin 20210A carrier , standard treatment guidelines for anticoagulation should be followed .\",\n \"NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .\",\n \"Interpretation of point - of - care INR results in patients treated with dabigatran . BACKGROUND : Point - of - care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . DB06695 , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point - of - care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature + point - of - care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2 - to 4 - fold with the point - of - care device compared with laboratory measures across the plasma dabigatran concentration range 50 - 1400 ng / mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60 - 275 ng / mL ) , whole blood point - of - care INR values increased from 1 . 7 to 4 . 0 , versus 1 . 1 to 1 . 5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr . point - of - care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran .\",\n \"Effect of zymogen domains and active site occupation on activation of prothrombin by P04275 - binding protein . P00734 is conformationally activated by P04275 - binding protein ( vWbp ) from Staphylococcus aureus through insertion of the NH ( 2 )- terminal residues of vWbp into the prothrombin catalytic domain . The rate of prothrombin activation by vWbp ( 1 - 263 ) is controlled by a hysteretic kinetic mechanism initiated by substrate binding . The present study evaluates activation of prothrombin by full - length vWbp ( 1 - 474 ) through activity progress curve analysis . Additional interactions from the COOH - terminal half of vWbp ( 1 - 474 ) strengthened the initial binding of vWbp to prothrombin , resulting in higher activity and an ∼ 100 - fold enhancement in affinity . The affinities of vWbp ( 1 - 263 ) or vWbp ( 1 - 474 ) were compared by equilibrium binding to the prothrombin derivatives prethrombin 1 , prethrombin 2 , thrombin , meizothrombin , and meizothrombin ( des - fragment 1 ) and their corresponding active site - blocked analogs . Loss of fragment 1 in prethrombin 1 enhanced affinity for both vWbp ( 1 - 263 ) and vWbp ( 1 - 474 ) , with a 30 - 45 % increase in Gibbs free energy , implicating a regulatory role for fragment 1 in the activation mechanism . Active site labeling of all prothrombin derivatives with D - DB00120 - Pro - DB00125 - chloromethyl ketone , analogous to irreversible binding of a substrate , decreased their K ( D ) values for vWbp into the subnanomolar range , reflecting the dependence of the activating conformational change on substrate binding . The results suggest a role for prothrombin domains in the pathophysiological activation of prothrombin by vWbp , and may reveal a function for autocatalysis of the vWbp · prothrombin complexes during initiation of blood coagulation .\",\n \"Bernard - Soulier syndrome ( hemorrhagiparous thrombocytic dystrophy ) . Bernard - Soulier syndrome ( BSS ) , also known as Hemorrhagiparous thrombocytic dystrophy , is a hereditary bleeding disorder affecting the megakaryocyte / platelet lineage and characterized by bleeding tendency , giant blood platelets and low platelet counts . This syndrome is extremely rare as only approximately 100 cases have been reported in the literature . Clinical manifestations usually include purpura , epistaxis , menorrhagia , gingival and gastrointestinal bleeding . The syndrome is transmitted as an autosomal recessive trait . The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb - V - IX complex , a platelet - restricted multisubunit receptor required for normal primary hemostasis . The GPIb - V - IX complex binds P04275 , allowing platelet adhesion and platelet plug formation at sites of vascular injury . Genes coding for the four subunits of the receptor , GPIBA , GPIBB , P40197 and P14770 , map to chromosomes 17p12 , 22q11 . 2 , 3q29 , and 3q21 , respectively . Defects have been identified in GPIBA , GPIBB , and P14770 but not in P40197 . Diagnosis is based on a prolonged skin bleeding time , the presence of a small number of very large platelets ( macrothrombocytopenia ) , defective ristocetin - induced platelet agglutination and low or absent expression of the GPIb - V - IX complex . P00734 consumption is markedly reduced . The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses , trauma and surgical procedures . Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion .\",\n \"Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .\",\n \"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK84___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK84___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK6___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"Inhibition of prothrombin kringle - 2 - induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo . P00734 kringle - 2 ( pKr - 2 ) , a domain of prothrombin , can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation . However , the chemical products that inhibit pKr - 2 - induced inflammatory activities in the brain are still not well known . The present study investigated whether minocycline , a semisynthetic tetracycline derivative , could inhibit pKr - 2 - induced microglial activation and prevent the loss of nigral dopaminergic ( DA ) neurons in vivo . To address this question , rats were administered a unilateral injection of pKr - 2 in the substantia nigra in the presence or absence of minocycline . Our results show that pKr - 2 induces the production of proinflammatory cytokines , such as tumor necrosis factor - α ( P01375 - α ) and interleukin - 1β ( IL - 1β ) , and inducible nitric oxide synthase from the activated microglia . In parallel , 7 days after pKr - 2 injection , tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons . This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor - α , interleukin - 1β , and nitric oxide synthase . These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr - 2 - induced microglial activation .\",\n \"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK50___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK50___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK50___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK50___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK50___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .\",\n \"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK31___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .\",\n \"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .\",\n \"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .\",\n \"Cellular mechanisms of the hemostatic effects of desmopressin ( ___MASK49___ ) . The synthetic analog of vasopressin desmopressin ( ___MASK49___ ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . ___MASK49___ induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of ___MASK49___ on FVIII plasma levels remains to be elucidated . The hemostatic effect of ___MASK49___ likely involves additional cellular effects that remain to be discovered .\",\n \"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK96___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .\",\n \"Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .\",\n \"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK3___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .\",\n \"___MASK33___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .\",\n \"___MASK17___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .\",\n \"Integrin alpha5 - induced P00533 activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway . We have previously shown that prothrombin , a blood coagulation factor , can cause an inhibition of DNA synthesis in normal rat hepatocytes . To explore the mechanisms of this prothrombin action , we examined its effects on the activation of fibronectin receptor integrin alpha5 , since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures . We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor ( P00533 ) , leading to P00533 tyrosine phosphorylation at tyrosine residues DB00135 - 845 and DB00135 - 1173 . P00533 tyrosine phosphorylation triggered phosphorylation of its down - stream target Shc and the activation of the c - Jun N - terminal kinase ( JNK ) pathway . P00734 also induced hepatocyte apoptosis , a change in cell shape and activation of caspase 3 pathway . The JNK pathway is most likely involved in prothrombin - induced hepatocyte apoptosis , because pre - treatment of hepatocytes with JNK kinase inhibitor II ( SP600125 ) antagonized these prothrombin actions . The data suggest that integrin - related P00533 activation by prothrombin can induce cell growth inhibition and apoptosis via an P00533 - JNK signaling pathway .\",\n \"Effects of G - P04141 on systemic inflammation , coagulation and platelet activation in patients with acute myocardial infarction . INTRODUCTION : In the prospective , randomised , double - blind , placebo - controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells ( REVIVAL ) - 2 trial patients with acute myocardial infarction ( AMI ) and successful mechanical reperfusion received granulocyte - colony stimulating factor ( DB00099 , 10 μg / kg KG s . c . ) or placebo for 5 days . Aim of this substudy was to assess the impact of G - P04141 on systemic inflammatory and procoagulant responses and platelet activation . METHODS AND RESULTS : Before and five days after DB00099 ( n = 56 ) or placebo ( n = 58 ) circulating cytokine concentrations of interleukin ( IL ) - 1ß , P05231 , P10145 , P22301 , IL - 12 and Tumor - Necrosis Factor - α ( P01375 - α were measured . P00734 fragment F1 + 2 and Tissue Factor activity served as a measure for activated coagulation . Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor ( O95456 ) , P16109 and P29965 by flow cytometry . Administration of G - P04141 was associated with elevated P01375 - α and CRP concentrations compared to the placebo group after 5 days . Other cytokines ( IL - 1ß , P05231 , P10145 , P22301 , IL - 12 ) were comparable after treatment with G - P21583 or placebo . Similarly , circulating prothrombin fragments F1 + 2 , TF activity and platelet activation did not differ in both groups . CONCLUSION : Treatment with G - P04141 in patients with AMI was associated with enhanced proinflammatory P01375 - α and CRP levels but no activation of coagulation .\"\n]"},"candidates":{"kind":"list like","value":["___MASK17___","___MASK31___","___MASK33___","___MASK3___","___MASK49___","___MASK50___","___MASK6___","___MASK84___","___MASK96___"],"string":"[\n \"___MASK17___\",\n \"___MASK31___\",\n \"___MASK33___\",\n \"___MASK3___\",\n \"___MASK49___\",\n \"___MASK50___\",\n \"___MASK6___\",\n \"___MASK84___\",\n \"___MASK96___\"\n]"},"answer":{"kind":"string","value":"___MASK6___"},"id":{"kind":"string","value":"MH_train_393"}}},{"rowIdx":394,"cells":{"query":{"kind":"string","value":"interacts_with DB08865?"},"supports":{"kind":"list like","value":["Circulating hepatocyte growth factor as an independent prognostic factor of disseminated intravascular coagulation . BACKGROUND : P14210 ( P14210 ) , a pleiotropic factor regulating development and wound healing , is secreted as inactive pro - P14210 and is converted into active P14210 by coagulation serine proteases . P08581 overexpression can cause massive venous thrombi , and factor Xa is reported to release soluble P14210 from granulocytes . We hypothesized that a hypercoagulable condition , such as disseminated intravascular coagulation ( DIC ) , may increase circulating P14210 through active cleavage by coagulation serine proteases . METHODS : In 172 DIC - suspected patients , plasma levels of total and active P14210 , thrombin - antithrombin complex ( TAT ) , plasmin - antiplasmin complex ( PAP ) , and interleukin ( IL ) - 6 were measured by ELISA . Active P14210 release in granulocytes was examined in patients with and without overt - DIC . P14210 - induced tissue factor expression in peripheral monocytes was measured by flow cytometry . RESULTS : Circulating levels of total and active P14210 correlated well with coagulopathy severity , including DIC score , D - dimer , TAT and PAP levels . P14210 positively correlated with P05231 and absolute neutrophil count . In contrast to the cancer group , P14210 levels were significantly increased in accordance with increased DIC scores in non - cancer group . Elevated circulating P14210 was an independent prognostic marker in the non - cancer group , while P14210 level failed to predict mortality in the cancer group . Amounts of P14210 released from stimulated granulocytes were not significantly different between overt - DIC and no overt - DIC patients . P14210 potentiated endotoxin - induced tissue factor expression of monocytes in vitro . CONCLUSION : These findings suggest that circulating P14210 is a potential laboratory marker reflecting coagulation activity and DIC prognosis in non - cancer patients and that P14210 may play a role in a vicious cycle of hypercoagulability .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK87___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK54___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK54___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK54___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .","The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK19___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK19___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK19___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK19___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .","Modulation of c - MET proto - oncogene ( P08581 ) mRNA abundance by cytokines and hormones : evidence for rapid decay of the 8 kb c - MET transcript . The c - MET proto - oncogene product is a transmembrane tyrosine kinase receptor which was recently shown to transmit an array of important cellular responses induced by Hepatocyte Growth Factor ( P14210 ) . These biological effects include induction of mitogenesis , motogenesis , morphogenesis , metastogenesis and anti - tumor activity on a variety of epithelial cells . All of these processes are known to be associated with normal and abnormal tissue growth and development . The 190 kDa c - MET protein is encoded by a major transcript of 8 kilobases ( kb ) , which is reported to be expressed predominantly in epithelial tissues . The expression pattern of c - MET mRNA and protein are drastically modified in many tumor tissues and cell lines . Currently , no information is available on the molecular mechanisms that regulate c - MET mRNA level . In the present communication , we report for the first time that the inflammatory cytokines such as P01583 , P05231 and P01375 , as well as TGF - beta 1 , P01133 , P14210 and the steroidal hormones ( estrogen , progesterone , tamoxifen and dexamethasone ) markedly influence the steady - state levels of the 8 kb c - MET mRNA in human carcinoma cell lines derived from human tissues such as ovary , breast and endometrium . We demonstrate that c - MET receptor protein is present at high levels in primary tumors of human ovaries ( clear cell carcinomas ) . We present evidence that the 8 kb c - MET mRNA undergoes rapid degradation with a half - life of less than 30 min and that this decay can be quickly inhibited by cycloheximide . Our results suggest that the expression of the c - met proto - oncogene resembles that of an immediate early response gene .","STK / Q04912 receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the P08581 family . STK / Q04912 tyrosine kinase , a member of the hepatocyte growth factor ( P14210 ) receptor family , is a receptor for macrophage - stimulating protein ( MSP ) . To examine the STK / Q04912 signalling pathway , we generated STK / Q04912 transfectants showing opposite features in growth . STK / Q04912 - expressing Ba / P13726 pro - B cells ( BaF / STK ) exhibited MSP - dependent growth , whereas STK / Q04912 - expressing mouse erythroleukaemia cells ( P61006 / STK ) displayed MSP - induced apoptosis . This apoptosis was accompanied by the prolonged activation of c - Jun N - terminal kinase ( JNK ) , which has recently been implicated in the initiation of apoptosis . Co - immunoprecipitation analyses showed that autophosphorylated STK / Q04912 associated with P98160 - gamma , P13 - kinase , Shc and Grb2 in both transfectants . However , major tyrosine - phosphorylated proteins , p61 and p65 , specifically associated with STK / Q04912 in P61006 / STK cells . Mutations at two C - terminal tyrosine residues , Y1330 and Y1337 , in the counterpart of the multifunctional docking site of the P08581 abolished both MSP - induced growth and apoptosis . Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site . These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis . Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase .","___MASK36___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .","17 ___MASK42___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .","A Hepatocyte Growth Factor ( P14210 ) / receptor autocrine loop regulates constitutive self - renewal of human periodontal ligament cells but reduces sensitivity to exogenous P14210 . BACKGROUND : In addition to its prominent role in liver regeneration , hepatocyte growth factor ( P14210 ) is now generally thought to be produced by mesenchymal cells to promote the regeneration of epithelial tissue by a paracrine mechanism . However , it is not known how or if P14210 could be involved in the regeneration of periodontal tissues . The purpose of this study was to characterize the ability of normal human periodontal ligament ( PDL ) cells to produce or respond to P14210 . METHODS : PDL cells derived from healthy young volunteers were used from passages four through 10 . P14210 receptors were detected both by immunocytochemical staining and Western - blotting analysis . Both DNA synthesis ( by bromo - deoxyuridine [ BrdU ] - incorporation ) and secreted P14210 were quantified by enzyme - linked immunosorbent assays . Mitogen - activated protein kinase ( MAPK ) phosphorylation was also analyzed by Western blot . RESULTS : Despite the immunocytochemical demonstration of P08581 protein in the cytoplasm and on the plasma membrane of PDL cells , exogenous recombinant human P14210 did not exert the mitogenic effects expected . As reported for other mesenchymal cells , PDL cells were found to secrete P14210 . Treatments with neutralizing anti - P14210 antibody significantly suppressed constitutive PDL cell proliferation and sustained the receptor protein at higher levels than in non - treated cells . Under these conditions , exogenous P14210 rapidly phosphorylated extracellular signal - regulated kinase ( P29323 ) , an action linked to the cell proliferation and downregulation of cell - surface receptors . CONCLUSIONS : Unlike other known mesenchymal or epithelial cells , these findings suggest that normal PDL cells from young donors possess a constitutive P14210 / receptor autocrine loop that normally regulates their replacement self - proliferation but reduces sensitivity to exogenously applied P14210 by acute receptor downregulation .","P14210 and P04626 / neu downregulate expression of apoptosis - inducing factor in non - small cell lung cancer . Our previous study showed that patients with advanced stages of non - small cell lung cancer ( NSCLC ) were frequently detected with upregulation of hepatocyte growth factor ( P14210 ) . In vitro , P14210 reduced expression of apoptosis - inducing factor ( O95831 ) and cisplatin sensitivity in NSCLC cells . The effect of P14210 was via P08581 ( c - MET ) and the downstream effector , focal adhesion kinase ( Q05397 ) . In this study , we determined the prognostic value of O95831 in NSCLC patients . O95831 expression was determined by immunohistochemistry and immunoblotting . Our data show that O95831 expression was associated with better prognosis . Expression of O95831 inversely correlated with that of positive NSCLC markers , e . g . , dihydrodiol dehydrogenase ( Q04828 ) , c - MET , short oncostatin M receptor ( OSMRs ) , matrix metalloproteinase ( MMP ) - 1 , and P04626 / neu , which were closely associated with drug resistance , tumor recurrence , metastasis and poor prognosis . Noteworthy , silence of P04626 / neu gene expression increases O95831 level and drug sensitivity . Addition of P14210 inhibits O95831 expression in P04626 / neu - silenced cells . These results suggested that both P14210 and P04626 / neu affect drug resistance by regulating O95831 expression in NSCLC .","___MASK69___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK69___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .","Gab1 but not Grb2 mediates tumor progression in DB00134 overexpressing colorectal cancer cells . P08581 ( DB00134 ) plays an important role in the progression of multiple cancer types . The overexpression of DB00134 in DLD - 1 colon carcinoma cells with kirsten rat sarcoma oncogene homolog ( P01116 ) oncogene activation resulted in enhanced subcutaneous and orthotopic tumor growth rate and increased metastatic potential . To elucidate the mechanism of this effect , we stably expressed kinase - inactive DB00134 ( K1110A ) , Src homology 2 ( SH2 ) - binding domain - inactive DB00134 ( Y1349 / 1356F ) , growth factor receptor - bound protein 2 ( Grb2 ) non - binding DB00134 ( N1358H ) and mutant receptors with ability to selectively recruit signaling proteins Grb2 , src homology domain c - terminal adaptor homolog ( Shc ) , phospholipase c - gamma ( PLCgamma ) and p85 phosphatidyl inositol 3 kinase . As subcutaneous implants , DLD - 1 cells that expressed the majority of these receptor constructs failed to recapitulate the tumor growth - enhancing effect of the wild - type DB00134 receptor . The Grb2 - and Shc - recruiting DB00134 mutants demonstrated slight but consistent tumor - suppressive activity , whereas the expression of N1358H mutant stimulated tumor growth rate comparable with the wild - type receptor . This suggests that direct Grb2 / Shc binding does not contribute to the tumor progression activity of DB00134 receptor . The tumors expressing Grb2 - and Shc - recruiting DB00134 receptors demonstrated a marked loss in Grb2 - associated adaptor protein 1 ( Gab1 ) protein levels , which was not observed in the cell lines , consistent with a post - translationally regulated process . Moreover , a moderate level of Gab1 overexpression stimulated tumor growth . The findings suggest a delicate balance for intact Y1349 / 1356 SH2 - binding domain to mediate the tumor progression activity of the coactivated DB00134 - rat sarcoma oncogene homolog ( DB01367 ) pathways . Selectivity for specific adaptor protein involvement may be the key that determines the tissue - and cell - type specificity of DB00134 - mediated tumorigenicity in human cancers .","Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK94___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .","___MASK50___ increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : ___MASK50___ is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . ___MASK50___ and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : ___MASK50___ increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .","Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .","P08581 tyrosine kinase met is a substrate of the receptor protein - tyrosine phosphatase Q12913 . The receptor protein - tyrosine phosphatase ( PTP ) Q12913 ( CD148 / PTP - eta ) has been implicated in the regulation of cell growth , differentiation , and transformation , and most recently has been identified as a potential tumor suppressor gene mutated in colon , lung , and breast cancers . We have generated constructs comprising the cytoplasmic segment of Q12913 fused to the maltose - binding protein to identify potential substrates and thereby suggest a physiological function for Q12913 . We have shown that the substrate - trapping mutant form of Q12913 interacted with a small subset of tyrosine - phosphorylated proteins from lysates of the human breast tumor cell lines MDA - MB - 231 , T - 47D , and T - 47D / DB00134 and have identified the hepatocyte growth factor / scatter factor receptor DB00134 , the adapter protein Gab1 , and the junctional component O60716 as potential substrates . Following ligand stimulation , phosphorylation of specific tyrosyl residues in DB00134 induces mitogenic , motogenic , and morphogenic responses . When co - expressed in 293 cells , the full - length substrate - trapping mutant form of Q12913 formed a stable complex with the chimeric receptor colony stimulating factor 1 ( P04141 ) - DB00134 and wild type Q12913 dephosphorylated P04141 - DB00134 . Furthermore , we observed that Q12913 preferentially dephosphorylated a Gab1 binding site ( DB00135 ( 1349 ) ) and a COOH - terminal tyrosine implicated in morphogenesis ( DB00135 ( 1365 ) ) , whereas tyrosine residues in the activation loop of DB00134 ( DB00135 ( 1230 ) , DB00135 ( 1234 ) , and DB00135 ( 1235 ) ) were not preferred targets of the PTP . The ability of Q12913 preferentially to dephosphorylate particular tyrosine residues that are required for DB00134 - induced signaling suggests that Q12913 may function in controlling the specificity of signals induced by this PTK , rather than as a simple \" off - switch \" to counteract PTK activity .","Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK4___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .","P14210 triggers distinct mechanisms of Q9NR80 and Tiam1 activation to induce endothelial barrier enhancement . Previous reports described an important role of hepatocyte growth factor ( P14210 ) in mitigation of pulmonary endothelial barrier dysfunction and cell injury induced by pathologic agonists and mechanical forces . P14210 protective effects have been associated with Rac - GTPase signaling pathway activated by Rac - specific guanine nucleotide exchange factor Tiam1 and leading to enhancement of intercellular adherens junctions . This study tested involvement of a novel Rac - specific activator , Q9NR80 , in endothelial barrier enhancement by P14210 and investigated a mechanism of P14210 - induced Q9NR80 activation . Si - RNA - based knockdown of Tiam1 and Q9NR80 had an additive effect on attenuation of P14210 - induced Rac activation and endothelial cell ( EC ) barrier enhancement . Tiam1 and Q9NR80 activation was abolished by pharmacologic inhibitors of P08581 and P19957 - kinase . In contrast to Tiam1 , Q9NR80 interacted with P25054 and associated with microtubule fraction upon P14210 stimulation . EC treatment by low dose DB08313 to inhibit peripheral microtubule dynamics partially attenuated P14210 - induced Q9NR80 peripheral translocation , but had negligible effect on Tiam1 translocation . These effects were associated with attenuation of P14210 - induced barrier enhancement in EC pretreated with low ND dose and activation of Rac and its cytoskeletal effectors PAK1 and cortactin . These data demonstrate , that in addition to microtubule - independent Tiam1 activation , P14210 engages additional microtubule - and P25054 - dependent pathway of Q9NR80 activation . These mechanisms may complement each other to provide the fine tuning of Rac signaling and endothelial barrier enhancement in response to various agonists .","Protein Tyrosine Phosphatase 1B ( P18031 ) deficiency accelerates hepatic regeneration in mice . Protein tyrosine phosphatase 1B ( P18031 ) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors and modulate the intensity of their signaling cascades . Because liver regeneration involves tyrosine phosphorylation - mediated signaling , we investigated the role of P18031 in this process by performing partial hepatectomy in wild - type ( P18031 (+/+) ) and P18031 - deficient ( P18031 (-/-) ) mice . The expression of P12004 and cyclins D1 and E ( cell proliferation markers ) was enhanced in P18031 (-/-) regenerating livers , in parallel with 5 '- bromo - 2 '- deoxyuridine incorporation . Phosphorylation of P45983 / 2 and P40763 , early triggers of hepatic regeneration in response to P01375 - α and P05231 , was accelerated in P18031 (-/-) mice compared with P18031 (+/+) mice . These phosphorylations were increased in P18031 (-/-) hepatocytes or by silencing P18031 in wild - type cells and decreased further after the addition of recombinant P18031 . Enhanced P01133 - and P08581 - mediated signaling was observed in regenerating livers lacking P18031 and in P01133 - or P14210 - stimulated P18031 (-/-) hepatocytes . Moreover , P18031 (-/-) mice displayed a more rapid increase in intrahepatic lipid accumulation than P18031 (+/+) control mice . Late responses to partial hepatectomy revealed additional divergences because stress - mediated signaling was attenuated at 24 to 96 hours in P18031 (-/-) mice compared with P18031 (+/+) mice . Finally , P18031 deficiency also improves hepatic regeneration in mice fed a high - fat diet . These results suggest that pharmacological inhibition of P18031 would improve liver regeneration in patients with acute or chronic liver injury .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","DB08865 for the treatment of patients with advanced non - small cell lung cancer . DB08865 is a potent small - molecule inhibitor of Q9UM73 ( anaplastic lymphoma kinase ; Q9UM73 ) and hepatocyte growth factor receptor ( P08581 , proto - oncogene c - DB00134 ) . A range of tumors , including subsets of non - small cell lung cancer ( NSCLC ) , anaplastic large cell lymphoma and inflammatory myofibroblastic tumors harbor an Q9UM73 rearrangement that leads to oncogenic activation of Q9UM73 . DB08865 has demonstrated preclinical and clinical activity against such malignancies through inhibition of Q9UM73 , and patients harboring Q9UM73 - rearranged NSCLC have demonstrated high response rates and prolonged progression - free survival in phase I and II studies . In August 2011 , crizotinib was approved for the treatment of advanced Q9UM73 - positive NSCLC ."],"string":"[\n \"Circulating hepatocyte growth factor as an independent prognostic factor of disseminated intravascular coagulation . BACKGROUND : P14210 ( P14210 ) , a pleiotropic factor regulating development and wound healing , is secreted as inactive pro - P14210 and is converted into active P14210 by coagulation serine proteases . P08581 overexpression can cause massive venous thrombi , and factor Xa is reported to release soluble P14210 from granulocytes . We hypothesized that a hypercoagulable condition , such as disseminated intravascular coagulation ( DIC ) , may increase circulating P14210 through active cleavage by coagulation serine proteases . METHODS : In 172 DIC - suspected patients , plasma levels of total and active P14210 , thrombin - antithrombin complex ( TAT ) , plasmin - antiplasmin complex ( PAP ) , and interleukin ( IL ) - 6 were measured by ELISA . Active P14210 release in granulocytes was examined in patients with and without overt - DIC . P14210 - induced tissue factor expression in peripheral monocytes was measured by flow cytometry . RESULTS : Circulating levels of total and active P14210 correlated well with coagulopathy severity , including DIC score , D - dimer , TAT and PAP levels . P14210 positively correlated with P05231 and absolute neutrophil count . In contrast to the cancer group , P14210 levels were significantly increased in accordance with increased DIC scores in non - cancer group . Elevated circulating P14210 was an independent prognostic marker in the non - cancer group , while P14210 level failed to predict mortality in the cancer group . Amounts of P14210 released from stimulated granulocytes were not significantly different between overt - DIC and no overt - DIC patients . P14210 potentiated endotoxin - induced tissue factor expression of monocytes in vitro . CONCLUSION : These findings suggest that circulating P14210 is a potential laboratory marker reflecting coagulation activity and DIC prognosis in non - cancer patients and that P14210 may play a role in a vicious cycle of hypercoagulability .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK87___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK54___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK54___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK54___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .\",\n \"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK19___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK19___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK19___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK19___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .\",\n \"Modulation of c - MET proto - oncogene ( P08581 ) mRNA abundance by cytokines and hormones : evidence for rapid decay of the 8 kb c - MET transcript . The c - MET proto - oncogene product is a transmembrane tyrosine kinase receptor which was recently shown to transmit an array of important cellular responses induced by Hepatocyte Growth Factor ( P14210 ) . These biological effects include induction of mitogenesis , motogenesis , morphogenesis , metastogenesis and anti - tumor activity on a variety of epithelial cells . All of these processes are known to be associated with normal and abnormal tissue growth and development . The 190 kDa c - MET protein is encoded by a major transcript of 8 kilobases ( kb ) , which is reported to be expressed predominantly in epithelial tissues . The expression pattern of c - MET mRNA and protein are drastically modified in many tumor tissues and cell lines . Currently , no information is available on the molecular mechanisms that regulate c - MET mRNA level . In the present communication , we report for the first time that the inflammatory cytokines such as P01583 , P05231 and P01375 , as well as TGF - beta 1 , P01133 , P14210 and the steroidal hormones ( estrogen , progesterone , tamoxifen and dexamethasone ) markedly influence the steady - state levels of the 8 kb c - MET mRNA in human carcinoma cell lines derived from human tissues such as ovary , breast and endometrium . We demonstrate that c - MET receptor protein is present at high levels in primary tumors of human ovaries ( clear cell carcinomas ) . We present evidence that the 8 kb c - MET mRNA undergoes rapid degradation with a half - life of less than 30 min and that this decay can be quickly inhibited by cycloheximide . Our results suggest that the expression of the c - met proto - oncogene resembles that of an immediate early response gene .\",\n \"STK / Q04912 receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the P08581 family . STK / Q04912 tyrosine kinase , a member of the hepatocyte growth factor ( P14210 ) receptor family , is a receptor for macrophage - stimulating protein ( MSP ) . To examine the STK / Q04912 signalling pathway , we generated STK / Q04912 transfectants showing opposite features in growth . STK / Q04912 - expressing Ba / P13726 pro - B cells ( BaF / STK ) exhibited MSP - dependent growth , whereas STK / Q04912 - expressing mouse erythroleukaemia cells ( P61006 / STK ) displayed MSP - induced apoptosis . This apoptosis was accompanied by the prolonged activation of c - Jun N - terminal kinase ( JNK ) , which has recently been implicated in the initiation of apoptosis . Co - immunoprecipitation analyses showed that autophosphorylated STK / Q04912 associated with P98160 - gamma , P13 - kinase , Shc and Grb2 in both transfectants . However , major tyrosine - phosphorylated proteins , p61 and p65 , specifically associated with STK / Q04912 in P61006 / STK cells . Mutations at two C - terminal tyrosine residues , Y1330 and Y1337 , in the counterpart of the multifunctional docking site of the P08581 abolished both MSP - induced growth and apoptosis . Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site . These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis . Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase .\",\n \"___MASK36___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .\",\n \"17 ___MASK42___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .\",\n \"A Hepatocyte Growth Factor ( P14210 ) / receptor autocrine loop regulates constitutive self - renewal of human periodontal ligament cells but reduces sensitivity to exogenous P14210 . BACKGROUND : In addition to its prominent role in liver regeneration , hepatocyte growth factor ( P14210 ) is now generally thought to be produced by mesenchymal cells to promote the regeneration of epithelial tissue by a paracrine mechanism . However , it is not known how or if P14210 could be involved in the regeneration of periodontal tissues . The purpose of this study was to characterize the ability of normal human periodontal ligament ( PDL ) cells to produce or respond to P14210 . METHODS : PDL cells derived from healthy young volunteers were used from passages four through 10 . P14210 receptors were detected both by immunocytochemical staining and Western - blotting analysis . Both DNA synthesis ( by bromo - deoxyuridine [ BrdU ] - incorporation ) and secreted P14210 were quantified by enzyme - linked immunosorbent assays . Mitogen - activated protein kinase ( MAPK ) phosphorylation was also analyzed by Western blot . RESULTS : Despite the immunocytochemical demonstration of P08581 protein in the cytoplasm and on the plasma membrane of PDL cells , exogenous recombinant human P14210 did not exert the mitogenic effects expected . As reported for other mesenchymal cells , PDL cells were found to secrete P14210 . Treatments with neutralizing anti - P14210 antibody significantly suppressed constitutive PDL cell proliferation and sustained the receptor protein at higher levels than in non - treated cells . Under these conditions , exogenous P14210 rapidly phosphorylated extracellular signal - regulated kinase ( P29323 ) , an action linked to the cell proliferation and downregulation of cell - surface receptors . CONCLUSIONS : Unlike other known mesenchymal or epithelial cells , these findings suggest that normal PDL cells from young donors possess a constitutive P14210 / receptor autocrine loop that normally regulates their replacement self - proliferation but reduces sensitivity to exogenously applied P14210 by acute receptor downregulation .\",\n \"P14210 and P04626 / neu downregulate expression of apoptosis - inducing factor in non - small cell lung cancer . Our previous study showed that patients with advanced stages of non - small cell lung cancer ( NSCLC ) were frequently detected with upregulation of hepatocyte growth factor ( P14210 ) . In vitro , P14210 reduced expression of apoptosis - inducing factor ( O95831 ) and cisplatin sensitivity in NSCLC cells . The effect of P14210 was via P08581 ( c - MET ) and the downstream effector , focal adhesion kinase ( Q05397 ) . In this study , we determined the prognostic value of O95831 in NSCLC patients . O95831 expression was determined by immunohistochemistry and immunoblotting . Our data show that O95831 expression was associated with better prognosis . Expression of O95831 inversely correlated with that of positive NSCLC markers , e . g . , dihydrodiol dehydrogenase ( Q04828 ) , c - MET , short oncostatin M receptor ( OSMRs ) , matrix metalloproteinase ( MMP ) - 1 , and P04626 / neu , which were closely associated with drug resistance , tumor recurrence , metastasis and poor prognosis . Noteworthy , silence of P04626 / neu gene expression increases O95831 level and drug sensitivity . Addition of P14210 inhibits O95831 expression in P04626 / neu - silenced cells . These results suggested that both P14210 and P04626 / neu affect drug resistance by regulating O95831 expression in NSCLC .\",\n \"___MASK69___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK69___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .\",\n \"Gab1 but not Grb2 mediates tumor progression in DB00134 overexpressing colorectal cancer cells . P08581 ( DB00134 ) plays an important role in the progression of multiple cancer types . The overexpression of DB00134 in DLD - 1 colon carcinoma cells with kirsten rat sarcoma oncogene homolog ( P01116 ) oncogene activation resulted in enhanced subcutaneous and orthotopic tumor growth rate and increased metastatic potential . To elucidate the mechanism of this effect , we stably expressed kinase - inactive DB00134 ( K1110A ) , Src homology 2 ( SH2 ) - binding domain - inactive DB00134 ( Y1349 / 1356F ) , growth factor receptor - bound protein 2 ( Grb2 ) non - binding DB00134 ( N1358H ) and mutant receptors with ability to selectively recruit signaling proteins Grb2 , src homology domain c - terminal adaptor homolog ( Shc ) , phospholipase c - gamma ( PLCgamma ) and p85 phosphatidyl inositol 3 kinase . As subcutaneous implants , DLD - 1 cells that expressed the majority of these receptor constructs failed to recapitulate the tumor growth - enhancing effect of the wild - type DB00134 receptor . The Grb2 - and Shc - recruiting DB00134 mutants demonstrated slight but consistent tumor - suppressive activity , whereas the expression of N1358H mutant stimulated tumor growth rate comparable with the wild - type receptor . This suggests that direct Grb2 / Shc binding does not contribute to the tumor progression activity of DB00134 receptor . The tumors expressing Grb2 - and Shc - recruiting DB00134 receptors demonstrated a marked loss in Grb2 - associated adaptor protein 1 ( Gab1 ) protein levels , which was not observed in the cell lines , consistent with a post - translationally regulated process . Moreover , a moderate level of Gab1 overexpression stimulated tumor growth . The findings suggest a delicate balance for intact Y1349 / 1356 SH2 - binding domain to mediate the tumor progression activity of the coactivated DB00134 - rat sarcoma oncogene homolog ( DB01367 ) pathways . Selectivity for specific adaptor protein involvement may be the key that determines the tissue - and cell - type specificity of DB00134 - mediated tumorigenicity in human cancers .\",\n \"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK94___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .\",\n \"___MASK50___ increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : ___MASK50___ is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \\\" pleiotropic \\\" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . ___MASK50___ and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : ___MASK50___ increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .\",\n \"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .\",\n \"P08581 tyrosine kinase met is a substrate of the receptor protein - tyrosine phosphatase Q12913 . The receptor protein - tyrosine phosphatase ( PTP ) Q12913 ( CD148 / PTP - eta ) has been implicated in the regulation of cell growth , differentiation , and transformation , and most recently has been identified as a potential tumor suppressor gene mutated in colon , lung , and breast cancers . We have generated constructs comprising the cytoplasmic segment of Q12913 fused to the maltose - binding protein to identify potential substrates and thereby suggest a physiological function for Q12913 . We have shown that the substrate - trapping mutant form of Q12913 interacted with a small subset of tyrosine - phosphorylated proteins from lysates of the human breast tumor cell lines MDA - MB - 231 , T - 47D , and T - 47D / DB00134 and have identified the hepatocyte growth factor / scatter factor receptor DB00134 , the adapter protein Gab1 , and the junctional component O60716 as potential substrates . Following ligand stimulation , phosphorylation of specific tyrosyl residues in DB00134 induces mitogenic , motogenic , and morphogenic responses . When co - expressed in 293 cells , the full - length substrate - trapping mutant form of Q12913 formed a stable complex with the chimeric receptor colony stimulating factor 1 ( P04141 ) - DB00134 and wild type Q12913 dephosphorylated P04141 - DB00134 . Furthermore , we observed that Q12913 preferentially dephosphorylated a Gab1 binding site ( DB00135 ( 1349 ) ) and a COOH - terminal tyrosine implicated in morphogenesis ( DB00135 ( 1365 ) ) , whereas tyrosine residues in the activation loop of DB00134 ( DB00135 ( 1230 ) , DB00135 ( 1234 ) , and DB00135 ( 1235 ) ) were not preferred targets of the PTP . The ability of Q12913 preferentially to dephosphorylate particular tyrosine residues that are required for DB00134 - induced signaling suggests that Q12913 may function in controlling the specificity of signals induced by this PTK , rather than as a simple \\\" off - switch \\\" to counteract PTK activity .\",\n \"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK4___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .\",\n \"P14210 triggers distinct mechanisms of Q9NR80 and Tiam1 activation to induce endothelial barrier enhancement . Previous reports described an important role of hepatocyte growth factor ( P14210 ) in mitigation of pulmonary endothelial barrier dysfunction and cell injury induced by pathologic agonists and mechanical forces . P14210 protective effects have been associated with Rac - GTPase signaling pathway activated by Rac - specific guanine nucleotide exchange factor Tiam1 and leading to enhancement of intercellular adherens junctions . This study tested involvement of a novel Rac - specific activator , Q9NR80 , in endothelial barrier enhancement by P14210 and investigated a mechanism of P14210 - induced Q9NR80 activation . Si - RNA - based knockdown of Tiam1 and Q9NR80 had an additive effect on attenuation of P14210 - induced Rac activation and endothelial cell ( EC ) barrier enhancement . Tiam1 and Q9NR80 activation was abolished by pharmacologic inhibitors of P08581 and P19957 - kinase . In contrast to Tiam1 , Q9NR80 interacted with P25054 and associated with microtubule fraction upon P14210 stimulation . EC treatment by low dose DB08313 to inhibit peripheral microtubule dynamics partially attenuated P14210 - induced Q9NR80 peripheral translocation , but had negligible effect on Tiam1 translocation . These effects were associated with attenuation of P14210 - induced barrier enhancement in EC pretreated with low ND dose and activation of Rac and its cytoskeletal effectors PAK1 and cortactin . These data demonstrate , that in addition to microtubule - independent Tiam1 activation , P14210 engages additional microtubule - and P25054 - dependent pathway of Q9NR80 activation . These mechanisms may complement each other to provide the fine tuning of Rac signaling and endothelial barrier enhancement in response to various agonists .\",\n \"Protein Tyrosine Phosphatase 1B ( P18031 ) deficiency accelerates hepatic regeneration in mice . Protein tyrosine phosphatase 1B ( P18031 ) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors and modulate the intensity of their signaling cascades . Because liver regeneration involves tyrosine phosphorylation - mediated signaling , we investigated the role of P18031 in this process by performing partial hepatectomy in wild - type ( P18031 (+/+) ) and P18031 - deficient ( P18031 (-/-) ) mice . The expression of P12004 and cyclins D1 and E ( cell proliferation markers ) was enhanced in P18031 (-/-) regenerating livers , in parallel with 5 '- bromo - 2 '- deoxyuridine incorporation . Phosphorylation of P45983 / 2 and P40763 , early triggers of hepatic regeneration in response to P01375 - α and P05231 , was accelerated in P18031 (-/-) mice compared with P18031 (+/+) mice . These phosphorylations were increased in P18031 (-/-) hepatocytes or by silencing P18031 in wild - type cells and decreased further after the addition of recombinant P18031 . Enhanced P01133 - and P08581 - mediated signaling was observed in regenerating livers lacking P18031 and in P01133 - or P14210 - stimulated P18031 (-/-) hepatocytes . Moreover , P18031 (-/-) mice displayed a more rapid increase in intrahepatic lipid accumulation than P18031 (+/+) control mice . Late responses to partial hepatectomy revealed additional divergences because stress - mediated signaling was attenuated at 24 to 96 hours in P18031 (-/-) mice compared with P18031 (+/+) mice . Finally , P18031 deficiency also improves hepatic regeneration in mice fed a high - fat diet . These results suggest that pharmacological inhibition of P18031 would improve liver regeneration in patients with acute or chronic liver injury .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"DB08865 for the treatment of patients with advanced non - small cell lung cancer . DB08865 is a potent small - molecule inhibitor of Q9UM73 ( anaplastic lymphoma kinase ; Q9UM73 ) and hepatocyte growth factor receptor ( P08581 , proto - oncogene c - DB00134 ) . A range of tumors , including subsets of non - small cell lung cancer ( NSCLC ) , anaplastic large cell lymphoma and inflammatory myofibroblastic tumors harbor an Q9UM73 rearrangement that leads to oncogenic activation of Q9UM73 . DB08865 has demonstrated preclinical and clinical activity against such malignancies through inhibition of Q9UM73 , and patients harboring Q9UM73 - rearranged NSCLC have demonstrated high response rates and prolonged progression - free survival in phase I and II studies . In August 2011 , crizotinib was approved for the treatment of advanced Q9UM73 - positive NSCLC .\"\n]"},"candidates":{"kind":"list like","value":["___MASK19___","___MASK36___","___MASK42___","___MASK4___","___MASK50___","___MASK54___","___MASK69___","___MASK87___","___MASK94___"],"string":"[\n \"___MASK19___\",\n \"___MASK36___\",\n \"___MASK42___\",\n \"___MASK4___\",\n \"___MASK50___\",\n \"___MASK54___\",\n \"___MASK69___\",\n \"___MASK87___\",\n \"___MASK94___\"\n]"},"answer":{"kind":"string","value":"___MASK69___"},"id":{"kind":"string","value":"MH_train_394"}}},{"rowIdx":395,"cells":{"query":{"kind":"string","value":"interacts_with DB00773?"},"supports":{"kind":"list like","value":["DNA damage and S phase arrest induced by Ochratoxin A in human embryonic kidney cells ( P29320 293 ) . Ochratoxin A ( OTA ) is a ubiquitous mycotoxin with potential nephrotoxic , hepatotoxic and immunotoxic effects . The mechanisms underlying the nephrotoxicity of OTA remain obscure . To investigate DNA damage and the changes of the cell cycle distribution induced by OTA , human embryonic kidney cells ( P29320 293 cells ) were incubated with various concentrations of OTA for 24h in vitro . The results indicated that OTA treatment led to the production of reactive oxygen species ( ROS ) and to a decrease of the mitochondrial membrane potential ( ΔΨm ) . OTA - induced DNA damage in P29320 293 cells was evidenced by DNA comet tails formation and increased expression of γ - P16104 . In addition , OTA could induce cell cycle arrest at the S phase in P29320 293 cells . The expression of key cell cycle regulatory factors that were critical to the S phase , including cyclin A2 , cyclin E1 , and P24941 , were further detected . The expression of cyclin A2 , cyclin E1 , and P24941 were significantly decreased by OTA treatment at both the mRNA and protein levels . The apoptosis of P29320 293 cells after OTA treatment was observed using Hoechst 33342 staining . The results confirmed that OTA did induce apoptosis in P29320 293 cells . In conclusion , our results provided new insights into the molecular mechanisms by which OTA might promote nephrotoxicity .","Combinatorial antitumor effect of HDAC and the PI3K - Akt - P42345 pathway inhibition in a Pten defecient model of prostate cancer . Increased expression of histone deacetylases ( HDACs ) and activation of the PI3K - Akt - mTORC1 pathway are common aberrations in prostate cancer ( PCa ) . For this reason , inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa . Previous reports demonstrated that HDAC inhibitors ( HDACi ) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor ( AR ) . In this study we utilized the AR negative PCa cell line and observed that re - expression of AR ( PC3 - AR ) results in greater levels of apoptosis when treated with the pan - DACi , DB06603 ( PAN ) . PAN mediated apoptosis in PC3 and PC3 - AR cells was associated with increased levels of double strand DNA breaks , indicated by p - ɣ P16104 . Further , PAN treatment in PC3 - AR cells resulted in moderate attenuation of the Q13315 - Akt - P29323 DNA damage response pathway . For this reason , we combined PAN with the dual PI3K - P42345 inhibitor , BEZ235 . Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein Q13315 and significantly increased anti - tumor activity compared to each single treatment . Overall , superior anti - tumor activity with combination of PAN with BEZ235 was independent of AR status . These findings suggest that this therapeutic strategy should be further developed in clinical trials .","Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites .","Biological effects of alpha particle radiation exposure on human monocytic cells . Radon ( ( 222 ) Rn ) gas produces decay progeny that emits high energy alpha ( α )- particles . Epidemiological studies have shown that exposure to ( 222 ) Rn is linked with elevated risk of developing lung cancer , however clear mechanisms leading to such effects have not been delineated . Cytokines play a critical role in inflammation and their dysregulated production often contributes to disease pathogenesis . In this study , Bio - plex multiplex technology was employed to investigate modulations of 27 pro - inflammatory cytokines following exposure of human monocytic cells to 1 . 5 Gy of α - particle radiation . Concurrently , DNA damage was assessed by examining the formation of phosphorylated H2A histone family X ( γ - P16104 ) sites . Of the 27 cytokines assessed , 4 cytokines were shown to be statistically downregulated by ∼ 2 fold relative to the untreated controls and included the interleukin ( IL ) family of proteins ( P60568 , P40933 and Q16552 ) and macrophage inflammatory protein 1 beta ( MIP - 1b ) . Interferon - inducible protein - 12 ( IP - 12 ) , vascular endothelial growth factor and regulated on activation normal T cell expressed and secreted ( RANTES ) were shown to be high expressors and upregulated . Cells irradiated with α - particles ranging from 0 . 27 to 2 . 14 Gy showed statistically significant , dose - dependant increases in γ - P16104 formation . These data suggest that α - particle radiation causes dysregulation in the production of a number of pro - inflammatory cytokines and results in significant DNA damage .","Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK39___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .","___MASK23___ block of cloned human T - type voltage - gated calcium channels . ___MASK23___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK55___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )","Anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , a Korean traditional medicine . We investigated the anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , which is a crude extract of nine Korean medicinal substances of animal and plant origin . In human umbilical vein endothelial cells , WEHAD significantly inhibited P09038 - induced proliferation , adhesion , migration , and capillary tube formation . We used an antibody array to perform an analysis of signaling proteins , which showed up - regulated expression of various proteins including Q06609 , P43351 , and p73 , and down - regulated expression of pFAK . Blood vessel formation in a chick chorioallantoic membrane ( P62158 ) treated with WEHAD was markedly reduced in length compared with a PBS - treated control group . These results suggest that inhibition of angiogenesis by WEHAD may be the mechanism of action for the anti - cancer effects of HAD .","Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II . Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid - borne P11388 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide ( DB00773 ) . This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both P43351 + repair - proficient strains and rad52 mutants that are defective in the repair of double - stranded breaks . These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II , and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent .","Tyrosine phosphorylation enhances P43351 - mediated annealing by modulating its DNA binding . P43351 protein has an important role in homology - directed DNA repair by mediating Q06609 nucleoprotein filament formation on single - stranded DNA ( ssDNA ) protected by replication protein - A ( RPA ) and annealing of RPA - coated ssDNA . In human , cellular response to DNA damage includes phosphorylation of P43351 by c - P00519 kinase at tyrosine 104 . To address how this phosphorylation modulates P43351 function , we used an amber suppressor technology to substitute tyrosine 104 with chemically stable phosphotyrosine analogue ( p - Carboxymethyl - L - phenylalanine , pCMF ) . The P43351 ( Y104pCMF ) retained ssDNA - binding activity characteristic of unmodified P43351 but showed lower affinity for double - stranded DNA ( dsDNA ) binding . Single - molecule analyses revealed that P43351 ( Y104pCMF ) specifically targets and wraps ssDNA . While P43351 ( Y104pCMF ) is confined to ssDNA region , unmodified P43351 readily diffuses into dsDNA region . The Y104pCMF substitution also increased the ssDNA annealing rate and allowed overcoming the inhibitory effect of dsDNA . We propose that phosphorylation at Y104 enhances ssDNA annealing activity of P43351 by attenuating dsDNA binding . Implications of phosphorylation - mediated activation of P43351 annealing activity are discussed .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK21___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .","Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .","Cytoplasmic - nuclear shuttling of P62942 - rapamycin - associated protein is involved in rapamycin - sensitive signaling and translation initiation . Translation initiation is one of the key events regulated in response to mitogenic stimulation and nutrient availability , tightly coupled to mammalian cell cycle progression and growth . P62942 - rapamycin - associated protein ( P42345 ; also named P42345 or P42345 ) , a member of the ataxia telangiectasia mutated ( Q13315 ) - related kinase family , governs a rapamycin - sensitive membrane - to - cytoplasm signaling cascade that modulates translation initiation via P08133 S6 kinase ( P08133 ( s6k ) ) and P06730 binding protein 1 ( Q13541 ) . Our studies reported here reveal a surprising regulatory mechanism of this signaling , which involves cytoplasmic - nuclear shuttling of P42345 . By using leptomycin B ( LMB ) , a specific inhibitor of nuclear export receptor Crm1 , we show that P42345 is a cytoplasmic - nuclear shuttling protein . Inhibition of P42345 nuclear export by LMB coincides with diminished P08133 ( s6k ) activation and Q13541 phosphorylation . Further investigation by altering P42345 ' s nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of P42345 and mitogenic stimulation of P08133 ( s6k ) activation and Q13541 phosphorylation . Furthermore , by using a reporter system , we provide evidence suggesting that nuclear shuttling of P42345 regulates mitogen - stimulated rapamycin - sensitive translation initiation . These findings uncover a function for the nucleus in the direct regulation of the protein synthesis machinery via extracellular signals .","Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .","P00441 acts as a nuclear transcription factor to regulate oxidative stress resistance . P00441 ( Sod1 ) has been known for nearly half a century for catalysis of superoxide to hydrogen peroxide . Here we report a new Sod1 function in oxidative signalling : in response to elevated endogenous and exogenous reactive oxygen species ( ROS ) , Sod1 rapidly relocates into the nucleus , which is important for maintaining genomic stability . Interestingly , H2O2 is sufficient to promote Sod1 nuclear localization , indicating that it is responding to general ROS rather than Sod1 substrate superoxide . ROS signalling is mediated by Mec1 / Q13315 and its effector Dun1 / Cds1 kinase , through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60 , 99 . In the nucleus , Sod1 binds to promoters and regulates the expression of oxidative resistance and repair genes . Altogether , our study unravels an unorthodox function of Sod1 as a transcription factor and elucidates the regulatory mechanism for its localization .","Synergism between bosutinib ( ___MASK33___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .","Chronic myeloid leukemia . Progress has been made in understanding P11274 - P00519 - positive leukemias . A new transcript ( p230BCR - P00519 ) has been characterized that is associated with Ph - positive chronic neutrophilic leukemia . The Q13315 protein appears to be a regulator of P00519 activity in response to irradiation damage . Pathways linking P11274 - P00519 to the BCL - 2 family of proteins may be active in Philadelphia - positive cells and inhibit apoptosis . The 62 - kD protein constitutively phosphorylated in chronic myeloid leukemia progenitors has been cloned . Ph - negative long - term culture - initiating cells are detectable in many chronic myeloid leukemia patients . The combination of interferon alfa and cytarabine appears to be superior to interferon alfa alone . Autografting with in vivo - purged stem cells may induce prolonged remissions . Specific inhibitors of the P11274 - P00519 tyrosine kinase are becoming available .","Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK75___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .","Analysis of DNA recombination and repair proteins in living cells by photobleaching microscopy . DNA double strand break repair through homologous recombination has been shown biochemically to require the coordinated action of the P43351 group of proteins , including the DNA strand exchange protein Rad51 . We have started to develop experimental tools to investigate the close cooperation of homologous recombination proteins in living cells , where proteins operate in the context of chromatin and in the presence of other nuclear processes . This chapter describes in detail methods to establish cell lines stably expressing green fluorescent protein - tagged recombination proteins and photobleaching techniques to investigate the behavior of the proteins with the use of live cell video microscopy . Fluorescence recovery after photobleaching ( P42345 ) , fluorescence loss after photobleaching ( FLIP ) , and their combination in the same cell are useful techniques to gain insights into the dynamic behavior of the recombination proteins . Parameters such as diffusion rates and mobile versus immobile fractions before and after DNA damage induction can be obtained . In addition , residence times of recombination proteins at sites of DNA damage can be determined . Through the application of P42345 and FLIP it is possible to establish whether proteins are present in the same multiprotein complex , whether this is affected by DNA damage induction , and whether proteins dynamically associate with and dissociate from sites of DNA damage .","Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .","Signaling by retinol and its serum binding protein . DB00162 , retinol , circulates in blood bound to retinol - binding protein ( P02753 ) which , in turn , associates with transthyretin ( P02766 ) to form a retinol - P02753 - P02766 ternary complex . At some tissues , retinol - bound ( holo - ) P02753 is recognized by a membrane protein termed Q9BX79 , which transports retinol from extracellular P02753 into cells and , concomitantly , activates a O60674 / P40763 / 5 signaling cascade that culminates in induction of P35610 target genes . Q9BX79 - mediated retinol transport and cell signaling are critically inter - dependent , and they both require the presence of cellular retinol - binding protein 1 ( P09455 ) , an intracellular retinol acceptor , as well as a retinol - metabolizing enzyme such as lecithin : retinol acyltransferase ( O95237 ) . Q9BX79 thus functions as a \" cytokine signaling transporter \" which couples vitamin A homeostasis and metabolism to cell signaling , thereby regulating gene transcription . Recent studies provided molecular level insights into the mode of action of this unique protein .","Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft . Neurofibromatosis type 1 ( P21359 ) patients are prone to the development of malignant tumors , the most common being Malignant Peripheral Nerve Sheath Tumor ( MPNST ) . P21359 - MPNST patients have an overall poor survival due to systemic metastasis . Currently , the management of MPNSTs includes surgery and radiation ; however , conventional chemotherapy is not very effective , underscoring the need for effective biologically - targeted therapies . Recently , the P21359 gene product , neurofibromin , was shown to negatively regulate the phosphoinositide - 3 - kinase ( PI3K ) / Protein Kinase - B ( Akt ) / mammalian Target Of ___MASK87___ ( P42345 ) pathway , with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of P42345 activity . We developed and characterized a human P21359 - MPNST explant grown subcutaneously in NOD - SCID mice , to evaluate the effect of the P42345 inhibitor rapamycin . We demonstrate that rapamycin significantly inhibited human P21359 - MPNST P42345 pathway activation and explant growth in vivo at doses as low as 1 . 0 mg / kg / day , without systemic toxicities . While rapamycin was effective at reducing P21359 - MPNST proliferation and angiogenesis , with decreased CyclinD1 and P15692 respectively , there was no increase in tumor apoptosis . ___MASK87___ effectively decreased activation of S6 downstream of P42345 , but there was accompanied increased Akt activation . This study demonstrates the therapeutic potential and limitations of rapamycin in P21359 - associated , and likely sporadic , MPNSTs .","mRNA expression , functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray . AIM : To understand the local pathophysiological alterations and gene ontology - based functional classification of colonic biopsies into inflammatory and neoplastic diseases . METHODS : Total RNA was extracted from frozen biopsies and amplified by T7 - method . Expression profile was evaluated by Atlas Glass 1K microarrays . After microarray quality control , applicable data were available from 10 adenomas , 6 colorectal adenocarcinomas ( CRCs ) , and 6 inflammatory bowel diseases ( IBDs ) . Multivariate statistical and cell functional analyses were performed . Real - time RT - PCR and immunohistochemistry were used for validation . RESULTS : Discriminant analysis of selected genes , could correctly reclassify all 22 samples using 4 parameters ( heat shock transcription factor - 1 , bystin - like , calgranulin - A , O14798 ) . Q9UKU7 samples were characterized by overregulated chemokine ( C - X - C motif ) ligand 13 , replication protein A1 , Q15723 and downregulated Q9Y4K3 , P10415 - interacting killer genes . In adenomas upregulation of Q9Y4K3 , replication protein A1 , Q15723 and underexpression of P10415 - associated X protein , calgranulin - A genes were found . CRC cases had significantly increased epidermal growth factor receptor , topoisomerase - 1 , v - jun , Q9Y4K3 and O14798 , and decreased Q06609 and P43351 DNA repair gene , protein phosphatase - 2A and P10415 - interacting killer mRNA levels . P00533 RT - PCR and immunohistochemistry , topoisomerase - 1 RT - PCR confirmed the chip results . CONCLUSION : Different histological alterations can be reclassified by functional , multivariate analysis using cDNA microarrays . Further studies with expanded sample number are needed for subclassification of pathological alterations .","Constitutive Q12888 / γ P16104 foci are increased in cells of ALL patients dependent on P11274 - P00519 and P41212 - Q01196 preleukemic gene fusions . Childhood leukemia arises from hematopoietic stem cells by induction of mutations . Quite often chromosomal translocations arise prenatally as first key event in multistage process of leukemogenesis . These translocations result in so called preleukemic gene fusions ( PGFs ) , such as P11274 - P00519 and P41212 - Q01196 , which generate hybrid proteins with altered properties . Critical DNA damage resulting in translocations are DNA double - strand breaks ( DSBs ) . P11274 - P00519 and P41212 - Q01196 were shown to be associated with increased constitutive DSBs in various model systems . We analyzed cells from peripheral blood and P28906 -/ P28906 + cells from bone marrow of pediatric acute lymphoblastic leukemia ( ALL ) patients harboring P11274 - P00519 or P41212 - Q01196 . We used sensitive technique that is based on automated enumeration of DSB co - localizing proteins γ P16104 and Q12888 , which form so called DNA repair foci . We found that level of constitutive γ P16104 / Q12888 foci is significantly higher in cells of ALL pediatric patients than in healthy subjects . There was also significant increased level of constitutive γ P16104 / Q12888 foci in cells from ALL patients harboring P11274 - P00519 or P41212 - Q01196 compared to patients without PGFs . The same increase was observed regardless cell type for both PGFs . Our data on increased DSB levels in the P11274 - P00519 / P41212 - Q01196 patient ' s cells support a model where P11274 - P00519 / P41212 - Q01196 induces DNA instability through facilitating mutagenesis and appearance of additional genetic alterations driving leukemogenesis .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK75___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .","Loss of P38398 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo . BACKGROUND : Previous reports suggested a central role of P38398 in DNA - damage repair mechanisms elicited by cell exposure to anti - tumor agents . Here we studied if P38398 - defective HCC1937 or P38398 - reconstituted HCC1937 /( WT ) P38398 human breast cancer xenografts ( HBCXs ) generated in SCID mice were differentially sensitive to cisplatin ( DB00515 ) in vivo and we investigated potential molecular correlates of this effect . RESULTS : DB00515 induced almost complete growth inhibition of P38398 - defective HBCXs , while P38398 - reconstituted HBCXs were only partially inhibited . Cell cycle analysis showed a significant S - and G ( 2 )/ M blockade in P38398 - defective as compared with parental P38398 - reconstituted cells . Comparative gene expression profiling of HCC1937 and HCC1937 /( WT ) P38398 showed upregulation of P43351 and Q13426 , whereas P07992 and P23921 were downregulated . Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that P38398 is mostly involved in G ( 2 )/ M but also in G ( 1 )/ S - phase checkpoints as well as in several important signaling pathways , including IGF , P15692 , estrogen receptor , PI3K / AKT and P01133 . METHODS : HCC1937 or HCC1937 /( WT ) P38398 HBCXs were generated in SCID mice . Animals were then weekly treated with 5 mg / kg DB00515 i . p . or with vehicle for 4 w . Tumor volume and mice survival were evaluated . Tumors were retrieved from animals 12 hours after the last treatment with DB00515 or vehicle treatment and the cell suspension underwent cell cycle analysis . Differential gene expression and pathway modulation between HCC1937 and HCC1937 /( WT ) P38398 cells were also studied . CONCLUSION : Our data suggest that P38398 - defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum - derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer .","Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK44___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .","P38936 ( Waf1 ) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate . Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential . HDAC inhibitors ( HDACI ) induce senescence and / or apoptosis in many types of tumor cells . Here , we studied the role of cyclin - kinase inhibitor P38936 ( waf1 ) ( Cdkn1n gene ) in cell cycle arrest , senescence markers ( cell hypertrophy , SA - βGal staining and accumulation of γ P16104 foci ) in P38936 ( Waf1 +/+) versus P38936 ( Waf1 -/-) mouse embryonic fibroblast cells transformed with E1A and cHa - Ras oncogenes ( mERas ) . While short treatment with the HDACI sodium butyrate ( NaB ) induced a reversible G ( 1 ) cell cycle arrest in both parental and P38936 ( Waf1 -/-) cells , long - term treatment led to dramatic changes in P38936 ( Waf1 +/+) cells only : cell cycle arrest became irreversible and cells become hypertrophic , SA - βGal - positive and accumulated γ P16104 foci associated with mTORC1 activation . The P38936 ( Waf1 +/+) cells lost their ability to migrate into the wound and through a porous membrane . Suppression of migration was accompanied by accumulation of vinculin - staining focal adhesions and Ser3 - phosphorylation of cofilin , incapable for F - actin depolymerization . In contrast , the knockout of the P38936 ( Waf1 ) abolished most of the features of NaB - induced senescence , including irreversibility of cell cycle arrest , hypertrophy , additional focal adhesions and block of migration , γ P16104 foci accumulation and SA - βGal staining . ___MASK87___ , a specific inhibitor of mTORC1 kinase , decreased cellular hypertrophy , canceled coffilin phosphorylation and partially restored cell migration in P38936 ( Waf1 +/+) cells . Taken together , our data indicate a new role of P38936 ( Waf1 ) in cell senescence , which may be connected not only with execution of cell cycle arrest , but also with the development of P42345 - dependent markers of cellular senescence .","Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells . Stromal cells such as myofibroblasts influence tumor progression . The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow - derived mesenchymal stromal cells ( MSCs ) which then colonize tumors . Using iTRAQ and LC - MS / MS we identified the adipokine , chemerin , as overexpressed in esophageal squamous cancer associated myofibroblasts ( CAMs ) compared with adjacent tissue myofibroblasts ( ATMs ) . The chemerin receptor , ChemR23 , is expressed by MSCs . Conditioned media ( CM ) from CAMs significantly increased O60682 cell migration compared to Q13315 - CM ; the action of P62158 - CM was significantly reduced by chemerin - neutralising antibody , pretreatment of CAMs with chemerin siRNA , pretreatment of MSCs with ChemR23 siRNA , and by a ChemR23 receptor antagonist , CCX832 . Stimulation of MSCs by chemerin increased phosphorylation of Q8NFH3 / 44 , p38 and JNK - II kinases and inhibitors of these kinases and PKC reversed chemerin - stimulated O60682 migration . Q99969 stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor ( MIF ) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations . In a xenograft model consisting of OE21 esophageal cancer cells and CAMs , homing of MSCs administered i . v . was inhibited by CCX832 . Thus , chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression .","Acidic pH induces topoisomerase II - mediated DNA damage . Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models . Recent studies have also implicated acidic pH in the development of preneoplastic Barrett ' s esophagus in human . However , little is known about the molecular mechanism underlying acidic pH - induced carcinogenesis . In the current study , we show that acidic pH , like the topoisomerase II ( P11388 ) poison DB00773 ( demethylepipodophyllotoxin ethylidene - beta - D - glucoside ) , induces tumors in 9 , 10 - dimethyl - 1 , 2 - benzanthracene ( DMBA )- initiated mice . The following studies in tissue culture models have suggested that acidic pH acts like a P11388 poison to induce P11388 - mediated DNA damage : ( i ) acidic pH induces P11388 - dependent DNA damage signals as evidenced by up - regulation of p53 and DB00133 - 139 phosphorylation of P16104 [ a substrate for ataxia telangiectasia mutated ( Q13315 ) Q13315 and Rad3 - related ( ATR ) kinases ] ; ( ii ) acidic pH - induced cytotoxicity in tumor cells is reduced in P11388 - deficient cells ; ( iii ) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase ( P00492 ) gene in a P11388 - dependent manner ; and ( iv ) acidic pH induces reversible P11388 - mediated DNA strand breaks in vitro . We discuss the possibility that P11388 - mediated DNA damage may contribute to acidic pH - induced carcinogenesis .","___MASK38___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK38___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .","Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK87___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .","P01236 confers resistance against cisplatin in breast cancer cells by activating glutathione - S - transferase . Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients . Given that prolactin ( PRL ) acts as an anti - apoptotic / survival factor in the breast , we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs . Treatment of breast cancer cells with PRL caused variable resistance to taxol , vinblastine , doxorubicin and cisplatin . PRL prevented cisplatin - induced G ( 2 )/ M cell cycle arrest and apoptosis . In the presence of PRL , significantly less cisplatin was bound to DNA , as determined by mass spectroscopy , and little DNA damage was seen by gamma - P16104 staining . PRL dramatically increased the activity of glutathione - S - transferase ( Q86UG4 ) , which sequesters cisplatin in the cytoplasm ; this increase was abrogated by Jak and mitogen - activated protein kinase inhibitors . PRL upregulated the expression of the GSTmu , but not the pi , isozyme . A Q86UG4 inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL . In conclusion , PRL confers resistance against cisplatin by activating a detoxification enzyme , thereby reducing drug entry into the nucleus . These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer , which is characterized by high expression of both PRL and its receptor . Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options .","Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .","Mitoxantrone inhibits HIF - 1α expression in a topoisomerase II - independent pathway . PURPOSE : Solid tumors encounter a growth - limiting hypoxic microenvironment as they develop . Hypoxia - inducible factors ( HIF ) play important roles in hypoxia - associated tumor development and therapeutic resistance . Targeting the HIF pathway ( especially HIF - 1α ) represents a promising cancer treatment strategy . Here , we report a novel class of HIF - 1α inhibitors and the possible molecular basis of inhibition . EXPERIMENTAL DESIGN : We analyzed the inhibitory effects of clinically used topoisomerase II ( P11388 ) - targeting drugs on HIF - 1α expression with a primary focus on mitoxantrone . The potential role of P11388 in mitoxantrone - inhibited HIF - 1α expression was studied using pharmacologic inhibition , a knockdown approach , and P11388 mutant cells . Moreover , involvement of mitoxantrone in proteasome - mediated degradation , transcription , and translation of HIF - 1α was examined . RESULTS : The P11388 - targeting mitoxantrone , but neither doxorubicin nor etoposide ( DB00773 ) , strongly inhibited HIF - 1α expression under hypoxic conditions in a dose - and time - dependent manner . Surprisingly , the mitoxantrone - mediated inhibition of HIF - 1α expression was largely independent of two P11388 isozymes , proteasomal degradation , and transcription . Furthermore , mitoxantrone inhibited HIF - 1α expression and function in a similar fashion as cycloheximide , suggesting that mitoxantrone might inhibit HIF - 1α via a blockage at its translation step . In vitro translation experiments using HIF - 1α mRNA further confirmed inhibition of HIF - 1α translation by mitoxantrone . Interestingly , levels of the polysome - bound HIF - 1α and P15692 mRNA were elevated and decreased after mitoxantrone treatment , respectively . CONCLUSIONS : We have identified the P11388 - targeting compound , mitoxantrone , as an HIF - 1α inhibitor possibly through a translation inhibition mechanism , suggesting the possibility of an additional anticancer activity for mitoxantrone .","Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .","Gene expression profile of metastatic colon cancer cells resistant to cisplatin - induced apoptosis . The current chemotherapeutic modalities for advanced colorectal cancer are limited . DNA - platinating drugs such as cisplatin have poor efficacy against this malignancy . The aim of this study was to identify genes that render survival advantage after cisplatin treatment in metastatic colon cancer . Cell lines SW480 ( primary colon cancer ) and SW620 ( metastatic lesion from the same patient ) were obtained from ATCC . Apoptosis was measured by FACS analysis of cisplatin - treated ( 0 . 01 - 10 micro g / ml ) and untreated cells . Simultaneous analysis of approximately 1200 cDNAs was performed by microarray technique on untreated and treated cells from lines . Microarray results were confirmed by RT - PCR . The SW620 cell line was more resistant to apoptosis induced by cisplatin . Western blot analysis revealed equal expression of pro - caspases 3 , 8 , and 9 in both cell lines . Microarray analysis identified 15 genes and 9 expressed sequence tags ( ESTs ) significantly altered both by cell type ( metastatic vs . non - metastatic ) and treatment vs . non - treatment . Several of these transcripts are well - characterized genes including Q8IVS2 , Q99259 , P19 , P21266 , P12004 D1 , Q13315 , and CO - 029 that have been implicated in various malignancies . In the present study , we have identified a set of genes responsible for apoptosis resistance following treatment with cisplatin in the late stages of carcinogenesis . Targeting these genes may increase chemotherapy effectiveness in advanced colon cancer and reduce toxicity in normal tissue .","Ablation of microvessels in vivo upon dimerization of iCaspase - 9 . Anti - angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment . Inhibitors of the endothelial cell pro - survival pathway mediated by P15692 were shown to activate caspases and cause microvascular regression , but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways . Alternatively , if direct activation of an apical pro - apoptotic caspase is sufficient to disrupt microvessels in vivo , such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks . Here , we fused caspase - 9 to a mutated P62942 domain to express an inducible caspase - 9 molecule ( iCaspase - 9 ) that can be activated by a cell - permeable dimerizer drug , and transduced this construct into primary endothelial cells . We found that drug - induced dimerization of iCaspase - 9 is sufficient to activate endogenous caspase - 3 and trigger apoptosis even when endothelial cells are treated with the pro - survival factors P15692 or P09038 . A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase - 9 and elimination of human microvessels engineered in immunodeficient mice . These results demonstrate that the activation of iCaspase - 9 disrupts microvessels in vivo , and suggest a novel anti - angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells .","P11274 / P00519 and other kinases from chronic myeloproliferative disorders stimulate single - strand annealing , an unfaithful DNA double - strand break repair . Myeloproliferative disorders ( P53602 ) are stem cell - derived clonal diseases arising as a consequence of acquired aberrations in c - P00519 , Janus - activated kinase 2 ( O60674 ) , and platelet - derived growth factor receptor ( P09619 ) that generate oncogenic fusion tyrosine kinases ( FTK ) , including P11274 / P00519 , P41212 / P00519 , P41212 / O60674 , and P41212 / PDGFbetaR . Here , we show that FTKs stimulate the formation of reactive oxygen species and DNA double - strand breaks ( DSB ) both in hematopoietic cell lines and in P28906 (+) leukemic stem / progenitor cells from patients with chronic myelogenous leukemia ( CML ) . Single - strand annealing ( SSA ) represents a relatively rare but very unfaithful DSB repair mechanism causing chromosomal aberrations . Using a specific reporter cassette integrated into genomic DNA , we found that P11274 / P00519 and other FTKs stimulated SSA activity . Imatinib - mediated inhibition of P11274 / P00519 abrogated this effect , implicating a kinase - dependent mechanism . Y253F , E255K , T315I , and H396P mutants of P11274 / P00519 that confer imatinib resistance also stimulated SSA . Increased expression of either nonmutated or mutated P11274 / P00519 kinase , as is typical of blast phase cells and very primitive chronic phase CML cells , was associated with higher SSA activity . P11274 / P00519 - mediated stimulation of SSA was accompanied by enhanced nuclear colocalization of P43351 and P07992 , which play a key role in the repair . Taken together , these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair .","The dynamic alterations of P16104 complex during DNA repair detected by a proteomic approach reveal the critical roles of Ca ( 2 +)/ calmodulin in the ionizing radiation - induced cell cycle arrest . By using DNA nuclease digestion and a quantitative \" dual tagging \" proteomic approach that integrated mass spectrometry , stable isotope labeling , and affinity purification , we studied the histone P16104 - associating protein complex in chromatin in mammalian cells in response to ionizing radiation ( IR ) . In the non - irradiated control cells , calmodulin ( P62158 ) and the transcription elongation factor facilitates chromatin transcription ( FACT ) were associated with P16104 . Thirty minutes after exposing cells to IR the P62158 and FACT complexes dissociated , whereas two DNA repair proteins , poly ( ADP - ribose ) polymerase - 1 and DEAH box polypeptide 30 isoform 1 , interacted with P16104 . Two hours and 30 min after exposure , none of the above proteins were in the complex . H2B , nucleophosmin / B23 , and calreticulin were associated with P16104 in both non - irradiated and irradiated cells . The results suggest that the P16104 complex undergoes dynamic changes upon induction of DNA damage and during DNA repair . The genuine interactions between P16104 and H2B , nucleophosmin / B23 , calreticulin , poly ( ADP - ribose ) polymerase - 1 , and P62158 under each condition were validated by immunoprecipitation / Western blotting and mammalian two - hybrid assays . Because multiple Ca ( 2 +)- binding proteins were found in the P16104 complex , the roles of Ca ( 2 +) were examined . The results indicate that Ca ( 2 +)/ P62158 plays important roles in regulating IR - induced cell cycle arrest , possibly through mediating chromatin structure . The dataset presented here demonstrates that sensitive profiling of the dynamics of functional cellular protein - protein interactions can successfully lead to the dissection of important metabolic or signaling pathways .","Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer compared with Western countries . Epidemiological features , trends in morbidity and mortality , various age - specific incidence curves , migrant study results , and analysis of the risk factors , however , suggest that the incidence of breast cancer might be further increasing in Korea . The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis . These include older age , family history of breast cancer , early menarche , late menopause , late full - term pregnancy , and never a breast feeding . Both the establishment of high - risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer . Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea , and the five - year survival rate has been estimated as 80 - 83 % . Recent studies on the identification of susceptibility factors such as genetic polymorphisms of P09488 / T1 / P1 , P21964 , P05181 , P11511 , P05093 , P03372 , P18887 , O43542 , P43351 , TGF - alpha , P01375 , IL - 1B , IL - 1RN , P50613 etc . that predispose individuals to breast cancer by gene - environment or gene - gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy .","Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .","Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK44___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .","Genetic analysis of expression profile involved in retinoid metabolism in non - alcoholic fatty liver disease . AIM : The patients with non - alcoholic fatty liver disease ( NAFLD ) have been reported to be at greater risk for progression to chronic liver disease including liver cirrhosis ( LC ) . To examine the mechanisms for the progression of NAFLD , a genetic analysis of hepatic expression profile in retinoid metabolism in NAFLD was performed since the loss of retinoid signaling is associated with the progression of liver disease via reactive oxygen species ( ROS ) generation . METHODS : Fifty - one genes , which are associated with retinoid metabolism and action , were examined in thirty six subjects including 17 patients with simple steatosis , 11 with non - alcoholic steatohepatitis ( NASH ) and eight controls were examined by real - time reverse transcriptase polymerase chain reaction . Immunohistochemical study was also done by 3 kinds of antibodies . RESULTS : Higher expression of P09455 O95237 , DGT1 / 2 and CES1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively . Expression of P07327 / 2 / 3 , Q92781 / 10 / 11 , O75911 and RALDH1 / 3 was increased in NAFLD , suggesting that oxidation process from retinol to all - trans retinoic acid ( DB00755 ) was enhanced . Importantly , greater expression of O43174 indicated that degradation of DB00755 was enhanced in NAFLD . Further , expression of P00441 / 2 , catalase , thioredoxin and uncoupling protein 2 was also enhanced . CONCLUSION : Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD , which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC .","Q13224 - containing DB01221 receptors promote glutamate synapse development in hippocampal interneurons . In postnatal development , Q13224 - containing NMDARs are critical for the functional maturation of glutamatergic synapses . Q13224 - containing NMDARs prevail until the second postnatal week when Q12879 subunits are progressively added , conferring mature properties to NMDARs . In cortical principal neurons , deletion of Q13224 results in an increase in functional AMPAR synapses , suggesting that Q13224 - containing NMDARs set a brake on glutamate synapse maturation . The function of Q13224 in the maturation of glutamatergic inputs to cortical interneurons is not known . To examine the function of Q13224 in interneurons , we generated mutant mice with conditional deletion of Q13224 in interneurons ( Q13224 ( Δ Q99259 ) ) . In Q13224 ( Δ Q99259 ) mice interneurons distributed normally in cortical brain regions . After the second postnatal week , Q13224 ( Δ Q99259 ) mice developed hippocampal seizures and died shortly thereafter . Before the onset of seizures , Q13224 - deficient hippocampal interneurons received fewer glutamatergic synaptic inputs than littermate controls , indicating that Q13224 - containing NMDARs positively regulate the maturation of glutamatergic input synapses in interneurons . These findings suggest that Q13224 - containing NMDARs keep the circuit activity under control by promoting the maturation of excitatory synapses in interneurons .","Topoisomerase II - mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation - associated tumorigenesis . AIMS : Both cancer - suppressing and cancer - promoting properties of reactive nitrogen and oxygen species ( RNOS ) have been suggested to play a role in tumor pathology , particularly those activities associated with chronic inflammation . Here , we address the impact of nitric oxide ( NO ) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II ( P11388 ) . We also investigate the contribution of NO to the formation of skin melanoma in mice . RESULTS : Similar to the P11388 - targeting drug , etoposide ( DB00773 ) , the NO - donor , S - nitrosoglutathione ( GSNO ) , induces skin melanomas formation in 7 , 12 - dimethyl - benz [ a ] anthracene ( DMBA ) - initiated mice . To explore the mechanism ( s ) underlying this NO - induced tumorigenesis , we use a co - culture model system to demonstrate that inflamed macrophages with inducible NO synthase ( P35228 ) expression cause γ - P16104 activation , p53 phosphorylation , and chromosome DNA breaks in the target cells . Inhibitor experiments revealed that NO and P11388 isozymes are responsible for the above described cellular phenotypes . Notably , NO , unlike DB00773 , preferentially induces the formation of TOP2β cleavable complexes ( TOP2βcc ) in cells . Moreover , GSNO induced P11388 - dependent DNA sequence rearrangements and cytotoxicity . Furthermore , the incidences of GSNO - and DB00773 - induced skin melanomas were also observed to be lower in the skin - specific top2β - knockout mice . Our results suggest that P11388 isozymes contribute to NO - induced mutagenesis and subsequent cancer development during chronic inflammation . INNOVATION AND CONCLUSIONS : We provide the first experimental evidence for the functional role of P11388 in NO - caused DNA damage , mutagenesis , and carcinogenesis . Notably , these studies contribute to our molecular understanding of the cancer - promoting actions of RNOS during chronic inflammation .","DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .","P15692 activates Q13224 phosphorylation through Dab1 pathway . Vascular endothelial growth factor ( P15692 ) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration . Both P15692 and reelin have been shown to regulate DB01221 type glutamate receptor ( NMDAR ) activity via independent mechanisms . However , it is not known whether the above signaling pathways influence each other on NMDAR regulation . We demonstrate that Disabled 1 ( Dab1 ) , a downstream signaling molecule of reelin pathway mediates P15692 - induced regulation of NMDAR subunit Q13224 . Furthermore , P15692 treatment led to the association of P15692 receptor - 2 ( Flk1 ) and reelin receptor ( apolipoprotein E receptor 2 , ApoER2 ) , and Dab1 as well as Q13224 activation were Flk1 - dependent . Moreover , P15692 treatment could significantly rescue the deficits in phospho - Dab1 levels in reeler ( Reln -/- ) neurons . Our results suggest a major role of P15692 in the regulation of reelin signaling , and Dab1 as a key molecule in the cross talk between reelin and P15692 signaling pathways .","Characterization of rat P23510 by monoclonal antibody . OX40 ( CD134 ) is a member of the tumor necrosis factor ( P01375 ) receptor superfamily first identified as a rat T cell activation marker . We previously identified the rat ligand for OX40 ( P23510 ) by molecular cloning . In the present study , we newly generated an anti - rat P23510 mAb ( Q13315 - 2 ) that can inhibit the binding of OX40 to rat P23510 and thus efficiently inhibits the T cell costimulatory activity of rat P23510 . Flow cytometric analyses using Q13315 - 2 and an anti - rat OX40 mAb ( MRC OX40 ) indicated that OX40 was inducible on splenic P01730 (+) T cells by stimulation with immobilized anti - CD3 mAb , while P23510 was not expressed on resting or activated T cells . P23510 was expressed on splenic B cells after stimulation with lipopolysaccharide ( LPS ) , but not on peritoneal macrophages . Interestingly , splenic dendritic cells ( DC ) expressed P23510 constitutively , which was further upregulated by LPS stimulation . The potent costimulatory activities of splenic DC for anti - CD3 - stimulated rat P01730 (+) T cell proliferation and cytokine ( P60568 , P01579 , P22301 , and P35225 ) production were substantially inhibited by Q13315 - 2 . These results indicated that P23510 is expressed on professional antigen - presenting cells ( P25054 ) , and may be involved in humoral immune responses via T - B interaction and in cellular immune responses via T - DC interaction in the rat system .","Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .","Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK33___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK33___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .","Dysregulated expression of death , stress and mitochondrion related genes in the sciatic nerve of presymptomatic P00441 ( G93A ) mouse model of Amyotrophic Lateral Sclerosis . Schwann cells are the main source of paracrine support to motor neurons . Oxidative stress and mitochondrial dysfunction have been correlated to motor neuron death in Amyotrophic Lateral Sclerosis ( P35858 ) . Despite the involvement of Schwann cells in early neuromuscular disruption in P35858 , detailed molecular events of a dying - back triggering are unknown . Sciatic nerves of presymptomatic ( 60 - day - old ) P00441 ( G93A ) mice were submitted to a high - density oligonucleotide microarray analysis . DAVID demonstrated the deregulated genes related to death , stress and mitochondrion , which allowed the identification of Cell cycle , ErbB signaling , DB00150 metabolism and O95057 - I - like receptor signaling as the most representative KEGG pathways . The protein - protein interaction networks based upon deregulated genes have identified the top hubs ( TRAF2 , P16104 , Q01094 , O43524 , P43246 , P08138 , P36897 ) and bottlenecks ( TRAF2 , Q01094 , P46527 , Q15672 , O43524 ) . Schwann cells were enriched from the sciatic nerve of presymptomatic mice using flow cytometry cell sorting . qPCR showed the up regulated ( Ngfr , Cdnkn1b , E2f1 , Traf2 and Erbb3 , H2afx , Cdkn1a , Hspa1 , Prdx , Mapk10 ) and down - regulated ( Foxo3 , Mtor ) genes in the enriched Schwann cells . In conclusion , molecular analyses in the presymptomatic sciatic nerve demonstrated the involvement of death , oxidative stress , and mitochondrial pathways in the Schwann cell non - autonomous mechanisms in the early stages of P35858 ."],"string":"[\n \"DNA damage and S phase arrest induced by Ochratoxin A in human embryonic kidney cells ( P29320 293 ) . Ochratoxin A ( OTA ) is a ubiquitous mycotoxin with potential nephrotoxic , hepatotoxic and immunotoxic effects . The mechanisms underlying the nephrotoxicity of OTA remain obscure . To investigate DNA damage and the changes of the cell cycle distribution induced by OTA , human embryonic kidney cells ( P29320 293 cells ) were incubated with various concentrations of OTA for 24h in vitro . The results indicated that OTA treatment led to the production of reactive oxygen species ( ROS ) and to a decrease of the mitochondrial membrane potential ( ΔΨm ) . OTA - induced DNA damage in P29320 293 cells was evidenced by DNA comet tails formation and increased expression of γ - P16104 . In addition , OTA could induce cell cycle arrest at the S phase in P29320 293 cells . The expression of key cell cycle regulatory factors that were critical to the S phase , including cyclin A2 , cyclin E1 , and P24941 , were further detected . The expression of cyclin A2 , cyclin E1 , and P24941 were significantly decreased by OTA treatment at both the mRNA and protein levels . The apoptosis of P29320 293 cells after OTA treatment was observed using Hoechst 33342 staining . The results confirmed that OTA did induce apoptosis in P29320 293 cells . In conclusion , our results provided new insights into the molecular mechanisms by which OTA might promote nephrotoxicity .\",\n \"Combinatorial antitumor effect of HDAC and the PI3K - Akt - P42345 pathway inhibition in a Pten defecient model of prostate cancer . Increased expression of histone deacetylases ( HDACs ) and activation of the PI3K - Akt - mTORC1 pathway are common aberrations in prostate cancer ( PCa ) . For this reason , inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa . Previous reports demonstrated that HDAC inhibitors ( HDACi ) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor ( AR ) . In this study we utilized the AR negative PCa cell line and observed that re - expression of AR ( PC3 - AR ) results in greater levels of apoptosis when treated with the pan - DACi , DB06603 ( PAN ) . PAN mediated apoptosis in PC3 and PC3 - AR cells was associated with increased levels of double strand DNA breaks , indicated by p - ɣ P16104 . Further , PAN treatment in PC3 - AR cells resulted in moderate attenuation of the Q13315 - Akt - P29323 DNA damage response pathway . For this reason , we combined PAN with the dual PI3K - P42345 inhibitor , BEZ235 . Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein Q13315 and significantly increased anti - tumor activity compared to each single treatment . Overall , superior anti - tumor activity with combination of PAN with BEZ235 was independent of AR status . These findings suggest that this therapeutic strategy should be further developed in clinical trials .\",\n \"Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites .\",\n \"Biological effects of alpha particle radiation exposure on human monocytic cells . Radon ( ( 222 ) Rn ) gas produces decay progeny that emits high energy alpha ( α )- particles . Epidemiological studies have shown that exposure to ( 222 ) Rn is linked with elevated risk of developing lung cancer , however clear mechanisms leading to such effects have not been delineated . Cytokines play a critical role in inflammation and their dysregulated production often contributes to disease pathogenesis . In this study , Bio - plex multiplex technology was employed to investigate modulations of 27 pro - inflammatory cytokines following exposure of human monocytic cells to 1 . 5 Gy of α - particle radiation . Concurrently , DNA damage was assessed by examining the formation of phosphorylated H2A histone family X ( γ - P16104 ) sites . Of the 27 cytokines assessed , 4 cytokines were shown to be statistically downregulated by ∼ 2 fold relative to the untreated controls and included the interleukin ( IL ) family of proteins ( P60568 , P40933 and Q16552 ) and macrophage inflammatory protein 1 beta ( MIP - 1b ) . Interferon - inducible protein - 12 ( IP - 12 ) , vascular endothelial growth factor and regulated on activation normal T cell expressed and secreted ( RANTES ) were shown to be high expressors and upregulated . Cells irradiated with α - particles ranging from 0 . 27 to 2 . 14 Gy showed statistically significant , dose - dependant increases in γ - P16104 formation . These data suggest that α - particle radiation causes dysregulation in the production of a number of pro - inflammatory cytokines and results in significant DNA damage .\",\n \"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK39___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .\",\n \"___MASK23___ block of cloned human T - type voltage - gated calcium channels . ___MASK23___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK55___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , a Korean traditional medicine . We investigated the anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , which is a crude extract of nine Korean medicinal substances of animal and plant origin . In human umbilical vein endothelial cells , WEHAD significantly inhibited P09038 - induced proliferation , adhesion , migration , and capillary tube formation . We used an antibody array to perform an analysis of signaling proteins , which showed up - regulated expression of various proteins including Q06609 , P43351 , and p73 , and down - regulated expression of pFAK . Blood vessel formation in a chick chorioallantoic membrane ( P62158 ) treated with WEHAD was markedly reduced in length compared with a PBS - treated control group . These results suggest that inhibition of angiogenesis by WEHAD may be the mechanism of action for the anti - cancer effects of HAD .\",\n \"Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II . Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid - borne P11388 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide ( DB00773 ) . This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both P43351 + repair - proficient strains and rad52 mutants that are defective in the repair of double - stranded breaks . These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II , and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent .\",\n \"Tyrosine phosphorylation enhances P43351 - mediated annealing by modulating its DNA binding . P43351 protein has an important role in homology - directed DNA repair by mediating Q06609 nucleoprotein filament formation on single - stranded DNA ( ssDNA ) protected by replication protein - A ( RPA ) and annealing of RPA - coated ssDNA . In human , cellular response to DNA damage includes phosphorylation of P43351 by c - P00519 kinase at tyrosine 104 . To address how this phosphorylation modulates P43351 function , we used an amber suppressor technology to substitute tyrosine 104 with chemically stable phosphotyrosine analogue ( p - Carboxymethyl - L - phenylalanine , pCMF ) . The P43351 ( Y104pCMF ) retained ssDNA - binding activity characteristic of unmodified P43351 but showed lower affinity for double - stranded DNA ( dsDNA ) binding . Single - molecule analyses revealed that P43351 ( Y104pCMF ) specifically targets and wraps ssDNA . While P43351 ( Y104pCMF ) is confined to ssDNA region , unmodified P43351 readily diffuses into dsDNA region . The Y104pCMF substitution also increased the ssDNA annealing rate and allowed overcoming the inhibitory effect of dsDNA . We propose that phosphorylation at Y104 enhances ssDNA annealing activity of P43351 by attenuating dsDNA binding . Implications of phosphorylation - mediated activation of P43351 annealing activity are discussed .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK21___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .\",\n \"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .\",\n \"Cytoplasmic - nuclear shuttling of P62942 - rapamycin - associated protein is involved in rapamycin - sensitive signaling and translation initiation . Translation initiation is one of the key events regulated in response to mitogenic stimulation and nutrient availability , tightly coupled to mammalian cell cycle progression and growth . P62942 - rapamycin - associated protein ( P42345 ; also named P42345 or P42345 ) , a member of the ataxia telangiectasia mutated ( Q13315 ) - related kinase family , governs a rapamycin - sensitive membrane - to - cytoplasm signaling cascade that modulates translation initiation via P08133 S6 kinase ( P08133 ( s6k ) ) and P06730 binding protein 1 ( Q13541 ) . Our studies reported here reveal a surprising regulatory mechanism of this signaling , which involves cytoplasmic - nuclear shuttling of P42345 . By using leptomycin B ( LMB ) , a specific inhibitor of nuclear export receptor Crm1 , we show that P42345 is a cytoplasmic - nuclear shuttling protein . Inhibition of P42345 nuclear export by LMB coincides with diminished P08133 ( s6k ) activation and Q13541 phosphorylation . Further investigation by altering P42345 ' s nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of P42345 and mitogenic stimulation of P08133 ( s6k ) activation and Q13541 phosphorylation . Furthermore , by using a reporter system , we provide evidence suggesting that nuclear shuttling of P42345 regulates mitogen - stimulated rapamycin - sensitive translation initiation . These findings uncover a function for the nucleus in the direct regulation of the protein synthesis machinery via extracellular signals .\",\n \"Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .\",\n \"P00441 acts as a nuclear transcription factor to regulate oxidative stress resistance . P00441 ( Sod1 ) has been known for nearly half a century for catalysis of superoxide to hydrogen peroxide . Here we report a new Sod1 function in oxidative signalling : in response to elevated endogenous and exogenous reactive oxygen species ( ROS ) , Sod1 rapidly relocates into the nucleus , which is important for maintaining genomic stability . Interestingly , H2O2 is sufficient to promote Sod1 nuclear localization , indicating that it is responding to general ROS rather than Sod1 substrate superoxide . ROS signalling is mediated by Mec1 / Q13315 and its effector Dun1 / Cds1 kinase , through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60 , 99 . In the nucleus , Sod1 binds to promoters and regulates the expression of oxidative resistance and repair genes . Altogether , our study unravels an unorthodox function of Sod1 as a transcription factor and elucidates the regulatory mechanism for its localization .\",\n \"Synergism between bosutinib ( ___MASK33___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .\",\n \"Chronic myeloid leukemia . Progress has been made in understanding P11274 - P00519 - positive leukemias . A new transcript ( p230BCR - P00519 ) has been characterized that is associated with Ph - positive chronic neutrophilic leukemia . The Q13315 protein appears to be a regulator of P00519 activity in response to irradiation damage . Pathways linking P11274 - P00519 to the BCL - 2 family of proteins may be active in Philadelphia - positive cells and inhibit apoptosis . The 62 - kD protein constitutively phosphorylated in chronic myeloid leukemia progenitors has been cloned . Ph - negative long - term culture - initiating cells are detectable in many chronic myeloid leukemia patients . The combination of interferon alfa and cytarabine appears to be superior to interferon alfa alone . Autografting with in vivo - purged stem cells may induce prolonged remissions . Specific inhibitors of the P11274 - P00519 tyrosine kinase are becoming available .\",\n \"Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK75___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .\",\n \"Analysis of DNA recombination and repair proteins in living cells by photobleaching microscopy . DNA double strand break repair through homologous recombination has been shown biochemically to require the coordinated action of the P43351 group of proteins , including the DNA strand exchange protein Rad51 . We have started to develop experimental tools to investigate the close cooperation of homologous recombination proteins in living cells , where proteins operate in the context of chromatin and in the presence of other nuclear processes . This chapter describes in detail methods to establish cell lines stably expressing green fluorescent protein - tagged recombination proteins and photobleaching techniques to investigate the behavior of the proteins with the use of live cell video microscopy . Fluorescence recovery after photobleaching ( P42345 ) , fluorescence loss after photobleaching ( FLIP ) , and their combination in the same cell are useful techniques to gain insights into the dynamic behavior of the recombination proteins . Parameters such as diffusion rates and mobile versus immobile fractions before and after DNA damage induction can be obtained . In addition , residence times of recombination proteins at sites of DNA damage can be determined . Through the application of P42345 and FLIP it is possible to establish whether proteins are present in the same multiprotein complex , whether this is affected by DNA damage induction , and whether proteins dynamically associate with and dissociate from sites of DNA damage .\",\n \"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .\",\n \"Signaling by retinol and its serum binding protein . DB00162 , retinol , circulates in blood bound to retinol - binding protein ( P02753 ) which , in turn , associates with transthyretin ( P02766 ) to form a retinol - P02753 - P02766 ternary complex . At some tissues , retinol - bound ( holo - ) P02753 is recognized by a membrane protein termed Q9BX79 , which transports retinol from extracellular P02753 into cells and , concomitantly , activates a O60674 / P40763 / 5 signaling cascade that culminates in induction of P35610 target genes . Q9BX79 - mediated retinol transport and cell signaling are critically inter - dependent , and they both require the presence of cellular retinol - binding protein 1 ( P09455 ) , an intracellular retinol acceptor , as well as a retinol - metabolizing enzyme such as lecithin : retinol acyltransferase ( O95237 ) . Q9BX79 thus functions as a \\\" cytokine signaling transporter \\\" which couples vitamin A homeostasis and metabolism to cell signaling , thereby regulating gene transcription . Recent studies provided molecular level insights into the mode of action of this unique protein .\",\n \"Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft . Neurofibromatosis type 1 ( P21359 ) patients are prone to the development of malignant tumors , the most common being Malignant Peripheral Nerve Sheath Tumor ( MPNST ) . P21359 - MPNST patients have an overall poor survival due to systemic metastasis . Currently , the management of MPNSTs includes surgery and radiation ; however , conventional chemotherapy is not very effective , underscoring the need for effective biologically - targeted therapies . Recently , the P21359 gene product , neurofibromin , was shown to negatively regulate the phosphoinositide - 3 - kinase ( PI3K ) / Protein Kinase - B ( Akt ) / mammalian Target Of ___MASK87___ ( P42345 ) pathway , with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of P42345 activity . We developed and characterized a human P21359 - MPNST explant grown subcutaneously in NOD - SCID mice , to evaluate the effect of the P42345 inhibitor rapamycin . We demonstrate that rapamycin significantly inhibited human P21359 - MPNST P42345 pathway activation and explant growth in vivo at doses as low as 1 . 0 mg / kg / day , without systemic toxicities . While rapamycin was effective at reducing P21359 - MPNST proliferation and angiogenesis , with decreased CyclinD1 and P15692 respectively , there was no increase in tumor apoptosis . ___MASK87___ effectively decreased activation of S6 downstream of P42345 , but there was accompanied increased Akt activation . This study demonstrates the therapeutic potential and limitations of rapamycin in P21359 - associated , and likely sporadic , MPNSTs .\",\n \"mRNA expression , functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray . AIM : To understand the local pathophysiological alterations and gene ontology - based functional classification of colonic biopsies into inflammatory and neoplastic diseases . METHODS : Total RNA was extracted from frozen biopsies and amplified by T7 - method . Expression profile was evaluated by Atlas Glass 1K microarrays . After microarray quality control , applicable data were available from 10 adenomas , 6 colorectal adenocarcinomas ( CRCs ) , and 6 inflammatory bowel diseases ( IBDs ) . Multivariate statistical and cell functional analyses were performed . Real - time RT - PCR and immunohistochemistry were used for validation . RESULTS : Discriminant analysis of selected genes , could correctly reclassify all 22 samples using 4 parameters ( heat shock transcription factor - 1 , bystin - like , calgranulin - A , O14798 ) . Q9UKU7 samples were characterized by overregulated chemokine ( C - X - C motif ) ligand 13 , replication protein A1 , Q15723 and downregulated Q9Y4K3 , P10415 - interacting killer genes . In adenomas upregulation of Q9Y4K3 , replication protein A1 , Q15723 and underexpression of P10415 - associated X protein , calgranulin - A genes were found . CRC cases had significantly increased epidermal growth factor receptor , topoisomerase - 1 , v - jun , Q9Y4K3 and O14798 , and decreased Q06609 and P43351 DNA repair gene , protein phosphatase - 2A and P10415 - interacting killer mRNA levels . P00533 RT - PCR and immunohistochemistry , topoisomerase - 1 RT - PCR confirmed the chip results . CONCLUSION : Different histological alterations can be reclassified by functional , multivariate analysis using cDNA microarrays . Further studies with expanded sample number are needed for subclassification of pathological alterations .\",\n \"Constitutive Q12888 / γ P16104 foci are increased in cells of ALL patients dependent on P11274 - P00519 and P41212 - Q01196 preleukemic gene fusions . Childhood leukemia arises from hematopoietic stem cells by induction of mutations . Quite often chromosomal translocations arise prenatally as first key event in multistage process of leukemogenesis . These translocations result in so called preleukemic gene fusions ( PGFs ) , such as P11274 - P00519 and P41212 - Q01196 , which generate hybrid proteins with altered properties . Critical DNA damage resulting in translocations are DNA double - strand breaks ( DSBs ) . P11274 - P00519 and P41212 - Q01196 were shown to be associated with increased constitutive DSBs in various model systems . We analyzed cells from peripheral blood and P28906 -/ P28906 + cells from bone marrow of pediatric acute lymphoblastic leukemia ( ALL ) patients harboring P11274 - P00519 or P41212 - Q01196 . We used sensitive technique that is based on automated enumeration of DSB co - localizing proteins γ P16104 and Q12888 , which form so called DNA repair foci . We found that level of constitutive γ P16104 / Q12888 foci is significantly higher in cells of ALL pediatric patients than in healthy subjects . There was also significant increased level of constitutive γ P16104 / Q12888 foci in cells from ALL patients harboring P11274 - P00519 or P41212 - Q01196 compared to patients without PGFs . The same increase was observed regardless cell type for both PGFs . Our data on increased DSB levels in the P11274 - P00519 / P41212 - Q01196 patient ' s cells support a model where P11274 - P00519 / P41212 - Q01196 induces DNA instability through facilitating mutagenesis and appearance of additional genetic alterations driving leukemogenesis .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK75___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .\",\n \"Loss of P38398 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo . BACKGROUND : Previous reports suggested a central role of P38398 in DNA - damage repair mechanisms elicited by cell exposure to anti - tumor agents . Here we studied if P38398 - defective HCC1937 or P38398 - reconstituted HCC1937 /( WT ) P38398 human breast cancer xenografts ( HBCXs ) generated in SCID mice were differentially sensitive to cisplatin ( DB00515 ) in vivo and we investigated potential molecular correlates of this effect . RESULTS : DB00515 induced almost complete growth inhibition of P38398 - defective HBCXs , while P38398 - reconstituted HBCXs were only partially inhibited . Cell cycle analysis showed a significant S - and G ( 2 )/ M blockade in P38398 - defective as compared with parental P38398 - reconstituted cells . Comparative gene expression profiling of HCC1937 and HCC1937 /( WT ) P38398 showed upregulation of P43351 and Q13426 , whereas P07992 and P23921 were downregulated . Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that P38398 is mostly involved in G ( 2 )/ M but also in G ( 1 )/ S - phase checkpoints as well as in several important signaling pathways , including IGF , P15692 , estrogen receptor , PI3K / AKT and P01133 . METHODS : HCC1937 or HCC1937 /( WT ) P38398 HBCXs were generated in SCID mice . Animals were then weekly treated with 5 mg / kg DB00515 i . p . or with vehicle for 4 w . Tumor volume and mice survival were evaluated . Tumors were retrieved from animals 12 hours after the last treatment with DB00515 or vehicle treatment and the cell suspension underwent cell cycle analysis . Differential gene expression and pathway modulation between HCC1937 and HCC1937 /( WT ) P38398 cells were also studied . CONCLUSION : Our data suggest that P38398 - defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum - derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer .\",\n \"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK44___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .\",\n \"P38936 ( Waf1 ) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate . Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential . HDAC inhibitors ( HDACI ) induce senescence and / or apoptosis in many types of tumor cells . Here , we studied the role of cyclin - kinase inhibitor P38936 ( waf1 ) ( Cdkn1n gene ) in cell cycle arrest , senescence markers ( cell hypertrophy , SA - βGal staining and accumulation of γ P16104 foci ) in P38936 ( Waf1 +/+) versus P38936 ( Waf1 -/-) mouse embryonic fibroblast cells transformed with E1A and cHa - Ras oncogenes ( mERas ) . While short treatment with the HDACI sodium butyrate ( NaB ) induced a reversible G ( 1 ) cell cycle arrest in both parental and P38936 ( Waf1 -/-) cells , long - term treatment led to dramatic changes in P38936 ( Waf1 +/+) cells only : cell cycle arrest became irreversible and cells become hypertrophic , SA - βGal - positive and accumulated γ P16104 foci associated with mTORC1 activation . The P38936 ( Waf1 +/+) cells lost their ability to migrate into the wound and through a porous membrane . Suppression of migration was accompanied by accumulation of vinculin - staining focal adhesions and Ser3 - phosphorylation of cofilin , incapable for F - actin depolymerization . In contrast , the knockout of the P38936 ( Waf1 ) abolished most of the features of NaB - induced senescence , including irreversibility of cell cycle arrest , hypertrophy , additional focal adhesions and block of migration , γ P16104 foci accumulation and SA - βGal staining . ___MASK87___ , a specific inhibitor of mTORC1 kinase , decreased cellular hypertrophy , canceled coffilin phosphorylation and partially restored cell migration in P38936 ( Waf1 +/+) cells . Taken together , our data indicate a new role of P38936 ( Waf1 ) in cell senescence , which may be connected not only with execution of cell cycle arrest , but also with the development of P42345 - dependent markers of cellular senescence .\",\n \"Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells . Stromal cells such as myofibroblasts influence tumor progression . The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow - derived mesenchymal stromal cells ( MSCs ) which then colonize tumors . Using iTRAQ and LC - MS / MS we identified the adipokine , chemerin , as overexpressed in esophageal squamous cancer associated myofibroblasts ( CAMs ) compared with adjacent tissue myofibroblasts ( ATMs ) . The chemerin receptor , ChemR23 , is expressed by MSCs . Conditioned media ( CM ) from CAMs significantly increased O60682 cell migration compared to Q13315 - CM ; the action of P62158 - CM was significantly reduced by chemerin - neutralising antibody , pretreatment of CAMs with chemerin siRNA , pretreatment of MSCs with ChemR23 siRNA , and by a ChemR23 receptor antagonist , CCX832 . Stimulation of MSCs by chemerin increased phosphorylation of Q8NFH3 / 44 , p38 and JNK - II kinases and inhibitors of these kinases and PKC reversed chemerin - stimulated O60682 migration . Q99969 stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor ( MIF ) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations . In a xenograft model consisting of OE21 esophageal cancer cells and CAMs , homing of MSCs administered i . v . was inhibited by CCX832 . Thus , chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression .\",\n \"Acidic pH induces topoisomerase II - mediated DNA damage . Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models . Recent studies have also implicated acidic pH in the development of preneoplastic Barrett ' s esophagus in human . However , little is known about the molecular mechanism underlying acidic pH - induced carcinogenesis . In the current study , we show that acidic pH , like the topoisomerase II ( P11388 ) poison DB00773 ( demethylepipodophyllotoxin ethylidene - beta - D - glucoside ) , induces tumors in 9 , 10 - dimethyl - 1 , 2 - benzanthracene ( DMBA )- initiated mice . The following studies in tissue culture models have suggested that acidic pH acts like a P11388 poison to induce P11388 - mediated DNA damage : ( i ) acidic pH induces P11388 - dependent DNA damage signals as evidenced by up - regulation of p53 and DB00133 - 139 phosphorylation of P16104 [ a substrate for ataxia telangiectasia mutated ( Q13315 ) Q13315 and Rad3 - related ( ATR ) kinases ] ; ( ii ) acidic pH - induced cytotoxicity in tumor cells is reduced in P11388 - deficient cells ; ( iii ) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase ( P00492 ) gene in a P11388 - dependent manner ; and ( iv ) acidic pH induces reversible P11388 - mediated DNA strand breaks in vitro . We discuss the possibility that P11388 - mediated DNA damage may contribute to acidic pH - induced carcinogenesis .\",\n \"___MASK38___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK38___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .\",\n \"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK87___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .\",\n \"P01236 confers resistance against cisplatin in breast cancer cells by activating glutathione - S - transferase . Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients . Given that prolactin ( PRL ) acts as an anti - apoptotic / survival factor in the breast , we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs . Treatment of breast cancer cells with PRL caused variable resistance to taxol , vinblastine , doxorubicin and cisplatin . PRL prevented cisplatin - induced G ( 2 )/ M cell cycle arrest and apoptosis . In the presence of PRL , significantly less cisplatin was bound to DNA , as determined by mass spectroscopy , and little DNA damage was seen by gamma - P16104 staining . PRL dramatically increased the activity of glutathione - S - transferase ( Q86UG4 ) , which sequesters cisplatin in the cytoplasm ; this increase was abrogated by Jak and mitogen - activated protein kinase inhibitors . PRL upregulated the expression of the GSTmu , but not the pi , isozyme . A Q86UG4 inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL . In conclusion , PRL confers resistance against cisplatin by activating a detoxification enzyme , thereby reducing drug entry into the nucleus . These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer , which is characterized by high expression of both PRL and its receptor . Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options .\",\n \"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .\",\n \"Mitoxantrone inhibits HIF - 1α expression in a topoisomerase II - independent pathway . PURPOSE : Solid tumors encounter a growth - limiting hypoxic microenvironment as they develop . Hypoxia - inducible factors ( HIF ) play important roles in hypoxia - associated tumor development and therapeutic resistance . Targeting the HIF pathway ( especially HIF - 1α ) represents a promising cancer treatment strategy . Here , we report a novel class of HIF - 1α inhibitors and the possible molecular basis of inhibition . EXPERIMENTAL DESIGN : We analyzed the inhibitory effects of clinically used topoisomerase II ( P11388 ) - targeting drugs on HIF - 1α expression with a primary focus on mitoxantrone . The potential role of P11388 in mitoxantrone - inhibited HIF - 1α expression was studied using pharmacologic inhibition , a knockdown approach , and P11388 mutant cells . Moreover , involvement of mitoxantrone in proteasome - mediated degradation , transcription , and translation of HIF - 1α was examined . RESULTS : The P11388 - targeting mitoxantrone , but neither doxorubicin nor etoposide ( DB00773 ) , strongly inhibited HIF - 1α expression under hypoxic conditions in a dose - and time - dependent manner . Surprisingly , the mitoxantrone - mediated inhibition of HIF - 1α expression was largely independent of two P11388 isozymes , proteasomal degradation , and transcription . Furthermore , mitoxantrone inhibited HIF - 1α expression and function in a similar fashion as cycloheximide , suggesting that mitoxantrone might inhibit HIF - 1α via a blockage at its translation step . In vitro translation experiments using HIF - 1α mRNA further confirmed inhibition of HIF - 1α translation by mitoxantrone . Interestingly , levels of the polysome - bound HIF - 1α and P15692 mRNA were elevated and decreased after mitoxantrone treatment , respectively . CONCLUSIONS : We have identified the P11388 - targeting compound , mitoxantrone , as an HIF - 1α inhibitor possibly through a translation inhibition mechanism , suggesting the possibility of an additional anticancer activity for mitoxantrone .\",\n \"Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .\",\n \"Gene expression profile of metastatic colon cancer cells resistant to cisplatin - induced apoptosis . The current chemotherapeutic modalities for advanced colorectal cancer are limited . DNA - platinating drugs such as cisplatin have poor efficacy against this malignancy . The aim of this study was to identify genes that render survival advantage after cisplatin treatment in metastatic colon cancer . Cell lines SW480 ( primary colon cancer ) and SW620 ( metastatic lesion from the same patient ) were obtained from ATCC . Apoptosis was measured by FACS analysis of cisplatin - treated ( 0 . 01 - 10 micro g / ml ) and untreated cells . Simultaneous analysis of approximately 1200 cDNAs was performed by microarray technique on untreated and treated cells from lines . Microarray results were confirmed by RT - PCR . The SW620 cell line was more resistant to apoptosis induced by cisplatin . Western blot analysis revealed equal expression of pro - caspases 3 , 8 , and 9 in both cell lines . Microarray analysis identified 15 genes and 9 expressed sequence tags ( ESTs ) significantly altered both by cell type ( metastatic vs . non - metastatic ) and treatment vs . non - treatment . Several of these transcripts are well - characterized genes including Q8IVS2 , Q99259 , P19 , P21266 , P12004 D1 , Q13315 , and CO - 029 that have been implicated in various malignancies . In the present study , we have identified a set of genes responsible for apoptosis resistance following treatment with cisplatin in the late stages of carcinogenesis . Targeting these genes may increase chemotherapy effectiveness in advanced colon cancer and reduce toxicity in normal tissue .\",\n \"Ablation of microvessels in vivo upon dimerization of iCaspase - 9 . Anti - angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment . Inhibitors of the endothelial cell pro - survival pathway mediated by P15692 were shown to activate caspases and cause microvascular regression , but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways . Alternatively , if direct activation of an apical pro - apoptotic caspase is sufficient to disrupt microvessels in vivo , such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks . Here , we fused caspase - 9 to a mutated P62942 domain to express an inducible caspase - 9 molecule ( iCaspase - 9 ) that can be activated by a cell - permeable dimerizer drug , and transduced this construct into primary endothelial cells . We found that drug - induced dimerization of iCaspase - 9 is sufficient to activate endogenous caspase - 3 and trigger apoptosis even when endothelial cells are treated with the pro - survival factors P15692 or P09038 . A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase - 9 and elimination of human microvessels engineered in immunodeficient mice . These results demonstrate that the activation of iCaspase - 9 disrupts microvessels in vivo , and suggest a novel anti - angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells .\",\n \"P11274 / P00519 and other kinases from chronic myeloproliferative disorders stimulate single - strand annealing , an unfaithful DNA double - strand break repair . Myeloproliferative disorders ( P53602 ) are stem cell - derived clonal diseases arising as a consequence of acquired aberrations in c - P00519 , Janus - activated kinase 2 ( O60674 ) , and platelet - derived growth factor receptor ( P09619 ) that generate oncogenic fusion tyrosine kinases ( FTK ) , including P11274 / P00519 , P41212 / P00519 , P41212 / O60674 , and P41212 / PDGFbetaR . Here , we show that FTKs stimulate the formation of reactive oxygen species and DNA double - strand breaks ( DSB ) both in hematopoietic cell lines and in P28906 (+) leukemic stem / progenitor cells from patients with chronic myelogenous leukemia ( CML ) . Single - strand annealing ( SSA ) represents a relatively rare but very unfaithful DSB repair mechanism causing chromosomal aberrations . Using a specific reporter cassette integrated into genomic DNA , we found that P11274 / P00519 and other FTKs stimulated SSA activity . Imatinib - mediated inhibition of P11274 / P00519 abrogated this effect , implicating a kinase - dependent mechanism . Y253F , E255K , T315I , and H396P mutants of P11274 / P00519 that confer imatinib resistance also stimulated SSA . Increased expression of either nonmutated or mutated P11274 / P00519 kinase , as is typical of blast phase cells and very primitive chronic phase CML cells , was associated with higher SSA activity . P11274 / P00519 - mediated stimulation of SSA was accompanied by enhanced nuclear colocalization of P43351 and P07992 , which play a key role in the repair . Taken together , these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair .\",\n \"The dynamic alterations of P16104 complex during DNA repair detected by a proteomic approach reveal the critical roles of Ca ( 2 +)/ calmodulin in the ionizing radiation - induced cell cycle arrest . By using DNA nuclease digestion and a quantitative \\\" dual tagging \\\" proteomic approach that integrated mass spectrometry , stable isotope labeling , and affinity purification , we studied the histone P16104 - associating protein complex in chromatin in mammalian cells in response to ionizing radiation ( IR ) . In the non - irradiated control cells , calmodulin ( P62158 ) and the transcription elongation factor facilitates chromatin transcription ( FACT ) were associated with P16104 . Thirty minutes after exposing cells to IR the P62158 and FACT complexes dissociated , whereas two DNA repair proteins , poly ( ADP - ribose ) polymerase - 1 and DEAH box polypeptide 30 isoform 1 , interacted with P16104 . Two hours and 30 min after exposure , none of the above proteins were in the complex . H2B , nucleophosmin / B23 , and calreticulin were associated with P16104 in both non - irradiated and irradiated cells . The results suggest that the P16104 complex undergoes dynamic changes upon induction of DNA damage and during DNA repair . The genuine interactions between P16104 and H2B , nucleophosmin / B23 , calreticulin , poly ( ADP - ribose ) polymerase - 1 , and P62158 under each condition were validated by immunoprecipitation / Western blotting and mammalian two - hybrid assays . Because multiple Ca ( 2 +)- binding proteins were found in the P16104 complex , the roles of Ca ( 2 +) were examined . The results indicate that Ca ( 2 +)/ P62158 plays important roles in regulating IR - induced cell cycle arrest , possibly through mediating chromatin structure . The dataset presented here demonstrates that sensitive profiling of the dynamics of functional cellular protein - protein interactions can successfully lead to the dissection of important metabolic or signaling pathways .\",\n \"Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer compared with Western countries . Epidemiological features , trends in morbidity and mortality , various age - specific incidence curves , migrant study results , and analysis of the risk factors , however , suggest that the incidence of breast cancer might be further increasing in Korea . The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis . These include older age , family history of breast cancer , early menarche , late menopause , late full - term pregnancy , and never a breast feeding . Both the establishment of high - risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer . Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea , and the five - year survival rate has been estimated as 80 - 83 % . Recent studies on the identification of susceptibility factors such as genetic polymorphisms of P09488 / T1 / P1 , P21964 , P05181 , P11511 , P05093 , P03372 , P18887 , O43542 , P43351 , TGF - alpha , P01375 , IL - 1B , IL - 1RN , P50613 etc . that predispose individuals to breast cancer by gene - environment or gene - gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy .\",\n \"Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .\",\n \"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK44___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .\",\n \"Genetic analysis of expression profile involved in retinoid metabolism in non - alcoholic fatty liver disease . AIM : The patients with non - alcoholic fatty liver disease ( NAFLD ) have been reported to be at greater risk for progression to chronic liver disease including liver cirrhosis ( LC ) . To examine the mechanisms for the progression of NAFLD , a genetic analysis of hepatic expression profile in retinoid metabolism in NAFLD was performed since the loss of retinoid signaling is associated with the progression of liver disease via reactive oxygen species ( ROS ) generation . METHODS : Fifty - one genes , which are associated with retinoid metabolism and action , were examined in thirty six subjects including 17 patients with simple steatosis , 11 with non - alcoholic steatohepatitis ( NASH ) and eight controls were examined by real - time reverse transcriptase polymerase chain reaction . Immunohistochemical study was also done by 3 kinds of antibodies . RESULTS : Higher expression of P09455 O95237 , DGT1 / 2 and CES1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively . Expression of P07327 / 2 / 3 , Q92781 / 10 / 11 , O75911 and RALDH1 / 3 was increased in NAFLD , suggesting that oxidation process from retinol to all - trans retinoic acid ( DB00755 ) was enhanced . Importantly , greater expression of O43174 indicated that degradation of DB00755 was enhanced in NAFLD . Further , expression of P00441 / 2 , catalase , thioredoxin and uncoupling protein 2 was also enhanced . CONCLUSION : Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD , which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC .\",\n \"Q13224 - containing DB01221 receptors promote glutamate synapse development in hippocampal interneurons . In postnatal development , Q13224 - containing NMDARs are critical for the functional maturation of glutamatergic synapses . Q13224 - containing NMDARs prevail until the second postnatal week when Q12879 subunits are progressively added , conferring mature properties to NMDARs . In cortical principal neurons , deletion of Q13224 results in an increase in functional AMPAR synapses , suggesting that Q13224 - containing NMDARs set a brake on glutamate synapse maturation . The function of Q13224 in the maturation of glutamatergic inputs to cortical interneurons is not known . To examine the function of Q13224 in interneurons , we generated mutant mice with conditional deletion of Q13224 in interneurons ( Q13224 ( Δ Q99259 ) ) . In Q13224 ( Δ Q99259 ) mice interneurons distributed normally in cortical brain regions . After the second postnatal week , Q13224 ( Δ Q99259 ) mice developed hippocampal seizures and died shortly thereafter . Before the onset of seizures , Q13224 - deficient hippocampal interneurons received fewer glutamatergic synaptic inputs than littermate controls , indicating that Q13224 - containing NMDARs positively regulate the maturation of glutamatergic input synapses in interneurons . These findings suggest that Q13224 - containing NMDARs keep the circuit activity under control by promoting the maturation of excitatory synapses in interneurons .\",\n \"Topoisomerase II - mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation - associated tumorigenesis . AIMS : Both cancer - suppressing and cancer - promoting properties of reactive nitrogen and oxygen species ( RNOS ) have been suggested to play a role in tumor pathology , particularly those activities associated with chronic inflammation . Here , we address the impact of nitric oxide ( NO ) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II ( P11388 ) . We also investigate the contribution of NO to the formation of skin melanoma in mice . RESULTS : Similar to the P11388 - targeting drug , etoposide ( DB00773 ) , the NO - donor , S - nitrosoglutathione ( GSNO ) , induces skin melanomas formation in 7 , 12 - dimethyl - benz [ a ] anthracene ( DMBA ) - initiated mice . To explore the mechanism ( s ) underlying this NO - induced tumorigenesis , we use a co - culture model system to demonstrate that inflamed macrophages with inducible NO synthase ( P35228 ) expression cause γ - P16104 activation , p53 phosphorylation , and chromosome DNA breaks in the target cells . Inhibitor experiments revealed that NO and P11388 isozymes are responsible for the above described cellular phenotypes . Notably , NO , unlike DB00773 , preferentially induces the formation of TOP2β cleavable complexes ( TOP2βcc ) in cells . Moreover , GSNO induced P11388 - dependent DNA sequence rearrangements and cytotoxicity . Furthermore , the incidences of GSNO - and DB00773 - induced skin melanomas were also observed to be lower in the skin - specific top2β - knockout mice . Our results suggest that P11388 isozymes contribute to NO - induced mutagenesis and subsequent cancer development during chronic inflammation . INNOVATION AND CONCLUSIONS : We provide the first experimental evidence for the functional role of P11388 in NO - caused DNA damage , mutagenesis , and carcinogenesis . Notably , these studies contribute to our molecular understanding of the cancer - promoting actions of RNOS during chronic inflammation .\",\n \"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .\",\n \"P15692 activates Q13224 phosphorylation through Dab1 pathway . Vascular endothelial growth factor ( P15692 ) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration . Both P15692 and reelin have been shown to regulate DB01221 type glutamate receptor ( NMDAR ) activity via independent mechanisms . However , it is not known whether the above signaling pathways influence each other on NMDAR regulation . We demonstrate that Disabled 1 ( Dab1 ) , a downstream signaling molecule of reelin pathway mediates P15692 - induced regulation of NMDAR subunit Q13224 . Furthermore , P15692 treatment led to the association of P15692 receptor - 2 ( Flk1 ) and reelin receptor ( apolipoprotein E receptor 2 , ApoER2 ) , and Dab1 as well as Q13224 activation were Flk1 - dependent . Moreover , P15692 treatment could significantly rescue the deficits in phospho - Dab1 levels in reeler ( Reln -/- ) neurons . Our results suggest a major role of P15692 in the regulation of reelin signaling , and Dab1 as a key molecule in the cross talk between reelin and P15692 signaling pathways .\",\n \"Characterization of rat P23510 by monoclonal antibody . OX40 ( CD134 ) is a member of the tumor necrosis factor ( P01375 ) receptor superfamily first identified as a rat T cell activation marker . We previously identified the rat ligand for OX40 ( P23510 ) by molecular cloning . In the present study , we newly generated an anti - rat P23510 mAb ( Q13315 - 2 ) that can inhibit the binding of OX40 to rat P23510 and thus efficiently inhibits the T cell costimulatory activity of rat P23510 . Flow cytometric analyses using Q13315 - 2 and an anti - rat OX40 mAb ( MRC OX40 ) indicated that OX40 was inducible on splenic P01730 (+) T cells by stimulation with immobilized anti - CD3 mAb , while P23510 was not expressed on resting or activated T cells . P23510 was expressed on splenic B cells after stimulation with lipopolysaccharide ( LPS ) , but not on peritoneal macrophages . Interestingly , splenic dendritic cells ( DC ) expressed P23510 constitutively , which was further upregulated by LPS stimulation . The potent costimulatory activities of splenic DC for anti - CD3 - stimulated rat P01730 (+) T cell proliferation and cytokine ( P60568 , P01579 , P22301 , and P35225 ) production were substantially inhibited by Q13315 - 2 . These results indicated that P23510 is expressed on professional antigen - presenting cells ( P25054 ) , and may be involved in humoral immune responses via T - B interaction and in cellular immune responses via T - DC interaction in the rat system .\",\n \"Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .\",\n \"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK33___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK33___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .\",\n \"Dysregulated expression of death , stress and mitochondrion related genes in the sciatic nerve of presymptomatic P00441 ( G93A ) mouse model of Amyotrophic Lateral Sclerosis . Schwann cells are the main source of paracrine support to motor neurons . Oxidative stress and mitochondrial dysfunction have been correlated to motor neuron death in Amyotrophic Lateral Sclerosis ( P35858 ) . Despite the involvement of Schwann cells in early neuromuscular disruption in P35858 , detailed molecular events of a dying - back triggering are unknown . Sciatic nerves of presymptomatic ( 60 - day - old ) P00441 ( G93A ) mice were submitted to a high - density oligonucleotide microarray analysis . DAVID demonstrated the deregulated genes related to death , stress and mitochondrion , which allowed the identification of Cell cycle , ErbB signaling , DB00150 metabolism and O95057 - I - like receptor signaling as the most representative KEGG pathways . The protein - protein interaction networks based upon deregulated genes have identified the top hubs ( TRAF2 , P16104 , Q01094 , O43524 , P43246 , P08138 , P36897 ) and bottlenecks ( TRAF2 , Q01094 , P46527 , Q15672 , O43524 ) . Schwann cells were enriched from the sciatic nerve of presymptomatic mice using flow cytometry cell sorting . qPCR showed the up regulated ( Ngfr , Cdnkn1b , E2f1 , Traf2 and Erbb3 , H2afx , Cdkn1a , Hspa1 , Prdx , Mapk10 ) and down - regulated ( Foxo3 , Mtor ) genes in the enriched Schwann cells . In conclusion , molecular analyses in the presymptomatic sciatic nerve demonstrated the involvement of death , oxidative stress , and mitochondrial pathways in the Schwann cell non - autonomous mechanisms in the early stages of P35858 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK21___","___MASK23___","___MASK33___","___MASK38___","___MASK39___","___MASK44___","___MASK55___","___MASK75___","___MASK87___"],"string":"[\n \"___MASK21___\",\n \"___MASK23___\",\n \"___MASK33___\",\n \"___MASK38___\",\n \"___MASK39___\",\n \"___MASK44___\",\n \"___MASK55___\",\n \"___MASK75___\",\n \"___MASK87___\"\n]"},"answer":{"kind":"string","value":"___MASK44___"},"id":{"kind":"string","value":"MH_train_395"}}},{"rowIdx":396,"cells":{"query":{"kind":"string","value":"interacts_with DB00146?"},"supports":{"kind":"list like","value":["P98164 is downregulated via LPS - P01375 - α - P27361 / 2 signaling pathway in proximal tubule cells . Expression and function of megalin , an endocytic receptor in proximal tubule cells ( PTCs ) , are reduced in diabetic nephropathy , involved in the development of proteinuria / albuminuria . Lipopolysaccharide ( LPS ) is chronically increased in diabetic sera , by the mechanism called metabolic endotoxemia . We investigated low - level LPS - mediated signaling that regulates megalin expression in immortalized rat PTCs ( IRPTCs ) . Incubation of the cells with LPS ( 10 ng / ml ) for 48 h suppressed megalin protein expression and its endocytic function . P01375 - α mRNA expression was increased by LPS treatment , and knockdown of the mRNA with siRNA inhibited LPS - mediated downregulation of megalin mRNA expression at the 24 - h time point . Incubation of IRPTCs with exogenous P01375 - α also suppressed megalin mRNA and protein expression at the 24 - and 48 - h time points , respectively . Q02750 inhibitor PD98059 competed partially but significantly P01375 - α - mediated downregulation of megalin mRNA expression . Collectively , low - level LPS - mediated P01375 - α - P27361 / 2 signaling pathway is involved in downregulation of megalin expression in IRPTCs .","High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK98___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .","Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK32___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .","Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","P54252 represses transcription via chromatin binding , interaction with histone deacetylase 3 , and histone deacetylation . P54252 ( P01008 ) , the disease protein in spinocerebellar ataxia type 3 ( P54252 ) , has been associated with the ubiquitin - proteasome system and transcriptional regulation . Here we report that normal P01008 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase - 2 ( P08253 ) gene promoter and represses transcription by recruitment of the histone deacetylase 3 ( O15379 ) , the nuclear receptor corepressor ( NCoR ) , and deacetylation of histones bound to the promoter . Both normal and expanded P01008 physiologically interacted with O15379 and NCoR in a P54252 cell model and human pons tissue ; however , normal P01008 - containing protein complexes showed increased histone deacetylase activity , whereas expanded P01008 - containing complexes had reduced deacetylase activity . Consistently , histone analyses revealed an increased acetylation of total histone H3 in expanded P01008 - expressing cells and human P54252 pons . Expanded P01008 lost the repressor function and displayed altered DNA / chromatin binding that was not associated with recruitment of O15379 , NCoR , and deacetylation of the promoter , allowing aberrant P08253 transcription via the transcription factor GATA - 2 . For transcriptional repression normal P01008 cooperates with O15379 and requires its intact ubiquitin - interacting motifs ( UIMs ) , whereas aberrant transcriptional activation by expanded P01008 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain . These findings demonstrate that normal P01008 binds target promoter regions and represses transcription of a GATA - 2 - dependent target gene via formation of histone - deacetylating repressor complexes requiring its UIM - associated function . Expanded P01008 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions .","Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte / macrophage progenitor lineage commitment towards dendritic cell differentiation through down - regulation of receptor activator of nuclear factor - kappaB and c - Fos . Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models . To address this controversy , we used several modes of T lymphocyte activation in osteoclast differentiation -- mitogen - pulse , anti - CD3 / P10747 stimulation and in vivo and in vitro alloactivation . Osteoclast - like cells were generated from non - adherent immature haematopoietic monocyte / macrophage progenitors in murine bone - marrow in the presence of receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) and monocyte - macrophage colony - stimulating factor ( P09603 ) . All modes of in vivo and in vitro T lymphocyte activation and both P01730 (+) and CD8 (+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell ( DC ) differentiation . Osteoclast - inhibitory effect was associated with T lymphocyte activation and not proliferation , and could be replaced by their culture supernatants . The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis , because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts . Inhibition was associated specifically with increased granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down - regulated Q9Y6Q6 , CD115 , c - Fos and calcitonin receptor expression , and increased differentiation towards CD11c - positive DC . An activated T lymphocyte inhibitory role in osteoclastogenesis , confirmed in vitro and in vivo , mediated through GM - P04141 release , may be used to counteract activated bone resorption mediated by T lymphocyte - derived cytokines in inflammatory and immune disorders . We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis , thereby confirming the functional link between alloreaction and bone metabolism .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","24R , 25 - dihydroxyvitamin D3 promotes the osteoblastic differentiation of human DB05914 . Although 1α , 25 - dihydroxyvitamin D3 [ 1α , 25 ( OH ) 2D3 ] is considered the most biologically active vitamin D3 metabolite , the vitamin D3 prohormone , 25 - hydroxyvitamin D3 [ DB00146 ] , is metabolized into other forms , including 24R , 25 - dihydroxyvitamin D3 [ 24R , 25 ( OH ) 2D3 ] . Herein we show that 24R , 25 ( OH ) 2D3 is fundamental for osteoblastic differentiation of human DB05914 ( hMSCs ) . Our approach involved analyses of cell proliferation , alkaline phosphatase activity , and pro - osteogenic genes ( collagen 1A1 , osteocalcin , vitamin D receptor [ P11473 ] , vitamin D3 - hydroxylating enzymes [ cytochrome P450 hydroxylases : Q6VVX0 , Q02318 , O15528 and Q07973 ] ) and assessment of Ca ( 2 +) mineralization of extracellular matrix . 24R , 25 ( OH ) 2D3 inhibited hMSC proliferation , decreased 1α - hydroxylase ( O15528 ) expression , thereby reducing the ability of hMSCs to convert DB00146 to 1α , 25 ( OH ) 2D3 , and promoted osteoblastic differentiation through increased alkaline phosphatase activity and Ca ( 2 +) mineralization . 24R , 25 ( OH ) 2D3 decreased expression of the 1α , 25 ( OH ) 2D3 receptor , P11473 . 24R , 25 ( OH ) 2D3 but not 1α , 25 ( OH ) 2D3 induced Ca ( 2 +) mineralization dependent on the absence of the glucocorticoid analog , dexamethasone . To elucidate the mechanism ( s ) for dexamethasone - independent 1α , 25 ( OH ) 2D3 inhibition / 24R , 25 ( OH ) 2D3 induction of Ca ( 2 +) mineralization , we demonstrated that 1α , 25 ( OH ) 2D3 increased whereas 24R , 25 ( OH ) 2D3 decreased reactive oxygen species ( ROS ) production . DB00146 also decreased ROS production , potentially by conversion to 24R , 25 ( OH ) 2D3 . Upon inhibition of the vitamin D3 - metabolizing enzymes ( cytochrome P450s ) , DB00146 increased ROS production , potentially due to its known ( low ) affinity for P11473 . We hypothesize that vitamin D3 actions on osteoblastic differentiation involve a regulatory relationship between 24R , 25 ( OH ) 2D3 and 1α , 25 ( OH ) 2D3 . These results implicate 24R , 25 ( OH ) 2D3 as a key player during hMSC maturation and bone development and support the concept that 24R , 25 ( OH ) 2D3 has a bioactive role in the vitamin D3 endocrine system .","Vitamin D up - regulates the vitamin D receptor by protecting it from proteasomal degradation in human P01730 + T cells . The active form of vitamin D3 , 1 , 25 ( OH ) 2D3 , has significant immunomodulatory properties and is an important determinant in the differentiation of P01730 + effector T cells . The biological actions of 1 , 25 ( OH ) 2D3 are mediated by the vitamin D receptor ( P11473 ) and are believed to correlate with the P11473 protein expression level in a given cell . The aim of this study was to determine if and how 1 , 25 ( OH ) 2D3 by itself regulates P11473 expression in human P01730 + T cells . We found that activated P01730 + T cells have the capacity to convert the inactive DB00146 to the active 1 , 25 ( OH ) 2D3 that subsequently up - regulates P11473 protein expression approximately 2 - fold . 1 , 25 ( OH ) 2D3 does not increase P11473 mRNA expression but increases the half - life of the P11473 protein in activated P01730 + T cells . Furthermore , 1 , 25 ( OH ) 2D3 induces a significant intracellular redistribution of the P11473 . We show that 1 , 25 ( OH ) 2D3 stabilizes the P11473 by protecting it from proteasomal degradation . Finally , we demonstrate that proteasome inhibition leads to up - regulation of P11473 protein expression and increases 1 , 25 ( OH ) 2D3 - induced gene activation . In conclusion , our study shows that activated P01730 + T cells can produce 1 , 25 ( OH ) 2D3 , and that 1 , 25 ( OH ) 2D3 induces a 2 - fold up - regulation of the P11473 protein expression in activated P01730 + T cells by protecting the P11473 against proteasomal degradation .","Overexpression of cytochrome P450 4F2 in mice increases 20 - hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20 - hydroxyeicosatetraenoic acid ( 20 - HETE ) . We previously found that a gain - in - function P78329 variant in a Chinese cohort was associated with elevated urinary 20 - HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen - regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his - tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20 - HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20 - HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20 - HETE levels . Our results show that increased expression of P78329 in mice enhanced 20 - HETE production and elevated blood pressure .","Use of fuzzy neural networks in modeling relationships of HPV infection with apoptotic and proliferation markers in potentially malignant oral lesions . To evaluate in oral leukoplakia the relationship between HPV infection and markers of apoptosis ( bcl - 2 , survivin ) and proliferation ( P12004 ) , also conditionally to age , gender , smoking and drinking habits of patients , by means of Fuzzy neural networks ( FNN ) system 21 cases of oral leukopakia , clinically and histologically diagnosed , were examined for HPV DNA presence , bcl - 2 , survivin and P12004 expression . HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR ( nPCR : MY09 - MY11 / P40197 - Q9HCN6 ) , and the HPV genotype determined by direct DNA sequencing . All markers were investigated by means of standardised immunohistochemistry procedure . Data were analysed by chi - square test , crude OR and the 95 % CI ; in blindness , FNN was applied . HPV DNA was found in 8 / 21 OL ( 38 . 1 % ) ; survivin , P12004 , and tobacco smoking were associated in univariate analysis ( p = 0 . 04 ) with HPV DNA status . HPV - 18 was the most frequently detected genotype ( 6 / 8 ) , followed by HPV - 16 ( 2 / 8 ) . FNN revealed that survivin and P12004 , both being expressed in all of OL HPV + ve , were associated with HPV infection . In conclusion , the FNN allowed to hypothesise a model of specific variables associated to HPV infection in OL . The relevance of survivin and P12004 suggest that they may be involved in HPV - mediated deregulation of epithelial maturation and , conversely , that HPV may have a role in the expression level of these two markers . FNN system seems to be an effective tool in the analysis of correlates of OL and HPV infection .","Immunocytochemical profile of malignant pleural effusions of small - cell lung cancer . BACKGROUND : Small - cell lung carcinoma ( SCLC ) is a highly malignant tumour of a somewhat distinctive cell type . The aim of this study was to determine the immunocytochemical profile of tumor cells and lymphoid cell in SCLC pleural fluids . METHODS : Nine cases of malignant pleural fluids of SCLC were studied using cell block preparation . In pleural effusions cytologically proven to be malignant in 9 patients with SCLC , the immunocytological features of tumor cells , together with the determination of lymphocytic subsets were documented . RESULTS : In all 9 cases , tumor cells reacted with neuron - specific enolase ( P09104 ) ( 100 % ) , whereas in 6 of 9 cases ( 66 , 66 % ) tumor cell expressed synaptophysin , thyroid transciption factor - 1 ( Q15669 - 1 ) and chromogranin A antigens . Phenotyping of the lymphocytes revealed in the majority of cases an expression of CD3 and P01730 antigens ( 8 and 7 cases , respectively ) in contrast to CD8 and P11836 expression ( 1 and 1 case , respectively ) . CONCLUSIONS : The reactivity pattern of the tumor cells with the markers used in our study is a specific for SCLC . No significant difference in the distribution of lymphocytic subpopulations is observed in correlation with other malignant and no malignant processes involving the pleural cavity .","Antagonistic action of novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone analogs on differentiation of human leukemia cells ( HL - 60 ) induced by 1alpha , 25 - dihydroxyvitamin D3 . We examined the effects of two novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone ( 1alpha , 25 - lactone ) analogues on human promyelocytic leukemia cell ( HL - 60 ) differentiation using the evaluation system of the vitamin D nuclear receptor ( P11473 ) / vitamin D - responsive element ( DRE ) - mediated genomic action stimulated by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) and its analogues . We found that the 1alpha , 25 - lactone analogues ( 23S ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9647 ) , and ( 23R ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9648 ) bound much more strongly to the P11473 than the natural ( 23S , 25R ) - DB00136 - 26 , 23 - lactone , but did not induce cell differentiation even at high concentrations ( 10 (- 6 ) M ) . Intriguingly , the differentiation of HL - 60 cells induced by DB00136 was inhibited by either TEI - 9647 or TEI - 9648 but not by the natural lactone . In contrast , retinoic acid or 12 - O - tetradecanoylphorbol - 13 - acetate - induced HL - 60 cell differentiation was not blocked by TEI - 9647 or TEI - 9648 . In separate studies , TEI - 9647 ( 10 (- 7 ) M ) was found to be an effective antagonist of both DB00136 ( 10 (- 8 ) M ) mediated induction of P38936 ( P38936 , CIP1 ) in HL - 60 cells and activation of the luciferase reporter assay in COS - 7 cells transfected with cDNA containing the DRE of the rat DB00146 - 24 - hydroxylase gene and cDNA of the human P11473 . Collectively the results strongly suggest that our novel 1alpha , 25 - lactone analogues , TEI - 9647 and TEI - 9648 , are specific antagonists of 1alpha , 25 ( OH ) 2D3 action , specifically P11473 / DRE - mediated genomic action . As such , they represent the first examples of antagonists , which act on the nuclear P11473 .","Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .","___MASK15___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK15___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK15___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .","The role of cubilin gene polymorphisms and their influence on DB00146 and 1 , 25 ( OH ) 2D3 plasma levels in type 1 diabetes patients . BACKGROUND : P98164 and cubilin bind and internalize the DB00146 - DBP complex in the kidney . Once the complex is internalized , DB00146 is released and activated to 1 , 25 ( OH ) 2D3 the ligand for the vitamin D receptor ( P11473 ) . Supporting the important role of cubilin in this process recent findings showed that cubilin deficiency results in decrease of DB00146 and 1 , 25 ( OH ) 2D3 plasma levels . METHODS : Two hundred T1D patients and healthy controls ( n = 200 ) were genotyped for five polymorphisms ( rs3740168 , rs3740165 , rs1801233 , rs1801229 and rs2796835 ) within the cubilin gene . The polymorphisms were analyzed by RFLP or real time PCR . Statistic analyses were performed by using allele - wise and genotype - wise chi2 testing by using BiAS software . A p - value < 0 . 05 was considered as significant . RESULTS : We found that the genotype \" AA \" of the rs3740165 was more frequent in T1D patients compared to healthy controls ( 26 . 7 % vs . 5 . 1 % , p = 4x10 (- 7 ) ) . Nevertheless no association between the rs3740165 polymorphism and the DB00146 or 1 , 25 ( OH ) 2D3 plasma levels was found . No association with the other studied polymorphisms was observed . CONCLUSION : Thus our findings reveal a novel association of the cubilin rs3740165 polymorphism with type 1 diabetes . Nevertheless how exactly this polymorphism could increase the risk to develop type 1 diabetes is subject for further investigations .","DB08816 increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : DB08816 is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . DB08816 and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : DB08816 increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .","The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners . Mutations in the tumor suppressor genes Q92574 and P49815 , encoding hamartin and tuberin , respectively , cause the tumor syndrome tuberous sclerosis with similar phenotypes . Until now , over 50 proteins have been demonstrated to interact with hamartin and / or tuberin . Besides tuberin , the proteins Q96N67 , ezrin / radixin / moesin , Q8TDY2 , IKKbeta , Melted , P35240 , Q00994 ( p75NTR ) , P07196 , Plk1 and Q9P0N9 have been found to interact with hamartin . Whereas Plk1 and Q9P0N9 have been demonstrated not to bind to tuberin , for all the other hamartin - interacting proteins the question , whether they can also bind to tuberin , has not been studied . P49815 interacts with 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , AMPK , P62158 , Q9BUF7 / Q8NI35 , cyclin A , cyclins D1 , D2 , D3 , Dsh , ERalpha , Erk , FoxO1 , Q15751 , HPV16 E6 , HSCP - 70 , P0DMV8 , P49137 , Q96PY6 , p27KIP1 , Pam , PC1 , PP2Ac , Q15276 , Rheb , RxRalpha / P11473 and Q15796 / 3 . 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , Dsh , FoxO1 , Q15751 , p27KIP1 and PP2Ac are known not to bind to hamartin . For the other tuberin - interacting proteins this question remains elusive . The proteins axin , Cdk1 , cyclin B1 , O75807 , GSK3 , P42345 and Q15418 have been found to co - immunoprecipitate with both , hamartin and tuberin . The kinases Cdk1 and IKKbeta phosphorylate hamartin , Erk , Akt , P49137 , AMPK and Q15418 phosphorylate tuberin , and GSK3 phosphorylates both , hamartin and tuberin . This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin .","___MASK32___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK32___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .","Ligand - induced transrepression by P11473 through association of Q9UIG0 with acetylated histones . We have previously shown that the novel DB00171 - dependent chromatin - remodeling complex WINAC is required for the ligand - bound vitamin D receptor ( P11473 ) - mediated transrepression of the DB00146 1alpha - hydroxylase ( 1alpha ( OH ) ase ) gene . However , the molecular basis for P11473 promoter association , which does not involve its binding to specific DNA sequences , remains unclear . To address this issue , we investigated the function of Q9UIG0 in terms of the association between WINAC and chromatin for ligand - induced transrepression by P11473 . Results of in vitro experiments using chromatin templates showed that the association of unliganded P11473 with the promoter required physical interactions between Q9UIG0 and both P11473 and acetylated histones prior to P11473 association with chromatin . The acetylated histone - interacting region of Q9UIG0 was mapped to the bromodomain , and a Q9UIG0 mutant lacking the bromodomain served as a dominant - negative mutant in terms of ligand - induced transrepression of the 1alpha ( OH ) ase gene . Thus , our findings indicate that WINAC associates with chromatin through a physical interaction between the Q9UIG0 bromodomain and acetylated his tones , which appears to be indispensable for P11473 / promoter association for ligand - induced transrepression of 1alpha ( OH ) ase gene expression .","P98164 mediates the transport of leptin across the blood - P04141 barrier . Leptin , a peptide hormone secreted by adipose tissue , exhibits a large range of central and peripheral actions . It has been proposed that the participation of leptin in diseases such as obesity is due to , at least in part , its impaired transport across the blood - brain barrier ( BBB ) . Since , the mechanisms by which brain takes up leptin remain unclear , we set out to study how leptin may cross the BBB . We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans . We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium . Indeed , the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer ' s disease was correlated with poor entry of leptin into the brain . Moreover , amyloid beta ( Abeta ) deposits of choroid plexus could be disturbing megalin function . The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain .","Molecular cloning and characterization of O75197 , a novel P01130 family protein with mitogenic activity . We report molecular cloning and initial functional characterization of a novel member of the low density lipoprotein receptor ( P01130 ) gene family . The cDNA was isolated from a human osteoblast cDNA library and encoded a 1 , 615 amino acids protein designated as O75197 . It has , in the extracellular region , a cluster of three P01130 ligand binding repeats at a juxtamembrane position and four P01133 precursor homology domains separated by YWTD spacer repeats . The entire ectodomain shares the same modular organization with the middle portion of the extracellular regions of two P01130 family members , P01130 - related protein ( Q14764 ) , and P98164 / megalin . O75197 mRNA was expressed in most of the adult and fetal tissues examined . The highest expression level was seen in aorta . In human osteosarcoma cells examined , O75197 mRNA was highly enriched in TE85 cells , moderately expressed in MG63 cells and primary human osteoblasts , and undetectable in SaOS - 2 cells . NIH 3T3 cells transfected with either full length O75197 or its ectodomain showed significantly increased proliferation , whereas transfection of intracellular domain had no proliferative effect . We predict that O75197 is a multi - functional protein with potential mitogenic activity .","Regulatory role of promoter and 3 ' UTR variants of vitamin D receptor gene on cytokine response in pulmonary tuberculosis . Vitamin D receptor ( P11473 ) gene variants are shown to regulate immune response in tuberculosis . We studied the influence of P11473 promoter ( Cdx - 2 and A1012G ) , 3 ' untranslated region ( Apa I , Bsm I , and Taq I ) and start codon ( Fok I ) polymorphisms on 1 , 25 ( OH )( 2 ) D ( 3 )- modulated IL - 12p40 , P01579 , P22301 , and P05113 response to live Mycobacterium tuberculosis and its culture filtrate antigen ( O75347 ) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients . In peripheral blood mononuclear cell cultures with O75347 and 1 , 25 ( OH )( 2 ) D ( 3 ) , IL - 12p40 , and P01579 levels were significantly decreased ( p < 0 . 05 ) and P22301 levels were significantly increased ( p < 0 . 05 ) in patients with GG genotype . The extended genotype bbaaTT ( baT haplotype ) was associated with decreased IL - 12p40 and P01579 levels and significantly increased P22301 levels ( p < 0 . 05 ) . The Cdx - 2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased P22301 response , which suggests that 1 , 25 ( OH )( 2 ) D ( 3 ) probably through the P11473 polymorphic variants augments the anti - inflammatory response at the site of M . tuberculosis infection .","Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK1___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .","[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK15___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .","Integration of hormone signaling in the regulation of human DB00146 24 - hydroxylase transcription . The current study sought to define the molecular mechanisms involved in the cross talk between 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] and activators of PKC in the regulation of 25 ( OH ) D ( 3 ) 24 - hydroxlyase [ 24 ( OH ) ase ] . Transfection of the h24 ( OH ) ase promoter construct [ - 5 , 500 /- 22 luciferase ; vitamin D response elements at - 294 /- 274 and - 174 /- 151 ; AP - 1 site at - 1 , 167 /- 1 , 160 ] in vitamin D receptor ( P11473 ) - transfected COS - 7 cells resulted in strong activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . In these cells , cotreatment with the PKC activator TPA and 1 , 25 ( OH )( 2 ) D ( 3 ) yielded a 27 - fold increase in luciferase activity , which was 2 - to 3 - fold greater than activation obtained with 1 , 25 ( OH )( 2 ) D ( 3 ) alone ( P < 0 . 05 ) . Similar results were observed using LLCPK - 1 kidney cells , suggesting that the previously observed enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- induced renal 24 ( OH ) ase mRNA and activity by PKC activation occurs at the level of transcription . The functional cooperation between PKC activation and P11473 was not found to be mediated by the AP - 1 site in the h24 ( OH ) ase promoter or by enhanced binding of GRIP or Q15648 to P11473 and was also not due to PKC - mediated phosphorylation of P11473 on DB00133 ( 51 ) . Our study demonstrates that , in LLCPK - 1 kidney cells , the PKC enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- stimulated transcription may be due , in part , to an increase in P11473 concentration . In addition , inhibitors of the MAPK pathway were found to decrease the TPA enhancement ( P < 0 . 05 ) . Because activation of MAPK has been reported to result in the phosphorylation of Q15788 and in functional cooperation between Q15788 and CREB binding protein , we propose that the potentiation of P11473 - mediated transcription may also be mediated through changes in the phosphorylation of specific P11473 coregulators .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Identification of novel human Cdt1 - binding proteins by a proteomics approach : proteolytic regulation by P25054 / CCdh1 . In mammalian cells , Cdt1 activity is strictly controlled by multiple independent mechanisms , implying that it is central to the regulation of DNA replication during the cell cycle . In fact , unscheduled Cdt1 hyperfunction results in rereplication and / or chromosomal damage . Thus , it is important to understand its function and regulations precisely . We sought to comprehensively identify human Cdt1 - binding proteins by a combination of Cdt1 affinity chromatography and liquid chromatography and tandem mass spectrometry analysis . Through this approach , we could newly identify 11 proteins , including subunits of anaphase - promoting complex / cyclosome ( P25054 / C ) , O60264 and Q9UIG0 , topoisomerase I and IIalpha , Q9BQ67 / Q9BQ67 , nucleophosmin / nucleoplasmin , and importins . In vivo interactions of Cdt1 with P25054 / C ( Cdh1 ) , O60264 , topoisomerase I and IIalpha , and Q9BQ67 / Q9BQ67 were confirmed by coimmunoprecipitation assays . A further focus on P25054 / C ( Cdh1 ) indicated that this ubiquitin ligase controls the levels of Cdt1 during the cell cycle via three destruction boxes in the Cdt1 N - terminus . Notably , elimination of these destruction boxes resulted in induction of strong rereplication and chromosomal damage . Thus , in addition to P21583 ( Skp2 ) and cullin4 - based ubiquitin ligases , P25054 / C ( Cdh1 ) is a third ubiquitin ligase that plays a crucial role in proteolytic regulation of Cdt1 in mammalian cells .","O60603 signaling protects mice from tumor development in a mouse model of colitis - induced cancer . Inflammatory bowel disease ( Q9UKU7 ) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer . The etiology of Q9UKU7 is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host . Toll - like receptor ( TLR ) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis , innate immunity and the enhancement of intestinal epithelial cell ( IEC ) integrity . However , the role of O60603 in the development of colorectal cancer has not been studied . We utilized the AOM - DSS model for colitis - associated colorectal cancer ( CAC ) in wild type ( WT ) and O60603 (-/-) mice . Colons harvested from WT and O60603 (-/-) mice were used for histopathology , immunohistochemistry , immunofluorescence and cytokine analysis . Mice deficient in O60603 developed significantly more and larger colorectal tumors than their WT controls . We provide evidence that colonic epithelium of O60603 (-/-) mice have altered immune responses and dysregulated proliferation under steady - state conditions and during colitis , which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth . At the earliest time - points assessed , O60603 (-/-) colons exhibited a significant increase in aberrant crypt foci ( Q9NQ94 ) , resulting in tumors that developed earlier and grew larger . In addition , the intestinal microenvironment revealed significantly higher levels of P05231 and Q16552 concomitant with increased phospho - P40763 within Q9NQ94 . These observations indicate that in colitis , O60603 plays a protective role against the development of CAC .","Activation of the interleukin - 6 / Janus kinase / P40763 pathway in pleomorphic adenoma of the parotid gland . The interleukin - 6 ( P05231 ) / Janus kinase ( JAK ) / signal transducer and activator of transcription 3 ( P40763 ) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors , e . g . , of pleomorphic adenoma ( PA ) . In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs ( miRNAs ) regulated by this pathway in isolated duct - and myoepithelial cells in PA . 46 PAs were immunostained and 10 of these were used for in situ hybridization ( ISH ) . Six frozen specimens were analyzed using reverse transcription - polymerase chain reaction ( RT - PCR ) . Using immunohistochemistry , P05231 , P23458 , O60674 and P40763 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue . Using RT - PCR cyclin D1 , fibroblast growth factor 2 , and P38936 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland . ISH showed significant overexpression of miR - 181b in PA , while miR - 21 was undetectable in PA and normal tissue . Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs . Our findings brings us one step closer to targeted treatment of this tumor entity , although in vitro studies are warranted to confirm this .","Structure - activity relationships in Q9NYK1 agonistic 1H - imidazo [ 4 , 5 - c ] pyridines . Engagement of Q9NYK1 in plasmacytoid dendritic cells leads to the induction of IFN - α / β which plays essential functions in the control of adaptive immunity . We had previously examined structure - activity relationships ( SAR ) in Q9NYK1 / 8 - agonistic imidazoquinolines with a focus on substituents at the N ( 1 ) , C ( 2 ) , N ( 3 ) and N ( 4 ) positions , and we now report SAR on 1H - imidazo [ 4 , 5 - c ] pyridines . 1 - Benzyl - 2 - butyl - 1H - imidazo [ 4 , 5 - c ] pyridin - 4 - amine was found to be a pure Q9NYK1 - agonist with negligible activity on Q9NR97 . Increase in potency was observed in N ( 6 )- substituted analogues , especially in those compounds with electron - rich substituents . Direct aryl - aryl connections at P13671 abrogated activity , but Q9NYK1 agonism was reinstated in 6 - benzyl and 6 - phenethyl analogues . Consistent with the pure Q9NYK1 - agonistic behavior , prominent IFN - α induction in human PBMCs was observed with minimal proinflammatory cytokine induction . A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine . Distinct differences in N ( 6 )- substituted analogues were observed with respect to IFN - α induction in human PBMCs on the one hand , and Q07108 upregulation in lymphocytic subsets , on the other .","Expression of vitamin D receptor ( P11473 ) , cyclooxygenase - 2 ( P35354 ) and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) in benign and malignant ovarian tissue and DB00146 ( 25 ( OH2 ) D3 ) and prostaglandin E2 ( DB00917 ) serum level in ovarian cancer patients . Ovarian carcinomas are associated with increased inflammation which is based upon an up - regulation of inducible cyclooxygenase - 2 ( P35354 ) . Moreover , based on our previous published data , the extra - renal vitamin D metabolism seems to be dysregulated in comparison to healthy tissue . In order to gain further insight into the prostaglandin ( PG ) - and vitamin D - metabolism in ovarian carcinomas , the study aimed to evaluate the expression of the PG metabolising enzymes P35354 and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) compared to the vitamin D receptor ( P11473 ) in benign and malignant ovarian tissues . Additionally , we determined the DB00146 ( 25 ( OH2 ) D3 ) serum levels . Expression of P11473 , P35354 and P15428 was determined by Western blot analysis . Serum levels of 25 ( OH2 ) D3 and DB00917 were measured by chemiluminescence - based and colorimetric immunoassay . We detected significantly higher expressions of the PG metabolising enzymes P15428 and P35354 in malignant tissue and DB00917 serum levels were 2 - fold higher in tumour patients . Furthermore , we found an inverse correlation to the P11473 - expression which was 62 . 1 % lower in malignant tissues compared to that in benign tissues . Surprisingly , we could not detect any differences between the 25 ( OH2 ) D3 serum levels in either group ( n = 20 ) . These data suggest a correlation between PG - and vitamin D - metabolism in ovarian carcinomas .","The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK54___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .","Membrane receptors for vitamin D metabolites . Membrane - initiated signaling by steroid hormones is now widely accepted . Current debate is centered upon which protein moieties act as membrane - associated receptors . In this review , we consider evidence for the classical vitamin D receptor ( P11473 ) in this role , as well as the more recently identified 1 , 25D3 - MARRS ( membrane - associated , rapid response steroid binding ) receptor , also known as P30101 / GRp58 . The structure of the 1 , 25D3 - MARRS receptor is discussed , with emphasis on two thioredoxin domains that promote dimerization and ligand binding . We then summarize recent studies on a 24 , 25 ( OH ) 2D3 binding protein -- catalase -- and how ligand - induced decreases in enzymatic activity produce increased reactive oxygen species that target both the 1 , 25D3 - MARRS receptor -- but not the P11473 -- and the protein kinase C signaling pathway . Finally , we briefly discuss the available literature suggesting that the metabolite DB00146 may also be biologically active .","Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .","The use of the VerifyNow Q9H244 point - of - care device to monitor platelet function across a range of Q9H244 inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point - of - care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 ( VN - Q9H244 ) POC device with light transmission aggregometry ( P01374 ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 and VN - Q9H244 at baseline and after dosing . ___MASK98___ 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device - reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 showed a very similar pattern to that found with VN - Q9H244 measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 appeared to be narrower than that of P01374 . With two different thienopyridines , the VN - Q9H244 device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .","Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .","Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .","Vitamin D receptor - mediated suppression of RelB in antigen presenting cells : a paradigm for ligand - augmented negative transcriptional regulation . The immunological effects of vitamin D receptor ( P11473 ) ligands include inhibition of dendritic cell ( DC ) maturation , suppression of T - helper type 1 ( Th1 ) T - cell responses and facilitation of antigen - specific immune tolerance in vivo . While studying the molecular profile of DCs cultured in the presence of 1alpha , DB00146 or synthetic D3 analogs we observed that expression of the NF - kappaB family member RelB , which plays an essential role in DC differentiation and maturation , is selectively suppressed by P11473 ligands . Further in vitro and in vivo studies of P11473 - mediated RelB suppression indicated that the mechanism for this effect involves direct binding of P11473 / RXR alpha to a defined region of the relB promoter and assembly of a negative regulatory complex containing O15379 , Q13547 , Q9Y618 and , most likely , other factors . Interestingly , promoter engagement by P11473 and O15379 , but not the other identified components , is enhanced by addition of a P11473 ligand and inhibited by a pro - maturational stimulus ( LPS ) that results in RelB upregulation . Promoter assays in a panel of cell lines suggest that the P11473 ligand - dependent component of relB suppression may occur selectively in antigen presenting cells . Cell type - specific , ligand - enhanced negative transcriptional regulation represents a potentially novel paradigm for P11473 - controlled genes . In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process .","Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK38___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK38___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .","Characterization of background anti - trinitrophenyl plaque - forming cells observed in several strains of mice . Normal mice have a large number of background anti - trinitrophenyl ( TNP ) antibody - forming cells ( AFC ) in their spleens ( about 40 - 50 anti - TNP P27918 / 10 ( 6 ) cells ) . We investigated this among several mouse strains , i . e . , C57BL / 6 , C3H / He , Balb / c , ddd , and ICR mice , and found that all strains had a similar number of anti - TNP P27918 ( plaque - forming cells ) . Developmental aspects of background anti - TNP P27918 in the ontogenic process were also investigated . The number of anti - TNP P27918 increased logari thmically during the first few days of age , reached a peak on the 13th day and attained a constant value within 30 days . Neonatal thymectomy did not decrease the number of background anti - TNP P27918 but such treatment decreased the anti - TNP P27918 response to TNP - HRBC ( horse red blood cells ) immunization . Germ - free ICR mice had a number of background anti - TNP P27918 similar to that of conventional ICR mice . Avidity of background anti - TNP P27918 was compared among mice of several ages and it was shown that there were no differences among them . These results suggest that the occurrence of these background anti - TNP P27918 is not elicited by the immune response but by the natural maturation of precursors of Q9NQ94 without antigenic stimulation .","Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK98___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK98___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .","Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK47___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK47___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK47___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .","Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid - mediated responses in the mammary glands of cycling rats . Prenatal exposure to Q03001 disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after Q03001 exposure . Our aim was to assess the effect of prenatal Q03001 exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats . Pregnant Wistar rats were exposed to either 25 or 250 g / kg / day ( 25 and 250 Q03001 , respectively ) or to vehicle . Female offspring were autopsied on postnatal day ( P01160 ) 50 or 110 . Ovarian steroid serum levels , the expression of steroid receptors and their co - regulators Q9Y6Q9 and Q9Y618 in the mammary gland , and angiogenesis were evaluated . At P01160 50 , all Q03001 - treated animals had lower serum levels of progesterone , while estradiol levels remained unchanged . The higher dose of Q03001 increased mammary ERα and decreased Q9Y6Q9 expression at P01160 50 and P01160 110 . Q9Y618 protein levels were similar among groups at P01160 50 , whereas at P01160 110 , animals exposed to 250 Q03001 showed a lower Q9Y618 expression . Interestingly , in the control and 25 Q03001 groups , Q9Y618 increased from P01160 50 to P01160 110 . At P01160 50 , an increased vascular area associated with higher P15692 expression was observed in the 250 Q03001 - treated rats . At P01160 110 , the vascular area was still increased , but P15692 expression was similar to that of control rats . The present results demonstrate that prenatal exposure to Q03001 alters the endocrine environment of the mammary gland and its angiogenic process . Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre - neoplastic lesions found later in life . This article is part of a Special Issue entitled ' Endocrine disruptors ' .","Comparison of human B cell activation by Q9NYK1 and Q9NR96 agonists . BACKGROUND : Human B cells and plasmacytoid dendritic cells ( pDC ) are the only cells known to express both Q9NYK1 and Q9NR96 . Plasmacytoid dendritic cells are the primary IFN - alpha producing cells in response to Q9NYK1 and Q9NR96 agonists . The direct effects of Q9NYK1 stimulation on human B cells is less understood . The objective of this study was to compare the effects of Q9NYK1 and Q9NR96 stimulation on human B cell function . RESULTS : Gene expression and protein production of cytokines , chemokines , various B cell activation markers , and immunoglobulins were evaluated . Purified human P15391 + B cells ( 99 . 9 % , containing both naïve and memory populations ) from peripheral blood were stimulated with a Q9NYK1 - selective agonist ( 852A ) , Q9NYK1 / 8 agonist ( 3M - 003 ) , or Q9NR96 selective agonist CpG ODN ( CpG2006 ) . Q9NYK1 and Q9NR96 agonists similarly modulated the expression of cytokine and chemokine genes ( P05231 , MIP1 alpha , MIP1 beta , P01375 alpha and P01374 ) , co - stimulatory molecules ( P33681 , P25942 and P19256 ) , Fc receptors ( CD23 , CD32 ) , anti - apoptotic genes ( Q07817 ) , certain transcription factors ( MYC , Q9UL49 ) , and genes critical for B cell proliferation and differentiation ( P21854 , Q9HBE5 ) . Both agonists also induced protein expression of the above cytokines and chemokines . Additionally , Q9NYK1 and Q9NR96 agonists induced the production of IgM and IgG . A Q9NR97 - selective agonist was comparatively ineffective at stimulating purified human B cells . CONCLUSION : These results demonstrate that despite their molecular differences , the Q9NYK1 and Q9NR96 agonists induce similar genes and proteins in purified human B cells .","Q9NR97 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1 . Toll - like receptors ( TLR ) are important in recognizing microbial pathogens and triggering host innate immune responses , including autophagy , and in the mediation of immune activation during human immunodeficiency virus type - 1 ( HIV ) infection . We report here that Q9NR97 activation in human macrophages induces the expression of the human cathelicidin microbial peptide ( CAMP ) , the vitamin D receptor ( P11473 ) and cytochrome P450 , family 27 , subfamily B , polypeptide 1 ( O15528 ) , which 1α - hydroxylates the inactive form of vitamin D , DB00146 , into its biologically active metabolite . Moreover , we demonstrate using RNA interference , chemical inhibitors and vitamin D deficient media that Q9NR97 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism . These data support an important role for vitamin D in the control of HIV infection , and provide a biological explanation for the benefits of vitamin D . These findings also provide new insights into potential novel targets to prevent and treat HIV infection .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK93___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","DB00146 attenuates experimental periodontitis through downregulation of O00206 and P23458 / P40763 signaling in diabetic mice . Vitamin D has been known to be closely associated with diabetes and periodontitis while the underlying mechanism has yet to be clarified . The present study aimed to discover the effect of 25 - hydroxyvitamin D3 ( 25 - OHD3 ) on glycemic control and periodontal health in mice with periodontitis superimposed on experimental diabetes ( known as diabetic periodontitis ) . We showed that 25 - OHD3 intraperitoneal injection attenuated diabetic periodontitis by reducing serum fasting blood glucose , glycosylated hemoglobin and P01375 - α levels , which led to decreased alveolar bone loss . Immunohistochemical staining and western blot analysis of gingival epithelia revealed that vitamin D receptor ( P11473 ) expression was enhanced upon 25 - OHD3 treatment , while toll - like receptor 4 ( O00206 ) expression was reduced . The expressions of Janus family kinase ( JAK ) 1 and signal transducer and activator of transcription ( P35610 ) 3 as well as their phosphorylation were inhibited in gingival epithelia of diabetic periodontitis mice , whereas the expression and phosphorylation of P42224 remained unchanged . These results suggest that 25 - OHD3 could improve diabetic periodontitis through downregulation of O00206 and P23458 / P40763 signaling in the gingival epithelium . Our study extends the previous findings on the regulation of diabetes with periodontitis , and may also provide a potential therapy for the patients with this disease .","Tumor progression in the LPB - Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status . Previous studies have suggested that 1 , 25 dihydroxyvitamin D ( 3 ) ( 1 , 25 ( OH ) 2D3 ) induces cell cycle arrest and / or apoptosis in prostate cancer cells in vitro , suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent . Most epidemiological data however shows a weak link between serum DB00146 and risk of prostate cancer . To explore this dichotomy we have compared tumor progression in the LPB - Tag model of prostate in P11473 knock out ( VDRKO ) and wild type ( VDRWT ) mice . On the C57BL / 6 background LPB - Tag tumors progress significantly more rapidly in the VDRKO mice . VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors . In mice supplemented with testosterone to restore the serum levels to the normal range , these differences in tumor progression , and proliferation are abrogated , suggesting that there is considerable cross - talk between the androgen receptor ( AR ) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR , P12004 , cdk2 survivin and P12314 and 2 genes . These alterations may explain the differences between the in vitro data and the epidemiological studies .","Tumor Necrosis Factor alpha ( TNFalpha ) regulates P25942 expression through Q8N9N5 phosphorylation . P25942 plays an important role in mediating inflammatory response and is mainly induced by JAK / P35610 phosphorylation cascade . TNFalpha is the key cytokine that activates P25942 during inflammation and tumorigenesis . We have earlier shown that Q8N9N5 can repress the transcription of P12004 D1 promoter by forming a Q13547 dependent repressor complex . In this study , we show that Q8N9N5 regulates the transcription of NF - kappaB target gene P25942 . Q8N9N5 recruits Q13547 and forms a repressor complex on P25942 promoter and keeps its basal transcription in check . Further , we show that TNFalpha stimulation induces Q8N9N5 phosphorylation at DB00133 - 347 and promotes its cytoplasmic translocation , thus releasing its negative effect . Concomitantly , TNFalpha induced phosphorylation of P42224 at DB00135 - 701 by P23458 facilitates its nuclear translocation and activation of P25942 through p300 recruitment and core Histone - 3 acetylation . Thus , TNFalpha mediated regulation of P25942 expression occurs by dual phosphorylation of Q8N9N5 and P42224 .","Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK86___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK86___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK86___ .","Plasma membrane rafts and chaperones in cytokine / P35610 signaling . We and others have recently obtained data suggesting that cytokine - P35610 signaling in many different cell - types is a chaperoned pathway initiated at the level of specialized plasma membrane microdomains called \" rafts \" ( the \" raft - P35610 signaling hypothesis \" ) . These findings are of broad significance in that all cytokines and growth factors initiate signaling in target cells by interacting with respective cell - surface receptors . The new data suggest that raft microdomains represent the units of function at the cell - surface through which ligand - stimulated P35610 signaling is initiated . Moreover , recent evidence shows the involvement of chaperone proteins in regulating the P35610 signaling pathway . These chaperones include the human homolog of the tumorous imaginal disc 1 protein ( hTid1 ) which associates with O60674 ( O60674 ) at the level of the plasma membrane , heat shock protein 90 ( HSP90 ) which associates with P40763 and P42224 proteins in caveolin - 1 - containing raft and cytoplasmic complexes , and glucose regulated protein 58 ( P30101 / ER - 60 / P30101 ) , a thiol dependent protein - disulfide isomerase , found in association with P40763 \" statosome \" complexes in the cytosol and in the raft fraction . We suggest a function of the HSP90 chaperone system in preserving P05231 / P40763 signaling in liver cells in the context of fever . The identification and function of protein partners associated with specific P35610 species in rafts and in cytosolic complexes , and in the efficient departure of cytokine - activated STATs from the cytosolic face of rafts towards the cell nucleus are now areas of active investigation .","The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .","Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .","P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .","___MASK86___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK86___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK86___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK86___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .","Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK93___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .","Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case - controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . ___MASK47___ , the addictive component of cigarettes , accelerates cell proliferation through nicotinic acetylcholine receptors ( nAChR ) . In this study , we show that human BACs produce acetylcholine ( ACh ) and contain several cholinergic factors including acetylcholinesterase ( P22303 ) , choline acetyltransferase ( P28329 ) , choline transporter 1 ( Q9GZV3 , Q9GZV3 ) , vesicular acetylcholine transporter ( Q16572 , Q16572 ) , and nACh receptors ( AChRs , CHRNAs ) . ___MASK47___ increased the production of ACh in human BACs , and ACh acts as a growth factor for these cells . ___MASK47___ - induced ACh production was mediated by α7 - , α3β2 - , and β3 - nAChRs , P28329 and Q16572 pathways . We observed that nicotine upregulated P28329 and Q16572 . Therefore , we conjectured that Q16572 antagonists , such as vesamicol , may suppress the growth of human BACs . Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models . Vesamicol did not have any effect on P01133 or insulin - like growth factor - II - induced growth of human BACs . siRNA - mediated attenuation of Q16572 reversed the apoptotic activity of vesamicol . We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol . Taken together , our results suggested that disruption of nicotine - induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy .","Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .","Increased vitamin D - driven signalling and expression of the vitamin D receptor , P35548 , and O14788 in tooth resorption in cats . Tooth resorption occurs in 20 - 75 % of cats ( Felis catus ) . The aetiology is not known , but vitamin D is suggested to be involved . Vitamin D acts through a nuclear receptor ( P11473 ) and increases the expression of receptor activator of nuclear factor - kappaB ligand ( rankl ) and muscle segment homeobox 2 ( msx2 ) genes . Mice lacking the muscle segment homeobox 2 ( msx2 ) gene show decreased levels of rankl , suggesting an interaction among P11473 , P35548 , and O14788 . Here , we investigated the expression of P11473 , P35548 , and O14788 proteins , and the activity of the P11473 - mediated signalling pathway ( using the quantitative polymerase chain reaction on P11473 target genes ) , in tooth resorption , and measured the serum levels of vitamin D metabolites in cats . Tooth resorption was categorized into either resorptive or reparative stages . In the resorptive stage , odontoclasts expressed P35548 and O14788 ( 100 % and 88 % , respectively ) and fibroblasts expressed P11473 and P35548 ( both at 100 % ) , whereas fibroblasts expressed O14788 in only 29 % of the sites analysed . In the reparative stage , cementoblasts expressed P11473 , P35548 , and O14788 , whereas fibroblasts expressed P11473 and P35548 , but not O14788 . The vitamin D status did not differ between the groups , based on the serum levels of DB00146 . However , increased expression of P11473 protein , and the relative gene expression levels of 1alpha - hydroxylase and the P11473 - target gene , 24 - hydroxylase , indicated the involvement of an active vitamin D signalling in the pathophysiology of tooth resorption in cats .","Expression of vitamin D receptor and 25 - hydroxyvitamin D3 - 1 { alpha }- hydroxylase in normal and malignant human colon . Considerable evidence exists to support the use of vitamin D to prevent and / or treat colorectal cancer . However , the routine use of bioactive vitamin D , 1 , 25 - dihydroxyvitamin D3 , is limited by the side effect of toxic hypercalcemia . Recent studies , however , suggest that colonic epithelial cells express 25 - hydroxyvitamin D3 - 1alpha - hydroxylase , an enzyme that converts nontoxic pro - vitamin D , DB00146 [ DB00146 ] , to its bioactive form . Yet , nothing is known as to the cellular expression of 1alpha - hydroxylase and the vitamin D receptor ( P11473 ) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci ( Q9NQ94 ) and polyps [ addressing the possibility of using nontoxic DB00146 for chemoprevention ] , nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [ relevant to using DB00146 for chemotherapy ] . In this study , we show that 1alpha - hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs , polyps , and colorectal cancer irrespective of tumor cell differentiation . In contrast , P11473 levels were low in normal colonic epithelial cells ; were increased in ACFs , polyps , and well - differentiated tumor cells ; and then declined as a function of tumor cell de - differentiation . Both 1alpha - hydroxylase and P11473 levels were negligible in tumor cells metastasizing to regional lymph nodes . Overall , these data support using DB00146 for colorectal cancer chemoprevention but suggest that pro - vitamin D is less likely to be useful for colorectal cancer chemotherapy ."],"string":"[\n \"P98164 is downregulated via LPS - P01375 - α - P27361 / 2 signaling pathway in proximal tubule cells . Expression and function of megalin , an endocytic receptor in proximal tubule cells ( PTCs ) , are reduced in diabetic nephropathy , involved in the development of proteinuria / albuminuria . Lipopolysaccharide ( LPS ) is chronically increased in diabetic sera , by the mechanism called metabolic endotoxemia . We investigated low - level LPS - mediated signaling that regulates megalin expression in immortalized rat PTCs ( IRPTCs ) . Incubation of the cells with LPS ( 10 ng / ml ) for 48 h suppressed megalin protein expression and its endocytic function . P01375 - α mRNA expression was increased by LPS treatment , and knockdown of the mRNA with siRNA inhibited LPS - mediated downregulation of megalin mRNA expression at the 24 - h time point . Incubation of IRPTCs with exogenous P01375 - α also suppressed megalin mRNA and protein expression at the 24 - and 48 - h time points , respectively . Q02750 inhibitor PD98059 competed partially but significantly P01375 - α - mediated downregulation of megalin mRNA expression . Collectively , low - level LPS - mediated P01375 - α - P27361 / 2 signaling pathway is involved in downregulation of megalin expression in IRPTCs .\",\n \"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK98___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .\",\n \"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK32___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .\",\n \"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"P54252 represses transcription via chromatin binding , interaction with histone deacetylase 3 , and histone deacetylation . P54252 ( P01008 ) , the disease protein in spinocerebellar ataxia type 3 ( P54252 ) , has been associated with the ubiquitin - proteasome system and transcriptional regulation . Here we report that normal P01008 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase - 2 ( P08253 ) gene promoter and represses transcription by recruitment of the histone deacetylase 3 ( O15379 ) , the nuclear receptor corepressor ( NCoR ) , and deacetylation of histones bound to the promoter . Both normal and expanded P01008 physiologically interacted with O15379 and NCoR in a P54252 cell model and human pons tissue ; however , normal P01008 - containing protein complexes showed increased histone deacetylase activity , whereas expanded P01008 - containing complexes had reduced deacetylase activity . Consistently , histone analyses revealed an increased acetylation of total histone H3 in expanded P01008 - expressing cells and human P54252 pons . Expanded P01008 lost the repressor function and displayed altered DNA / chromatin binding that was not associated with recruitment of O15379 , NCoR , and deacetylation of the promoter , allowing aberrant P08253 transcription via the transcription factor GATA - 2 . For transcriptional repression normal P01008 cooperates with O15379 and requires its intact ubiquitin - interacting motifs ( UIMs ) , whereas aberrant transcriptional activation by expanded P01008 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain . These findings demonstrate that normal P01008 binds target promoter regions and represses transcription of a GATA - 2 - dependent target gene via formation of histone - deacetylating repressor complexes requiring its UIM - associated function . Expanded P01008 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions .\",\n \"Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte / macrophage progenitor lineage commitment towards dendritic cell differentiation through down - regulation of receptor activator of nuclear factor - kappaB and c - Fos . Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models . To address this controversy , we used several modes of T lymphocyte activation in osteoclast differentiation -- mitogen - pulse , anti - CD3 / P10747 stimulation and in vivo and in vitro alloactivation . Osteoclast - like cells were generated from non - adherent immature haematopoietic monocyte / macrophage progenitors in murine bone - marrow in the presence of receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) and monocyte - macrophage colony - stimulating factor ( P09603 ) . All modes of in vivo and in vitro T lymphocyte activation and both P01730 (+) and CD8 (+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell ( DC ) differentiation . Osteoclast - inhibitory effect was associated with T lymphocyte activation and not proliferation , and could be replaced by their culture supernatants . The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis , because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts . Inhibition was associated specifically with increased granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down - regulated Q9Y6Q6 , CD115 , c - Fos and calcitonin receptor expression , and increased differentiation towards CD11c - positive DC . An activated T lymphocyte inhibitory role in osteoclastogenesis , confirmed in vitro and in vivo , mediated through GM - P04141 release , may be used to counteract activated bone resorption mediated by T lymphocyte - derived cytokines in inflammatory and immune disorders . We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis , thereby confirming the functional link between alloreaction and bone metabolism .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"24R , 25 - dihydroxyvitamin D3 promotes the osteoblastic differentiation of human DB05914 . Although 1α , 25 - dihydroxyvitamin D3 [ 1α , 25 ( OH ) 2D3 ] is considered the most biologically active vitamin D3 metabolite , the vitamin D3 prohormone , 25 - hydroxyvitamin D3 [ DB00146 ] , is metabolized into other forms , including 24R , 25 - dihydroxyvitamin D3 [ 24R , 25 ( OH ) 2D3 ] . Herein we show that 24R , 25 ( OH ) 2D3 is fundamental for osteoblastic differentiation of human DB05914 ( hMSCs ) . Our approach involved analyses of cell proliferation , alkaline phosphatase activity , and pro - osteogenic genes ( collagen 1A1 , osteocalcin , vitamin D receptor [ P11473 ] , vitamin D3 - hydroxylating enzymes [ cytochrome P450 hydroxylases : Q6VVX0 , Q02318 , O15528 and Q07973 ] ) and assessment of Ca ( 2 +) mineralization of extracellular matrix . 24R , 25 ( OH ) 2D3 inhibited hMSC proliferation , decreased 1α - hydroxylase ( O15528 ) expression , thereby reducing the ability of hMSCs to convert DB00146 to 1α , 25 ( OH ) 2D3 , and promoted osteoblastic differentiation through increased alkaline phosphatase activity and Ca ( 2 +) mineralization . 24R , 25 ( OH ) 2D3 decreased expression of the 1α , 25 ( OH ) 2D3 receptor , P11473 . 24R , 25 ( OH ) 2D3 but not 1α , 25 ( OH ) 2D3 induced Ca ( 2 +) mineralization dependent on the absence of the glucocorticoid analog , dexamethasone . To elucidate the mechanism ( s ) for dexamethasone - independent 1α , 25 ( OH ) 2D3 inhibition / 24R , 25 ( OH ) 2D3 induction of Ca ( 2 +) mineralization , we demonstrated that 1α , 25 ( OH ) 2D3 increased whereas 24R , 25 ( OH ) 2D3 decreased reactive oxygen species ( ROS ) production . DB00146 also decreased ROS production , potentially by conversion to 24R , 25 ( OH ) 2D3 . Upon inhibition of the vitamin D3 - metabolizing enzymes ( cytochrome P450s ) , DB00146 increased ROS production , potentially due to its known ( low ) affinity for P11473 . We hypothesize that vitamin D3 actions on osteoblastic differentiation involve a regulatory relationship between 24R , 25 ( OH ) 2D3 and 1α , 25 ( OH ) 2D3 . These results implicate 24R , 25 ( OH ) 2D3 as a key player during hMSC maturation and bone development and support the concept that 24R , 25 ( OH ) 2D3 has a bioactive role in the vitamin D3 endocrine system .\",\n \"Vitamin D up - regulates the vitamin D receptor by protecting it from proteasomal degradation in human P01730 + T cells . The active form of vitamin D3 , 1 , 25 ( OH ) 2D3 , has significant immunomodulatory properties and is an important determinant in the differentiation of P01730 + effector T cells . The biological actions of 1 , 25 ( OH ) 2D3 are mediated by the vitamin D receptor ( P11473 ) and are believed to correlate with the P11473 protein expression level in a given cell . The aim of this study was to determine if and how 1 , 25 ( OH ) 2D3 by itself regulates P11473 expression in human P01730 + T cells . We found that activated P01730 + T cells have the capacity to convert the inactive DB00146 to the active 1 , 25 ( OH ) 2D3 that subsequently up - regulates P11473 protein expression approximately 2 - fold . 1 , 25 ( OH ) 2D3 does not increase P11473 mRNA expression but increases the half - life of the P11473 protein in activated P01730 + T cells . Furthermore , 1 , 25 ( OH ) 2D3 induces a significant intracellular redistribution of the P11473 . We show that 1 , 25 ( OH ) 2D3 stabilizes the P11473 by protecting it from proteasomal degradation . Finally , we demonstrate that proteasome inhibition leads to up - regulation of P11473 protein expression and increases 1 , 25 ( OH ) 2D3 - induced gene activation . In conclusion , our study shows that activated P01730 + T cells can produce 1 , 25 ( OH ) 2D3 , and that 1 , 25 ( OH ) 2D3 induces a 2 - fold up - regulation of the P11473 protein expression in activated P01730 + T cells by protecting the P11473 against proteasomal degradation .\",\n \"Overexpression of cytochrome P450 4F2 in mice increases 20 - hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20 - hydroxyeicosatetraenoic acid ( 20 - HETE ) . We previously found that a gain - in - function P78329 variant in a Chinese cohort was associated with elevated urinary 20 - HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen - regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his - tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20 - HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20 - HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20 - HETE levels . Our results show that increased expression of P78329 in mice enhanced 20 - HETE production and elevated blood pressure .\",\n \"Use of fuzzy neural networks in modeling relationships of HPV infection with apoptotic and proliferation markers in potentially malignant oral lesions . To evaluate in oral leukoplakia the relationship between HPV infection and markers of apoptosis ( bcl - 2 , survivin ) and proliferation ( P12004 ) , also conditionally to age , gender , smoking and drinking habits of patients , by means of Fuzzy neural networks ( FNN ) system 21 cases of oral leukopakia , clinically and histologically diagnosed , were examined for HPV DNA presence , bcl - 2 , survivin and P12004 expression . HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR ( nPCR : MY09 - MY11 / P40197 - Q9HCN6 ) , and the HPV genotype determined by direct DNA sequencing . All markers were investigated by means of standardised immunohistochemistry procedure . Data were analysed by chi - square test , crude OR and the 95 % CI ; in blindness , FNN was applied . HPV DNA was found in 8 / 21 OL ( 38 . 1 % ) ; survivin , P12004 , and tobacco smoking were associated in univariate analysis ( p = 0 . 04 ) with HPV DNA status . HPV - 18 was the most frequently detected genotype ( 6 / 8 ) , followed by HPV - 16 ( 2 / 8 ) . FNN revealed that survivin and P12004 , both being expressed in all of OL HPV + ve , were associated with HPV infection . In conclusion , the FNN allowed to hypothesise a model of specific variables associated to HPV infection in OL . The relevance of survivin and P12004 suggest that they may be involved in HPV - mediated deregulation of epithelial maturation and , conversely , that HPV may have a role in the expression level of these two markers . FNN system seems to be an effective tool in the analysis of correlates of OL and HPV infection .\",\n \"Immunocytochemical profile of malignant pleural effusions of small - cell lung cancer . BACKGROUND : Small - cell lung carcinoma ( SCLC ) is a highly malignant tumour of a somewhat distinctive cell type . The aim of this study was to determine the immunocytochemical profile of tumor cells and lymphoid cell in SCLC pleural fluids . METHODS : Nine cases of malignant pleural fluids of SCLC were studied using cell block preparation . In pleural effusions cytologically proven to be malignant in 9 patients with SCLC , the immunocytological features of tumor cells , together with the determination of lymphocytic subsets were documented . RESULTS : In all 9 cases , tumor cells reacted with neuron - specific enolase ( P09104 ) ( 100 % ) , whereas in 6 of 9 cases ( 66 , 66 % ) tumor cell expressed synaptophysin , thyroid transciption factor - 1 ( Q15669 - 1 ) and chromogranin A antigens . Phenotyping of the lymphocytes revealed in the majority of cases an expression of CD3 and P01730 antigens ( 8 and 7 cases , respectively ) in contrast to CD8 and P11836 expression ( 1 and 1 case , respectively ) . CONCLUSIONS : The reactivity pattern of the tumor cells with the markers used in our study is a specific for SCLC . No significant difference in the distribution of lymphocytic subpopulations is observed in correlation with other malignant and no malignant processes involving the pleural cavity .\",\n \"Antagonistic action of novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone analogs on differentiation of human leukemia cells ( HL - 60 ) induced by 1alpha , 25 - dihydroxyvitamin D3 . We examined the effects of two novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone ( 1alpha , 25 - lactone ) analogues on human promyelocytic leukemia cell ( HL - 60 ) differentiation using the evaluation system of the vitamin D nuclear receptor ( P11473 ) / vitamin D - responsive element ( DRE ) - mediated genomic action stimulated by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) and its analogues . We found that the 1alpha , 25 - lactone analogues ( 23S ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9647 ) , and ( 23R ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9648 ) bound much more strongly to the P11473 than the natural ( 23S , 25R ) - DB00136 - 26 , 23 - lactone , but did not induce cell differentiation even at high concentrations ( 10 (- 6 ) M ) . Intriguingly , the differentiation of HL - 60 cells induced by DB00136 was inhibited by either TEI - 9647 or TEI - 9648 but not by the natural lactone . In contrast , retinoic acid or 12 - O - tetradecanoylphorbol - 13 - acetate - induced HL - 60 cell differentiation was not blocked by TEI - 9647 or TEI - 9648 . In separate studies , TEI - 9647 ( 10 (- 7 ) M ) was found to be an effective antagonist of both DB00136 ( 10 (- 8 ) M ) mediated induction of P38936 ( P38936 , CIP1 ) in HL - 60 cells and activation of the luciferase reporter assay in COS - 7 cells transfected with cDNA containing the DRE of the rat DB00146 - 24 - hydroxylase gene and cDNA of the human P11473 . Collectively the results strongly suggest that our novel 1alpha , 25 - lactone analogues , TEI - 9647 and TEI - 9648 , are specific antagonists of 1alpha , 25 ( OH ) 2D3 action , specifically P11473 / DRE - mediated genomic action . As such , they represent the first examples of antagonists , which act on the nuclear P11473 .\",\n \"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .\",\n \"___MASK15___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK15___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK15___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .\",\n \"The role of cubilin gene polymorphisms and their influence on DB00146 and 1 , 25 ( OH ) 2D3 plasma levels in type 1 diabetes patients . BACKGROUND : P98164 and cubilin bind and internalize the DB00146 - DBP complex in the kidney . Once the complex is internalized , DB00146 is released and activated to 1 , 25 ( OH ) 2D3 the ligand for the vitamin D receptor ( P11473 ) . Supporting the important role of cubilin in this process recent findings showed that cubilin deficiency results in decrease of DB00146 and 1 , 25 ( OH ) 2D3 plasma levels . METHODS : Two hundred T1D patients and healthy controls ( n = 200 ) were genotyped for five polymorphisms ( rs3740168 , rs3740165 , rs1801233 , rs1801229 and rs2796835 ) within the cubilin gene . The polymorphisms were analyzed by RFLP or real time PCR . Statistic analyses were performed by using allele - wise and genotype - wise chi2 testing by using BiAS software . A p - value < 0 . 05 was considered as significant . RESULTS : We found that the genotype \\\" AA \\\" of the rs3740165 was more frequent in T1D patients compared to healthy controls ( 26 . 7 % vs . 5 . 1 % , p = 4x10 (- 7 ) ) . Nevertheless no association between the rs3740165 polymorphism and the DB00146 or 1 , 25 ( OH ) 2D3 plasma levels was found . No association with the other studied polymorphisms was observed . CONCLUSION : Thus our findings reveal a novel association of the cubilin rs3740165 polymorphism with type 1 diabetes . Nevertheless how exactly this polymorphism could increase the risk to develop type 1 diabetes is subject for further investigations .\",\n \"DB08816 increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : DB08816 is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \\\" pleiotropic \\\" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . DB08816 and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : DB08816 increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .\",\n \"The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners . Mutations in the tumor suppressor genes Q92574 and P49815 , encoding hamartin and tuberin , respectively , cause the tumor syndrome tuberous sclerosis with similar phenotypes . Until now , over 50 proteins have been demonstrated to interact with hamartin and / or tuberin . Besides tuberin , the proteins Q96N67 , ezrin / radixin / moesin , Q8TDY2 , IKKbeta , Melted , P35240 , Q00994 ( p75NTR ) , P07196 , Plk1 and Q9P0N9 have been found to interact with hamartin . Whereas Plk1 and Q9P0N9 have been demonstrated not to bind to tuberin , for all the other hamartin - interacting proteins the question , whether they can also bind to tuberin , has not been studied . P49815 interacts with 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , AMPK , P62158 , Q9BUF7 / Q8NI35 , cyclin A , cyclins D1 , D2 , D3 , Dsh , ERalpha , Erk , FoxO1 , Q15751 , HPV16 E6 , HSCP - 70 , P0DMV8 , P49137 , Q96PY6 , p27KIP1 , Pam , PC1 , PP2Ac , Q15276 , Rheb , RxRalpha / P11473 and Q15796 / 3 . 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , Dsh , FoxO1 , Q15751 , p27KIP1 and PP2Ac are known not to bind to hamartin . For the other tuberin - interacting proteins this question remains elusive . The proteins axin , Cdk1 , cyclin B1 , O75807 , GSK3 , P42345 and Q15418 have been found to co - immunoprecipitate with both , hamartin and tuberin . The kinases Cdk1 and IKKbeta phosphorylate hamartin , Erk , Akt , P49137 , AMPK and Q15418 phosphorylate tuberin , and GSK3 phosphorylates both , hamartin and tuberin . This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin .\",\n \"___MASK32___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK32___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .\",\n \"Ligand - induced transrepression by P11473 through association of Q9UIG0 with acetylated histones . We have previously shown that the novel DB00171 - dependent chromatin - remodeling complex WINAC is required for the ligand - bound vitamin D receptor ( P11473 ) - mediated transrepression of the DB00146 1alpha - hydroxylase ( 1alpha ( OH ) ase ) gene . However , the molecular basis for P11473 promoter association , which does not involve its binding to specific DNA sequences , remains unclear . To address this issue , we investigated the function of Q9UIG0 in terms of the association between WINAC and chromatin for ligand - induced transrepression by P11473 . Results of in vitro experiments using chromatin templates showed that the association of unliganded P11473 with the promoter required physical interactions between Q9UIG0 and both P11473 and acetylated histones prior to P11473 association with chromatin . The acetylated histone - interacting region of Q9UIG0 was mapped to the bromodomain , and a Q9UIG0 mutant lacking the bromodomain served as a dominant - negative mutant in terms of ligand - induced transrepression of the 1alpha ( OH ) ase gene . Thus , our findings indicate that WINAC associates with chromatin through a physical interaction between the Q9UIG0 bromodomain and acetylated his tones , which appears to be indispensable for P11473 / promoter association for ligand - induced transrepression of 1alpha ( OH ) ase gene expression .\",\n \"P98164 mediates the transport of leptin across the blood - P04141 barrier . Leptin , a peptide hormone secreted by adipose tissue , exhibits a large range of central and peripheral actions . It has been proposed that the participation of leptin in diseases such as obesity is due to , at least in part , its impaired transport across the blood - brain barrier ( BBB ) . Since , the mechanisms by which brain takes up leptin remain unclear , we set out to study how leptin may cross the BBB . We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans . We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium . Indeed , the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer ' s disease was correlated with poor entry of leptin into the brain . Moreover , amyloid beta ( Abeta ) deposits of choroid plexus could be disturbing megalin function . The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain .\",\n \"Molecular cloning and characterization of O75197 , a novel P01130 family protein with mitogenic activity . We report molecular cloning and initial functional characterization of a novel member of the low density lipoprotein receptor ( P01130 ) gene family . The cDNA was isolated from a human osteoblast cDNA library and encoded a 1 , 615 amino acids protein designated as O75197 . It has , in the extracellular region , a cluster of three P01130 ligand binding repeats at a juxtamembrane position and four P01133 precursor homology domains separated by YWTD spacer repeats . The entire ectodomain shares the same modular organization with the middle portion of the extracellular regions of two P01130 family members , P01130 - related protein ( Q14764 ) , and P98164 / megalin . O75197 mRNA was expressed in most of the adult and fetal tissues examined . The highest expression level was seen in aorta . In human osteosarcoma cells examined , O75197 mRNA was highly enriched in TE85 cells , moderately expressed in MG63 cells and primary human osteoblasts , and undetectable in SaOS - 2 cells . NIH 3T3 cells transfected with either full length O75197 or its ectodomain showed significantly increased proliferation , whereas transfection of intracellular domain had no proliferative effect . We predict that O75197 is a multi - functional protein with potential mitogenic activity .\",\n \"Regulatory role of promoter and 3 ' UTR variants of vitamin D receptor gene on cytokine response in pulmonary tuberculosis . Vitamin D receptor ( P11473 ) gene variants are shown to regulate immune response in tuberculosis . We studied the influence of P11473 promoter ( Cdx - 2 and A1012G ) , 3 ' untranslated region ( Apa I , Bsm I , and Taq I ) and start codon ( Fok I ) polymorphisms on 1 , 25 ( OH )( 2 ) D ( 3 )- modulated IL - 12p40 , P01579 , P22301 , and P05113 response to live Mycobacterium tuberculosis and its culture filtrate antigen ( O75347 ) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients . In peripheral blood mononuclear cell cultures with O75347 and 1 , 25 ( OH )( 2 ) D ( 3 ) , IL - 12p40 , and P01579 levels were significantly decreased ( p < 0 . 05 ) and P22301 levels were significantly increased ( p < 0 . 05 ) in patients with GG genotype . The extended genotype bbaaTT ( baT haplotype ) was associated with decreased IL - 12p40 and P01579 levels and significantly increased P22301 levels ( p < 0 . 05 ) . The Cdx - 2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased P22301 response , which suggests that 1 , 25 ( OH )( 2 ) D ( 3 ) probably through the P11473 polymorphic variants augments the anti - inflammatory response at the site of M . tuberculosis infection .\",\n \"Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK1___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .\",\n \"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK15___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .\",\n \"Integration of hormone signaling in the regulation of human DB00146 24 - hydroxylase transcription . The current study sought to define the molecular mechanisms involved in the cross talk between 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] and activators of PKC in the regulation of 25 ( OH ) D ( 3 ) 24 - hydroxlyase [ 24 ( OH ) ase ] . Transfection of the h24 ( OH ) ase promoter construct [ - 5 , 500 /- 22 luciferase ; vitamin D response elements at - 294 /- 274 and - 174 /- 151 ; AP - 1 site at - 1 , 167 /- 1 , 160 ] in vitamin D receptor ( P11473 ) - transfected COS - 7 cells resulted in strong activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . In these cells , cotreatment with the PKC activator TPA and 1 , 25 ( OH )( 2 ) D ( 3 ) yielded a 27 - fold increase in luciferase activity , which was 2 - to 3 - fold greater than activation obtained with 1 , 25 ( OH )( 2 ) D ( 3 ) alone ( P < 0 . 05 ) . Similar results were observed using LLCPK - 1 kidney cells , suggesting that the previously observed enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- induced renal 24 ( OH ) ase mRNA and activity by PKC activation occurs at the level of transcription . The functional cooperation between PKC activation and P11473 was not found to be mediated by the AP - 1 site in the h24 ( OH ) ase promoter or by enhanced binding of GRIP or Q15648 to P11473 and was also not due to PKC - mediated phosphorylation of P11473 on DB00133 ( 51 ) . Our study demonstrates that , in LLCPK - 1 kidney cells , the PKC enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- stimulated transcription may be due , in part , to an increase in P11473 concentration . In addition , inhibitors of the MAPK pathway were found to decrease the TPA enhancement ( P < 0 . 05 ) . Because activation of MAPK has been reported to result in the phosphorylation of Q15788 and in functional cooperation between Q15788 and CREB binding protein , we propose that the potentiation of P11473 - mediated transcription may also be mediated through changes in the phosphorylation of specific P11473 coregulators .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Identification of novel human Cdt1 - binding proteins by a proteomics approach : proteolytic regulation by P25054 / CCdh1 . In mammalian cells , Cdt1 activity is strictly controlled by multiple independent mechanisms , implying that it is central to the regulation of DNA replication during the cell cycle . In fact , unscheduled Cdt1 hyperfunction results in rereplication and / or chromosomal damage . Thus , it is important to understand its function and regulations precisely . We sought to comprehensively identify human Cdt1 - binding proteins by a combination of Cdt1 affinity chromatography and liquid chromatography and tandem mass spectrometry analysis . Through this approach , we could newly identify 11 proteins , including subunits of anaphase - promoting complex / cyclosome ( P25054 / C ) , O60264 and Q9UIG0 , topoisomerase I and IIalpha , Q9BQ67 / Q9BQ67 , nucleophosmin / nucleoplasmin , and importins . In vivo interactions of Cdt1 with P25054 / C ( Cdh1 ) , O60264 , topoisomerase I and IIalpha , and Q9BQ67 / Q9BQ67 were confirmed by coimmunoprecipitation assays . A further focus on P25054 / C ( Cdh1 ) indicated that this ubiquitin ligase controls the levels of Cdt1 during the cell cycle via three destruction boxes in the Cdt1 N - terminus . Notably , elimination of these destruction boxes resulted in induction of strong rereplication and chromosomal damage . Thus , in addition to P21583 ( Skp2 ) and cullin4 - based ubiquitin ligases , P25054 / C ( Cdh1 ) is a third ubiquitin ligase that plays a crucial role in proteolytic regulation of Cdt1 in mammalian cells .\",\n \"O60603 signaling protects mice from tumor development in a mouse model of colitis - induced cancer . Inflammatory bowel disease ( Q9UKU7 ) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer . The etiology of Q9UKU7 is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host . Toll - like receptor ( TLR ) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis , innate immunity and the enhancement of intestinal epithelial cell ( IEC ) integrity . However , the role of O60603 in the development of colorectal cancer has not been studied . We utilized the AOM - DSS model for colitis - associated colorectal cancer ( CAC ) in wild type ( WT ) and O60603 (-/-) mice . Colons harvested from WT and O60603 (-/-) mice were used for histopathology , immunohistochemistry , immunofluorescence and cytokine analysis . Mice deficient in O60603 developed significantly more and larger colorectal tumors than their WT controls . We provide evidence that colonic epithelium of O60603 (-/-) mice have altered immune responses and dysregulated proliferation under steady - state conditions and during colitis , which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth . At the earliest time - points assessed , O60603 (-/-) colons exhibited a significant increase in aberrant crypt foci ( Q9NQ94 ) , resulting in tumors that developed earlier and grew larger . In addition , the intestinal microenvironment revealed significantly higher levels of P05231 and Q16552 concomitant with increased phospho - P40763 within Q9NQ94 . These observations indicate that in colitis , O60603 plays a protective role against the development of CAC .\",\n \"Activation of the interleukin - 6 / Janus kinase / P40763 pathway in pleomorphic adenoma of the parotid gland . The interleukin - 6 ( P05231 ) / Janus kinase ( JAK ) / signal transducer and activator of transcription 3 ( P40763 ) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors , e . g . , of pleomorphic adenoma ( PA ) . In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs ( miRNAs ) regulated by this pathway in isolated duct - and myoepithelial cells in PA . 46 PAs were immunostained and 10 of these were used for in situ hybridization ( ISH ) . Six frozen specimens were analyzed using reverse transcription - polymerase chain reaction ( RT - PCR ) . Using immunohistochemistry , P05231 , P23458 , O60674 and P40763 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue . Using RT - PCR cyclin D1 , fibroblast growth factor 2 , and P38936 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland . ISH showed significant overexpression of miR - 181b in PA , while miR - 21 was undetectable in PA and normal tissue . Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs . Our findings brings us one step closer to targeted treatment of this tumor entity , although in vitro studies are warranted to confirm this .\",\n \"Structure - activity relationships in Q9NYK1 agonistic 1H - imidazo [ 4 , 5 - c ] pyridines . Engagement of Q9NYK1 in plasmacytoid dendritic cells leads to the induction of IFN - α / β which plays essential functions in the control of adaptive immunity . We had previously examined structure - activity relationships ( SAR ) in Q9NYK1 / 8 - agonistic imidazoquinolines with a focus on substituents at the N ( 1 ) , C ( 2 ) , N ( 3 ) and N ( 4 ) positions , and we now report SAR on 1H - imidazo [ 4 , 5 - c ] pyridines . 1 - Benzyl - 2 - butyl - 1H - imidazo [ 4 , 5 - c ] pyridin - 4 - amine was found to be a pure Q9NYK1 - agonist with negligible activity on Q9NR97 . Increase in potency was observed in N ( 6 )- substituted analogues , especially in those compounds with electron - rich substituents . Direct aryl - aryl connections at P13671 abrogated activity , but Q9NYK1 agonism was reinstated in 6 - benzyl and 6 - phenethyl analogues . Consistent with the pure Q9NYK1 - agonistic behavior , prominent IFN - α induction in human PBMCs was observed with minimal proinflammatory cytokine induction . A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine . Distinct differences in N ( 6 )- substituted analogues were observed with respect to IFN - α induction in human PBMCs on the one hand , and Q07108 upregulation in lymphocytic subsets , on the other .\",\n \"Expression of vitamin D receptor ( P11473 ) , cyclooxygenase - 2 ( P35354 ) and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) in benign and malignant ovarian tissue and DB00146 ( 25 ( OH2 ) D3 ) and prostaglandin E2 ( DB00917 ) serum level in ovarian cancer patients . Ovarian carcinomas are associated with increased inflammation which is based upon an up - regulation of inducible cyclooxygenase - 2 ( P35354 ) . Moreover , based on our previous published data , the extra - renal vitamin D metabolism seems to be dysregulated in comparison to healthy tissue . In order to gain further insight into the prostaglandin ( PG ) - and vitamin D - metabolism in ovarian carcinomas , the study aimed to evaluate the expression of the PG metabolising enzymes P35354 and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) compared to the vitamin D receptor ( P11473 ) in benign and malignant ovarian tissues . Additionally , we determined the DB00146 ( 25 ( OH2 ) D3 ) serum levels . Expression of P11473 , P35354 and P15428 was determined by Western blot analysis . Serum levels of 25 ( OH2 ) D3 and DB00917 were measured by chemiluminescence - based and colorimetric immunoassay . We detected significantly higher expressions of the PG metabolising enzymes P15428 and P35354 in malignant tissue and DB00917 serum levels were 2 - fold higher in tumour patients . Furthermore , we found an inverse correlation to the P11473 - expression which was 62 . 1 % lower in malignant tissues compared to that in benign tissues . Surprisingly , we could not detect any differences between the 25 ( OH2 ) D3 serum levels in either group ( n = 20 ) . These data suggest a correlation between PG - and vitamin D - metabolism in ovarian carcinomas .\",\n \"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK54___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .\",\n \"Membrane receptors for vitamin D metabolites . Membrane - initiated signaling by steroid hormones is now widely accepted . Current debate is centered upon which protein moieties act as membrane - associated receptors . In this review , we consider evidence for the classical vitamin D receptor ( P11473 ) in this role , as well as the more recently identified 1 , 25D3 - MARRS ( membrane - associated , rapid response steroid binding ) receptor , also known as P30101 / GRp58 . The structure of the 1 , 25D3 - MARRS receptor is discussed , with emphasis on two thioredoxin domains that promote dimerization and ligand binding . We then summarize recent studies on a 24 , 25 ( OH ) 2D3 binding protein -- catalase -- and how ligand - induced decreases in enzymatic activity produce increased reactive oxygen species that target both the 1 , 25D3 - MARRS receptor -- but not the P11473 -- and the protein kinase C signaling pathway . Finally , we briefly discuss the available literature suggesting that the metabolite DB00146 may also be biologically active .\",\n \"Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .\",\n \"The use of the VerifyNow Q9H244 point - of - care device to monitor platelet function across a range of Q9H244 inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point - of - care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 ( VN - Q9H244 ) POC device with light transmission aggregometry ( P01374 ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 and VN - Q9H244 at baseline and after dosing . ___MASK98___ 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device - reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 showed a very similar pattern to that found with VN - Q9H244 measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 appeared to be narrower than that of P01374 . With two different thienopyridines , the VN - Q9H244 device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .\",\n \"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .\",\n \"Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .\",\n \"Vitamin D receptor - mediated suppression of RelB in antigen presenting cells : a paradigm for ligand - augmented negative transcriptional regulation . The immunological effects of vitamin D receptor ( P11473 ) ligands include inhibition of dendritic cell ( DC ) maturation , suppression of T - helper type 1 ( Th1 ) T - cell responses and facilitation of antigen - specific immune tolerance in vivo . While studying the molecular profile of DCs cultured in the presence of 1alpha , DB00146 or synthetic D3 analogs we observed that expression of the NF - kappaB family member RelB , which plays an essential role in DC differentiation and maturation , is selectively suppressed by P11473 ligands . Further in vitro and in vivo studies of P11473 - mediated RelB suppression indicated that the mechanism for this effect involves direct binding of P11473 / RXR alpha to a defined region of the relB promoter and assembly of a negative regulatory complex containing O15379 , Q13547 , Q9Y618 and , most likely , other factors . Interestingly , promoter engagement by P11473 and O15379 , but not the other identified components , is enhanced by addition of a P11473 ligand and inhibited by a pro - maturational stimulus ( LPS ) that results in RelB upregulation . Promoter assays in a panel of cell lines suggest that the P11473 ligand - dependent component of relB suppression may occur selectively in antigen presenting cells . Cell type - specific , ligand - enhanced negative transcriptional regulation represents a potentially novel paradigm for P11473 - controlled genes . In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process .\",\n \"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK38___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK38___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .\",\n \"Characterization of background anti - trinitrophenyl plaque - forming cells observed in several strains of mice . Normal mice have a large number of background anti - trinitrophenyl ( TNP ) antibody - forming cells ( AFC ) in their spleens ( about 40 - 50 anti - TNP P27918 / 10 ( 6 ) cells ) . We investigated this among several mouse strains , i . e . , C57BL / 6 , C3H / He , Balb / c , ddd , and ICR mice , and found that all strains had a similar number of anti - TNP P27918 ( plaque - forming cells ) . Developmental aspects of background anti - TNP P27918 in the ontogenic process were also investigated . The number of anti - TNP P27918 increased logari thmically during the first few days of age , reached a peak on the 13th day and attained a constant value within 30 days . Neonatal thymectomy did not decrease the number of background anti - TNP P27918 but such treatment decreased the anti - TNP P27918 response to TNP - HRBC ( horse red blood cells ) immunization . Germ - free ICR mice had a number of background anti - TNP P27918 similar to that of conventional ICR mice . Avidity of background anti - TNP P27918 was compared among mice of several ages and it was shown that there were no differences among them . These results suggest that the occurrence of these background anti - TNP P27918 is not elicited by the immune response but by the natural maturation of precursors of Q9NQ94 without antigenic stimulation .\",\n \"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK98___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK98___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .\",\n \"Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK47___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK47___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK47___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .\",\n \"Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid - mediated responses in the mammary glands of cycling rats . Prenatal exposure to Q03001 disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after Q03001 exposure . Our aim was to assess the effect of prenatal Q03001 exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats . Pregnant Wistar rats were exposed to either 25 or 250 g / kg / day ( 25 and 250 Q03001 , respectively ) or to vehicle . Female offspring were autopsied on postnatal day ( P01160 ) 50 or 110 . Ovarian steroid serum levels , the expression of steroid receptors and their co - regulators Q9Y6Q9 and Q9Y618 in the mammary gland , and angiogenesis were evaluated . At P01160 50 , all Q03001 - treated animals had lower serum levels of progesterone , while estradiol levels remained unchanged . The higher dose of Q03001 increased mammary ERα and decreased Q9Y6Q9 expression at P01160 50 and P01160 110 . Q9Y618 protein levels were similar among groups at P01160 50 , whereas at P01160 110 , animals exposed to 250 Q03001 showed a lower Q9Y618 expression . Interestingly , in the control and 25 Q03001 groups , Q9Y618 increased from P01160 50 to P01160 110 . At P01160 50 , an increased vascular area associated with higher P15692 expression was observed in the 250 Q03001 - treated rats . At P01160 110 , the vascular area was still increased , but P15692 expression was similar to that of control rats . The present results demonstrate that prenatal exposure to Q03001 alters the endocrine environment of the mammary gland and its angiogenic process . Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre - neoplastic lesions found later in life . This article is part of a Special Issue entitled ' Endocrine disruptors ' .\",\n \"Comparison of human B cell activation by Q9NYK1 and Q9NR96 agonists . BACKGROUND : Human B cells and plasmacytoid dendritic cells ( pDC ) are the only cells known to express both Q9NYK1 and Q9NR96 . Plasmacytoid dendritic cells are the primary IFN - alpha producing cells in response to Q9NYK1 and Q9NR96 agonists . The direct effects of Q9NYK1 stimulation on human B cells is less understood . The objective of this study was to compare the effects of Q9NYK1 and Q9NR96 stimulation on human B cell function . RESULTS : Gene expression and protein production of cytokines , chemokines , various B cell activation markers , and immunoglobulins were evaluated . Purified human P15391 + B cells ( 99 . 9 % , containing both naïve and memory populations ) from peripheral blood were stimulated with a Q9NYK1 - selective agonist ( 852A ) , Q9NYK1 / 8 agonist ( 3M - 003 ) , or Q9NR96 selective agonist CpG ODN ( CpG2006 ) . Q9NYK1 and Q9NR96 agonists similarly modulated the expression of cytokine and chemokine genes ( P05231 , MIP1 alpha , MIP1 beta , P01375 alpha and P01374 ) , co - stimulatory molecules ( P33681 , P25942 and P19256 ) , Fc receptors ( CD23 , CD32 ) , anti - apoptotic genes ( Q07817 ) , certain transcription factors ( MYC , Q9UL49 ) , and genes critical for B cell proliferation and differentiation ( P21854 , Q9HBE5 ) . Both agonists also induced protein expression of the above cytokines and chemokines . Additionally , Q9NYK1 and Q9NR96 agonists induced the production of IgM and IgG . A Q9NR97 - selective agonist was comparatively ineffective at stimulating purified human B cells . CONCLUSION : These results demonstrate that despite their molecular differences , the Q9NYK1 and Q9NR96 agonists induce similar genes and proteins in purified human B cells .\",\n \"Q9NR97 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1 . Toll - like receptors ( TLR ) are important in recognizing microbial pathogens and triggering host innate immune responses , including autophagy , and in the mediation of immune activation during human immunodeficiency virus type - 1 ( HIV ) infection . We report here that Q9NR97 activation in human macrophages induces the expression of the human cathelicidin microbial peptide ( CAMP ) , the vitamin D receptor ( P11473 ) and cytochrome P450 , family 27 , subfamily B , polypeptide 1 ( O15528 ) , which 1α - hydroxylates the inactive form of vitamin D , DB00146 , into its biologically active metabolite . Moreover , we demonstrate using RNA interference , chemical inhibitors and vitamin D deficient media that Q9NR97 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism . These data support an important role for vitamin D in the control of HIV infection , and provide a biological explanation for the benefits of vitamin D . These findings also provide new insights into potential novel targets to prevent and treat HIV infection .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK93___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"DB00146 attenuates experimental periodontitis through downregulation of O00206 and P23458 / P40763 signaling in diabetic mice . Vitamin D has been known to be closely associated with diabetes and periodontitis while the underlying mechanism has yet to be clarified . The present study aimed to discover the effect of 25 - hydroxyvitamin D3 ( 25 - OHD3 ) on glycemic control and periodontal health in mice with periodontitis superimposed on experimental diabetes ( known as diabetic periodontitis ) . We showed that 25 - OHD3 intraperitoneal injection attenuated diabetic periodontitis by reducing serum fasting blood glucose , glycosylated hemoglobin and P01375 - α levels , which led to decreased alveolar bone loss . Immunohistochemical staining and western blot analysis of gingival epithelia revealed that vitamin D receptor ( P11473 ) expression was enhanced upon 25 - OHD3 treatment , while toll - like receptor 4 ( O00206 ) expression was reduced . The expressions of Janus family kinase ( JAK ) 1 and signal transducer and activator of transcription ( P35610 ) 3 as well as their phosphorylation were inhibited in gingival epithelia of diabetic periodontitis mice , whereas the expression and phosphorylation of P42224 remained unchanged . These results suggest that 25 - OHD3 could improve diabetic periodontitis through downregulation of O00206 and P23458 / P40763 signaling in the gingival epithelium . Our study extends the previous findings on the regulation of diabetes with periodontitis , and may also provide a potential therapy for the patients with this disease .\",\n \"Tumor progression in the LPB - Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status . Previous studies have suggested that 1 , 25 dihydroxyvitamin D ( 3 ) ( 1 , 25 ( OH ) 2D3 ) induces cell cycle arrest and / or apoptosis in prostate cancer cells in vitro , suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent . Most epidemiological data however shows a weak link between serum DB00146 and risk of prostate cancer . To explore this dichotomy we have compared tumor progression in the LPB - Tag model of prostate in P11473 knock out ( VDRKO ) and wild type ( VDRWT ) mice . On the C57BL / 6 background LPB - Tag tumors progress significantly more rapidly in the VDRKO mice . VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors . In mice supplemented with testosterone to restore the serum levels to the normal range , these differences in tumor progression , and proliferation are abrogated , suggesting that there is considerable cross - talk between the androgen receptor ( AR ) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR , P12004 , cdk2 survivin and P12314 and 2 genes . These alterations may explain the differences between the in vitro data and the epidemiological studies .\",\n \"Tumor Necrosis Factor alpha ( TNFalpha ) regulates P25942 expression through Q8N9N5 phosphorylation . P25942 plays an important role in mediating inflammatory response and is mainly induced by JAK / P35610 phosphorylation cascade . TNFalpha is the key cytokine that activates P25942 during inflammation and tumorigenesis . We have earlier shown that Q8N9N5 can repress the transcription of P12004 D1 promoter by forming a Q13547 dependent repressor complex . In this study , we show that Q8N9N5 regulates the transcription of NF - kappaB target gene P25942 . Q8N9N5 recruits Q13547 and forms a repressor complex on P25942 promoter and keeps its basal transcription in check . Further , we show that TNFalpha stimulation induces Q8N9N5 phosphorylation at DB00133 - 347 and promotes its cytoplasmic translocation , thus releasing its negative effect . Concomitantly , TNFalpha induced phosphorylation of P42224 at DB00135 - 701 by P23458 facilitates its nuclear translocation and activation of P25942 through p300 recruitment and core Histone - 3 acetylation . Thus , TNFalpha mediated regulation of P25942 expression occurs by dual phosphorylation of Q8N9N5 and P42224 .\",\n \"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK86___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK86___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK86___ .\",\n \"Plasma membrane rafts and chaperones in cytokine / P35610 signaling . We and others have recently obtained data suggesting that cytokine - P35610 signaling in many different cell - types is a chaperoned pathway initiated at the level of specialized plasma membrane microdomains called \\\" rafts \\\" ( the \\\" raft - P35610 signaling hypothesis \\\" ) . These findings are of broad significance in that all cytokines and growth factors initiate signaling in target cells by interacting with respective cell - surface receptors . The new data suggest that raft microdomains represent the units of function at the cell - surface through which ligand - stimulated P35610 signaling is initiated . Moreover , recent evidence shows the involvement of chaperone proteins in regulating the P35610 signaling pathway . These chaperones include the human homolog of the tumorous imaginal disc 1 protein ( hTid1 ) which associates with O60674 ( O60674 ) at the level of the plasma membrane , heat shock protein 90 ( HSP90 ) which associates with P40763 and P42224 proteins in caveolin - 1 - containing raft and cytoplasmic complexes , and glucose regulated protein 58 ( P30101 / ER - 60 / P30101 ) , a thiol dependent protein - disulfide isomerase , found in association with P40763 \\\" statosome \\\" complexes in the cytosol and in the raft fraction . We suggest a function of the HSP90 chaperone system in preserving P05231 / P40763 signaling in liver cells in the context of fever . The identification and function of protein partners associated with specific P35610 species in rafts and in cytosolic complexes , and in the efficient departure of cytokine - activated STATs from the cytosolic face of rafts towards the cell nucleus are now areas of active investigation .\",\n \"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .\",\n \"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .\",\n \"P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .\",\n \"___MASK86___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK86___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK86___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK86___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .\",\n \"Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK93___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .\",\n \"Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case - controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . ___MASK47___ , the addictive component of cigarettes , accelerates cell proliferation through nicotinic acetylcholine receptors ( nAChR ) . In this study , we show that human BACs produce acetylcholine ( ACh ) and contain several cholinergic factors including acetylcholinesterase ( P22303 ) , choline acetyltransferase ( P28329 ) , choline transporter 1 ( Q9GZV3 , Q9GZV3 ) , vesicular acetylcholine transporter ( Q16572 , Q16572 ) , and nACh receptors ( AChRs , CHRNAs ) . ___MASK47___ increased the production of ACh in human BACs , and ACh acts as a growth factor for these cells . ___MASK47___ - induced ACh production was mediated by α7 - , α3β2 - , and β3 - nAChRs , P28329 and Q16572 pathways . We observed that nicotine upregulated P28329 and Q16572 . Therefore , we conjectured that Q16572 antagonists , such as vesamicol , may suppress the growth of human BACs . Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models . Vesamicol did not have any effect on P01133 or insulin - like growth factor - II - induced growth of human BACs . siRNA - mediated attenuation of Q16572 reversed the apoptotic activity of vesamicol . We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol . Taken together , our results suggested that disruption of nicotine - induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy .\",\n \"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .\",\n \"Increased vitamin D - driven signalling and expression of the vitamin D receptor , P35548 , and O14788 in tooth resorption in cats . Tooth resorption occurs in 20 - 75 % of cats ( Felis catus ) . The aetiology is not known , but vitamin D is suggested to be involved . Vitamin D acts through a nuclear receptor ( P11473 ) and increases the expression of receptor activator of nuclear factor - kappaB ligand ( rankl ) and muscle segment homeobox 2 ( msx2 ) genes . Mice lacking the muscle segment homeobox 2 ( msx2 ) gene show decreased levels of rankl , suggesting an interaction among P11473 , P35548 , and O14788 . Here , we investigated the expression of P11473 , P35548 , and O14788 proteins , and the activity of the P11473 - mediated signalling pathway ( using the quantitative polymerase chain reaction on P11473 target genes ) , in tooth resorption , and measured the serum levels of vitamin D metabolites in cats . Tooth resorption was categorized into either resorptive or reparative stages . In the resorptive stage , odontoclasts expressed P35548 and O14788 ( 100 % and 88 % , respectively ) and fibroblasts expressed P11473 and P35548 ( both at 100 % ) , whereas fibroblasts expressed O14788 in only 29 % of the sites analysed . In the reparative stage , cementoblasts expressed P11473 , P35548 , and O14788 , whereas fibroblasts expressed P11473 and P35548 , but not O14788 . The vitamin D status did not differ between the groups , based on the serum levels of DB00146 . However , increased expression of P11473 protein , and the relative gene expression levels of 1alpha - hydroxylase and the P11473 - target gene , 24 - hydroxylase , indicated the involvement of an active vitamin D signalling in the pathophysiology of tooth resorption in cats .\",\n \"Expression of vitamin D receptor and 25 - hydroxyvitamin D3 - 1 { alpha }- hydroxylase in normal and malignant human colon . Considerable evidence exists to support the use of vitamin D to prevent and / or treat colorectal cancer . However , the routine use of bioactive vitamin D , 1 , 25 - dihydroxyvitamin D3 , is limited by the side effect of toxic hypercalcemia . Recent studies , however , suggest that colonic epithelial cells express 25 - hydroxyvitamin D3 - 1alpha - hydroxylase , an enzyme that converts nontoxic pro - vitamin D , DB00146 [ DB00146 ] , to its bioactive form . Yet , nothing is known as to the cellular expression of 1alpha - hydroxylase and the vitamin D receptor ( P11473 ) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci ( Q9NQ94 ) and polyps [ addressing the possibility of using nontoxic DB00146 for chemoprevention ] , nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [ relevant to using DB00146 for chemotherapy ] . In this study , we show that 1alpha - hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs , polyps , and colorectal cancer irrespective of tumor cell differentiation . In contrast , P11473 levels were low in normal colonic epithelial cells ; were increased in ACFs , polyps , and well - differentiated tumor cells ; and then declined as a function of tumor cell de - differentiation . Both 1alpha - hydroxylase and P11473 levels were negligible in tumor cells metastasizing to regional lymph nodes . Overall , these data support using DB00146 for colorectal cancer chemoprevention but suggest that pro - vitamin D is less likely to be useful for colorectal cancer chemotherapy .\"\n]"},"candidates":{"kind":"list like","value":["___MASK15___","___MASK1___","___MASK32___","___MASK38___","___MASK47___","___MASK54___","___MASK86___","___MASK93___","___MASK98___"],"string":"[\n \"___MASK15___\",\n \"___MASK1___\",\n \"___MASK32___\",\n \"___MASK38___\",\n \"___MASK47___\",\n \"___MASK54___\",\n \"___MASK86___\",\n \"___MASK93___\",\n \"___MASK98___\"\n]"},"answer":{"kind":"string","value":"___MASK93___"},"id":{"kind":"string","value":"MH_train_396"}}},{"rowIdx":397,"cells":{"query":{"kind":"string","value":"interacts_with DB00120?"},"supports":{"kind":"list like","value":["Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .","HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .","Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK38___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .","Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .","P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK61___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .","Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK89___ and Tissue P00747 Activator in Occluded Arteries .","Differential radiosensitisation by ZD1839 ( ___MASK34___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK34___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .","Novel roles of Akt and P42345 in suppressing TGF - beta / P36897 - mediated P84022 activation . P01308 - like growth factor - I inhibits transforming growth factor - beta ( TGF - beta ) signaling by blocking activation of P84022 ( S3 ) , via a phosphatidylinositol 3 - kinase ( PI3K ) / Akt - dependent pathway . Here we provide the first report that the kinase activity of Akt is necessary for its ability to suppress many TGF - beta responses , including S3 activation and induction of apoptosis . Wild - type and myristoylated Akts ( Akt ( WT ) and Akt ( Myr ) ) suppress TGF - beta - induced phospho - activation of S3 but not Q15796 ( S2 ) , whereas kinase - dead Akt1 ( Akt1K179M ) or dominant - negative PI3K enhances TGF - beta - induced phospho - activation of both S2 and S3 . Using siRNA , rapamycin ( Rap ) , and adenoviral expression for P62942 - resistant and constitutively active P36897 ( P36897 ) , we demonstrate that mammalian target of Rap ( P42345 ) mediates Akt1 suppression of phospho - activation of S3 . These and further data on Akt1 - S3 binding do not support a recently proposed model that Akt blocks S3 activation through physical interaction and sequestration of S3 from TGF - beta receptors . We propose a novel model whereby Akt suppresses activation of S3 in an Akt kinase - dependent manner through P42345 , a likely route for loss of tumor suppression by TGF - beta in cancers .","P01308 - like growth factor - 1 receptor and ligand targeting in head and neck squamous cell carcinoma . DB01277 receptor ( IGF - 1R ) signaling is associated with increased tumorigenesis of epithelial cancers . In light of recent epidemiological studies correlating high circulating levels of DB01277 with increased risk of second primary tumors ( SPTs ) of the head and neck , we examined IGF system and epidermal growth factor receptor ( P00533 ) expression in human head and neck squamous cell carcinoma ( HNSCC ) matched pairs and a cross - section of HNSCC cell lines . Employing the latter , we demonstrated that DB01277 stimulated S - phase transition in a PI 3 - K / Akt and Erk - dependent manner in 5 of 8 cell lines , with Erk activation being dependent upon P00533 kinase activity . DB01277 stimulated thymidine incorporation was inhibited by treatment with P17936 , the IGF - 1R tyrosine kinase inhibitor DB00238 - AEW541 , or the P00533 tyrosine kinase inhibitor AG1478 . Combining P17936 with DB00238 - AEW541 or AG1478 abrogated DB01277 responses at 10 - fold lower doses than either compound alone . These results demonstrate the potential for co - targeting the IGF system and P00533 in HNSCC .","Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK51___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK51___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .","Role of - 675 4G / 5G in the plasminogen activator inhibitor - 1 gene and - 308G / A tumor necrosis factor - α gene polymorphisms in obese Argentinean patients . AIM : P00747 activator inhibitor - 1 ( P05121 ) and tumor necrosis factor - α ( P01375 - α ) are increased in the circulation of obese persons . Because a direct link between P05121 and P01375 - α in obesity has been observed , they are candidate genes for the development of obesity . We sought to evaluate the relation between the genotypic and allelic frequencies of the - 675 4G / 5G P05121 and - 308 G / A P01375 - α polymorphisms and their association with the risk for obesity in an Argentinean population . METHODS : A group of 110 consecutive obese persons and a group of 111 lean controls were recruited . Polymerase chain reaction was used to determine the frequency of P05121 and P01375 - α polymorphisms ; serum fasting glucose , insulin , and lipid levels were measured by standard methods . P01308 sensitivity was evaluated by using homeostasis model assessment . RESULTS : The - 308 P01375 - α and - 675 4G / 5G P05121 genotype distribution did not significantly differ between the groups ( p = 0 . 544 and p = 0 . 327 , respectively ) . Homeostasis model assessment was the only positive independent determinant of body mass index ( R ( 2 )= 0 . 493 ; p < 0 . 001 ) . CONCLUSION : The - 675 4G / 5G P05121 and the - 308 P01375 - α polymorphism variants tested in this study , individually or combined , were not associated with obesity in an Argentinean population .","Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .","[ ___MASK98___ : A new drug of B - cell malignancies ] . ___MASK98___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK98___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK98___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .","Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK45___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .","P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK3___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .","Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .","Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .","P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .","Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux ."],"string":"[\n \"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .\",\n \"HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .\",\n \"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK38___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .\",\n \"Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .\",\n \"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK61___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .\",\n \"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK89___ and Tissue P00747 Activator in Occluded Arteries .\",\n \"Differential radiosensitisation by ZD1839 ( ___MASK34___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK34___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .\",\n \"Novel roles of Akt and P42345 in suppressing TGF - beta / P36897 - mediated P84022 activation . P01308 - like growth factor - I inhibits transforming growth factor - beta ( TGF - beta ) signaling by blocking activation of P84022 ( S3 ) , via a phosphatidylinositol 3 - kinase ( PI3K ) / Akt - dependent pathway . Here we provide the first report that the kinase activity of Akt is necessary for its ability to suppress many TGF - beta responses , including S3 activation and induction of apoptosis . Wild - type and myristoylated Akts ( Akt ( WT ) and Akt ( Myr ) ) suppress TGF - beta - induced phospho - activation of S3 but not Q15796 ( S2 ) , whereas kinase - dead Akt1 ( Akt1K179M ) or dominant - negative PI3K enhances TGF - beta - induced phospho - activation of both S2 and S3 . Using siRNA , rapamycin ( Rap ) , and adenoviral expression for P62942 - resistant and constitutively active P36897 ( P36897 ) , we demonstrate that mammalian target of Rap ( P42345 ) mediates Akt1 suppression of phospho - activation of S3 . These and further data on Akt1 - S3 binding do not support a recently proposed model that Akt blocks S3 activation through physical interaction and sequestration of S3 from TGF - beta receptors . We propose a novel model whereby Akt suppresses activation of S3 in an Akt kinase - dependent manner through P42345 , a likely route for loss of tumor suppression by TGF - beta in cancers .\",\n \"P01308 - like growth factor - 1 receptor and ligand targeting in head and neck squamous cell carcinoma . DB01277 receptor ( IGF - 1R ) signaling is associated with increased tumorigenesis of epithelial cancers . In light of recent epidemiological studies correlating high circulating levels of DB01277 with increased risk of second primary tumors ( SPTs ) of the head and neck , we examined IGF system and epidermal growth factor receptor ( P00533 ) expression in human head and neck squamous cell carcinoma ( HNSCC ) matched pairs and a cross - section of HNSCC cell lines . Employing the latter , we demonstrated that DB01277 stimulated S - phase transition in a PI 3 - K / Akt and Erk - dependent manner in 5 of 8 cell lines , with Erk activation being dependent upon P00533 kinase activity . DB01277 stimulated thymidine incorporation was inhibited by treatment with P17936 , the IGF - 1R tyrosine kinase inhibitor DB00238 - AEW541 , or the P00533 tyrosine kinase inhibitor AG1478 . Combining P17936 with DB00238 - AEW541 or AG1478 abrogated DB01277 responses at 10 - fold lower doses than either compound alone . These results demonstrate the potential for co - targeting the IGF system and P00533 in HNSCC .\",\n \"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK51___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK51___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .\",\n \"Role of - 675 4G / 5G in the plasminogen activator inhibitor - 1 gene and - 308G / A tumor necrosis factor - α gene polymorphisms in obese Argentinean patients . AIM : P00747 activator inhibitor - 1 ( P05121 ) and tumor necrosis factor - α ( P01375 - α ) are increased in the circulation of obese persons . Because a direct link between P05121 and P01375 - α in obesity has been observed , they are candidate genes for the development of obesity . We sought to evaluate the relation between the genotypic and allelic frequencies of the - 675 4G / 5G P05121 and - 308 G / A P01375 - α polymorphisms and their association with the risk for obesity in an Argentinean population . METHODS : A group of 110 consecutive obese persons and a group of 111 lean controls were recruited . Polymerase chain reaction was used to determine the frequency of P05121 and P01375 - α polymorphisms ; serum fasting glucose , insulin , and lipid levels were measured by standard methods . P01308 sensitivity was evaluated by using homeostasis model assessment . RESULTS : The - 308 P01375 - α and - 675 4G / 5G P05121 genotype distribution did not significantly differ between the groups ( p = 0 . 544 and p = 0 . 327 , respectively ) . Homeostasis model assessment was the only positive independent determinant of body mass index ( R ( 2 )= 0 . 493 ; p < 0 . 001 ) . CONCLUSION : The - 675 4G / 5G P05121 and the - 308 P01375 - α polymorphism variants tested in this study , individually or combined , were not associated with obesity in an Argentinean population .\",\n \"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .\",\n \"[ ___MASK98___ : A new drug of B - cell malignancies ] . ___MASK98___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK98___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK98___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .\",\n \"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK45___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .\",\n \"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK3___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .\",\n \"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .\",\n \"Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .\",\n \"P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .\",\n \"Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux .\"\n]"},"candidates":{"kind":"list like","value":["___MASK34___","___MASK38___","___MASK3___","___MASK45___","___MASK51___","___MASK61___","___MASK70___","___MASK89___","___MASK98___"],"string":"[\n \"___MASK34___\",\n \"___MASK38___\",\n \"___MASK3___\",\n \"___MASK45___\",\n \"___MASK51___\",\n \"___MASK61___\",\n \"___MASK70___\",\n \"___MASK89___\",\n \"___MASK98___\"\n]"},"answer":{"kind":"string","value":"___MASK45___"},"id":{"kind":"string","value":"MH_train_397"}}},{"rowIdx":398,"cells":{"query":{"kind":"string","value":"interacts_with DB06148?"},"supports":{"kind":"list like","value":["Identification of multiple binding sites for [ 3H ] 5 - hydroxytryptamine in the rat CNS . Recent studies indicate that there may be multiple subtypes of [ 3H ] 5 - hydroxytryptamine ( [ 3H ] 5 - HT ) binding sites . DB06148 and spiperone inhibited the specific binding of [ 3H ] 5 - HT ( 2 - 3 nM ) to rat brain cortical membranes with shallow displacement curves . The displacement data for spiperone were best described by the presence of three independent binding sites , for which spiperone had high , medium , and low affinities . The displacement data for mianserin were best fitted by two independent , high - and low - affinity sites . The inclusion of mianserin ( 250 nM ) to inhibit [ 3H ] 5 - HT binding to the mianserin - sensitive site selectively blocked one of the sites discriminated by spiperone . These results suggest the presence of three binding sites for [ 3H ] 5 - HT , one blocked by low concentrations of spiperone ( P08908 ) , one blocked by low concentrations of mianserin ( P28335 ) , and one blocked only by high concentrations of both mianserin and spiperone ( P28222 ) . Regional differences in the relative densities of the three sites were observed . The hippocampus was rich in P08908 sites , whereas the striatum contained mainly P28222 and P28335 sites . Selective degeneration of 5 - HT - containing nerve terminals induced by the neurotoxin 5 , 7 - dihydroxytryptamine increased binding to all three sites in the cerebral cortex . Binding of [ 3H ] 5 - HT to the three sites was differentially modulated by CaCl2 and guanylimidodiphosphate . The present data suggest the presence of three independent 5 - HT1 binding sites having different affinities for mianserin and spiperone and having different regional distributions .","The interaction of antidepressant drugs with enteric P34969 receptors . In this study the functional interaction of the antidepressant drugs amitriptyline , mianserin , maprotiline , imipramine , fluoxetine and the putative antidepressant drug flibanserin has been studied on P34969 - mediated responses to 5 - carboxamidotryptamine ( 5 - CT ) in the guinea - pig ileum . 5 - CT induced a concentration - dependent inhibition of the contractile response to DB05875 ( 100 nM ) . Except for fluoxetine and flibanserin , all the antidepressants antagonized by different degrees the 5 - CT inhibitory response with the following rank affinity order : mianserin > maprotiline > imipramine > amitriptyline . DB06148 was the only antidepressant to show a profile of competitive antagonism at P34969 receptors in a tenfold range of concentrations ( 0 . 1 - 1 microM ) , with an affinity ( pA2 ) value of 8 . 1 +/- 0 . 6 . The antagonism of the other antidepressants was not concentration - dependent ( amitriptyline ) or was associated with slight or moderate reduction of the maximal 5 - CT response ( imipramine or maprotiline ) . The apparent affinity ( pKB ) values were : amitriptyline , 7 . 0 +/- 0 . 2 ; maprotiline , 7 . 3 +/- 0 . 6 ; imipramine , 7 . 2 +/- 0 . 4 . Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric P34969 receptors through competitive or allosteric mechanisms . This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5 - HT receptors , namely 5 - Q9H205 and Q13639 receptors .","Serotonin increases P27361 / 2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 ( 1 / 2 ) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5 - HT ( 2B ) receptors ( Li et al . , 2008b ) . This raises the question whether this is also the case for serotonin ( 5 - HT ) itself . In the present study serotonin was found to induce P29323 ( 1 / 2 ) phosphorylation by stimulation of 5 - HT ( 2B ) receptors with high affinity ( EC ( 50 ) : 20 - 30 pM ) , and by stimulation of 5 - HT ( 2C ) receptor with low affinity ( EC ( 50 ) : 1 microM or higher ) . P29323 ( 1 / 2 ) phosphorylation induced by stimulation of either 5 - HT ( 2B ) or 5 - HT ( 2C ) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al . , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn - dependent metalloproteinases , and thus of 5 - HT ( 2B ) receptor - mediated P01133 receptor agonist release . It is discussed that the high potency of the 5 - HT ( 2B )- mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5 - HT ( 2B ) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality - dependent increase in specific brain areas to activate 5 - HT ( 2B ) receptors . In contrast the relevance of the observed 5 - HT ( 2C ) receptors on astrocytes is questioned .","Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .","Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK50___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .","Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .","Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .","Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK16___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK16___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .","Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK72___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK72___ who were treated with a single dose of mifepristone .","Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin ( Q11206 ) - induced diabetic rats . Contractile responses to serotonin ( 5 - HT ) of fundic smooth muscle strips isolated from both control and streptozotocin ( Q11206 ) - induced diabetic rats were investigated . Contrary to carbachol ( CCh ) which causes contractile hyperactivity in DM , 5 - HT response tended to decrease in DM compared to that of the control . Pindolol ( 10 (- 5 ) M ) increased the value of EC50 of the concentration - response to 5 - HT about 2 . 5 times in both the control and DM . After treatment with pindolol , the maximal tension to 5 - HT in DM significantly decreased compared to that of the control . Pindolol showed no effect on the contractile response to CCh . Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control . DB06148 ( 10 (- 5 ) M ) increased the EC50 of the response to 5 - HT about 2 - 2 . 5 times in both groups , but did not cause a significant difference between the control and DM . The Ca ( 2 +)- induced contraction caused hyperreactivity in DM in the presence of 10 (- 6 ) M CCh , but that in DM was not significantly different from the control in the presence of 10 (- 6 ) M 5 - HT . Pretreatment of phorbol 12 - myristate 13 - acetate ( PMA , 10 (- 5 ) M ) significantly attenuated the response to 5 - HT in the control , but not in DM . Results suggest that the contractile response to 5 - HT in DM is related to the altered Ca2 + signal transduction system via disturbed protein kinase C ( PKC ) activity , and that there are alterations of receptor characteristics and of the density in 5 - HT receptor subtypes , especially P08908 , during DM development .","DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .","Expression of serotonergic system components during early Xenopus embryogenesis . Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function , little is known about the molecular genetic mechanisms involved . The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT - PCR , real time PCR and in situ hybridization . Transcripts encoding the serotonin receptors P28335 and P34969 , as well as the vesicular monoamine transporter Q05940 , the serotonin transporter ( P31645 ) and the serotonin synthesis enzymes tryptophan hydroxylase ( Q8IWU9 ) and aromatic amino acid decarboxylase ( AAAD ) were found to be expressed during the cleavage division stages , whereas the degradation enzyme monoamine oxidase A ( P21397 ) was absent . The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development . The embryonic transmitter mechanism , its complexity , and its variability among various species are discussed .","Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","Comparison of the effects of aging on P34969 and P08908 receptors in discrete regions of the circadian timing system in hamsters . The circadian timekeeping system exhibits many functional changes with aging , including a loss of sensitivity to time cues such as systemic injections of the serotonergic agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) . In order to elucidate the neurochemical mechanisms responsible for this age - related loss of sensitivity of the circadian pacemaker to serotonin agonists , the present study used quantitative autoradiography to determine whether aging decreases serotonin receptor populations in male Syrian hamsters . Four neuroanatomical regions that regulate circadian timekeeping were studied ( the suprachiasmatic nuclei [ SCN ] , the lateral geniculate nuclei [ P81274 ] , and the median raphe nucleus [ MRN ] and dorsal raphe nucleus [ DRN ] ) . The specific binding of [ 3H ] 8 - OH - DPAT to serotonin7 ( P34969 ) and serotonin1A ( P08908 ) receptors was investigated by competitive inhibition with ritanserin and pindolol , respectively . The results showed that the SCN , IGL , MRN , and DRN of the male Syrian hamster exhibited specific binding of [ 3H ] 8 - OH - DPAT to both the P34969 and P08908 receptors , and that the latter receptor subtype is more abundant in all of these regions . At 17 - 19 months of age , a 50 % decrease in P34969 receptors was found in the DRN but not in any other regions . No significant age - related changes in P08908 receptors were observed in any regions examined . The finding that a marked decrease in P34969 receptors occurs in the DRN at the age previously characterized by loss of sensitivity to 8 - OH - DPAT suggests that this region and this receptor subtype play important roles in 8 - OH - DPAT induction of circadian phase shifts in vivo and that they constitute an important locus of aging in the circadian timing system .","A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .","Dexamethasone potentiates serotonin - 2 receptor - mediated intracellular Ca2 + mobilization in P13671 glioma cells . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) caused a transient increase in intracellular Ca2 + in C6BU - 1 glioma cells in a concentration - dependent manner ; half maximally at 73 nM . The 5 - HT2 agonist 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane also increased the levels of intracellular Ca2 + , whereas the P28335 agonist 1 -( 3 - chlorophenyl ) piperazine and P08908 agonist 8 - hydroxy - 2 - ( di - n - propylamino ) tetralin were completely ineffective . Ketanserin and spiperone blocked the response to 5 - HT at a nanomolar concentration , but the 5 - Q9H205 antagonist MDL 72222 had no effect on it . Thus 5 - HT2 receptors are responsible for activating Ca2 + mobilization in P13671 glioma cells . Treatment of P13671 glioma cells with dexamethasone potentiated the ability of 5 - HT to cause intracellular Ca2 + mobilization in both a dose - and time - dependent manner . The dose - response curve for 5 - HT was shifted 9 - fold to the left compared to controls , and the Vmax value was also significantly enhanced . This enhanced Ca2 + mobilization was completely inhibited by ketanserin dose - dependently . In addition , the treatment with dexamethasone enhanced fluoride - activated Ca2 + mobilization , suggesting that the enhanced GTP binding protein function is one of the mechanisms responsible for the enhancement of the 5 - HT response induced by dexamethasone treatment . This enhancement of agonist activity was mediated by the type II glucocorticoid receptor ( GR ) since RU 38486 , an inhibitor of the type II GR , antagonized the dexamethasone - induced enhancement .","Discriminative stimulus properties of mCPP : evidence for a P28335 receptor mode of action . Previous drug discrimination studies with the serotonergic drug m - chlorophenylpiperazine ( mCPP ) showed conflicting results , with some authors concluding that the cue was mediated by P28335 receptors , but others that it was definitively not . We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data . We trained rats to discriminate mCPP ( 2 . 0 mg / kg , PO ) from water . We found that the mCPP cue generalized to m - trifluoromethyl - phenylpiperazine ( TFMPP ) and 6 - chloro - 2 -( 1 - piperazinyl )- pyrazine ( MK - 212 ) , and partially to eltoprazine , 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ( DOI ) , fenfluramine and trazodone . A moderate level of generalization was obtained with quipazine , 1 -( m - chlorophenyl ) biguanide and clonidine . No generalization was found with flesinoxan , methiothepin , idazoxan and haloperidol . DB06148 and methysergide antagonized the mCPP stimulus , whereas ketanserin antagonized it partially . Metergoline , methiothepin and clozapine only marginally antagonized the mCPP stimulus . These results show that the discriminative stimulus effects of mCPP are predominantly mediated by P28335 receptors , and to some extent by P28222 receptors . When considering our results and other research together , the substitution tests clearly point to a P28335 receptor mediated stimulus , with an additional role for P28222 receptors . Antagonism studies are less clearcut , but are also suggestive of a P28335 receptor mediated effect . A definitive answer as to whether other receptors , e . g . P41595 and P34969 , are of any importance in mCPP ' s discriminative stimulus properties has to wait for more selective ligands .","___MASK73___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK73___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK73___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK73___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .","Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .","Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .","Modulation of multiple sclerosis by sunlight exposure : role of cis - urocanic acid . The role of cis - urocanic acid ( UCA ) as a UV - mediated immunomodulator in MS patients was investigated . Plasma levels of cis - UCA were significantly lower in MS patients compared to controls . Stimulation of MBP - and Q16653 - specific T cells in the presence of cis - UCA , significantly increased P22301 , and inhibited IFN - γ production . PBMCs cultured in the presence of cis - UCA increased P01730 (+) CD25 (+) FoxP3 (+) regulatory T cell percentages . Dendritic cells cultured in the presence of cis - UCA significantly reduced Ag presentation capacity . Finally , cis - UCA activated the 5 - Q13049 receptor , inducing the increase in phosphorylated forms of P29323 1 / 2 and P45984 . Thus , in addition to vitamin D , cis - UCA also appears to be an additional UV - mediated immunomodulator .","[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK37___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .","Rapid desensitization of serotonin P28335 receptor - stimulated intracellular calcium mobilization in CHO cells transfected with cloned human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in Chinese hamster ovary ( CHO ) cells transfected with P28335 receptors . Fura - 2 acetoxymethyl ester was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] mesulergine binding ( KD = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from a basal level of 99 +/- 1 . 8 up to 379 +/- 18 nM , with an EC50 value for 5 - HT of 0 . 029 microM . Exposure to 5 - HT , 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ( a P28335 agonist ) , and 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ( a P28335 and 5 - Q13049 agonist ) resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . The receptor was rapidly desensitized by preexposure to 5 - HT in a time - and concentration - dependent manner . Mezerein and phorbol 12 - myristate 13 - acetate , protein kinase C activators , weakly inhibited the intracellular Ca2 + mobilization induced by 10 microM 5 - HT . Furthermore , the protein kinase C inhibitor H - 7 partially prevented the protein kinase C activator - induced inhibition of the 5 - HT - mediated increase in intracellular Ca2 + concentration . The desensitization induced by pretreatment with 5 - HT was blocked by W - 7 , added in conjunction with 5 - HT , and partially inhibited by W - 5 , a nonselective inhibitor of protein kinases and weak analogue of W - 7 . ( ABSTRACT TRUNCATED AT 250 WORDS )","Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .","Mediation by 5 - hydroxytryptamine2B receptors of endothelium - dependent relaxation in rat jugular vein . 1 . An ' atypical ' 5 - HT2 receptor which is located on the endothelium of rat jugular vein has been described . In the present study we have further defined the nature of the 5 - HT2 receptor subtype present in this preparation . 2 . In experiments conducted in the presence of ketanserin to preclude involvement of 5 - HT2 receptors , the mixed P41595 / 2C antagonist , SB 200646 , acted as an antagonist of 5 - HT at the endothelial 5 - HT receptor ( pA2 = 7 . 2 ) . Yohimbine , which exhibits negligible affinity for rat P28335 receptors but has high P41595 receptor affinity , acted as a potent but non - surmountable antagonist ( pA2 > or = 7 . 3 ) in rat jugular vein . Neither yohimbine nor SB 200646 affected endothelium - dependent relaxations induced by carbachol . 3 . DB06148 also acted as a surmountable antagonist ( pA2 = 7 . 3 ) and the P41595 agonist , BW 723C86 , acted as a potent partial agonist ( pEC50 [ 95 % C L ] , intrinsic activity +/- s . e . mean = 7 . 9 [ 7 . 6 - 8 . 3 ] , 0 . 84 +/- 0 . 04 ) . Responses to BW 723C86 were antagonized by SB 200646 ( 0 . 3 microM ) yielding an ' apparent ' pA2 [ 95 % CL ] of 7 . 03 [ 6 . 76 - 7 . 32 ] . 4 . These data are consistent with the presence of P41595 receptors mediating endothelium - dependent relaxation of rat jugular vein .","Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .","[ Moclobemide ( ___MASK36___ ) , the first P21397 - inhibitor : really something new ? ] .","Thermoregulatory responses to serotonin ( 5 - HT ) receptor stimulation in the rat . Evidence for opposing roles of 5 - HT2 and P08908 receptors . The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated . The administration of the serotonin ( 5 - HT ) agonist 6 - chloro - 2 ( 1 - piperazinyl )- pyrazine ( MK - 212 ) produced a dose - related increase in body temperature . A maximal increase in body temperature of approx . 1 . 1 degrees C was observed 30 min after the administration of 3 mg / kg of MK - 212 . In contrast , administration of the putative P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) resulted in marked , dose - related hypothermic responses . Body temperatures were decreased approx . 3 degrees C 30 min after an injection of 0 . 3 mg / kg of 8 - OH - DPAT . Body temperatures were affected differentially by 5 - methoxy - N , N - dimethyltryptamine ( 5 - MeODMT ) . Large doses ( 3 - 10 mg / kg ) of 5 - MeODMT elicited hyperthermic responses , whereas small doses ( 0 . 5 - 1 . 0 mg / kg ) produced hypothermic responses . Treatment of rats with ketanserin ( 3 mg / kg ) completely prevented the hyperthermic effects of 5 - MeODMT , and , in fact , converted a hyperthermic response to 5 - MeODMT into a marked hypothermic response . Ketanserin ( 0 . 1 - 1 . 0 mg / kg ) selectively antagonized the hyperthermic response to MK - 212 but did not alter the hypothermic effect of 8 - OH - DPAT . DB06148 ( 10 mg / kg ) and pirenperone ( 0 . 03 mg / kg ) also selectively antagonized hyperthermia induced by MK - 212 . In contrast , pindolol ( 0 . 03 - 0 . 1 mg / kg ) and methiothepin ( 10 mg / kg ) selectively antagonized hypothermia induced by 8 - OH - DPAT but did not alter hyperthermia induced by MK - 212 . Spiperone ( 0 . 1 - 3 mg / kg ) and pizotifen ( 10 mg / kg ) attenuated the effects of both 8 - OH - DPAT and MK - 212 . Xylamidine , a peripheral 5 - HT antagonist , had no significant effect on hyperthermia induced by MK - 212 or hypothermia induced by 8 - OH - DPAT . ( ABSTRACT TRUNCATED AT 250 WORDS )","TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .","P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .","Effect of valproic acid on serotonin - 2A receptor signaling in P13671 glioma cells . Valproic acid ( DB00313 ) , which has demonstrated efficacy in the treatment of bipolar disorder , has been shown to alter components of the phosphoinositide ( PI ) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 ( AP - 1 ) . Central serotonin - 2A ( 5 - Q13049 ) receptors , which have been implicated in the pathophysiology of manic - depressive illness , are coupled to PI hydrolysis . The promoter region of the 5 - Q13049 receptor gene contains AP - 1 binding sites . We examined in P13671 glioma cells the effect of DB00313 on 5 - Q13049 receptor signaling . Treatment of cells with DB00313 ( 100 microg / mL ) for 20 h , but not 1 . 5 h , resulted in an enhancement of 5 - Q13049 receptor - stimulated PI hydrolysis . This effect of 20 - h DB00313 exposure appeared not to be at the level of G protein or effector ( i . e . phospholipase C : P98160 ) as inositol phosphate accumulation stimulated by aluminum fluoride or the P98160 activator 2 , 4 , 6 - trimethyl - N -( m - 3 - trifluromethylphenyl ) benzenesulfonamide was not increased . The number of 5 - Q13049 receptors , as determined in saturation binding experiments using [ 3H ] ketanserin , was increased by 20 - h DB00313 treatment , with no change in affinity ( KD ) . Taken together , our data suggest that the increase in 5 - Q13049 receptor - mediated PI hydrolysis following 20 - h DB00313 exposure is not due to a general effect of DB00313 on this signaling cascade , but due to the up - regulation of 5 - Q13049 receptor number .","Effects of antidepressants on intracellular Ca2 + mobilization in CHO cells transfected with the human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in P28335 receptors expressed in Chinese hamster ovary ( CHO ) cells ; and fura - 2 / AM was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] - mesulergine binding ( kd = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from basal level of 99 +/- 1 . 8 nM up to 246 +/- 21 . 2 nM , with an EC50 value for 5 - HT of . 015 microM . Exposure to 5 - HT , a 5 - HT receptor agonist , mCPP [ 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ] , a P28335 agonist , and DOI [ 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ] , a P28335 and 5 - HT2 agonist , resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . DB06148 and amoxapine inhibited 5 - HT - mediated intracellular Ca2 + mobilization completely ; amitriptyline , nortriptyline , and imipramine reduced it about 50 % . These results suggest that antagonism in CHO cells transfected with human P28335 receptors is a component of the serotonergic properties of a number of established antidepressants .","Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .","Involvement of P08908 and 5 - HT2 receptor in cisplatin induced emesis in dogs . The effect of drug acting on P08908 , 5 - HT2 and 5 - Q9H205 receptors were studied against cisplatin and apomorphine induced emesis in dogs . Buspirone , P08908 receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency . DB06148 , 5 - HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency . Buspirone prevented the apomorphine induced emesis while mianserin had no effect . The antiemetic activity of buspirone may be attributable to its agonistic activity at P08908 receptor and antagonistic activity at dopamine receptors . These findings further confirm the involvement of P08908 and 5 - HT2 receptor in cytotoxic drug induced emesis , though the species difference in their antiemetic action can not be ruled out .","P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK59___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .","Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK17___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .","Presence of a P34969 receptor positively coupled to adenylate cyclase activation in human granulosa - lutein cells . Although serotonin ( 5 - HT ) has been shown to stimulate progesterone production by human granulosa - lutein cells ( hGLC ) , the receptor type and associated signaling pathway remain uncharacterized . We report here that 5 - HT receptors in these cells are positively coupled to adenylate cyclase activity . Formation of DB02527 was stimulated by 5 - HT and its agonists in a dose - and time - dependent manner . DB06148 , amoxapine , and loxapine were equipotent in antagonizing 5 - HT - induced DB02527 formation . For both DB02527 formation in cells and adenylate cyclase assay using membrane fractions , the rank order of potency for agonists of 5 - HT were : 5 - carboxy - aminotryptamine > 5 - HT > or = 5 - methoxytryptamine , consistent with a typical pharmacological profile of human 5 - ht7 ( h5 - ht7 ) receptor . Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5 - ht7 receptor complementary DNA . Northern analysis showed the presence of 2 . 8 - kb h5 - ht7 transcripts in hGLC . The three variants h5 - ht7A , h5 - ht7B , and h5 - ht7D were also detected in hGLC . Preincubation of hGLC with 5 - HT ( 10 (- 8 )- 10 (- 6 ) M ) resulted in a marked reduction in the DB02527 response when the cells were subsequently stimulated with gonadotropin , and this heterologous desensitization could be reversed by 5 - ht7 receptor antagonist clozapine . These data demonstrate that h5 - ht7 receptor is present and stimulate DB02527 formation in hGLC . In addition , the h5 - ht7 receptor seems to be implicated in the heterologous down - regulation hCG - stimulated DB02527 response in hGLC , with a possible ramification for luteal insufficiency .","Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK15___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","Activating mutations of the serotonin P28335 receptor . Site - directed mutagenesis was performed to create a mutant serotonin P28335 receptor that would mimic the active conformation of the native receptor . Structural alteration of receptor conformation was achieved by changing amino acid no . 312 from serine to phenylalanine ( S312F ) or lysine ( S312K ) . After expression in COS - 7 cells , the binding affinity of 5 - HT for [ 3H ] mesulergine - labeled P28335 receptors increased from 203 nM ( native ) to 76 nM for S312F and 6 . 6 nM for S312K mutant receptors . 5 - HT potency for stimulation of phosphatidylinositol ( PI ) hydrolysis increased from 70 nM ( native ) to 28 nM for S312F and 2 . 7 nM for S312K mutant receptors . The mutant receptors were constitutively active , stimulating PI hydrolysis in the absence of agonist . S312F and S312K mutations resulted in twofold and five - fold increases , respectively , in basal levels of PI hydrolysis . DB06148 and mesulergine displayed inverse agonist activity by decreasing basal levels of PI hydrolysis stimulated by S312K mutant receptors . [ 3H ] 5 - HT and [ 3H ] mesulergine labeled the same number of S312K mutant receptors and 5 '- guanylylimidodiphosphate had no effect on [ 3H ] 5 - HT binding . These results indicate that serine --> lysine mutation at amino acid no . 312 produces an agonist high - affinity state of the P28335 receptor that spontaneously couples to G proteins and stimulates PI hydrolysis in the absence of agonist .","Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .","Roles of E3 ubiquitin ligases in cell adhesion and migration . Recent studies have demonstrated that a number of E3 ubiquitin ligases , including Cbl , Smurf1 , Smurf2 , HDM2 , BCA2 , P21583 ( beta - TRCP ) and XRNF185 , play important roles in cell adhesion and migration . Cbl negatively regulates cell adhesion via alpha integrin and Rap1 and inhibits actin polymerization by ubiquitinating mDab1 and Q9Y6W5 . Smurf1 regulates cell migration through ubiquitination of RhoA , talin head domain and hPEM2 , while Smurf2 ubiquitinates Smurf1 , TGFbeta type I receptor and RaplB to modulate cell migration and adhesion . HDM2 negatively regulates cell migration by targeting NFAT ( a transcription factor ) for ubiquitination and degradation , while P21583 ( beta - TRCP ) ubiquitinates Snail ( a transcriptional repressor of P12830 ) to inhibit cell migration . Q13049 promotes cell migration through ubiquitination of Q9NYB9 ( Abi2 ) , a tumor suppressor . Q99942 and XRNF185 modulate cell migration by ubiquitinating paxillin . Thus , these E3 ubiquitin ligases regulate cell adhesion and ( or ) migration through ubiquitination of their specific substrates .","Chronic mianserin or eltoprazine treatment in rats : effects on the elevated plus - maze test and on limbic P28335 receptor levels . Rats were chronically treated with mianserin ( 10 mg / kg i . p . ) or eltoprazine ( 1 mg / kg i . p . ) and were tested in the elevated plus - maze test for anxiety . P28335 ( previously P28335 , see Humphrey et al . , 1993 , Trends Pharmacol . Sci . 14 , 223 ) binding sites and their mRNA were evaluated in limbic structures ( i . e . , amygdala , hippocampus , septum ) of a sample of these rats by autoradiographic binding studies and in situ hybridization histochemistry . DB06148 and eltoprazine displayed opposite effects in the elevated plus - maze : mianserin induced anxiolytic - like effects , while eltoprazine showed anxiogenic - like ones . Within the amygdala , but not in other structures , the quantitative autoradiographic analysis of the P28335 binding sites showed a differential effect : mianserin treatment induced a decrease in the number of these sites , while eltoprazine treatment resulted in an increase . In spite of this , neither mianserin - nor eltoprazine - treated rats displayed an alteration in the P28335 receptor mRNA levels in the brain regions examined . Our results are suggestive of a relation between anxiolytic / anxiogenic - like effects and the level of P28335 binding sites in the amygdala .","Effects of antidepressants on the exploration , spontaneous motor activity and isolation - induced aggressiveness in mice . OBJECTIVE : To study the role of different antidepressants on exploration , spontaneous motor activity and isolation - induced aggressiveness in mice , further to discuss different mechanisms of their anti - aggression . METHODS : With an aggressive model induced by isolation housing in mice , antagonism of different antidepressants against isolation - induced aggression was evaluated . In the group - housed mice given the same treatment as aggressive test , exploration and spontaneous motor activity were measured . RESULTS : ( 1 ) DB06148 ( 0 . 5 - 5 mg / kg - 1 ) , buspirone ( 2 . 5 - 10 mg . kg - 1 ) and meclobemide ( 2 . 5 - 10 mg . kg - 1 ) significantly inhibited the exploration in the group - housed mice , but not fluoxetine ( 2 . 5 - 10 mg . kg - 1 ) , imipramine ( 2 . 5 - 10 mg . kg - 1 ) and DOI ( 0 . 5 - 2 mg . kg - 1 ) ; ( 2 ) Both mianserin and buspirone , but not fluoxetine , imipramine , meclobemide and DOI , obviously reduced spontaneous motor activity ; ( 3 ) DB00472 , miaserin , imipramine and buspirone significantly and dose - dependently antagonized isolation - induced aggressive behavior , whereas meclobemide failed to attenuate aggression . DOI dual - regulated aggressiveness in isolation mice . CONCLUSION : Our findings suggest that the effects of fluoxetine , mianserin , buspirone , imipramine , meclobemide and DOI on exploration , spontaneous motor activity and isolation - induced aggression in mice are different , which may involve different pharmacological mechanisms underlying their anti - aggression in isolation mice . P08908 and 5 - Q13049 / 2C receptors may mediate isolation - induced aggressive behavior in mice . The involvement of 5 - HT receptor subtypes needs further clarification .","[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD .","Involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory P21554 receptors . The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia . In this review , we will firstly provide a background , brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia . We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal P34969 , 5 - Q13049 and alpha - 2 adrenoceptors activation .","Beneficial effect of low - dose mianserin on fluvoxamine - induced akathisia in an obsessive - compulsive patient . Extrapyramidal side effects induced by some selective serotonin reuptake inhibitors ( SSRIs ) , i . e . fluoxetine and sertraline , have been previously reported in patients with depression and obsessive - compulsive disorder ( OCD ) . However , the occurrence and management of akathisia induced by fluvoxamine have not been described . In the presented case fluvoxamine - induced akathisia in an OCD patient was partially resistant to the anticholinergic agent biperiden , and was successfully treated with the 5 - Q13049 / P28335 antagonist mianserin . DB06148 ( 15 mg / day at 21 . 00 h ) was discontinued and then reinstituted ( off - on - off - on design ) . DB00810 was transiently effective in the acute akathisia , while the more persistent akathisia was alleviated by mianserin . Discontinuation of mianserin resulted in recurrence of akathisia , while full amelioration of the symptoms of akathisia was noted when mianserin was reinstituted . No aggravation of OCD symptoms was noted during mianserin administration .","Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells . Serotonin ( 5 - HT ) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis . In this study , we evaluated the role of 5 - HT on the functional features in neurospheres derived from adult neural stem cells ( ANSC ) . We cultured neurospheres derived from mouse hippocampus in serum - free medium containing epidermal ( P01133 ) and type - 2 fibroblast growth factor ( P09038 ) . Under these conditions ANSC expressed both isoforms of tryptophane - hydroxylase ( P17752 ) and produced 5 - HT . Blocking P17752 function by para - chlorophenylalanine ( PCPA ) reduced ANSC proliferation , which was rescued by exogenous 5 - HT . 5 - HT action on ANSC was mediated predominantly by the serotonin receptor subtype P08908 and , to a lesser extent , through the P28335 ( receptor ) subtype , as shown by selectively antagonizing these receptors . Finally , we documented a 5 - HT - induced increase of ANSC migration activity . In summary , we demonstrated a powerful serotonergic impact on ANSC functional features , which was mainly mediated by P08908 receptors .","Modulation of antipsychotic - induced extrapyramidal side effects by medications for mood disorders . Antipsychotic drugs are widely used not only for schizophrenia , but also for mood disorders such as bipolar disorder and depression . To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects ( EPS ) , we examined the effects of antidepressants and mood - stabilizing drugs on haloperidol ( P42357 ) - induced bradykinesia and catalepsy in mice and rats . The selective serotonin reuptake inhibitors ( SSRIs ) , fluoxetine and paroxetine , and the tricyclic antidepressant ( TCA ) clomipramine , which showed no EPS by themselves , significantly potentiated P42357 - induced bradykinesia and catalepsy in a dose - dependent manner . In contrast , the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine failed to augment , but rather attenuated P42357 - induced bradykinesia and catalepsy . DB06148 also tended to reduce the EPS induction . In addition , neither treatment with lithium , sodium valproate nor carbamazepine potentiated P42357 - induced EPS . Furthermore , treatment of animals with ritanserin ( 5 - Q13049 / 2C antagonist ) , ondansetron ( 5 - Q9H205 antagonist ) , and SB - 258585 ( P50406 antagonist ) significantly antagonized the EPS augmentation by fluoxetine . Intrastriatal injection of ritanserin or SB - 258585 , but not ondansetron , also attenuated the EPS induction . The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction . In addition , 5 - Q13049 / 2C , 5 - Q9H205 and P50406 receptors seem to be responsible for the augmentation of antipsychotic - induced EPS by serotonin reuptake inhibitors .","DB06148 - induced down - regulation of human 5 - hydroxytryptamine2A and 5 - hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5 - hydroxytryptamine2A ( 5 - Q13049 ) and P28335 receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . Incubation of cells expressing the 5 - Q13049 receptor with mianserin ( 100 nM ) for 24 h caused a significant decrease ( 48 % ) in the binding capacity of [ 3H ] ketanserin . This receptor down - regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5 - HT but not by carbachol . Exposure of cells expressing the P28335 receptor to mianserin ( 100 nM ) for 72 h but not for 24 h similarly resulted in a significant reduction ( 44 % ) in [ 3H ] mesulergine binding . Corresponding analysis of inositol phosphate production by 5 - HT at the P28335 receptor after incubation with mianserin showed no change in maximal response after 24 h . No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h . A decrease in the binding affinity of both radioligands was also observed after mianserin treatment , but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h , and was probably due to the retention of mianserin within the tissue . We conclude that antagonist down - regulation is evident at human 5 - Q13049 and P28335 receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor .","DB00502 , but not clozapine , produces dramatic catalepsy in delta9 - THC - treated rats : possible clinical implications . The effect on rat catalepsy induced by Delta9 - tetrahydrocannabinol ( Delta9 - THC ) in association with haloperidol ( HP ) or clozapine ( CLOZ ) administration was investigated . Delta9 - THC dose - dependently increased HP ( 0 . 05 - 1 mg kg - 1 , s . c . ) - induced rat catalepsy , while no catalepsy was observed after CLOZ ( 1 - 20 mg kg - 1 , s . c . ) or Delta9 - THC + CLOZ administration . The P21554 antagonist SR141716A ( 0 . 5 - 5 mg kg - 1 , i . p . ) reversed the increase mediated by Delta9 - THC on HP - induced catalepsy . The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP + Delta9 - THC ; however , higher doses of quinpirole were needed in the presence of Delta9 - THC . The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP + Delta9 - THC in a similar manner . CLOZ and the 5 - Q13049 / 2C antagonists ritanserin , RS102221 and SB242084 were more effective in antagonizing HP than HP + Delta9 - THC - induced catalepsy . 7 HP and CLOZ failed to inhibit in vitro [ 3H ] CP - 55 , 940 binding , while Delta9 - THC and SR141716A did not show an appreciable affinity for the D2 receptor . It was suggested that the different effects on rat catalepsy induced by Delta9 - THC following HP or CLOZ administration may depend on the receptor - binding profiles of the two antipsychotics . The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed ."],"string":"[\n \"Identification of multiple binding sites for [ 3H ] 5 - hydroxytryptamine in the rat CNS . Recent studies indicate that there may be multiple subtypes of [ 3H ] 5 - hydroxytryptamine ( [ 3H ] 5 - HT ) binding sites . DB06148 and spiperone inhibited the specific binding of [ 3H ] 5 - HT ( 2 - 3 nM ) to rat brain cortical membranes with shallow displacement curves . The displacement data for spiperone were best described by the presence of three independent binding sites , for which spiperone had high , medium , and low affinities . The displacement data for mianserin were best fitted by two independent , high - and low - affinity sites . The inclusion of mianserin ( 250 nM ) to inhibit [ 3H ] 5 - HT binding to the mianserin - sensitive site selectively blocked one of the sites discriminated by spiperone . These results suggest the presence of three binding sites for [ 3H ] 5 - HT , one blocked by low concentrations of spiperone ( P08908 ) , one blocked by low concentrations of mianserin ( P28335 ) , and one blocked only by high concentrations of both mianserin and spiperone ( P28222 ) . Regional differences in the relative densities of the three sites were observed . The hippocampus was rich in P08908 sites , whereas the striatum contained mainly P28222 and P28335 sites . Selective degeneration of 5 - HT - containing nerve terminals induced by the neurotoxin 5 , 7 - dihydroxytryptamine increased binding to all three sites in the cerebral cortex . Binding of [ 3H ] 5 - HT to the three sites was differentially modulated by CaCl2 and guanylimidodiphosphate . The present data suggest the presence of three independent 5 - HT1 binding sites having different affinities for mianserin and spiperone and having different regional distributions .\",\n \"The interaction of antidepressant drugs with enteric P34969 receptors . In this study the functional interaction of the antidepressant drugs amitriptyline , mianserin , maprotiline , imipramine , fluoxetine and the putative antidepressant drug flibanserin has been studied on P34969 - mediated responses to 5 - carboxamidotryptamine ( 5 - CT ) in the guinea - pig ileum . 5 - CT induced a concentration - dependent inhibition of the contractile response to DB05875 ( 100 nM ) . Except for fluoxetine and flibanserin , all the antidepressants antagonized by different degrees the 5 - CT inhibitory response with the following rank affinity order : mianserin > maprotiline > imipramine > amitriptyline . DB06148 was the only antidepressant to show a profile of competitive antagonism at P34969 receptors in a tenfold range of concentrations ( 0 . 1 - 1 microM ) , with an affinity ( pA2 ) value of 8 . 1 +/- 0 . 6 . The antagonism of the other antidepressants was not concentration - dependent ( amitriptyline ) or was associated with slight or moderate reduction of the maximal 5 - CT response ( imipramine or maprotiline ) . The apparent affinity ( pKB ) values were : amitriptyline , 7 . 0 +/- 0 . 2 ; maprotiline , 7 . 3 +/- 0 . 6 ; imipramine , 7 . 2 +/- 0 . 4 . Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric P34969 receptors through competitive or allosteric mechanisms . This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5 - HT receptors , namely 5 - Q9H205 and Q13639 receptors .\",\n \"Serotonin increases P27361 / 2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 ( 1 / 2 ) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5 - HT ( 2B ) receptors ( Li et al . , 2008b ) . This raises the question whether this is also the case for serotonin ( 5 - HT ) itself . In the present study serotonin was found to induce P29323 ( 1 / 2 ) phosphorylation by stimulation of 5 - HT ( 2B ) receptors with high affinity ( EC ( 50 ) : 20 - 30 pM ) , and by stimulation of 5 - HT ( 2C ) receptor with low affinity ( EC ( 50 ) : 1 microM or higher ) . P29323 ( 1 / 2 ) phosphorylation induced by stimulation of either 5 - HT ( 2B ) or 5 - HT ( 2C ) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al . , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn - dependent metalloproteinases , and thus of 5 - HT ( 2B ) receptor - mediated P01133 receptor agonist release . It is discussed that the high potency of the 5 - HT ( 2B )- mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5 - HT ( 2B ) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality - dependent increase in specific brain areas to activate 5 - HT ( 2B ) receptors . In contrast the relevance of the observed 5 - HT ( 2C ) receptors on astrocytes is questioned .\",\n \"Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .\",\n \"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK50___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .\",\n \"Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .\",\n \"Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .\",\n \"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK16___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK16___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .\",\n \"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK72___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK72___ who were treated with a single dose of mifepristone .\",\n \"Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin ( Q11206 ) - induced diabetic rats . Contractile responses to serotonin ( 5 - HT ) of fundic smooth muscle strips isolated from both control and streptozotocin ( Q11206 ) - induced diabetic rats were investigated . Contrary to carbachol ( CCh ) which causes contractile hyperactivity in DM , 5 - HT response tended to decrease in DM compared to that of the control . Pindolol ( 10 (- 5 ) M ) increased the value of EC50 of the concentration - response to 5 - HT about 2 . 5 times in both the control and DM . After treatment with pindolol , the maximal tension to 5 - HT in DM significantly decreased compared to that of the control . Pindolol showed no effect on the contractile response to CCh . Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control . DB06148 ( 10 (- 5 ) M ) increased the EC50 of the response to 5 - HT about 2 - 2 . 5 times in both groups , but did not cause a significant difference between the control and DM . The Ca ( 2 +)- induced contraction caused hyperreactivity in DM in the presence of 10 (- 6 ) M CCh , but that in DM was not significantly different from the control in the presence of 10 (- 6 ) M 5 - HT . Pretreatment of phorbol 12 - myristate 13 - acetate ( PMA , 10 (- 5 ) M ) significantly attenuated the response to 5 - HT in the control , but not in DM . Results suggest that the contractile response to 5 - HT in DM is related to the altered Ca2 + signal transduction system via disturbed protein kinase C ( PKC ) activity , and that there are alterations of receptor characteristics and of the density in 5 - HT receptor subtypes , especially P08908 , during DM development .\",\n \"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .\",\n \"Expression of serotonergic system components during early Xenopus embryogenesis . Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function , little is known about the molecular genetic mechanisms involved . The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT - PCR , real time PCR and in situ hybridization . Transcripts encoding the serotonin receptors P28335 and P34969 , as well as the vesicular monoamine transporter Q05940 , the serotonin transporter ( P31645 ) and the serotonin synthesis enzymes tryptophan hydroxylase ( Q8IWU9 ) and aromatic amino acid decarboxylase ( AAAD ) were found to be expressed during the cleavage division stages , whereas the degradation enzyme monoamine oxidase A ( P21397 ) was absent . The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development . The embryonic transmitter mechanism , its complexity , and its variability among various species are discussed .\",\n \"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"Comparison of the effects of aging on P34969 and P08908 receptors in discrete regions of the circadian timing system in hamsters . The circadian timekeeping system exhibits many functional changes with aging , including a loss of sensitivity to time cues such as systemic injections of the serotonergic agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) . In order to elucidate the neurochemical mechanisms responsible for this age - related loss of sensitivity of the circadian pacemaker to serotonin agonists , the present study used quantitative autoradiography to determine whether aging decreases serotonin receptor populations in male Syrian hamsters . Four neuroanatomical regions that regulate circadian timekeeping were studied ( the suprachiasmatic nuclei [ SCN ] , the lateral geniculate nuclei [ P81274 ] , and the median raphe nucleus [ MRN ] and dorsal raphe nucleus [ DRN ] ) . The specific binding of [ 3H ] 8 - OH - DPAT to serotonin7 ( P34969 ) and serotonin1A ( P08908 ) receptors was investigated by competitive inhibition with ritanserin and pindolol , respectively . The results showed that the SCN , IGL , MRN , and DRN of the male Syrian hamster exhibited specific binding of [ 3H ] 8 - OH - DPAT to both the P34969 and P08908 receptors , and that the latter receptor subtype is more abundant in all of these regions . At 17 - 19 months of age , a 50 % decrease in P34969 receptors was found in the DRN but not in any other regions . No significant age - related changes in P08908 receptors were observed in any regions examined . The finding that a marked decrease in P34969 receptors occurs in the DRN at the age previously characterized by loss of sensitivity to 8 - OH - DPAT suggests that this region and this receptor subtype play important roles in 8 - OH - DPAT induction of circadian phase shifts in vivo and that they constitute an important locus of aging in the circadian timing system .\",\n \"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .\",\n \"Dexamethasone potentiates serotonin - 2 receptor - mediated intracellular Ca2 + mobilization in P13671 glioma cells . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) caused a transient increase in intracellular Ca2 + in C6BU - 1 glioma cells in a concentration - dependent manner ; half maximally at 73 nM . The 5 - HT2 agonist 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane also increased the levels of intracellular Ca2 + , whereas the P28335 agonist 1 -( 3 - chlorophenyl ) piperazine and P08908 agonist 8 - hydroxy - 2 - ( di - n - propylamino ) tetralin were completely ineffective . Ketanserin and spiperone blocked the response to 5 - HT at a nanomolar concentration , but the 5 - Q9H205 antagonist MDL 72222 had no effect on it . Thus 5 - HT2 receptors are responsible for activating Ca2 + mobilization in P13671 glioma cells . Treatment of P13671 glioma cells with dexamethasone potentiated the ability of 5 - HT to cause intracellular Ca2 + mobilization in both a dose - and time - dependent manner . The dose - response curve for 5 - HT was shifted 9 - fold to the left compared to controls , and the Vmax value was also significantly enhanced . This enhanced Ca2 + mobilization was completely inhibited by ketanserin dose - dependently . In addition , the treatment with dexamethasone enhanced fluoride - activated Ca2 + mobilization , suggesting that the enhanced GTP binding protein function is one of the mechanisms responsible for the enhancement of the 5 - HT response induced by dexamethasone treatment . This enhancement of agonist activity was mediated by the type II glucocorticoid receptor ( GR ) since RU 38486 , an inhibitor of the type II GR , antagonized the dexamethasone - induced enhancement .\",\n \"Discriminative stimulus properties of mCPP : evidence for a P28335 receptor mode of action . Previous drug discrimination studies with the serotonergic drug m - chlorophenylpiperazine ( mCPP ) showed conflicting results , with some authors concluding that the cue was mediated by P28335 receptors , but others that it was definitively not . We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data . We trained rats to discriminate mCPP ( 2 . 0 mg / kg , PO ) from water . We found that the mCPP cue generalized to m - trifluoromethyl - phenylpiperazine ( TFMPP ) and 6 - chloro - 2 -( 1 - piperazinyl )- pyrazine ( MK - 212 ) , and partially to eltoprazine , 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ( DOI ) , fenfluramine and trazodone . A moderate level of generalization was obtained with quipazine , 1 -( m - chlorophenyl ) biguanide and clonidine . No generalization was found with flesinoxan , methiothepin , idazoxan and haloperidol . DB06148 and methysergide antagonized the mCPP stimulus , whereas ketanserin antagonized it partially . Metergoline , methiothepin and clozapine only marginally antagonized the mCPP stimulus . These results show that the discriminative stimulus effects of mCPP are predominantly mediated by P28335 receptors , and to some extent by P28222 receptors . When considering our results and other research together , the substitution tests clearly point to a P28335 receptor mediated stimulus , with an additional role for P28222 receptors . Antagonism studies are less clearcut , but are also suggestive of a P28335 receptor mediated effect . A definitive answer as to whether other receptors , e . g . P41595 and P34969 , are of any importance in mCPP ' s discriminative stimulus properties has to wait for more selective ligands .\",\n \"___MASK73___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK73___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK73___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK73___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .\",\n \"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .\",\n \"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \\\" dominant negative \\\" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .\",\n \"Modulation of multiple sclerosis by sunlight exposure : role of cis - urocanic acid . The role of cis - urocanic acid ( UCA ) as a UV - mediated immunomodulator in MS patients was investigated . Plasma levels of cis - UCA were significantly lower in MS patients compared to controls . Stimulation of MBP - and Q16653 - specific T cells in the presence of cis - UCA , significantly increased P22301 , and inhibited IFN - γ production . PBMCs cultured in the presence of cis - UCA increased P01730 (+) CD25 (+) FoxP3 (+) regulatory T cell percentages . Dendritic cells cultured in the presence of cis - UCA significantly reduced Ag presentation capacity . Finally , cis - UCA activated the 5 - Q13049 receptor , inducing the increase in phosphorylated forms of P29323 1 / 2 and P45984 . Thus , in addition to vitamin D , cis - UCA also appears to be an additional UV - mediated immunomodulator .\",\n \"[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK37___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .\",\n \"Rapid desensitization of serotonin P28335 receptor - stimulated intracellular calcium mobilization in CHO cells transfected with cloned human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in Chinese hamster ovary ( CHO ) cells transfected with P28335 receptors . Fura - 2 acetoxymethyl ester was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] mesulergine binding ( KD = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from a basal level of 99 +/- 1 . 8 up to 379 +/- 18 nM , with an EC50 value for 5 - HT of 0 . 029 microM . Exposure to 5 - HT , 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ( a P28335 agonist ) , and 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ( a P28335 and 5 - Q13049 agonist ) resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . The receptor was rapidly desensitized by preexposure to 5 - HT in a time - and concentration - dependent manner . Mezerein and phorbol 12 - myristate 13 - acetate , protein kinase C activators , weakly inhibited the intracellular Ca2 + mobilization induced by 10 microM 5 - HT . Furthermore , the protein kinase C inhibitor H - 7 partially prevented the protein kinase C activator - induced inhibition of the 5 - HT - mediated increase in intracellular Ca2 + concentration . The desensitization induced by pretreatment with 5 - HT was blocked by W - 7 , added in conjunction with 5 - HT , and partially inhibited by W - 5 , a nonselective inhibitor of protein kinases and weak analogue of W - 7 . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .\",\n \"Mediation by 5 - hydroxytryptamine2B receptors of endothelium - dependent relaxation in rat jugular vein . 1 . An ' atypical ' 5 - HT2 receptor which is located on the endothelium of rat jugular vein has been described . In the present study we have further defined the nature of the 5 - HT2 receptor subtype present in this preparation . 2 . In experiments conducted in the presence of ketanserin to preclude involvement of 5 - HT2 receptors , the mixed P41595 / 2C antagonist , SB 200646 , acted as an antagonist of 5 - HT at the endothelial 5 - HT receptor ( pA2 = 7 . 2 ) . Yohimbine , which exhibits negligible affinity for rat P28335 receptors but has high P41595 receptor affinity , acted as a potent but non - surmountable antagonist ( pA2 > or = 7 . 3 ) in rat jugular vein . Neither yohimbine nor SB 200646 affected endothelium - dependent relaxations induced by carbachol . 3 . DB06148 also acted as a surmountable antagonist ( pA2 = 7 . 3 ) and the P41595 agonist , BW 723C86 , acted as a potent partial agonist ( pEC50 [ 95 % C L ] , intrinsic activity +/- s . e . mean = 7 . 9 [ 7 . 6 - 8 . 3 ] , 0 . 84 +/- 0 . 04 ) . Responses to BW 723C86 were antagonized by SB 200646 ( 0 . 3 microM ) yielding an ' apparent ' pA2 [ 95 % CL ] of 7 . 03 [ 6 . 76 - 7 . 32 ] . 4 . These data are consistent with the presence of P41595 receptors mediating endothelium - dependent relaxation of rat jugular vein .\",\n \"Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .\",\n \"[ Moclobemide ( ___MASK36___ ) , the first P21397 - inhibitor : really something new ? ] .\",\n \"Thermoregulatory responses to serotonin ( 5 - HT ) receptor stimulation in the rat . Evidence for opposing roles of 5 - HT2 and P08908 receptors . The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated . The administration of the serotonin ( 5 - HT ) agonist 6 - chloro - 2 ( 1 - piperazinyl )- pyrazine ( MK - 212 ) produced a dose - related increase in body temperature . A maximal increase in body temperature of approx . 1 . 1 degrees C was observed 30 min after the administration of 3 mg / kg of MK - 212 . In contrast , administration of the putative P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) resulted in marked , dose - related hypothermic responses . Body temperatures were decreased approx . 3 degrees C 30 min after an injection of 0 . 3 mg / kg of 8 - OH - DPAT . Body temperatures were affected differentially by 5 - methoxy - N , N - dimethyltryptamine ( 5 - MeODMT ) . Large doses ( 3 - 10 mg / kg ) of 5 - MeODMT elicited hyperthermic responses , whereas small doses ( 0 . 5 - 1 . 0 mg / kg ) produced hypothermic responses . Treatment of rats with ketanserin ( 3 mg / kg ) completely prevented the hyperthermic effects of 5 - MeODMT , and , in fact , converted a hyperthermic response to 5 - MeODMT into a marked hypothermic response . Ketanserin ( 0 . 1 - 1 . 0 mg / kg ) selectively antagonized the hyperthermic response to MK - 212 but did not alter the hypothermic effect of 8 - OH - DPAT . DB06148 ( 10 mg / kg ) and pirenperone ( 0 . 03 mg / kg ) also selectively antagonized hyperthermia induced by MK - 212 . In contrast , pindolol ( 0 . 03 - 0 . 1 mg / kg ) and methiothepin ( 10 mg / kg ) selectively antagonized hypothermia induced by 8 - OH - DPAT but did not alter hyperthermia induced by MK - 212 . Spiperone ( 0 . 1 - 3 mg / kg ) and pizotifen ( 10 mg / kg ) attenuated the effects of both 8 - OH - DPAT and MK - 212 . Xylamidine , a peripheral 5 - HT antagonist , had no significant effect on hyperthermia induced by MK - 212 or hypothermia induced by 8 - OH - DPAT . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .\",\n \"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .\",\n \"Effect of valproic acid on serotonin - 2A receptor signaling in P13671 glioma cells . Valproic acid ( DB00313 ) , which has demonstrated efficacy in the treatment of bipolar disorder , has been shown to alter components of the phosphoinositide ( PI ) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 ( AP - 1 ) . Central serotonin - 2A ( 5 - Q13049 ) receptors , which have been implicated in the pathophysiology of manic - depressive illness , are coupled to PI hydrolysis . The promoter region of the 5 - Q13049 receptor gene contains AP - 1 binding sites . We examined in P13671 glioma cells the effect of DB00313 on 5 - Q13049 receptor signaling . Treatment of cells with DB00313 ( 100 microg / mL ) for 20 h , but not 1 . 5 h , resulted in an enhancement of 5 - Q13049 receptor - stimulated PI hydrolysis . This effect of 20 - h DB00313 exposure appeared not to be at the level of G protein or effector ( i . e . phospholipase C : P98160 ) as inositol phosphate accumulation stimulated by aluminum fluoride or the P98160 activator 2 , 4 , 6 - trimethyl - N -( m - 3 - trifluromethylphenyl ) benzenesulfonamide was not increased . The number of 5 - Q13049 receptors , as determined in saturation binding experiments using [ 3H ] ketanserin , was increased by 20 - h DB00313 treatment , with no change in affinity ( KD ) . Taken together , our data suggest that the increase in 5 - Q13049 receptor - mediated PI hydrolysis following 20 - h DB00313 exposure is not due to a general effect of DB00313 on this signaling cascade , but due to the up - regulation of 5 - Q13049 receptor number .\",\n \"Effects of antidepressants on intracellular Ca2 + mobilization in CHO cells transfected with the human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in P28335 receptors expressed in Chinese hamster ovary ( CHO ) cells ; and fura - 2 / AM was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] - mesulergine binding ( kd = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from basal level of 99 +/- 1 . 8 nM up to 246 +/- 21 . 2 nM , with an EC50 value for 5 - HT of . 015 microM . Exposure to 5 - HT , a 5 - HT receptor agonist , mCPP [ 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ] , a P28335 agonist , and DOI [ 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ] , a P28335 and 5 - HT2 agonist , resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . DB06148 and amoxapine inhibited 5 - HT - mediated intracellular Ca2 + mobilization completely ; amitriptyline , nortriptyline , and imipramine reduced it about 50 % . These results suggest that antagonism in CHO cells transfected with human P28335 receptors is a component of the serotonergic properties of a number of established antidepressants .\",\n \"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .\",\n \"Involvement of P08908 and 5 - HT2 receptor in cisplatin induced emesis in dogs . The effect of drug acting on P08908 , 5 - HT2 and 5 - Q9H205 receptors were studied against cisplatin and apomorphine induced emesis in dogs . Buspirone , P08908 receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency . DB06148 , 5 - HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency . Buspirone prevented the apomorphine induced emesis while mianserin had no effect . The antiemetic activity of buspirone may be attributable to its agonistic activity at P08908 receptor and antagonistic activity at dopamine receptors . These findings further confirm the involvement of P08908 and 5 - HT2 receptor in cytotoxic drug induced emesis , though the species difference in their antiemetic action can not be ruled out .\",\n \"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK59___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .\",\n \"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK17___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .\",\n \"Presence of a P34969 receptor positively coupled to adenylate cyclase activation in human granulosa - lutein cells . Although serotonin ( 5 - HT ) has been shown to stimulate progesterone production by human granulosa - lutein cells ( hGLC ) , the receptor type and associated signaling pathway remain uncharacterized . We report here that 5 - HT receptors in these cells are positively coupled to adenylate cyclase activity . Formation of DB02527 was stimulated by 5 - HT and its agonists in a dose - and time - dependent manner . DB06148 , amoxapine , and loxapine were equipotent in antagonizing 5 - HT - induced DB02527 formation . For both DB02527 formation in cells and adenylate cyclase assay using membrane fractions , the rank order of potency for agonists of 5 - HT were : 5 - carboxy - aminotryptamine > 5 - HT > or = 5 - methoxytryptamine , consistent with a typical pharmacological profile of human 5 - ht7 ( h5 - ht7 ) receptor . Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5 - ht7 receptor complementary DNA . Northern analysis showed the presence of 2 . 8 - kb h5 - ht7 transcripts in hGLC . The three variants h5 - ht7A , h5 - ht7B , and h5 - ht7D were also detected in hGLC . Preincubation of hGLC with 5 - HT ( 10 (- 8 )- 10 (- 6 ) M ) resulted in a marked reduction in the DB02527 response when the cells were subsequently stimulated with gonadotropin , and this heterologous desensitization could be reversed by 5 - ht7 receptor antagonist clozapine . These data demonstrate that h5 - ht7 receptor is present and stimulate DB02527 formation in hGLC . In addition , the h5 - ht7 receptor seems to be implicated in the heterologous down - regulation hCG - stimulated DB02527 response in hGLC , with a possible ramification for luteal insufficiency .\",\n \"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK15___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"Activating mutations of the serotonin P28335 receptor . Site - directed mutagenesis was performed to create a mutant serotonin P28335 receptor that would mimic the active conformation of the native receptor . Structural alteration of receptor conformation was achieved by changing amino acid no . 312 from serine to phenylalanine ( S312F ) or lysine ( S312K ) . After expression in COS - 7 cells , the binding affinity of 5 - HT for [ 3H ] mesulergine - labeled P28335 receptors increased from 203 nM ( native ) to 76 nM for S312F and 6 . 6 nM for S312K mutant receptors . 5 - HT potency for stimulation of phosphatidylinositol ( PI ) hydrolysis increased from 70 nM ( native ) to 28 nM for S312F and 2 . 7 nM for S312K mutant receptors . The mutant receptors were constitutively active , stimulating PI hydrolysis in the absence of agonist . S312F and S312K mutations resulted in twofold and five - fold increases , respectively , in basal levels of PI hydrolysis . DB06148 and mesulergine displayed inverse agonist activity by decreasing basal levels of PI hydrolysis stimulated by S312K mutant receptors . [ 3H ] 5 - HT and [ 3H ] mesulergine labeled the same number of S312K mutant receptors and 5 '- guanylylimidodiphosphate had no effect on [ 3H ] 5 - HT binding . These results indicate that serine --> lysine mutation at amino acid no . 312 produces an agonist high - affinity state of the P28335 receptor that spontaneously couples to G proteins and stimulates PI hydrolysis in the absence of agonist .\",\n \"Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .\",\n \"Roles of E3 ubiquitin ligases in cell adhesion and migration . Recent studies have demonstrated that a number of E3 ubiquitin ligases , including Cbl , Smurf1 , Smurf2 , HDM2 , BCA2 , P21583 ( beta - TRCP ) and XRNF185 , play important roles in cell adhesion and migration . Cbl negatively regulates cell adhesion via alpha integrin and Rap1 and inhibits actin polymerization by ubiquitinating mDab1 and Q9Y6W5 . Smurf1 regulates cell migration through ubiquitination of RhoA , talin head domain and hPEM2 , while Smurf2 ubiquitinates Smurf1 , TGFbeta type I receptor and RaplB to modulate cell migration and adhesion . HDM2 negatively regulates cell migration by targeting NFAT ( a transcription factor ) for ubiquitination and degradation , while P21583 ( beta - TRCP ) ubiquitinates Snail ( a transcriptional repressor of P12830 ) to inhibit cell migration . Q13049 promotes cell migration through ubiquitination of Q9NYB9 ( Abi2 ) , a tumor suppressor . Q99942 and XRNF185 modulate cell migration by ubiquitinating paxillin . Thus , these E3 ubiquitin ligases regulate cell adhesion and ( or ) migration through ubiquitination of their specific substrates .\",\n \"Chronic mianserin or eltoprazine treatment in rats : effects on the elevated plus - maze test and on limbic P28335 receptor levels . Rats were chronically treated with mianserin ( 10 mg / kg i . p . ) or eltoprazine ( 1 mg / kg i . p . ) and were tested in the elevated plus - maze test for anxiety . P28335 ( previously P28335 , see Humphrey et al . , 1993 , Trends Pharmacol . Sci . 14 , 223 ) binding sites and their mRNA were evaluated in limbic structures ( i . e . , amygdala , hippocampus , septum ) of a sample of these rats by autoradiographic binding studies and in situ hybridization histochemistry . DB06148 and eltoprazine displayed opposite effects in the elevated plus - maze : mianserin induced anxiolytic - like effects , while eltoprazine showed anxiogenic - like ones . Within the amygdala , but not in other structures , the quantitative autoradiographic analysis of the P28335 binding sites showed a differential effect : mianserin treatment induced a decrease in the number of these sites , while eltoprazine treatment resulted in an increase . In spite of this , neither mianserin - nor eltoprazine - treated rats displayed an alteration in the P28335 receptor mRNA levels in the brain regions examined . Our results are suggestive of a relation between anxiolytic / anxiogenic - like effects and the level of P28335 binding sites in the amygdala .\",\n \"Effects of antidepressants on the exploration , spontaneous motor activity and isolation - induced aggressiveness in mice . OBJECTIVE : To study the role of different antidepressants on exploration , spontaneous motor activity and isolation - induced aggressiveness in mice , further to discuss different mechanisms of their anti - aggression . METHODS : With an aggressive model induced by isolation housing in mice , antagonism of different antidepressants against isolation - induced aggression was evaluated . In the group - housed mice given the same treatment as aggressive test , exploration and spontaneous motor activity were measured . RESULTS : ( 1 ) DB06148 ( 0 . 5 - 5 mg / kg - 1 ) , buspirone ( 2 . 5 - 10 mg . kg - 1 ) and meclobemide ( 2 . 5 - 10 mg . kg - 1 ) significantly inhibited the exploration in the group - housed mice , but not fluoxetine ( 2 . 5 - 10 mg . kg - 1 ) , imipramine ( 2 . 5 - 10 mg . kg - 1 ) and DOI ( 0 . 5 - 2 mg . kg - 1 ) ; ( 2 ) Both mianserin and buspirone , but not fluoxetine , imipramine , meclobemide and DOI , obviously reduced spontaneous motor activity ; ( 3 ) DB00472 , miaserin , imipramine and buspirone significantly and dose - dependently antagonized isolation - induced aggressive behavior , whereas meclobemide failed to attenuate aggression . DOI dual - regulated aggressiveness in isolation mice . CONCLUSION : Our findings suggest that the effects of fluoxetine , mianserin , buspirone , imipramine , meclobemide and DOI on exploration , spontaneous motor activity and isolation - induced aggression in mice are different , which may involve different pharmacological mechanisms underlying their anti - aggression in isolation mice . P08908 and 5 - Q13049 / 2C receptors may mediate isolation - induced aggressive behavior in mice . The involvement of 5 - HT receptor subtypes needs further clarification .\",\n \"[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD .\",\n \"Involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory P21554 receptors . The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia . In this review , we will firstly provide a background , brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia . We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal P34969 , 5 - Q13049 and alpha - 2 adrenoceptors activation .\",\n \"Beneficial effect of low - dose mianserin on fluvoxamine - induced akathisia in an obsessive - compulsive patient . Extrapyramidal side effects induced by some selective serotonin reuptake inhibitors ( SSRIs ) , i . e . fluoxetine and sertraline , have been previously reported in patients with depression and obsessive - compulsive disorder ( OCD ) . However , the occurrence and management of akathisia induced by fluvoxamine have not been described . In the presented case fluvoxamine - induced akathisia in an OCD patient was partially resistant to the anticholinergic agent biperiden , and was successfully treated with the 5 - Q13049 / P28335 antagonist mianserin . DB06148 ( 15 mg / day at 21 . 00 h ) was discontinued and then reinstituted ( off - on - off - on design ) . DB00810 was transiently effective in the acute akathisia , while the more persistent akathisia was alleviated by mianserin . Discontinuation of mianserin resulted in recurrence of akathisia , while full amelioration of the symptoms of akathisia was noted when mianserin was reinstituted . No aggravation of OCD symptoms was noted during mianserin administration .\",\n \"Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells . Serotonin ( 5 - HT ) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis . In this study , we evaluated the role of 5 - HT on the functional features in neurospheres derived from adult neural stem cells ( ANSC ) . We cultured neurospheres derived from mouse hippocampus in serum - free medium containing epidermal ( P01133 ) and type - 2 fibroblast growth factor ( P09038 ) . Under these conditions ANSC expressed both isoforms of tryptophane - hydroxylase ( P17752 ) and produced 5 - HT . Blocking P17752 function by para - chlorophenylalanine ( PCPA ) reduced ANSC proliferation , which was rescued by exogenous 5 - HT . 5 - HT action on ANSC was mediated predominantly by the serotonin receptor subtype P08908 and , to a lesser extent , through the P28335 ( receptor ) subtype , as shown by selectively antagonizing these receptors . Finally , we documented a 5 - HT - induced increase of ANSC migration activity . In summary , we demonstrated a powerful serotonergic impact on ANSC functional features , which was mainly mediated by P08908 receptors .\",\n \"Modulation of antipsychotic - induced extrapyramidal side effects by medications for mood disorders . Antipsychotic drugs are widely used not only for schizophrenia , but also for mood disorders such as bipolar disorder and depression . To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects ( EPS ) , we examined the effects of antidepressants and mood - stabilizing drugs on haloperidol ( P42357 ) - induced bradykinesia and catalepsy in mice and rats . The selective serotonin reuptake inhibitors ( SSRIs ) , fluoxetine and paroxetine , and the tricyclic antidepressant ( TCA ) clomipramine , which showed no EPS by themselves , significantly potentiated P42357 - induced bradykinesia and catalepsy in a dose - dependent manner . In contrast , the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine failed to augment , but rather attenuated P42357 - induced bradykinesia and catalepsy . DB06148 also tended to reduce the EPS induction . In addition , neither treatment with lithium , sodium valproate nor carbamazepine potentiated P42357 - induced EPS . Furthermore , treatment of animals with ritanserin ( 5 - Q13049 / 2C antagonist ) , ondansetron ( 5 - Q9H205 antagonist ) , and SB - 258585 ( P50406 antagonist ) significantly antagonized the EPS augmentation by fluoxetine . Intrastriatal injection of ritanserin or SB - 258585 , but not ondansetron , also attenuated the EPS induction . The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction . In addition , 5 - Q13049 / 2C , 5 - Q9H205 and P50406 receptors seem to be responsible for the augmentation of antipsychotic - induced EPS by serotonin reuptake inhibitors .\",\n \"DB06148 - induced down - regulation of human 5 - hydroxytryptamine2A and 5 - hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5 - hydroxytryptamine2A ( 5 - Q13049 ) and P28335 receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . Incubation of cells expressing the 5 - Q13049 receptor with mianserin ( 100 nM ) for 24 h caused a significant decrease ( 48 % ) in the binding capacity of [ 3H ] ketanserin . This receptor down - regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5 - HT but not by carbachol . Exposure of cells expressing the P28335 receptor to mianserin ( 100 nM ) for 72 h but not for 24 h similarly resulted in a significant reduction ( 44 % ) in [ 3H ] mesulergine binding . Corresponding analysis of inositol phosphate production by 5 - HT at the P28335 receptor after incubation with mianserin showed no change in maximal response after 24 h . No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h . A decrease in the binding affinity of both radioligands was also observed after mianserin treatment , but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h , and was probably due to the retention of mianserin within the tissue . We conclude that antagonist down - regulation is evident at human 5 - Q13049 and P28335 receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor .\",\n \"DB00502 , but not clozapine , produces dramatic catalepsy in delta9 - THC - treated rats : possible clinical implications . The effect on rat catalepsy induced by Delta9 - tetrahydrocannabinol ( Delta9 - THC ) in association with haloperidol ( HP ) or clozapine ( CLOZ ) administration was investigated . Delta9 - THC dose - dependently increased HP ( 0 . 05 - 1 mg kg - 1 , s . c . ) - induced rat catalepsy , while no catalepsy was observed after CLOZ ( 1 - 20 mg kg - 1 , s . c . ) or Delta9 - THC + CLOZ administration . The P21554 antagonist SR141716A ( 0 . 5 - 5 mg kg - 1 , i . p . ) reversed the increase mediated by Delta9 - THC on HP - induced catalepsy . The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP + Delta9 - THC ; however , higher doses of quinpirole were needed in the presence of Delta9 - THC . The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP + Delta9 - THC in a similar manner . CLOZ and the 5 - Q13049 / 2C antagonists ritanserin , RS102221 and SB242084 were more effective in antagonizing HP than HP + Delta9 - THC - induced catalepsy . 7 HP and CLOZ failed to inhibit in vitro [ 3H ] CP - 55 , 940 binding , while Delta9 - THC and SR141716A did not show an appreciable affinity for the D2 receptor . It was suggested that the different effects on rat catalepsy induced by Delta9 - THC following HP or CLOZ administration may depend on the receptor - binding profiles of the two antipsychotics . The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed .\"\n]"},"candidates":{"kind":"list like","value":["___MASK15___","___MASK16___","___MASK17___","___MASK36___","___MASK37___","___MASK50___","___MASK59___","___MASK72___","___MASK73___"],"string":"[\n \"___MASK15___\",\n \"___MASK16___\",\n \"___MASK17___\",\n \"___MASK36___\",\n \"___MASK37___\",\n \"___MASK50___\",\n \"___MASK59___\",\n \"___MASK72___\",\n \"___MASK73___\"\n]"},"answer":{"kind":"string","value":"___MASK36___"},"id":{"kind":"string","value":"MH_train_398"}}},{"rowIdx":399,"cells":{"query":{"kind":"string","value":"interacts_with DB00987?"},"supports":{"kind":"list like","value":["Characterization of the region of the short arm of chromosome 8 amplified in breast carcinoma . Chromosomal region 8p11 . 2 - p12 is consistently amplified in human breast cancer . We have constructed a 2 . 8 Mb YAC contig of this region , centered on the human Fibroblast Growth Factor Receptor 1 ( P11362 ) locus and encompassing the Adrenergic beta 3 Receptor ( P13945 ) locus . A smaller centromeric YAC contig spanning 1 . 4 Mb was also assembled , and included the Ankyrin 1 ( P16157 ) and Tissue - type P00747 Activator ( P00750 ) genes . Results from mapping of the contigs showed physical linkage of the P13945 and P11362 genes , which were colocalized within the same YAC clone and separated by about 900 kb , P11362 being in centromeric position . It also showed physical linkage of P16157 and P00750 genes , which appear to be separated by a maximum of 700 kb . In parallel , several loci were mapped according to their amplification status in a large panel of breast tumor samples . The overall amplification pattern suggested a continuous amplicon with a core around P11362 . Data from both the detailed physical map and the amplification status allowed to establish the following gene order , from telomere to centromere : P13945 - D8S105 - P11362 - P16157 - P00750 - P06746 . The precise localization and YAC cloning of the core of the amplicon will allow to isolate a putative oncogene involved in mammary carcinogenesis .","P49674 / P35222 are synthetic lethal to P04637 in colorectal cancer and are markers for prognosis . Two genes are called synthetic lethal ( SL ) if their simultaneous mutations lead to cell death , but each individual mutation does not . Targeting SL partners of mutated cancer genes can kill cancer cells specifically , but leave normal cells intact . We present an integrated approach to uncovering SL pairs in colorectal cancer ( CRC ) . Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues , we first identified potential functionally relevant ( simultaneously differentially expressed ) gene pairs . From the top - ranked pairs , ~ 20 genes were chosen for immunohistochemistry ( IHC ) staining in 171 CRC patients . To find novel SL pairs , all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features , e . g . overall survival . Of the 11 predicted SL pairs , P43246 - P06746 and P49674 - MYC were consistent with literature , and we validated the top two pairs , P49674 - P04637 and P35222 - P04637 using RNAi knockdown and small molecule inhibitors of P49674 in isogenic HCT - 116 and RKO cells . Furthermore , synthetic lethality of P49674 and P04637 was verified in mouse model . Importantly , multivariate analysis revealed that P49674 - P04637 , P35222 - P04637 , P43246 - P06400 , and P38398 - P41221 were independent prognosis markers from stage , with P49674 - P04637 applicable to early - stage and the remaining three throughout all stages . Our findings suggest that P49674 is a promising target for P04637 - mutant CRC patients which constitute ~ 40 % to 50 % of patients , while to date safety regarding inhibition of P04637 is controversial . Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics , and it is readily accessible and applicable to other cancers .","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK67___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK99___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","The P06746 replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots . We have found a significant concordance between the in vitro replication errors of human P06746 and in vivo point mutations of the adenomatous polyposis coli ( P25054 ) gene that leads to colon cancer . We determined the error spectrum of P06746 in the human P25054 gene under PCR conditions and compared it with the set of mutations reported in human colon tumors . Polymerase beta created seven hotspot mutations within 141 target bp analyzed in P25054 exon 15 . Three of these polymerase beta hotspots , 2 frameshifts and a bp substitution mutation , were concordant with 3 of 13 P25054 hotspots detected in human colon cancers in the same DNA sequences . These 3 concordant hotspots accounted for some 54 % of reported in vivo P25054 hotspot mutations . Using the assumption of a hypergeometric distribution of hotspot mutations among bp of the scanned sequences , the probability of this concordance occurring by chance is < 4 x 10 (- 4 ) . These data support the hypothesis that P06746 errors are an important fraction of cancer - causing P25054 mutations .","Involvement of base excision repair in response to therapy targeted at thymidylate synthase . P04818 ( TS ) is an important target of several classes of chemotherapeutic agents . Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure , uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation . Base excision repair ( BER ) plays a primary role in removing damaged or modified bases from the genome , including uracil . Because of uracil misincorporation , BER is hypothesized to play a role in the cellular response to thymidylate deprivation . In this study , we used murine embryo fibroblasts wild - type or homozygous null for P06746 ( beta - pol ) , which plays a central role in BER . We found that , compared with wild - type , beta - pol null cells were resistant to the toxic effects of raltitrexed ( ___MASK84___ , ___MASK84___ ) , a folate inhibitor of TS . There was little difference in TS levels or in TS - ligand complex formation between the cell lines . Furthermore , cells deficient in P18887 , a scaffold protein for the final steps of BER , were also modestly resistant to raltitrexed compared with P18887 - proficient cells . Cell cycle analysis revealed that the responses of the wild - type and beta - pol null cells were similar during drug exposure . However , following drug removal , the beta - pol null cells appeared to resume cell cycle progression more rapidly than the wild - type cells . The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors , and that this role occurs during recovery from TS inhibition .","Effects of 1 - beta - D - arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by P06746 . DB00987 ( ara - C ) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis . The precise mechanism responsible for this inhibitory effect , however , remains unclear . The present work has examined the effects of the triphosphate derivative , ara - P53007 , on purified P06746 . These studies were performed on M13 phage DNA templates of defined sequence . The results demonstrate that ara - C is incorporated into DNA by P06746 . The results also demonstrate that the incorporated ara - C residue acts as a relative chain terminator . Moreover , the relative chain terminating effects of ara - C are sequence specific . In this regard , DNA strand elongation was progressively slowed at sequences of two , three , and four contiguous sites for cytosine incorporation . We also demonstrate that the inhibitory effects of ara - C are reversed by competition with deoxycytidine - triphosphate for incorporation into the DNA strand . Taken together , these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3 '- terminus and thereby inhibit chain elongation . These findings also provide new insights regarding the inhibitory effects of ara - C on elongation of specific DNA sequences .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK80___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","Inhibition of mammalian DNA polymerases by recombinant alpha - interferon and gamma - interferon . Interferons ( IFNs ) have been shown to suppress the growth of both normal and malignant cells . We examined the effect of gene - cloned IFN - alpha and P01579 on the in vitro activities of human , calf , or rat DNA polymerases . IFN - alpha strongly inhibited the reactions of DNA polymerase alpha and beta at apparent Ki values of 1 . 25 and 0 . 35 x 10 ( 5 ) antiviral units / ml , respectively , but inhibited DNA polymerase gamma only slightly . P01579 inhibited the reaction of DNA polymerase alpha more strongly ( Ki , 1 . 2 x 10 ( 4 ) units / ml ) than IFN - alpha , but not that of P06746 . On the other hand , neither IFN - alpha nor P01579 inhibited the reactions of DNA polymerase I from Escherichia coli , Klenow fragment , T - 4 DNA polymerase , and RNA polymerase . The fact that Ki values for IFN - alpha of DNA polymerase from calf thymus , human leukemic cells , and rat liver were similar suggests the absence of species specificity among animals with regard to the inhibition of DNA polymerases by IFNs . These results indicate that DNA polymerase may be one of the targets of the action of IFNs .","Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant P00441 gene . Growing evidence has recently shown that mutant P00441 accumulate in the mitochondria and cause vacuolation in transgenic mice carrying mutant P00441 , an animal model of amyotrophic lateral sclerosis ( P35858 ) . In this study , the expressions of DNA repair enzymes , oxoguanine glycosylase 1 ( ogg1 ) , P06746 ( polbeta ) , and DNA polymerase gamma ( polgamma ) were examined in transgenic mice with an P35858 - linked mutant P00441 gene , a valuable model for human P35858 . In presymptomatic Tg mice , the nuclear form of ogg1 was upregulated , whereas mitochondrial ogg1 remained at the same level . DNA polymerase was selectively downregulated in the mitochondria . This study suggests an impaired protective mechanism against oxidative stress in mitochondria . The expressions of these enzymes are predominant in spinal motor neurons , suggesting a mechanism of selective motor neuron death in this animal model of P35858 .","Modulation of 3 - hydroxy - 3 - methylglutaryl - DB01992 reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells . The homeostasis of intracellular cholesterol in animal cells is highly regulated by a complex system in which the microsomal rate - limiting enzyme 3 - hydroxy - 3 - methylglutaryl DB01992 ( HMG - DB01992 ) reductase plays a key role in cholesterol synthesis . Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase ( P00441 ) inhibits the P04035 activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis . Although these data suggest that P00441 exerts a physiological role in cholesterol metabolism , it is still unclear whether the decrease of P04035 activity is mediated by transcriptional or by posttranscriptional events . The results of the present study , obtained by one - step RT - PCR assay , demonstrated that both P00441 and the metal - free form of enzyme ( Apo P00441 ) inhibit P04035 gene expression in hepatocarcinoma HepG2 cells , in normal human fibroblasts , and in fibroblasts of subjects affected by familiar hypercholesterolemia . Accordingly , P00441 could be used as a potential agent in the treatment of hypercholesterolemia , even in subjects lacking a functional P01130 pathway .","Modulation of arsenic - induced epidermal growth factor receptor pathway signalling by resveratrol . Arsenic ( As ) is both a human carcinogen and an effective anticancer drug . These aspects of arsenic toxicity develop as a consequence of arsenic - induced oxidative stress and modifications to signal pathway activity which alter gene expression . DB02709 ( RVL ) a food antioxidant found in grapes and other fruits , exhibits anti - carcinogenic properties by reducing oxidative stress and restoring signal pathway control . This study investigated the impact of RVL on arsenite [ As ( III ) ] - induced cell signalling in HaCaT keratinocytes by assaying phosphorylation status of epidermal growth factor receptor ( P00533 ) signalling intermediates and measuring changes in expression of Phase II and DNA repair biomarkers . As ( III ) exposure produced dose - dependent toxicity which was associated with increased activation of P00533 pathway intermediates , cSrc , Rac1 and extracellular signal - regulated kinases 1 and 2 ( P27361 / 2 ) . Arsenic - mediated P27361 / 2 activation negatively regulated P06746 expression and up regulated heme - oxygenase - 1 at toxic concentrations . RVL treatment modulated As ( III )- mediated P27361 / 2 activation by shifting the balance of cSrc regulatory domain phosphorylation . These effects significantly altered the response of the P00533 pathway to growth factor - induced stimulation . Our research provides evidence that treatment with pharmacologically relevant doses of RVL influences cellular responses to As ( III ) , largely due to RVL - mediated changes to Src and P27361 / 2 activation .","___MASK37___ enhances neurogenesis and oligodendrogenesis in ischemic brain of middle - aged mouse . Adult neural stem cells give rise to neurons , oligodendrocytes and astrocytes . Aging reduces neural stem cells . Using an inducible nestin - CreER ( P24752 )/ R26R - yellow fluorescent protein ( YFP ) mouse , we investigated the effect of ___MASK37___ , a phosphodiesterase type 5 ( O76074 ) inhibitor , on nestin lineage neural stem cells and their progeny in the ischemic brain of the middle - aged mouse . We showed that focal cerebral ischemia induced nestin lineage neural stem cells in the subventricular zone ( SVZ ) of the lateral ventricles and nestin expressing NeuN positive neurons and adenomatous polyposis coli ( P25054 ) positive mature oligodendrocytes in the ischemic striatum and corpus callosum in the aged mouse . Treatment of the ischemic middle - aged mouse with ___MASK37___ increased nestin expressing neural stem cells , mature neurons , and oligodendrocytes by 33 , 75 , and 30 % , respectively , in the ischemic brain . These data indicate that ___MASK37___ amplifies nestin expressing neural stem cells and their neuronal and oligodendrocyte progeny in the ischemic brain of the middle - aged mouse .","The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .","Effect of pulsed estrogen therapy on hemostatic markers in comparison with oral estrogen regimen in postmenopausal women . BACKGROUND / AIMS : Hormone replacement therapy ( HRT ) is associated with an increased risk of thromboembolism dependent on the type of HRT ; therefore , we compared therapy effects of intranasal with oral estrogens on coagulation and fibrinolysis markers in postmenopausal women . METHODS : A randomized study in which 29 healthy hysterectomized women received intranasal 17beta - estradiol or oral estrogens for 3 months . RESULTS : There were no significant differences in the baseline characteristics between groups . Those women receiving intranasal estradiol showed a mild increment in plasminogen activator inhibitor - 1 ( P05121 - I ) ( from 6 . 8 +/- 3 . 5 to 9 . 6 +/- 3 . 9 U / ml , p < 0 . 01 ) ; however , fibrinogen , factor VII - tissue factor complex ( VIIa - rTF ) , antithrombin III ( P01008 ) , protein C ( PC ) activity , protein S ( PS ) activity , plasminogen ( P00747 ) , and tissue - type plasminogen activator antigen ( t - PA ) were unchanged . In contrast , oral unopposed estrogens elevated t - PA ( from 4 . 9 +/- 2 . 9 to 9 . 6 +/- 5 . 1 ng / ml , p < 0 . 01 ) in parallel with a decrement in P05121 - I ( from 5 . 2 +/- 4 . 0 to 2 . 7 +/- 1 . 7 U / ml , p < 0 . 05 ) and VIIa - rTF ( from 201 . 2 +/- 181 . 0 to 140 . 6 +/- 108 . 7 mU / ml , p < 0 . 05 ) . DB09222 , P01008 , PC , PS , and P00747 were unchanged . CONCLUSIONS : Nasal 17beta - estradiol had no effect on the coagulation markers , except a moderate increment in P05121 . In contrast , oral estrogens elicited a decrement in both VIIa - rTF and P05121 ; however , those changes did not surpass normal limits .","Anti - clastogenic effect of beta - glucan extracted from barley towards chemically induced DNA damage in rodent cells . beta - Glucan ( BG ) was tested in vitro to determine its potential clastogenic and / or anti - clastogenic activity , and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase . The study was carried out on cells deficient ( CHO - k1 ) and cells proficient ( HTC ) in phases I and II enzymes , and the DNA damage was assessed by the chromosomal aberration assay . BG did not show a clastogenic effect , but was anti - clastogenic in both cell lines used , and at all concentrations tested ( 2 . 5 , 5 and 10 microg / mL ) in combination with damage inducing agents ( methylmethane sulfonate in cell line CHO - k1 , and methylmethane sulfonate or 2 - aminoanthracene in cell line HTC ) . BG also showed a protective effect in the presence of a P06746 inhibitor ( cytosine arabinoside - 3 - phosphate , DB00987 ) , demonstrating that BG does not act through an anti - mutagenic mechanism of action involving P06746 .","[ ___MASK63___ sodium ( Photofrin - II ) ] . ___MASK63___ sodium ( ___MASK63___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK63___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .","Transient overexpression of mitochondrial transcription factor A ( Q00059 ) is sufficient to stimulate mitochondrial DNA transcription , but not sufficient to increase mtDNA copy number in cultured cells . Mitochondrial transcription factor A ( Q00059 ) stimulates transcription from mitochondrial DNA ( mtDNA ) promoters in vitro and in organello . To investigate whether changes of Q00059 levels also modulate transcription and replication in situ , the protein was transiently overexpressed in cultured cells . Mitochondrial mRNAs were significantly elevated at early time points , when no expansion of the Q00059 pool was yet observed , but were decreased when Q00059 levels had doubled , resemb - ling in vitro results . P29320 cells contain about 35 molecules of Q00059 per mtDNA . High levels of Q00059 were not associated with increases of full - length mtDNA , but nucleic acid species sensitive to RNAse H increased . Stimulation of transcription was more evident when Q00059 was transiently overexpressed in cells pre - treated with ethidium bromide ( EBr ) having lowered mtDNA , Q00059 and mitochondrial transcript levels . EBr rapidly inhibited mtDNA transcription , while decay of mtDNA was delayed and preferentially slowly migrating , relaxed mtDNA species were depleted . In conclusion , we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of Q00059 within the matrix is sufficient to stimulate mitochondrial transcription . Thus , this protein meets all criteria for being a key factor regulating mitochondrial transcription in vivo , but other factors are necessary for increasing mtDNA copy number , at least in cultured cells .","___MASK86___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK86___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .","Effects of DNA polymerase inhibitors on replicative and repair DNA synthesis in ultraviolet - irradiated HeLa cells . Aphidicolin specifically inhibits eukaryotic DNA polymerase alpha , while 2 ', 3 '- dideoxythymidine 5 '- triphosphate ( d2TTP ) inhibits P06746 and gamma but not alpha . DB00987 5 '- triphosphate ( araCTP ) inhibits both DNA polymerase alpha and beta although to a different extent . Here we measured the effects of these inhibitors on repair DNA synthesis of U . V .- irradiated HeLa cells by two different methods . Firstly , aphidicolin , 1 - beta - D - arabinofuranosylcytosine ( araC , a precursor of araCTP ) and 2 ', 3 '- dideoxythimidine ( d2Thd , a precursor of d2TTP ) were added directly to the culture medium . In this case , aphidicolin and araC strongly inhibited replicative DNA synthesis of HeLa cells , and they also inhibited repair synthesis after U . V .- irradiation but to a much lesser extent . In contrast , high concentrations of d2Thd inhibited repair DNA synthesis to a higher extent than replicative DNA synthesis . Secondly , the active form of inhibitor , d2TTP , was microinjection directly into cytoplasm or nuclei or U . V .- irradiated HeLa cells . Microinjection of d2TTP effectively inhibited repair synthesis . The microinjection of d2TTP , into either cytoplasm or nucleus , strongly inhibited replicative synthesis . These results might indicate that multiple DNA polymerases are involved in repair synthesis as well as in replicative synthesis .","P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK42___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK39___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .","New features of mitochondrial DNA replication system in yeast and man . In this review , we sum up the research carried out over two decades on mitochondrial DNA ( mtDNA ) replication , primarily by comparing this system in Saccharomyces cerevisiae and Homo sapiens . Brief incursions into systems of other organisms have also been achieved when they provide new information . S . cerevisiae and H . sapiens mitochondrial DNA ( mtDNA ) have been thought for a long time to share closely related architecture and replication mechanisms . However , recent studies suggest that mitochondrial genome of S . cerevisiae may be formed , at least partially , from linear multimeric molecules , while human mtDNA is circular . Although several proteins involved in the replication of these two genomes are very similar , divergences are also now increasingly evident . As an example , the recently cloned human mitochondrial P06746 - subunit has no counterpart in yeast . Yet , yeast Abf2p and human Q00059 are probably not as closely functionally related as thought previously . Some mtDNA metabolism factors , like DNA ligases , were until recently largely uncharacterized , and have been found to be derived from alternative nuclear products . Many factors involved in the metabolism of mitochondrial DNA are linked through genetic or biochemical interconnections . These links are presented on a map . Finally , we discuss recent studies suggesting that the yeast mtDNA replication system diverges from that observed in man , and may involve recombination , possibly coupled to alternative replication mechanisms like rolling circle replication ."],"string":"[\n \"Characterization of the region of the short arm of chromosome 8 amplified in breast carcinoma . Chromosomal region 8p11 . 2 - p12 is consistently amplified in human breast cancer . We have constructed a 2 . 8 Mb YAC contig of this region , centered on the human Fibroblast Growth Factor Receptor 1 ( P11362 ) locus and encompassing the Adrenergic beta 3 Receptor ( P13945 ) locus . A smaller centromeric YAC contig spanning 1 . 4 Mb was also assembled , and included the Ankyrin 1 ( P16157 ) and Tissue - type P00747 Activator ( P00750 ) genes . Results from mapping of the contigs showed physical linkage of the P13945 and P11362 genes , which were colocalized within the same YAC clone and separated by about 900 kb , P11362 being in centromeric position . It also showed physical linkage of P16157 and P00750 genes , which appear to be separated by a maximum of 700 kb . In parallel , several loci were mapped according to their amplification status in a large panel of breast tumor samples . The overall amplification pattern suggested a continuous amplicon with a core around P11362 . Data from both the detailed physical map and the amplification status allowed to establish the following gene order , from telomere to centromere : P13945 - D8S105 - P11362 - P16157 - P00750 - P06746 . The precise localization and YAC cloning of the core of the amplicon will allow to isolate a putative oncogene involved in mammary carcinogenesis .\",\n \"P49674 / P35222 are synthetic lethal to P04637 in colorectal cancer and are markers for prognosis . Two genes are called synthetic lethal ( SL ) if their simultaneous mutations lead to cell death , but each individual mutation does not . Targeting SL partners of mutated cancer genes can kill cancer cells specifically , but leave normal cells intact . We present an integrated approach to uncovering SL pairs in colorectal cancer ( CRC ) . Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues , we first identified potential functionally relevant ( simultaneously differentially expressed ) gene pairs . From the top - ranked pairs , ~ 20 genes were chosen for immunohistochemistry ( IHC ) staining in 171 CRC patients . To find novel SL pairs , all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features , e . g . overall survival . Of the 11 predicted SL pairs , P43246 - P06746 and P49674 - MYC were consistent with literature , and we validated the top two pairs , P49674 - P04637 and P35222 - P04637 using RNAi knockdown and small molecule inhibitors of P49674 in isogenic HCT - 116 and RKO cells . Furthermore , synthetic lethality of P49674 and P04637 was verified in mouse model . Importantly , multivariate analysis revealed that P49674 - P04637 , P35222 - P04637 , P43246 - P06400 , and P38398 - P41221 were independent prognosis markers from stage , with P49674 - P04637 applicable to early - stage and the remaining three throughout all stages . Our findings suggest that P49674 is a promising target for P04637 - mutant CRC patients which constitute ~ 40 % to 50 % of patients , while to date safety regarding inhibition of P04637 is controversial . Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics , and it is readily accessible and applicable to other cancers .\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK67___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK99___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"The P06746 replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots . We have found a significant concordance between the in vitro replication errors of human P06746 and in vivo point mutations of the adenomatous polyposis coli ( P25054 ) gene that leads to colon cancer . We determined the error spectrum of P06746 in the human P25054 gene under PCR conditions and compared it with the set of mutations reported in human colon tumors . Polymerase beta created seven hotspot mutations within 141 target bp analyzed in P25054 exon 15 . Three of these polymerase beta hotspots , 2 frameshifts and a bp substitution mutation , were concordant with 3 of 13 P25054 hotspots detected in human colon cancers in the same DNA sequences . These 3 concordant hotspots accounted for some 54 % of reported in vivo P25054 hotspot mutations . Using the assumption of a hypergeometric distribution of hotspot mutations among bp of the scanned sequences , the probability of this concordance occurring by chance is < 4 x 10 (- 4 ) . These data support the hypothesis that P06746 errors are an important fraction of cancer - causing P25054 mutations .\",\n \"Involvement of base excision repair in response to therapy targeted at thymidylate synthase . P04818 ( TS ) is an important target of several classes of chemotherapeutic agents . Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure , uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation . Base excision repair ( BER ) plays a primary role in removing damaged or modified bases from the genome , including uracil . Because of uracil misincorporation , BER is hypothesized to play a role in the cellular response to thymidylate deprivation . In this study , we used murine embryo fibroblasts wild - type or homozygous null for P06746 ( beta - pol ) , which plays a central role in BER . We found that , compared with wild - type , beta - pol null cells were resistant to the toxic effects of raltitrexed ( ___MASK84___ , ___MASK84___ ) , a folate inhibitor of TS . There was little difference in TS levels or in TS - ligand complex formation between the cell lines . Furthermore , cells deficient in P18887 , a scaffold protein for the final steps of BER , were also modestly resistant to raltitrexed compared with P18887 - proficient cells . Cell cycle analysis revealed that the responses of the wild - type and beta - pol null cells were similar during drug exposure . However , following drug removal , the beta - pol null cells appeared to resume cell cycle progression more rapidly than the wild - type cells . The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors , and that this role occurs during recovery from TS inhibition .\",\n \"Effects of 1 - beta - D - arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by P06746 . DB00987 ( ara - C ) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis . The precise mechanism responsible for this inhibitory effect , however , remains unclear . The present work has examined the effects of the triphosphate derivative , ara - P53007 , on purified P06746 . These studies were performed on M13 phage DNA templates of defined sequence . The results demonstrate that ara - C is incorporated into DNA by P06746 . The results also demonstrate that the incorporated ara - C residue acts as a relative chain terminator . Moreover , the relative chain terminating effects of ara - C are sequence specific . In this regard , DNA strand elongation was progressively slowed at sequences of two , three , and four contiguous sites for cytosine incorporation . We also demonstrate that the inhibitory effects of ara - C are reversed by competition with deoxycytidine - triphosphate for incorporation into the DNA strand . Taken together , these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3 '- terminus and thereby inhibit chain elongation . These findings also provide new insights regarding the inhibitory effects of ara - C on elongation of specific DNA sequences .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK80___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"Inhibition of mammalian DNA polymerases by recombinant alpha - interferon and gamma - interferon . Interferons ( IFNs ) have been shown to suppress the growth of both normal and malignant cells . We examined the effect of gene - cloned IFN - alpha and P01579 on the in vitro activities of human , calf , or rat DNA polymerases . IFN - alpha strongly inhibited the reactions of DNA polymerase alpha and beta at apparent Ki values of 1 . 25 and 0 . 35 x 10 ( 5 ) antiviral units / ml , respectively , but inhibited DNA polymerase gamma only slightly . P01579 inhibited the reaction of DNA polymerase alpha more strongly ( Ki , 1 . 2 x 10 ( 4 ) units / ml ) than IFN - alpha , but not that of P06746 . On the other hand , neither IFN - alpha nor P01579 inhibited the reactions of DNA polymerase I from Escherichia coli , Klenow fragment , T - 4 DNA polymerase , and RNA polymerase . The fact that Ki values for IFN - alpha of DNA polymerase from calf thymus , human leukemic cells , and rat liver were similar suggests the absence of species specificity among animals with regard to the inhibition of DNA polymerases by IFNs . These results indicate that DNA polymerase may be one of the targets of the action of IFNs .\",\n \"Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant P00441 gene . Growing evidence has recently shown that mutant P00441 accumulate in the mitochondria and cause vacuolation in transgenic mice carrying mutant P00441 , an animal model of amyotrophic lateral sclerosis ( P35858 ) . In this study , the expressions of DNA repair enzymes , oxoguanine glycosylase 1 ( ogg1 ) , P06746 ( polbeta ) , and DNA polymerase gamma ( polgamma ) were examined in transgenic mice with an P35858 - linked mutant P00441 gene , a valuable model for human P35858 . In presymptomatic Tg mice , the nuclear form of ogg1 was upregulated , whereas mitochondrial ogg1 remained at the same level . DNA polymerase was selectively downregulated in the mitochondria . This study suggests an impaired protective mechanism against oxidative stress in mitochondria . The expressions of these enzymes are predominant in spinal motor neurons , suggesting a mechanism of selective motor neuron death in this animal model of P35858 .\",\n \"Modulation of 3 - hydroxy - 3 - methylglutaryl - DB01992 reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells . The homeostasis of intracellular cholesterol in animal cells is highly regulated by a complex system in which the microsomal rate - limiting enzyme 3 - hydroxy - 3 - methylglutaryl DB01992 ( HMG - DB01992 ) reductase plays a key role in cholesterol synthesis . Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase ( P00441 ) inhibits the P04035 activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis . Although these data suggest that P00441 exerts a physiological role in cholesterol metabolism , it is still unclear whether the decrease of P04035 activity is mediated by transcriptional or by posttranscriptional events . The results of the present study , obtained by one - step RT - PCR assay , demonstrated that both P00441 and the metal - free form of enzyme ( Apo P00441 ) inhibit P04035 gene expression in hepatocarcinoma HepG2 cells , in normal human fibroblasts , and in fibroblasts of subjects affected by familiar hypercholesterolemia . Accordingly , P00441 could be used as a potential agent in the treatment of hypercholesterolemia , even in subjects lacking a functional P01130 pathway .\",\n \"Modulation of arsenic - induced epidermal growth factor receptor pathway signalling by resveratrol . Arsenic ( As ) is both a human carcinogen and an effective anticancer drug . These aspects of arsenic toxicity develop as a consequence of arsenic - induced oxidative stress and modifications to signal pathway activity which alter gene expression . DB02709 ( RVL ) a food antioxidant found in grapes and other fruits , exhibits anti - carcinogenic properties by reducing oxidative stress and restoring signal pathway control . This study investigated the impact of RVL on arsenite [ As ( III ) ] - induced cell signalling in HaCaT keratinocytes by assaying phosphorylation status of epidermal growth factor receptor ( P00533 ) signalling intermediates and measuring changes in expression of Phase II and DNA repair biomarkers . As ( III ) exposure produced dose - dependent toxicity which was associated with increased activation of P00533 pathway intermediates , cSrc , Rac1 and extracellular signal - regulated kinases 1 and 2 ( P27361 / 2 ) . Arsenic - mediated P27361 / 2 activation negatively regulated P06746 expression and up regulated heme - oxygenase - 1 at toxic concentrations . RVL treatment modulated As ( III )- mediated P27361 / 2 activation by shifting the balance of cSrc regulatory domain phosphorylation . These effects significantly altered the response of the P00533 pathway to growth factor - induced stimulation . Our research provides evidence that treatment with pharmacologically relevant doses of RVL influences cellular responses to As ( III ) , largely due to RVL - mediated changes to Src and P27361 / 2 activation .\",\n \"___MASK37___ enhances neurogenesis and oligodendrogenesis in ischemic brain of middle - aged mouse . Adult neural stem cells give rise to neurons , oligodendrocytes and astrocytes . Aging reduces neural stem cells . Using an inducible nestin - CreER ( P24752 )/ R26R - yellow fluorescent protein ( YFP ) mouse , we investigated the effect of ___MASK37___ , a phosphodiesterase type 5 ( O76074 ) inhibitor , on nestin lineage neural stem cells and their progeny in the ischemic brain of the middle - aged mouse . We showed that focal cerebral ischemia induced nestin lineage neural stem cells in the subventricular zone ( SVZ ) of the lateral ventricles and nestin expressing NeuN positive neurons and adenomatous polyposis coli ( P25054 ) positive mature oligodendrocytes in the ischemic striatum and corpus callosum in the aged mouse . Treatment of the ischemic middle - aged mouse with ___MASK37___ increased nestin expressing neural stem cells , mature neurons , and oligodendrocytes by 33 , 75 , and 30 % , respectively , in the ischemic brain . These data indicate that ___MASK37___ amplifies nestin expressing neural stem cells and their neuronal and oligodendrocyte progeny in the ischemic brain of the middle - aged mouse .\",\n \"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .\",\n \"Effect of pulsed estrogen therapy on hemostatic markers in comparison with oral estrogen regimen in postmenopausal women . BACKGROUND / AIMS : Hormone replacement therapy ( HRT ) is associated with an increased risk of thromboembolism dependent on the type of HRT ; therefore , we compared therapy effects of intranasal with oral estrogens on coagulation and fibrinolysis markers in postmenopausal women . METHODS : A randomized study in which 29 healthy hysterectomized women received intranasal 17beta - estradiol or oral estrogens for 3 months . RESULTS : There were no significant differences in the baseline characteristics between groups . Those women receiving intranasal estradiol showed a mild increment in plasminogen activator inhibitor - 1 ( P05121 - I ) ( from 6 . 8 +/- 3 . 5 to 9 . 6 +/- 3 . 9 U / ml , p < 0 . 01 ) ; however , fibrinogen , factor VII - tissue factor complex ( VIIa - rTF ) , antithrombin III ( P01008 ) , protein C ( PC ) activity , protein S ( PS ) activity , plasminogen ( P00747 ) , and tissue - type plasminogen activator antigen ( t - PA ) were unchanged . In contrast , oral unopposed estrogens elevated t - PA ( from 4 . 9 +/- 2 . 9 to 9 . 6 +/- 5 . 1 ng / ml , p < 0 . 01 ) in parallel with a decrement in P05121 - I ( from 5 . 2 +/- 4 . 0 to 2 . 7 +/- 1 . 7 U / ml , p < 0 . 05 ) and VIIa - rTF ( from 201 . 2 +/- 181 . 0 to 140 . 6 +/- 108 . 7 mU / ml , p < 0 . 05 ) . DB09222 , P01008 , PC , PS , and P00747 were unchanged . CONCLUSIONS : Nasal 17beta - estradiol had no effect on the coagulation markers , except a moderate increment in P05121 . In contrast , oral estrogens elicited a decrement in both VIIa - rTF and P05121 ; however , those changes did not surpass normal limits .\",\n \"Anti - clastogenic effect of beta - glucan extracted from barley towards chemically induced DNA damage in rodent cells . beta - Glucan ( BG ) was tested in vitro to determine its potential clastogenic and / or anti - clastogenic activity , and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase . The study was carried out on cells deficient ( CHO - k1 ) and cells proficient ( HTC ) in phases I and II enzymes , and the DNA damage was assessed by the chromosomal aberration assay . BG did not show a clastogenic effect , but was anti - clastogenic in both cell lines used , and at all concentrations tested ( 2 . 5 , 5 and 10 microg / mL ) in combination with damage inducing agents ( methylmethane sulfonate in cell line CHO - k1 , and methylmethane sulfonate or 2 - aminoanthracene in cell line HTC ) . BG also showed a protective effect in the presence of a P06746 inhibitor ( cytosine arabinoside - 3 - phosphate , DB00987 ) , demonstrating that BG does not act through an anti - mutagenic mechanism of action involving P06746 .\",\n \"[ ___MASK63___ sodium ( Photofrin - II ) ] . ___MASK63___ sodium ( ___MASK63___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK63___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .\",\n \"Transient overexpression of mitochondrial transcription factor A ( Q00059 ) is sufficient to stimulate mitochondrial DNA transcription , but not sufficient to increase mtDNA copy number in cultured cells . Mitochondrial transcription factor A ( Q00059 ) stimulates transcription from mitochondrial DNA ( mtDNA ) promoters in vitro and in organello . To investigate whether changes of Q00059 levels also modulate transcription and replication in situ , the protein was transiently overexpressed in cultured cells . Mitochondrial mRNAs were significantly elevated at early time points , when no expansion of the Q00059 pool was yet observed , but were decreased when Q00059 levels had doubled , resemb - ling in vitro results . P29320 cells contain about 35 molecules of Q00059 per mtDNA . High levels of Q00059 were not associated with increases of full - length mtDNA , but nucleic acid species sensitive to RNAse H increased . Stimulation of transcription was more evident when Q00059 was transiently overexpressed in cells pre - treated with ethidium bromide ( EBr ) having lowered mtDNA , Q00059 and mitochondrial transcript levels . EBr rapidly inhibited mtDNA transcription , while decay of mtDNA was delayed and preferentially slowly migrating , relaxed mtDNA species were depleted . In conclusion , we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of Q00059 within the matrix is sufficient to stimulate mitochondrial transcription . Thus , this protein meets all criteria for being a key factor regulating mitochondrial transcription in vivo , but other factors are necessary for increasing mtDNA copy number , at least in cultured cells .\",\n \"___MASK86___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK86___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .\",\n \"Effects of DNA polymerase inhibitors on replicative and repair DNA synthesis in ultraviolet - irradiated HeLa cells . Aphidicolin specifically inhibits eukaryotic DNA polymerase alpha , while 2 ', 3 '- dideoxythymidine 5 '- triphosphate ( d2TTP ) inhibits P06746 and gamma but not alpha . DB00987 5 '- triphosphate ( araCTP ) inhibits both DNA polymerase alpha and beta although to a different extent . Here we measured the effects of these inhibitors on repair DNA synthesis of U . V .- irradiated HeLa cells by two different methods . Firstly , aphidicolin , 1 - beta - D - arabinofuranosylcytosine ( araC , a precursor of araCTP ) and 2 ', 3 '- dideoxythimidine ( d2Thd , a precursor of d2TTP ) were added directly to the culture medium . In this case , aphidicolin and araC strongly inhibited replicative DNA synthesis of HeLa cells , and they also inhibited repair synthesis after U . V .- irradiation but to a much lesser extent . In contrast , high concentrations of d2Thd inhibited repair DNA synthesis to a higher extent than replicative DNA synthesis . Secondly , the active form of inhibitor , d2TTP , was microinjection directly into cytoplasm or nuclei or U . V .- irradiated HeLa cells . Microinjection of d2TTP effectively inhibited repair synthesis . The microinjection of d2TTP , into either cytoplasm or nucleus , strongly inhibited replicative synthesis . These results might indicate that multiple DNA polymerases are involved in repair synthesis as well as in replicative synthesis .\",\n \"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK42___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK39___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .\",\n \"New features of mitochondrial DNA replication system in yeast and man . In this review , we sum up the research carried out over two decades on mitochondrial DNA ( mtDNA ) replication , primarily by comparing this system in Saccharomyces cerevisiae and Homo sapiens . Brief incursions into systems of other organisms have also been achieved when they provide new information . S . cerevisiae and H . sapiens mitochondrial DNA ( mtDNA ) have been thought for a long time to share closely related architecture and replication mechanisms . However , recent studies suggest that mitochondrial genome of S . cerevisiae may be formed , at least partially , from linear multimeric molecules , while human mtDNA is circular . Although several proteins involved in the replication of these two genomes are very similar , divergences are also now increasingly evident . As an example , the recently cloned human mitochondrial P06746 - subunit has no counterpart in yeast . Yet , yeast Abf2p and human Q00059 are probably not as closely functionally related as thought previously . Some mtDNA metabolism factors , like DNA ligases , were until recently largely uncharacterized , and have been found to be derived from alternative nuclear products . Many factors involved in the metabolism of mitochondrial DNA are linked through genetic or biochemical interconnections . These links are presented on a map . Finally , we discuss recent studies suggesting that the yeast mtDNA replication system diverges from that observed in man , and may involve recombination , possibly coupled to alternative replication mechanisms like rolling circle replication .\"\n]"},"candidates":{"kind":"list like","value":["___MASK37___","___MASK39___","___MASK42___","___MASK63___","___MASK67___","___MASK80___","___MASK84___","___MASK86___","___MASK99___"],"string":"[\n \"___MASK37___\",\n \"___MASK39___\",\n \"___MASK42___\",\n \"___MASK63___\",\n \"___MASK67___\",\n \"___MASK80___\",\n \"___MASK84___\",\n \"___MASK86___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK86___"},"id":{"kind":"string","value":"MH_train_399"}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":3,"numItemsPerPage":100,"numTotalItems":1620,"offset":300,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc2NTUwODEwNiwic3ViIjoiL2RhdGFzZXRzL2NvbW11bml0eS1kYXRhc2V0cy9xYW5nYXJvbyIsImV4cCI6MTc2NTUxMTcwNiwiaXNzIjoiaHR0cHM6Ly9odWdnaW5nZmFjZS5jbyJ9.ohbG0jnlPoVdVBJM1n6EJnU06CFS7Ws7eODrG-wKBzWTWw8B8fSRj8-T1RYiP8HdMGBGRvWjoR_YzUQXBzjfCQ","displayUrls":true,"splitSizeSummaries":[{"config":"masked_medhop","split":"train","numRows":1620,"numBytesParquet":50027308},{"config":"masked_medhop","split":"validation","numRows":342,"numBytesParquet":8774415},{"config":"masked_wikihop","split":"train","numRows":43738,"numBytesParquet":187716381},{"config":"masked_wikihop","split":"validation","numRows":5129,"numBytesParquet":23586614},{"config":"medhop","split":"train","numRows":1620,"numBytesParquet":49190527},{"config":"medhop","split":"validation","numRows":342,"numBytesParquet":8647233},{"config":"wikihop","split":"train","numRows":43738,"numBytesParquet":179876427},{"config":"wikihop","split":"validation","numRows":5129,"numBytesParquet":22578535}]},"discussionsStats":{"closed":6,"open":0,"total":6},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
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"Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .",
"DB08916 in non - small cell lung cancer . INTRODUCTION : P00533 targeting is a valid and vital approach in the treatment of patients with lung cancer . However , all patients treated with reversible inhibitors develop acquired resistance over time . It is of paramount importance that novel agents are designed and developed to overcome such acquired resistance . AREAS COVERED : The role of P00533 targeting in NSCLC , mechanisms of primary and acquired resistance to reversible inhibitors , and strategies to overcome resistance are examined . Preclinical and clinical data pertaining to DB08916 in advanced solid tumors , and particularly in NSCLC , are also thoroughly reviewed . We hope that the reader will gain a comprehensive knowledge of the emerging field of resistance to P00533 inhibition , specifically relating to drugs being developed for lung cancer patients . EXPERT OPINION : Irreversible dual inhibitors of P00533 - P04626 such as DB08916 provide a promising approach to overcoming acquired resistance to erlotinib and gefitinib in lung cancer . It is yet to be seen whether the drug can overcome primary drug resistance or delay time to development of acquired resistance to P00533 - targeted agents in NSCLC .",
"Capture and identification of proteins that bind to a GGA - rich sequence from the P04626 gene promoter region . The P04626 gene ( P04626 / neu ) is overexpressed in many human breast cancers . It is an important therapeutic target and its product protein is a key biomarker for breast cancer . A 28 - bp GGA repeat sequence ( Pu28 - mer ) in the nuclease hypersensitive site of the P04626 promoter region may play an important role in the regulation of P04626 transcription , possibly involving the formation of a G - quadruplex . In order to investigate this possibility , an affinity MALDI - MS approach was used for in vitro protein capture from nuclear extracts from cultured MCF - 7 and BT - 474 cancer cells at Pu28 - mer and control oligonucleotide - modified surfaces . Captured proteins from MCF - 7 cells were analyzed by LC - MS / MS . Based on these results , Western blot was then used to interrogate captured proteins from both MCF - 7 and the Her - 2 / neu - positive BT - 474 cells . Results support the formation of a G - quadruplex by Pu28 - mer , indicated by circular dichroism spectroscopy , that selectively captures transcription factors including P12956 , P13010 , Q00577 , nucleolin , and P61978 . Chromatin immunoprecipitation confirmed binding of P12956 , P13010 , Q00577 , and nucleolin to P04626 promoter in the live BT - 474 cells . These findings may lead to a better understanding of the role of non - duplex DNA structures in gene regulation and provide a more complete picture of the regulation of ErbB2 expression in breast cancer . The results also provide a blueprint for development of \" genome - inspired \" aptamers based on the Pu28 - mer sequence for in vitro and in vivo detection of proteins related to regulation of P04626 gene expression and breast cancer .",
"Combined effects of C225 and 125 - iodine seed radiation on colorectal cancer cells . BACKGROUND : To characterize the effect of combined treatment of the anti - epidermal growth factor receptor ( P00533 ) monoclonal antibody C225 and 125 - iodine ( 125I ) seed radiation in human colorectal cancer . METHODS : We treated LS180 cells with 125I continuous low dose rate radiation in the presence and absence of 100 nM C225 . The clonogenic capacity , cellular proliferation , cell cycle distribution , apoptosis , and molecular pathways of the cells following the treatments were analyzed in vitro . RESULTS : The sensitizer enhancement ratio of C225 was approximately 1 . 4 . Treatment with C225 and radiation alone produced significant inhibition of cell growth , but combination therapy produced greater inhibition than either treatment administered alone . C225 increased the radiation - induced apoptosis and the fraction of γ - P16104 foci positive cells at 48 h after treatment . The Akt phosphorylation level was lower in the cells receiving the combination treatment than in the cells treated with radiation or C225 alone . CONCLUSIONS : These findings indicate that C225 sensitizes LS180 cells to 125I seed radiation . Growth inhibition is mediated by inducing apoptosis and not cell cycle arrest . Additionally , we confirmed that C225 impairs DNA repair by reducing the cellular level of the P78527 and P12956 proteins . Furthermore , the inhibition of Akt signaling activation may be responsible for the C225 - mediated radiosensitization .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK82___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"Anti - P04626 cancer therapy and cardiotoxicity . A significant milestone in the treatment of breast cancer is the identification of the P04626 receptor as a drug target for cancer therapies . DB00072 ( Herceptin ) , a monoclonal antibody that blocks the P04626 receptor , is among the first of such drugs approved by the US Food and Drug Administration for targeted cancer therapy . Clinical studies have shown that DB00072 significantly improves the overall survival of breast cancer patients . However , an unforeseen significant side - effect of cardiotoxicity manifested as left ventricular dysfunction and heart failure . Concurrent studies have demonstrated the essential role of the P04626 receptor in cardiac development and maintaining the physiological function of an adult heart . The P04626 receptor , therefore , has become a critical link between the oncology and cardiology fields . In addition to DB00072 , new drugs targeting the P04626 receptor , such as DB01259 , DB06366 and DB08916 , are either approved or being evaluated in clinical trials for cancer therapy . With the concern of cardiotoxicity caused by P04626 inhibition , it becomes clear that new therapeutic strategies for preventing such cardiac side effects need to be developed . It is the intent of this paper to review the potential cardiac impact of anti - P04626 cancer therapy .",
"___MASK90___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK90___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Concerted activation of ETS protein P50549 by P52701 coactivators , the acetyltransferase p300 and the receptor tyrosine kinase P04626 / Neu . Activator of thyroid and retinoic acid receptor ( Q9Y6Q9 ) is overexpressed in approximately 60 % of primary human breast tumors and belongs to the P52701 steroid receptor coactivator family . In this study , we identified a novel interaction partner of Q9Y6Q9 , the ETS transcription factor P50549 that is also heavily implicated in mammary tumor formation . Q9Y6Q9 and related P52701 family members ( steroid receptor coactivator - 1 and glucocorticoid receptor - interacting protein - 1 ( Q9Y3R0 ) ) augment P50549 - mediated transcription . Although Q9Y6Q9 and Q9Y3R0 can acetylate P50549 , this posttranslational modification of P50549 is not required for its stimulation by Q9Y6Q9 or Q9Y3R0 . In addition , Q9Y6Q9 collaborates with the p300 coactivator , a joint interaction partner of Q9Y6Q9 and P50549 , to stimulate P50549 function and the ability of p300 to acetylate P50549 is indispensable for this collaboration . Furthermore , the receptor tyrosine kinase P04626 / Neu , an oncoprotein particularly found overexpressed in breast tumors , cooperates with both Q9Y6Q9 and p300 to stimulate P50549 - mediated transcription . Thus , oncogenic P04626 / Neu and Q9Y6Q9 may synergize to orchestrate mammary tumorigenesis through the dysregulation of the transcription factor P50549 and its target genes .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Dual kinase inhibition of P00533 and P04626 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance . PURPOSE : Acquired resistance to cetuximab , a chimeric epidermal growth factor receptor ( P00533 ) - targeting monoclonal antibody , is a widespread problem in the treatment of solid tumors . The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance , thereby limiting the development of effective treatments . The purpose of this study was to generate cetuximab - resistant tumors in vivo to characterize mechanisms of acquired resistance . EXPERIMENTAL DESIGN : We generated cetuximab - resistant clones from a cetuximab - sensitive bladder cancer cell line in vivo by exposing cetuximab - sensitive xenografts to increasing concentrations of cetuximab , followed by validation of the resistant phenotype in vivo and in vitro using invasion assays . A candidate - based approach was used to examine the role of P04626 on mediating cetuximab resistance both in vitro and in vivo . RESULTS : We generated a novel model of cetuximab resistance , and , for the first time in the context of P00533 - inhibitor resistance , we identified increased phosphorylation of a C - terminal fragment of P04626 ( 611 - CTF ) in cetuximab - resistant cells . DB08916 ( BIBW - 2992 ) , an irreversible kinase inhibitor targeting P00533 and P04626 , successfully inhibited growth of the cetuximab - resistant cells in vitro . When afatinib was combined with cetuximab in vivo , we observed an additive growth inhibitory effect in cetuximab - resistant xenografts . CONCLUSIONS : These data suggest that the use of dual P00533 - P04626 kinase inhibitors can enhance responses to cetuximab , perhaps in part due to downregulation of 611 - CTF . This study conducted in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality .",
"Diarrhea associated with afatinib : an oral ErbB family blocker . Gastrointestinal ( GI ) adverse events ( AEs ) are frequently observed in patients receiving P01133 receptor ( P00533 ; also known as P00533 or ErbB1 ) tyrosine kinase inhibitor therapy . GI AEs are among the most common and most impactful on a patient ' s quality of life . Severe diarrhea can result in fluid and electrolyte losses , leading to dehydration , electrolyte imbalances and renal insufficiency . DB08916 is an irreversible , oral , ErbB family blocker , inhibiting P00533 ( ErbB1 ) , P04626 ( ErbB2 ) and ErbB4 receptor kinases . It also inhibits transphosphorylation of ErbB3 . Similar to reversible tyrosine kinase inhibitors of P00533 , GI AEs - in particular , diarrhea - have frequently been observed in afatinib - treated patients . This article summarizes current data on afatinib - associated diarrhea and provides strategies for its management . Patient education , early identification , timely management and ongoing assessment will help to prevent aggravation , afatinib dose reductions or therapy discontinuation , encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent .",
"Next generation tyrosine kinase inhibitor ( TKI ) : afatinib . DB08916 is a recently introduced new tyrosine kinase inhibitor , approved by the USFDA on July 12 , 2013 . DB08916 is marketed under the trade name Gilotrif and developed by Boehringer Ingelheim GmbH . It is indicated for the first - line treatment of patients with metastatic non - small cell lung cancer ( NSCLC ) carrying P00533 exon 19 deletions or exon 21 ( L858R ) mutations . DB08916 is a covalent , irreversible inhibitor of epidermal growth factor receptor ( P00533 ) , human epidermal growth factor receptor 2 ( P04626 ) and Q15303 . Chemically afatinib is a 4 - anilinoquinazoline derivative , having an acrylamide warhead . Gilotrif is the formulation of DB08916 di - meleate salt . Presently , afatinib has been approved in the USA , the European Union , Taiwan and Mexico . In this review , we have summarized the chemical characterization of afatinib , its synthesis , patent status , marketed formulation , available crystalline form and current clinical trials .",
"Temporal molecular and biological assessment of an erlotinib - resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response . Patients with lung cancer with activating mutations in the P01133 receptor ( P00533 ) kinase , who are treated long - term with tyrosine kinase inhibitors ( TKI ) , often develop secondary mutations in P00533 associated with resistance . Mice engineered to develop lung adenocarcinomas driven by the human P00533 T790M resistance mutation are similarly resistant to the P00533 TKI erlotinib . By tumor volume endpoint analysis , these mouse tumors respond to DB08916 ( an irreversible P00533 / P04626 TKI ) and rapamycin combination therapy . To correlate P00533 - driven changes in the lung with response to drug treatment , we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment . Responses to single - drug treatments were temporary , whereas combination therapy elicited a sustained response . During tumor development , metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood . Combination drug treatment reversed many of the molecular changes found in tumored lung . Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments . Results from combination drug treatment suggest that metabolic transcriptional control through C - MYC and SREBP , as well as ELK1 , NRF1 , and Q16236 , depends on both P00533 and mTORC1 signaling . Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI - mediated antiproliferative effects also manifest in specific metabolic regulation .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK51___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"[ Adverse events of afatinib as first - line treatment for five cases of advanced lung adenocarcinoma and review of literature ] . BACKGROUND AND OBJECTIVE : DB08916 is an irreversible ErbB - family blocker with a clinical activity in non - small cell lung cancer with epidermal growth factor receptor ( P00533 ) mutations . The aim of this study is to assess the safety of afatinib in patients with advanced lung adenocarcinoma . METHODS : Patients with lung adenocarcinoma ( stage IIIb or IV ) with P00533 mutations were first - line treated with an oral administration of afatinib ( 40 mg / d ) until disease progression . Adverse events , effects , and survival condition were observed . RESULTS : The most common adverse events were diarrhea ( n = 5 , 100 % ) , skin rash ( n = 4 , 80 % ) , and mucositis / stomatitis ( n = 4 , 80 % ) . Moderate toxicities not exceeding grade 3 were observed . Relatively , the most serious adverse reaction was mucositis / stomatitis . Mild diarrhea occurred in all patients . Three patients experienced temporary drug withdrawal and dose reduction because of adverse reaction . Among the four patients who were evaluated , partial response was observed in two patients ( 50 % ) , one with stable disease ( 25 % ) and one with progressive disease ( 25 % ) . Median progression - free survival was 9 . 7 months , whereas median overall survival was 18 . 4 months . CONCLUSIONS : DB08916 was approved as first - line treatment for patients with advanced lung adenocarcinoma . The most common adverse events were diarrhea and skin rash . However , mucositis / stomatitis related to afatinib should also be considered . Considering the small number of cases , the conclusion requires more trials for confirmation .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK34___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .",
"Second - generation irreversible epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) : a better mousetrap ? A review of the clinical evidence . The discovery of activating epidermal growth factor receptor ( P00533 ) mutations in non - small cell lung cancer ( NSCLC ) in 2004 heralded the era of molecular targeted therapy in NSCLC . First - generation small molecule , reversible tyrosine kinase inhibitors ( TKIs ) of P00533 , gefitinib and erlotinib , had been approved for second - or third - line treatment of NSCLC prior to the knowledge of these mutations . However , resistance to gefitinib and erlotinib invariably develops after prolonged clinical use . Two second - generation irreversible P00533 TKIs , afatinib ( DB08916 ) and dacomitinib ( PF - 00299804 ) , that can potentially overcome the majority of these resistances are in late stage clinical development . Here I will review the clinical data of P00533 TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC : whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches .",
"Integration of P00533 inhibitors and conventional chemotherapy in the treatment of non - small - cell lung cancer . INTRODUCTION / BACKGROUND : Given the limited gains of traditional chemotherapy in improving outcomes in patients with advanced non - small - cell lung cancer ( NSCLC ) , recent research efforts have investigated the integration of targeted agents into the treatment algorithm . MATERIALS AND METHODS : Searches of PubMed and of recent results from key oncology congresses were performed to identify relevant articles and abstracts . Initial phase III trials combining the reversible epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) gefitinib and erlotinib with platinum - based doublets as first - line therapy failed to demonstrate an overall survival advantage in unselected patients with NSCLC . However , in recent years , there has been substantial progress in understanding the determinants of response to P00533 TKI therapy , including the presence of activating P00533 mutations , which has been reflected in clinical trials specifically evaluating these patient populations . In addition , evidence suggesting potential mechanistic interference between concurrent P00533 TKIs and chemotherapy has also been observed , fueling interest in sequential or intermittent dosing . P00533 - targeted agents such as the multitargeted TKI vandetanib and the next - generation P00533 TKIs afatinib ( DB08916 ) and PF00299804 are also under clinical investigation for the treatment of NSCLC , both alone and in combination with chemotherapy . CONCLUSIONS : Trials evaluating various regimens of P00533 - targeted agents and chemotherapy are planned and / or underway and will hopefully define the role of integrated therapy in NSCLC .",
"Effect of siRNAs targeting the P00533 T790M mutation in a non - small cell lung cancer cell line resistant to P00533 tyrosine kinase inhibitors and combination with various agents . The epidermal growth factor receptor ( P00533 ) is a validated therapeutic target in non - small cell lung cancer ( NSCLC ) . However , some mutations confer resistance to current available agents , especially the frequently occurring T790M mutation . In the current study , we have examined , in a NSCLC cell line H1975 containing both L858R and T790M mutations , the effect of T790M - specific - siRNAs versus other P00533 - specific - siRNAs . T790M - specific - siRNAs were able to inhibit T790M and P00533 mRNA , to reduce P00533 protein expression , as well as to reduce the cell growth and induce cell caspase activity in H1975 cells . However , this effect showed less potency compared to the other P00533 - specific - siRNAs . P00533 - specific - siRNAs strongly inhibited cell growth and induced apoptosis in H358 , H1650 , H292 , HCC827 and also in H1975 cells , which showed weak response to tyrosine kinase inhibitors ( TKIs ) or cetuximab . The addition of T790M - specific - siRNAs could rescue the sensitivity of T790M mutant H1975 cells to TKIs . The combination of T790M - specific - siRNAs and cetuximab also additively enhanced cell growth inhibition and induction of apoptosis in H1975 cells . Among the anti - P00533 agents tested , the strongest biological effect was observed when afatinib was combined with T790M - specific - siRNAs . DB08916 also offered extra effect when combined with cetuximab in H1975 cells . In conclusion , knock - down of T790M transcript by siRNAs further decreases the cell growth of T790M mutant lung cancer cells that are treated with TKIs or cetuximab . The combination of a potent , irreversible kinase inhibitor such as afatinib , with T790M - specific - siRNAs should be further investigated as a new strategy in the treatment of lung cancer containing the resistant T790M mutation .",
"Genome - wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome - wide transcriptional consequences are poorly understood . In this study , to reveal the impact of CNAs on genome - wide expression in gastric cancer , we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization ( array CGH ) and 24 of these 30 cases for their expression profiles by oligonucleotide - expression microarray . We found that with the application of laser microdissection , most CNAs were detected at higher frequency than in previous studies . Notably , gain at 20q13 was detected in almost all cases ( 97 % ) , suggesting that this may play an important role in the pathogenesis of gastric cancer . By comparing the array CGH data with expression profiles of the same samples , we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions . Furthermore , we identified 125 candidate genes , consisting of 114 up - regulated genes located in recurrent regions ( > 10 % ) of amplification and 11 down - regulated genes located in recurrent regions of deletion . Up - regulation of several candidate genes , such as Q99741 , P60059 , Q9BTT0 , Q13895 and P37268 , was confirmed by immunohistochemistry . Interestingly , some candidate genes were localized at genomic loci adjacent to well - known genes such as P00533 , P04626 and Q13485 , and concordantly deregulated by genomic alterations . Based on these results , we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer .",
"Integrin alpha5 - induced P00533 activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway . We have previously shown that prothrombin , a blood coagulation factor , can cause an inhibition of DNA synthesis in normal rat hepatocytes . To explore the mechanisms of this prothrombin action , we examined its effects on the activation of fibronectin receptor integrin alpha5 , since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures . We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor ( P00533 ) , leading to P00533 tyrosine phosphorylation at tyrosine residues DB00135 - 845 and DB00135 - 1173 . P00533 tyrosine phosphorylation triggered phosphorylation of its down - stream target Shc and the activation of the c - Jun N - terminal kinase ( JNK ) pathway . P00734 also induced hepatocyte apoptosis , a change in cell shape and activation of caspase 3 pathway . The JNK pathway is most likely involved in prothrombin - induced hepatocyte apoptosis , because pre - treatment of hepatocytes with JNK kinase inhibitor II ( SP600125 ) antagonized these prothrombin actions . The data suggest that integrin - related P00533 activation by prothrombin can induce cell growth inhibition and apoptosis via an P00533 - JNK signaling pathway .",
"DB08916 and lung cancer . P00533 tyrosine kinase inhibitors ( P00533 - TKI ) have an established role in the treatment of non - small - cell lung cancer ( NSCLC ) . First - generation reversible DB00171 - competitive P00533 - TKIs are approved for the initial treatment of patients with P00533 mutation - positive advanced NSCLC . DB08916 is an irreversible second - generation P00533 - TKI with potent preclinical activity against P00533 ( wild type and mutant ) , P04626 , Q15303 and P00533 - mutant NSCLC with acquired resistance to reversible P00533 - TKI . LUX - Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment - naïve patients with advanced adenocarcinoma of the lung and P00533 mutation . Based on these results , afatinib was recently approved for the first - line treatment of NSCLC patients with P00533 mutation . This article summarizes current status of preclinical and clinical development of afatinib in NSCLC .",
"Specific blockade of P15692 and P04626 pathways results in greater growth inhibition of breast cancer xenografts that overexpress P04626 . We have previously reported that breast cancer cells which overexpress P04626 produce higher levels of P15692 than cells with low levels of P04626 . This study tested the hypothesis that dual targeting of the P15692 ( with P15692 - Q8NHU6 ) and P04626 ( with trastuzumab ) pathways would result in greater growth inhibition of P04626 - overexpressing breast cancer xenografts than either agent alone . In this study we found that human and murine endothelial cells expressed high levels of P15692 receptors ( P17948 , P35968 , & P35916 ) . P15692 - Q8NHU6 decreased levels of secreted P15692 derived from both human and murine cells and effectively blocked P15692 - induced tyrosine phosphorylation of P35968 . P15692 - Q8NHU6 as a single treatment inhibited tumor microvessel density ( P53602 ) , tumor vasculature , cell proliferation and tumor growth of BT474 xenografts in a dose - dependent manner from 2 . 5 mg / kg to 25 mg / kg . P15692 - Q8NHU6 decreased levels of both human P15692 and P49763 protein in vivo . DB00072 as a single agent effectively inhibited BT474 tumor growth in a dose - dependent manner , associated with a decrease in human P15692 , tumor P53602 and tumor cell proliferation . Treatment with a combination of P15692 - Q8NHU6 ( 2 . 5 - 10 mg / kg ) and trastuzumab ( 1 mg / kg ) produced significantly greater inhibition of BT474 tumor growth than either individual agent , associated with greater inhibition of tumor P53602 and tumor cell proliferation . Thus , P15692 - Q8NHU6 in combination with trastuzumab produces superior growth inhibition of tumor xenografts which overexpress P04626 , which may result from inhibition of both tumor angiogenesis and proliferation . Similar mechanisms may contribute to the clinical anti - tumor activity of trastuzumab in combination with inhibitors of P15692 signaling pathway in women with breast cancers which overexpress P04626 .",
"Phase II Study of DB08916 as Third - Line Treatment for Patients in Korea With Stage IIIB / IV Non - Small Cell Lung Cancer Harboring Wild - Type P00533 .",
"Dermatologic adverse events associated with afatinib : an oral ErbB family blocker . Dermatologic adverse events ( AEs ) are frequently observed in patients receiving P01133 receptor ( P00533 ; also known as ErbB1 ) tyrosine kinase inhibitor therapy . The impact of these AEs goes beyond cosmesis to the discomfort from itching , pain and secondary infections , all of which may significantly impact on patient well - being , adherence and clinical outcomes . DB08916 is a potent , irreversible , oral , ErbB family blocker , inhibiting P00533 ( ErbB1 ) , P04626 ( ErbB2 ) and ErbB4 receptor kinases . It also inhibits transphosphorylation of ErbB3 . Similar to P00533 inhibitors , dermatologic AEs have been frequently observed in patients treated with afatinib . Papulopustular ( acneiform ) rash , pruritus , xerosis , paronychia and alopecia will require patient education and proactive treatment interventions . This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program , and provides strategies for their effective management .",
"DB08916 with concurrent radiotherapy in a patient with metastatic non - small cell lung cancer . BACKGROUND : The combination of radiotherapy and epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) such as erlotinib and gefitinib in patients with advanced or metastatic non - small cell lung cancer ( NSCLC ) has not been widely investigated . For afatinib , a new second generation irreversible pan - P00533 TKI , no clinical trials in this setting have as yet been performed . CASE REPORT : We report a patient with a pretreated metastatic NSCLC receiving afatinib in combination with concomitant palliative radiotherapy to the mediastinum and primary lung tumor . The treatment was feasible and well tolerated . The patient achieved a partial response in the irradiated tumor region and the metastatic sites . CONCLUSION : The combination of afatinib and radiotherapy is promising and should be investigated further . However , because of the limited experience and potential side effects known for other P00533 TKIs , a decision for treatment outside a clinical trial has to be made very carefully , balancing the risk and benefit on an individual patient basis .",
"[ Hange - Shashin - to for preventing diarrhea during afatinib therapy ] . DB08916 is an epidermal growth factor receptor - tyrosine kinase inhibitor ( P00533 - TKI ) . In a randomized phase III study ( Lux - Lung 3 study ) employing patients harboring P00533 mutations , patients administered afatinib show a significantly longer progression free survival time ( PFS ) than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However , most of the patients ( 95 . 2 % ) treatedwith afatinib experiencedd iarrhea . In the present report , 16 patients with P00533 mutations were treatedby afatinib at our institution from May 2014 to December 2014 . Twelve patients were administered a diarrhea prevention herbal medicine , Hange - shashin - to . Seven of 12 patients ( 58 % ) had no diarrhea during the 28 days of therapy . All 4 of the patients who did not receive Hange - shashin - to experienced diarrhea above Grade 1 within 6 days of starting therapy . The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin - to . In conclusion , preventive administration of Hange - shashin - to may reduce the occurrence of diarrhea during afatinib treatment .",
"Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .",
"[ Treatment strategy for activating P00533 - mutated non - small cell lung cancer after failure of first - generation P00533 - TKIs ] . Somatic activating mutations such as a deletion in exon 19 or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor ( P00533 ) are important mediators of cancer cell oncogenesis , proliferation , and survival . In the last decade , two P00533 target agents have significantly contributed to the understanding of non - small cell lung cancer ( NSCLC ) . Gefitinib and erlotinib are first - generation P00533 - tyrosine kinase inhibitors ( P00533 - TKIs ) that play a key role in activating P00533 - mutated NSCLC . Although these reversible , small , molecular target agents provide a significant response and survival benefit , all responders eventually acquire resistance . Although various mechanisms of resistance have been identified , nearly 3 0 % of patients who acquire resistance to P00533 - TKIs have an unknown mechanism of resistance . Approximately half the patients with P00533 - mutated NSCLC who develop acquired resistance to these molecular target agents have a secondary mutation T790M in the threonine gatekeeper residue that coexists with a primary P00533 activating mutation . The strategy for overcoming acquired resistance to first - generation P00533 - TKIs is a major clinical concept . DB08916 is a second - generation P00533 - targeting agent and an irreversible pan - HER inhibitor . It may improve survival further and help in potentially overcoming resistance to first - generation P00533 - TKIs in P00533 - mutated NSCLC . In patients harboring activating P00533 mutations , certain treatments could be suggested for subsequent therapy after failure of first - generation P00533 - TKIs . This review discusses novel therapeutic strategies for activating P00533 - mutated , advanced NSCLC after failure of first - generation P00533 - TKIs .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK49___ ( ___MASK49___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK49___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK49___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"DB08916 combined with cetuximab for lung adenocarcinoma with leptomeningeal carcinomatosis . We report a patient with non - small cell lung cancer ( NSCLC ) developed leptomeningeal carcinomatosis ( O15467 ) after 4 years of multiple treatments . High - dose tyrosine kinase inhibitor ( TKI ) was given for O15467 at first but was not effective . She then received dual therapy combining of afatinib and cetuximab . Brain magnetic resonance imaging ( Q9BWK5 ) showed a partial response of disease and the patient experienced a clinical benefit . Our case suggests that dual targeting of epidermal growth factor receptor ( P00533 ) by a combination of afatinib and cetuximab can be a potential novel treatment option in treating O15467 when high - dose TKI failed .",
"P00533 inhibition in lung cancer : the evolving role of individualized therapy . Non - small cell lung cancer ( NSCLC ) is the major cause of cancer - related deaths in the USA and worldwide . Most patients present with advanced disease , and treatment options for these patients are generally limited to platinum - based chemotherapy and a few targeted therapies . Targeted agents currently in use for NSCLC inhibit oncogenic receptor tyrosine kinase pathways , such as the epidermal growth factor receptor ( P00533 ) pathway . While current P00533 - targeted agents , including erlotinib and gefitinib , may result in dramatic responses , they demonstrate efficacy in only a fraction of patients , and resistance to these agents frequently develops . In order to select patients most likely to benefit from blockade of P00533 pathways , investigators have focused on identifying molecular correlates of response to anti - P00533 therapy . New strategies to minimize the risk of resistance to P00533 inhibition have been employed in the development of next - generation P00533 tyrosine kinase inhibitors , such as PF00299804 and DB08916 ; these include irreversibility of target binding , inhibition of multiple P00533 family receptors , and / or simultaneous inhibition of P00533 and other oncogenic pathways .",
"Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non - small cell lung cancer : comparative pharmacokinetics and drug - drug interactions . The development of orally active small molecule inhibitors of the epidermal growth factor receptor ( P00533 ) has led to new treatment options for non - small cell lung cancer ( NSCLC ) . Patients with activating mutations of the P00533 gene show sensitivity to , and clinical benefit from , treatment with P00533 tyrosine kinase inhibitors ( P00533 - TKls ) . First generation reversible DB00171 - competitive P00533 - TKls , gefitinib and erlotinib , are effective as first , second - line or maintenance therapy . Despite initial benefit , most patients develop resistance within a year , 50 - 60 % of cases being related to the appearance of a T790M gatekeeper mutation . Newer , irreversible P00533 - TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family ( P00533 , P04626 and Q15303 ) . These agents have been mainly evaluated for first - line treatment but also in the setting of acquired resistance to first - generation P00533 - TKls . DB08916 is the first ErbB family blocker approved for patients with NSCLC with activating P00533 mutations ; dacomitinib is in late stage clinical development . Mutant - selective P00533 inhibitors ( AZD9291 , CO - 1686 , HM61713 ) that specifically target the T790M resistance mutation are in early development . The P00533 - TKIs differ in their spectrum of target kinases , reversibility of binding to P00533 receptor , pharmacokinetics and potential for drug - drug interactions , as discussed in this review . For the clinician , these differences are relevant in the setting of polymedicated patients with NSCLC , as well as from the perspective of innovative anticancer drug combination strategies .",
"A phase I dose escalation study of DB08916 , an irreversible dual inhibitor of epidermal growth factor receptor 1 ( P00533 ) and 2 ( P04626 ) tyrosine kinase in a 2 - week on , 2 - week off schedule in patients with advanced solid tumours . To assess tolerability , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) and clinical activity of the dual epidermal growth factor receptor ( P00533 ) 1 and 2 ( P04626 ) tyrosine kinase inhibitor DB08916 . An escalating schedule of once - daily ( OD ) DB08916 for 14 days followed by 14 days off medication was explored . Thirty - eight patients were enrolled . Dose levels were 10 , 20 , 30 , 45 , 70 , 85 , and 100 mg . At 100 mg dose - limiting toxicity ( DLT ) ( common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide ) occurred in two patients . In the next - lower dose of 70 mg , DLT ( grade 3 fatigue and ALAT elevation ) occurred in one of six patients . An intermediate dose level of 85 mg was studied . Here DLT occurred in two patients ( grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment ) . An additional 12 patients were treated at 70 mg . DB08916 PK after single and multiple doses revealed moderately fast absorption , and no deviation from dose proportionality . Pharmacodynamics analysis in skin biopsies did not show significant changes in P00533 - associated biomarkers . However , a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed . No partial or complete responses were observed , stable disease lasting more than four cycles was seen in seven patients . The recommended dose for studies with DB08916 for 14 days followed by 14 days off medication is 70 mg OD .",
"The role of afatinib in the management of non - small cell lung carcinoma . INTRODUCTION : Despite initial patient benefit , drug resistance to first - generation P00533 tyrosine kinase inhibitors ( TKIs ) is inevitable . One of the key mechanisms responsible for the development of acquired drug resistance is the secondary T790M missense mutation in exon 20 of the P00533 kinase domain . DB08916 is an DB00171 - competitive small molecule inhibitor that potently and irreversibly inhibits P00533 and mutated P00533 including the T790M variant , as well as other members of the ErbB family in preclinical studies . AREAS COVERED : The authors describe the rationale and provide the preclinical background to afatinib and its potential as a NSCLC therapy . Specifically , the authors detail the drug ' s pharmaco - kinetic profile and review its clinical efficacy and toxicity profile . EXPERT OPINION : DB08916 is an effective treatment option for therapy - naive advanced NSCLC harboring an activating P00533 mutation . Furthermore , it is also of potential benefit to patients with acquired resistance to P00533 kinase inhibitors . In the future , the authors envision the clinical development of third - generation P00533 mutation - specific inhibitors in NSCLC , which may potentially spare normal tissue toxicity . Nevertheless , afatinib currently represents a bona fide treatment option in the NSCLC therapeutic armamentarium .",
"DB08916 monotherapy in P00533 - mutant lung adenocarcinoma .",
"___MASK92___ potentiation of multiple P13569 channels with gating mutations . BACKGROUND : The investigational P13569 potentiator ivacaftor ( VX - 770 ) increased P13569 channel activity and improved lung function in subjects with CF who have the G551D P13569 gating mutation . The aim of this in vitro study was to determine whether ivacaftor potentiates mutant P13569 with gating defects caused by other P13569 gating mutations . METHODS : The effects of ivacaftor on P13569 channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid ( P17948 ) cells expressing different P13569 gating mutations . RESULTS : ___MASK92___ potentiated multiple mutant P13569 forms with defects in P13569 channel gating . These included the G551D , G178R , S549N , S549R , G551S , G970R , G1244E , S1251N , S1255P and G1349D P13569 gating mutations . CONCLUSION : These in vitro data suggest that ivacaftor has a similar effect on all P13569 forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have P13569 gating mutations beyond G551D .",
"DB08916 enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem - like cells . Cancer stem cells ( CSC ) have garnered significant attention as a therapeutic focus , based on evidence that they may represent an etiologic root of treatment - resistant cells . Indeed , expression of the multidrug resistance protein DB00171 - binding cassette subfamily G member 2 ( Q9UNQ0 ) confers chemoresistance to CSCs , where it serves as a potential biomarker and therapeutic target . Here , we show that afatinib , a small - molecule inhibitor of the tyrosine kinases P00533 , P04626 , and Q15303 , preferentially eliminated side population cells with CSC character , in both cell lines and patient - derived leukemia cells , by decreasing Q9UNQ0 expression . In these cells , afatinib also acted in parallel to suppress self - renewal capacity and tumorigenicity . Combining afatinib with the DNA - damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo . Mechanistic investigations suggested that Q9UNQ0 suppression by afatinib did not proceed by proteolysis through the ubiquitin - dependent proteosome , lysosome , or calpain . Instead , we found that afatinib increased DNA methyltransferase activity , thereby leading to methylation of the Q9UNQ0 promoter and to a decrease in Q9UNQ0 message level . Taken together , our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication .",
"Clinical perspective of afatinib in non - small cell lung cancer . Reversible DB00171 - competitive inhibitors targeting the epidermal growth factor receptor ( P00533 ) have been established as the most effective treatment of patients with advanced non - small cell lung cancer ( NSCLC ) harboring \" activating \" mutations in exons 19 and 21 of the P00533 gene . However , clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment . The mechanisms for acquired resistance include selection of the P00533 T790M mutation in approximately 50 % of cases , and MET gene amplification , P42336 gene mutation , transdifferentiation into small - cell lung cancer and additional rare or unkown mechanisms . DB08916 is a small molecule covalently binding and inhibiting the P00533 , P04626 and Q15303 receptor tyrosine kinases . In preclinical studies , afatinib not only inhibited the growth of models with common activating P00533 mutations , but was also active in lung cancer models harboring wild - type P00533 or the P00533 L858R / T790M double mutant . Clinical efficacy of afatinib has been extensively studied in the LUX - Lung study program . These trials showed promising efficacy in patients with P00533 - mutant NSCLC or enriched for clinical benefit from P00533 tyrosine kinase inhibitors gefitinib or erlotinib . Here we review the current status of clinical application of afatinib in NSCLC . We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK56___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK56___ .",
"A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .",
"Discovery and structure - activity relationship of ( 1R ) - 8 - chloro - 2 , 3 , 4 , 5 - tetrahydro - 1 - methyl - 1H - 3 - benzazepine ( ___MASK61___ ) , a selective serotonin P28335 receptor agonist for the treatment of obesity . The synthesis and SAR of a novel 3 - benzazepine series of P28335 agonists is described . Compound 7d ( lorcaserin , APD356 ) was identified as one of the more potent and selective compounds in vitro ( pEC50 values in functional assays measuring [( 3 ) H ] phosphoinositol turnover : P28335 = 8 . 1 ; 5 - Q13049 = 6 . 8 ; P41595 = 6 . 1 ) and was potent in an acute in vivo rat food intake model upon oral administration ( ED50 at 6 h = 18 mg / kg ) . ___MASK61___ was further characterized in a single - dose pharmacokinetic study in rat ( t1 / 2 = 3 . 7 h ; F = 86 % ) and a 28 - day model of weight gain in growing Sprague - Dawley rat ( 8 . 5 % decrease in weight gain observed at 36 mg / kg b . i . d . ) . ___MASK61___ was selected for further evaluation in clinical trials for the treatment of obesity .",
"Q92574 involvement in bladder cancer : diverse effects and therapeutic implications . Q92574 is often mutated in bladder cancer . However the importance of this event in disease pathogenesis and its implications for therapy are uncertain . We used genomic sequencing to examine the involvement of Q92574 in bladder cancer , and signalling pathway analysis and small - molecule screening to identify targeted therapeutic strategies in Q92574 mutant bladder cancer cell lines . Q92574 loss of heterozygosity was seen in 54 % of bladder cancers . Two ( 4 . 9 % ) of these 41 bladder cancers had Q92574 mutations by exon - based sequencing . Analysis of 27 bladder cancer cell lines demonstrated inactivating Q92574 mutations in three : RT - 4 , HCV29 , 97 - 1 . Interestingly , only RT - 4 showed classic feedback inhibition of AKT , and was highly sensitive to treatment with P42345 inhibitors rapamycin and Torin1 . 97 - 1 cells showed constitutive P00533 activation , and were highly sensitive to combined treatment with the P42345 inhibitor Torin1 and P00533 inhibitors DB01259 or DB08916 . A P15056 missense mutation G469V was found in HCV29 cells , and AKT activation was dependent on P15056 , but independent of P29323 . A kinase inhibitor screen of HCV29 cells showed strong growth inhibition by the Hsp90 inhibitor DB00238 - AUY922 , and we then found synergistic inhibitory effects of DB00238 - AUY922 combined with either Torin1 or rapamycin on cell survival for both HCV29 and 97 - 1 cells . In aggregate , these findings indicate that there are highly variable mutation profiles and signalling pathway activation in Q92574 - mutant bladder cancer . Furthermore , combined Hsp90 / P42345 inhibition is a promising therapeutic approach for Q92574 mutant bladder cancer .",
"Specific properties of a C - terminal truncated androgen receptor detected in hormone refractory prostate cancer . Mutations in the human androgen receptor ( AR ) gene that lead to C - terminus truncated AR variants are frequently detected in prostate cancer ( PC ) . These AR variants lack both the ligand - binding domain ( LBD ) and the AF - 2 region . The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation , and to outline consequences of the loss of the LBD / AF - 2 region on their functional properties . By using an MMTV - luciferase reporter construct and LY294002 , UO126 , or ZD1839 , inhibitor of PI3K , Q02750 / 2 , and P00533 signaling pathway respectively , we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants , the Q640X mutant AR . Western - blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant . Furthermore , studies of the intranuclear colocalization of the Q640X AR with cofactors , such as CBP , Q9Y3R0 , and c - Jun , reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR . We demonstrated that CBP and c - Jun are highly recruited by the mutant AR , and this leads to an unexpected activation of AP - 1 , NFAT , and NFkappaB transcriptional activities . Similar enhanced activities of these transcription factors were not observed with the wild type AR . The importance of the LBD / AF - 2 for the regulation of AR transcriptional activities , the impact of the presence of such AR variants on PC cells proliferation and survival , and on progression to androgen independence are discussed .",
"Clinical and comparative utility of afatinib in non - small cell lung cancer . The first targeted agents approved for non - small cell lung cancer ( NSCLC ) treatment , the epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) gefitinib and erlotinib , have an impressive activity in the presence of activating mutations of the P00533 gene . However , all patients develop acquired resistance principally through secondary mutations ( T790M ) , P04626 amplification , MET amplification , and other molecular aberrations . An attempt to overcome P00533 TKI resistance has been through the development of irreversible blockers . DB08916 is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family . The pharmacologic properties of afatinib ( formation of covalent bonds , inhibition of other family members , and in vitro and in vivo activity on T790M mutation positive tumors ) made this drug particularly appealing to study in clinic . Therefore , an intense program of clinical research ( LUX - Lung program ) was started and clinical results have shown very encouraging activity profiles in patients harboring P00533 activating mutations and in those with acquired resistance to reversible TKIs .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK88___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK88___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK88___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"DB08916 demonstrates remarkable activity against P04626 - amplified uterine serous endometrial cancer in vitro and in vivo . BACKGROUND : Uterine serous carcinomas ( USCs ) are an aggressive form of uterine cancer that may rely on P04626 / neu amplification as a driver of proliferation . The objective of this paper is to assess the sensitivity of USC cell lines with and without P04626 / neu gene amplification to afatinib , an irreversible ErbB tyrosine kinase inhibitor , and to test the efficacy of afatinib in the treatment of P04626 - amplified USC xenografts . METHODS : Eight of fifteen primary USC cell lines ( four with P04626 amplification and four without ) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib . Effects on cell growth , signalling and cell cycle distribution were determined by flow cytometry assays . Mice harbouring xenografts of P04626 / neu - amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival . RESULTS : Primary chemotherapy - resistant USC cell lines harbouring P04626 / neu gene amplification were exquisitely sensitive to afatinib exposure ( mean ± s . e . m . IC50 = 0 . 0056 ± 0 . 0006 μM ) and significantly more sensitive than P04626 / neu - non - amplified USC cell lines ( mean ± s . e . m . IC50 = 0 . 563 ± 0 . 092 μM , P < 0 . 0001 ) . DB08916 exposure resulted in abrogation of cell survival , inhibition of P04626 / neu autophosphorylation and S6 transcription factor phosphorylation in P04626 / neu overexpressing USC and inhibited the growth of P04626 - amplified tumour xenografts improving overall survival ( P = 0 . 0017 ) . CONCLUSIONS : DB08916 may be highly effective against P04626 / neu - amplified chemotherapy - resistant USC . The investigation of afatinib in patients harbouring P04626 / neu - amplified USC is warranted .",
"DB09280 - ___MASK92___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"DB08916 prolongs survival compared with gefitinib in an epidermal growth factor receptor - driven lung cancer model . An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor ( P00533 ) mutations more strongly than reversible P00533 tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation . Eleven - week - old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib , gefitinib , or vehicle for 4 weeks . All mice were sacrificed at 15 weeks of age , and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted . The afatinib - treated group had significantly fewer tumors than the vehicle group ( P < 0 . 01 ) and tended to have fewer tumors than the gefitinib - treated group ( P = 0 . 06 ) . Pathologically , gefitinib - treated mice had clearer , more nodular tumors than afatinib - treated mice . Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2 , and induced apoptosis for longer periods than gefitinib . Subsequently , when each drug was administered 5 days per week until death , afatinib significantly enhanced mouse survival compared with gefitinib ( median survival time : 456 days vs . 376 . 5 days ; log - rank test , P < 0 . 01 ) . Finally , the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion / T790M and L858R / T790M xenograft tumors . Overall , afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation , and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation .",
"A phase II study of afatinib ( DB08916 ) , an irreversible ErbB family blocker , in patients with P04626 - positive metastatic breast cancer progressing after trastuzumab . DB08916 is an oral , ErbB family blocker , which covalently binds and irreversibly blocks all kinase - competent ErbB family members . This phase II , open - label , single - arm study explored afatinib activity in human epidermal growth factor receptor 2 ( P04626 ) - positive breast cancer patients progressing after trastuzumab treatment . Patients had stage IIIB / IV P04626 - positive metastatic breast cancer , with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 . Patients received 50 mg afatinib once - daily until disease progression . Primary endpoint was objective response rate ( Response Evaluation Criteria in Solid Tumors 1 . 0 ) , with tumor assessments every 8 weeks . Forty - one patients were treated . Patients had received a median of three prior chemotherapy lines ( range , 0 - 15 ) and 68 . 3 % had received trastuzumab for > 1 year . Four patients ( 10 % of 41 treated ; 11 % of evaluable patients ) had partial response . Fifteen patients ( 37 % of 41 ) had stable disease as best response and 19 ( 46 % of 41 ) achieved clinical benefit . Median progression - free survival was 15 . 1 weeks ( 95 % confidence interval [ CI ] : 8 . 1 - 16 . 7 ) ; median overall survival was 61 . 0 weeks ( 95 % CI : 56 . 7 - not evaluable ) . Most frequent common terminology criteria for adverse events grade 3 treatment - related adverse events were diarrhea ( 24 . 4 % ) and rash ( 9 . 8 % ) . DB08916 monotherapy was associated with promising clinical activity in extensively pretreated P04626 - positive breast cancer patients who had progressed following trastuzumab treatment .",
"[ Retrospective Analysis of the DB08916 Clinical Pathway during the 28 - Day Introductory Period - The Japanese Style of Collaborative Drug Therapy Management ( J - CDTM ) ] . DB08916 is a newly approved second - generation epidermal growth factor receptor - tyrosine kinase inhibito r ( P00533 - TKI ) . DB08916 has been shown to prolongthe overall survival of patients with non - small cell lungcancer ( NSCLC ) with P00533 mutations compared with the standard chemotherapy . However , Grade 3 or 4 toxicities , includingdiarrhea , rash , paronychia , and stomatitis , have been observed more frequently in patients treated with afatinib than in those treated with first - generation P00533 - TKIs . Accordingly , our institution developed an afatinib clinical pathway ( the afatinib pathway ) , which was designed by certified nurses , medical physicians , and certified pharmacists , with the goal of reducing the severity of diarrhea and rash that occur most frequently duringthe 28 - day introductory period of afatinib treatment . Between May and October 2014 , afatinib was administered accordingto the afatinib pathway to 14 patients with NSCLC and P00533 mutations . Of these patients , only one ( 7 . 1 % ) experienced Grade 3 diarrhea . No other patient experienced Grade 3 or 4 toxicity . The afatinib pathway was effective in reducingthe severities of the diarrhea and rash duringthe 28 - day introductory period of the afatinib treatment . Our implementation of the afatinib pathway could be considered the Japanese style of collaborative drugtherapy management ( J - CDTM ) .",
"Irreversible P00533 inhibitors in the treatment of advanced NSCLC . The epidermal growth factor receptor ( P00533 ) is among the most important targets in the treatment of advanced non - small cell lung cancer ( NSCLC ) . Erlotinib and gefitinib , two small molecules , are reversible P00533 tyrosine kinase inhibitors ( TKIs ) . Non - small cell lung cancers with P00533 mutations , are characterized by excellent responses when treated with the P00533 - TKIs gefitinib and erlotinib . However , all the patients with tumors harbouring P00533 mutations experience disease progression after a median of 10 to 14 months of treatment with gefitinib or erlotinib . A group of new generation P00533 - TKIs irreversibly inhibit P00533 - TK and represent one of the strategies that may potentially overcome the acquired resistance to gefitinib and erlotinib or achieve better outcomes than reversible inhibitors in the first - line treatment of P00533 mutant lung cancers . DB08916 ( DB08916 ) and PF299804 are the irreversible P00533 - TKIs with the most relevant data in the treatment of advanced NSCLC , as primary P00533 - targeted therapy and after resistance to reversible P00533 - TKIs . However , to date , the role of irreversible P00533 inhibitors remains to be defined .",
"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .",
"DB08916 ( DB08916 ) development in non - small - cell lung cancer . DB08916 ( DB08916 ) , a novel aniline - quinazoline derivative , irreversibly and equipotently targets the intrinsic kinase activity of all active ErbB receptor family members . Preclinical results show that afatinib is effective in lung cancer models , including those with P01133 receptor ( P00533 ) mutations resistant to reversible first - generation P00533 inhibitors . DB08916 is being investigated in the LUX - Lung program , which will evaluate afatinib as a first - line treatment in patients with P00533 - activating mutations ( LUX - Lung 2 , 3 and 6 ) and as a second - or third - line treatment in patients that have acquired resistance to gefitinib and / or erlotinib ( LUX - Lung 1 , 4 and 5 ) . LUX - Lung 1 and 2 have demonstrated , within their respective target groups , a significant increase in the disease control rate of 58 and 86 % , respectively , and significant prolongation of progression - free survival . Further Phase III clinical trials are currently ongoing to assess afatinib in combination with paclitaxel ( LUX - Lung 5 ) , and compared with cisplatin / pemetrexed ( LUX - Lung 3 ) or cisplatin / gemcitabine ( LUX - Lung 6 ) .",
"The LUX - Lung clinical trial program of afatinib for non - small - cell lung cancer . P00533 ( P00533 ) - mutant non - small - cell lung cancer ( NSCLC ) represents a distinct disease entity whose molecular phenotype predicts exquisite sensitivity to the reversible P00533 - tyrosine kinase inhibitors ( TKIs ) gefitinib or erlotinib . However , primary or acquired resistance to these agents remains a major clinical problem . DB08916 is a novel dual irreversible P00533 / P04626 TKI that has been shown in preclinical studies to potentially prevent , delay or overcome resistance to reversible P00533 - TKIs . On this basis , the LUX - Lung clinical trial program has been recently launched for testing this molecule in advanced NSCLC patients . Notably , early results from the randomized LUX - Lung 1 trial indicate that afatinib significantly prolongs progression - free survival compared with placebo in pretreated patients with clinically acquired resistance to gefitinib or erlotinib . On the other hand , the LUX - Lung 2 trial shows that afatinib is highly active in the P00533 - mutant subgroup of patients . While these preliminary data open a new exciting scenario for the future development of anti - P00533 therapies in NSCLC , ongoing afatinib trials will definitively establish a role for this molecule in the treatment of advanced NSCLC .",
"Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via DB02527 and P00533 - Src - MEK pathways . In autosomal - dominant polycystic kidney disease ( ADPKD ) , renal cysts develop by aberrant epithelial cell proliferation and transepithelial fluid secretion . We previously showed that ouabain increases proliferation of cultured human ADPKD cells via stimulation of the P01133 receptor ( P00533 ) - Src - MEK / P29323 signaling pathway . We examined whether ouabain affects fluid secretion and in vitro cyst growth of human ADPKD cell monolayers , ADPKD cell microcysts cultured in a three - dimensional collagen matrix , and metanephric organ cultures from Pkd1 ( m1Bei ) mice . Physiological concentrations of ouabain alone did not affect net transepithelial basal - to - apical fluid transport in ADPKD monolayers or growth of cultured ADPKD microcysts . In contrast , in the presence of forskolin or 8 - bromo - DB02527 , ouabain significantly enhanced ADPKD fluid secretion and microcyst expansion . Ouabain exerted this effect by enhancing DB02527 - dependent Cl (-) secretion via the P13569 . Similarly , ouabain accelerated DB02527 - dependent cyst enlargement in Pkd1 ( m1Bei ) mice metanephroi , with a more prominent response in homozygous than heterozygous mice . Ouabain had no effect on fluid secretion and cystogenesis of normal human kidney cells and caused only slight cystic dilations in wild - type mouse kidneys . The effects of ouabain in ADPKD cells and Pkd1 ( m1Bei ) metanephroi were prevented by inhibitors of P00533 ( AG1478 ) , Src ( Q99463 ) , and MEK ( U0126 ) . Together , our results show that ouabain , used in physiological concentrations , has synergistic effects on DB02527 - mediated fluid secretion and cyst growth , via activation of the P00533 - Src - MEK pathway . These data provide important evidence for the role of ouabain as an endogenous hormone that exacerbates ADPKD cyst progression .",
"DB08916 , erlotinib and gefitinib in the first - line therapy of P00533 mutation - positive lung adenocarcinoma : a review . Non - small cell lung cancer ( NSCLC ) consists of several histomorphologically defined phenotypes that display an enormous genetic variability . In recent years , epidermal growth factor receptor ( P00533 ) mutation - positive lung adenocarcinoma has emerged as a unique subset of NSCLC in terms of etiopathogenesis and tumor biology . Since the introduction of the reversible P00533 tyrosine kinase inhibitors ( TKIs ) erlotinib and gefitinib , patients with metastatic P00533 mutation - positive lung cancer can be offered a therapeutic alternative that has proven its superiority over standard platinum - based chemotherapy . However , primary or acquired resistance limits the therapeutic success of these targeted agents . Irreversible inhibitors targeting all ErbB family receptor tyrosine kinases , such as afatinib and dacomitinib , have been developed to confer sustained disease control in ErbB - dependent cancers . The large LUX - Lung 3 phase III trial recently reported afatinib to be clearly superior over the most effective platinum doublet in patients with P00533 mutation - positive lung cancer . To fully exploit the clinical activity of afatinib , proactive management of its gastrointestinal and dermatologic toxicities is advised .",
"Second and third - generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer . PURPOSE OF REVIEW : The first - generation epidermal growth factor receptor tyrosine kinase inhibitors ( P00533 - TKIs ) , gefitinib and erlotinib , are effective as first - line treatment of advanced nonsmall cell lung cancer ( NSCLC ) harboring activating P00533 mutations ( deletions in exon 19 and exon 21 L858R mutation ) . P00533 T790 M resistance mutation ( P00533 T790 M ) ultimately emerged in most of these patients . The second and third - generation P00533 - TKIs were designed to have more potent inhibition of P00533 and to overcome P00533 T790 M . This review describes the recent developments of these novel P00533 - TKIs . RECENT FINDINGS : The second - generation P00533 - TKIs , afatinib and dacomitinib , irreversibly bind to the tyrosine kinase of P00533 and other ErbB - family members . DB08916 has been approved as first - line treatment of advanced NSCLC harboring activating P00533 mutations . Dacomitinib is under development . Third - generation P00533 - TKIs , AZD9291 , CO - 1686 , and HM61713 , inhibit both P00533 activating and resistance mutations , while sparing wild - type P00533 . In early - phase studies , these drugs demonstrated promising response rates against tumors with acquired P00533 T790 M . SUMMARY : Second - generation P00533 - TKI , afatinib , is available as first - line treatment of advanced NSCLC harboring activating P00533 mutations . Third - generation P00533 - TKIs are under development for tumors harboring acquired P00533 T790 M .",
"An P01133 receptor inhibitor induces P10826 expression in breast and ovarian cancer cells . Inhibition of the epidermal growth factor ( P01133 ) - receptor ( P00533 ) has become a promising anticancer treatment strategy . In addition , application of retinoids yields encouraging results for cancer prevention and therapy . Many tumors express no or low amounts of retinoic acid receptor - beta2 ( RAR - beta2 ) due to epigenetic silencing via DNA hypermethylation . RAR - beta2 is the main mediator of the antiproliferative effect of retinoids . RAR - beta2 re - expression causes reversal of transformation , cell cycle arrest , and restoration of retinoid sensitivity . RAR - beta2 is thus a tumor suppressor . Western blotting , colorimetric in vitro cell proliferation assays , and reverse transcription - polymerase chain reaction demonstrated that the P00533 inhibitor PD153035 not only blocked activation of P00533 and inhibited cell growth , but also stimulated P10826 expression in MDA - MB - 468 breast and OVCAR - 3 ovarian carcinoma cells . Upregulation of P10826 by PD153035 was confirmed by real - time reverse transcription - polymerase chain reaction . In contrast , expression of other retinoid receptors and of estrogen receptor - alpha was not affected . PD153035 - mediated re - induction of P10826 was associated with demethylation of the RAR - beta2 gene promoter P2 as demonstrated by methylation - specific polymerase chain reaction . These novel results on the ErbB / retinoid receptor cross - talk may be useful for designing future anticancer combination regimens ."
] |
[
"___MASK34___",
"___MASK49___",
"___MASK51___",
"___MASK56___",
"___MASK61___",
"___MASK82___",
"___MASK88___",
"___MASK90___",
"___MASK92___"
] |
___MASK92___
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MH_train_300
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interacts_with DB00583?
|
[
"High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production . Treatments with high doses of 3 - hydroxy - 3 - methylglutaryl - coenzyme A ( HMG - DB01992 ) reductase inhibitors may induce the expression of sterol regulatory element binding protein ( SREBP ) - target genes , causing different effects from those attributed to the reduction of hepatic cholesterol content . The aim of this study was to investigate the effects of high doses of statins on the key enzymes involved in VLDL production in normolipidemic rats . To examine whether the effects caused by statin treatment are a consequence of P04035 inhibition , we tested the effect of atorvastatin on these enzymes in mevalonate - fed rats . ___MASK21___ and simvastatin enhanced not only P04035 but also the expression of the Q12772 gene itself . As a result of the overexpression of Q12772 caused by the statin treatment , genes regulated basically by P36956 , as FA synthase and acetyl - coenzyme A carboxylase , were also induced and their mRNA levels increased . DAG acyltransferase and microsomal TG transfer protein mRNA levels as well as phosphatidate phosphohydrolase activity were increased by both statins . Simvastatin raised liver cholesterol content , ACAT mRNA levels , and P53007 : phosphocholine cytidylyltransferase activity , whereas it reduced liver DAG and phospholipid content . Mevalonate feeding reversed all changes induced by the atorvastatin treatment . These results show that treatment with high doses of statins induces key enzymes controlling rat liver lipid synthesis and VLDL assembly , probably as a result of Q12772 overexpression . Despite the induction of the key enzymes involved in VLDL production , both statins markedly reduced plasma TG levels , suggesting that different mechanisms may be involved in the hypotriglyceridemic effect of statins at high or low doses .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK97___ and Tissue P00747 Activator in Occluded Arteries .",
"Decreased mitochondrial carnitine translocase in skeletal muscles impairs utilization of fatty acids in insulin - resistant patients . P01308 resistance ( IR ) and its health consequences ( diabetes , hypertension , cardiovascular disease , obesity etc . ) affect between 25 and 35 % of Westernized populations . Decreased fatty acid ( FA ) oxidation in skeletal muscle is implicated in obesity - related IR . DB00583 - acylcarnitine translocase ( O43772 ) transports long - chain FAs both into mitochondria ( as carnitine esters for energy - generating processes ) and out of mitochondria . To determine whether O43772 activity correlates with decreased FA oxidation we measured O43772 concentrations in cellular and mitochondrial extracts from the skeletal muscle of 19 obese IR individuals and of 19 lean controls . We also evaluated carnitine transport in skeletal muscle mitochondria in both groups . Mitochondrial O43772 was decreased at translational and transductional level , and carnitine - carnitine and acylcarnitine - carnitine exchange rates were significantly lower in IR subjects . Aberrant acylcarnitine flux into mitochondria was not correlated with decreased activity of other components of the mitochondrial carnitine system ( i . e . , carnitine palmitoyl transferase - I and II ) . Our data suggest that by restraining entry of FA - coenzyme A into mitochondria , low O43772 levels increase cytosolic FA levels and their incorporation into glycerolipids . The low level of O43772 in IR muscle may contribute to the elevated muscle concentrations of triglycerides , diacylglycerol , and FA - coenzyme A characteristic of IR muscle .",
"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .",
"Characterization of L - aminocarnitine , an inhibitor of fatty acid oxidation . The pathogenesis of hypoketotic hypoglycemia and cardiomyopathy in patients with fatty acid oxidation ( FAO ) disorders is still poorly understood . In vitro studies are hampered by the lack of natural mutants to asses the effect of FAO inhibition . In addition , only a few inhibitors of FAO are known . Furthermore , most inhibitors of FAO are activating ligands of peroxisome proliferator - activated receptors ( PPARs ) . We show that l - aminocarnitine ( L - AC ) , a carnitine analog , inhibits FAO efficiently , but does not activate Q07869 . L - AC inhibits carnitine palmitoyltransferase ( CPT ) with different sensitivities towards CPT1 and P23786 , as well as carnitine acylcarnitine translocase ( O43772 ) . We further characterized L - AC using fibroblasts cell lines from controls and patients with different FAO defects . In these cell lines acylcarnitine profiles were determined in culture medium after loading with [ U -( 13 ) C ] palmitic acid . In control fibroblasts , L - AC inhibits FAO leading to a reduction of P06681 - acylcarnitine and elevation of C16 - acylcarnitine . In very long - chain acyl - DB01992 dehydrogenase ( P49748 ) - deficient fibroblasts , L - AC decreased the elevated C14 - acylcarnitine and increased C16 - acylcarnitine . In O43772 and P23786 - deficient cell lines , L - AC did not change the already elevated C16 - acylcarnitine level , showing that CPT1 is not inhibited . Oxidation of pristanic acid was only partly inhibited at high L - AC concentrations , indicating minimal O43772 inhibition . Therefore , we conclude that in intact cells L - AC inhibits P23786 . Combined with our observation that l - AC does not activate Q07869 , we suggest that L - AC is useful to simulate a FAO defect in cells from different origin .",
"Metabolic studies in a patient with severe carnitine palmitoyltransferase type II deficiency . Here we report on a patient with severe ( \" non - classic \" ) carnitine palmitoyltransferase type II ( P23786 ) deficiency . Hypoglycemia prompted by an infectious episode and associated with non - ketotic dicarboxylic aciduria orientated diagnosis towards beta - oxidation deficiency disorders . Blood carnitine levels revealed a secondary carnitine deficiency that was responsive to oral L - carnitine supplementation . Blood acylcarnitine profiles were abnormal and included acetyl ( P06681 : 0 ) , butyryl / isobutyryl ( C4 : 0 ) , isovaleryl / 2 - methylbutyryl ( P01031 : 0 ) , hexanoyl ( P13671 : 0 ) , myristoyl ( C14 : 0 ) , palmitoyl ( C16 : 0 ) , hexadecenoyl ( C16 : 1 ) , oleyl ( C18 : 1 ) and stearoyl ( C18 : 0 ) carnitine . In urine , excess excretion of dicarboxylylcarnitines , mainly dodecanedioylcarnitine , was noticed . Upon carnitine supplementation , Q99618 to C12 fatty acylcarnitines , with decanoylcarnitine as well as Q99622 to C14 dicarboxylylcarnitines being prominent , were observed in urine . Biochemical measurements disclosed a severe reduction of mitochondrial P23786 activity ( 7 % of normal values ) . Correlations of metabolic findings in the patient and physiological roles of P23786 are briefly discussed .",
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK21___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"Activation of protease - activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth - regulated oncogene / cytokine - induced neutrophil chemoattractant family . Activation of protease - activated receptors ( PARs ) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied . However , the mechanism of protection is still unclear . Here , we showed that activation of multiple PARs , including P25116 , P55085 and Q96RI0 , was able to elevate the release of the chemokine cytokine - induced neutrophil chemoattractant ( CINC ) - 3 from rat astrocytes , in addition to evoking CINC - 1 secretion . Different molecular mechanisms were identified as being involved in the secretion of CINC - 1 and CINC - 3 , upon activation of different PARs . Importantly , we found that both CINC - 1 and CINC - 3 could signal to rat cortical neurons . Both chemokines acted via P25025 to prevent P06681 - ceramide - induced cytochrome c release from mitochondria . Consequently CINC - 1 and CINC - 3 protected neurons from apoptosis . We further revealed that conditioned media obtained from PAR - activated astrocytes similarly protected cortical neurons against P06681 - ceramide - induced cell death . The neuroprotection was considerably suppressed by a P25025 antagonist . P25025 is the cognate receptor for CINC . Therefore , our findings demonstrate that PAR - activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC - 1 and CINC - 3 . These data indicate a previously unknown mechanism for astrocyte - mediated neuroprotection achieved by PAR activation .",
"Integrative analysis of transcriptomics , proteomics , and metabolomics data of white adipose and liver tissue of high - fat diet and rosiglitazone - treated insulin - resistant mice identified pathway alterations and molecular hubs . The incidences of obesity and type 2 diabetes are rapidly increasing and have evolved into a global epidemic . In this study , we analyzed the molecular effects of high - fat diet ( HFD ) - induced insulin - resistance on mice in two metabolic target tissues , the white adipose tissue ( WAT ) and the liver . Additionally , we analyzed the effects of drug treatment using the specific PPARγ ligand rosiglitazone . We integrated transcriptome , proteome , and metabolome data sets for a combined holistic view of molecular mechanisms in type 2 diabetes . Using network and pathway analyses , we identified hub proteins such as P21912 and P53597 in WAT and deregulation of major metabolic pathways in the insulin - resistant state , including the TCA cycle , oxidative phosphorylation , and branched chain amino acid metabolism . Rosiglitazone treatment resulted mainly in modulation via Q07869 signaling and oxidative phosphorylation in WAT only . Interestingly , in HFD liver , we could observe a decrease of proteins involved in vitamin B metabolism such as Q6P996 and P00374 and the according metabolites . Furthermore , we could identify sphingosine ( Sph ) and sphingosine 1 - phosphate ( SP1 ) as a drug - specific marker pair in the liver . In summary , our data indicate physiological plasticity gained by interconnected molecular pathways to counteract metabolic dysregulation due to high calorie intake and drug treatment .",
"Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet - induced obese mice is associated with gut microbial changes and reduction in obesity . OBJECTIVE : To investigate the functional effects of probiotic treatment on the gut microbiota , as well as liver and adipose gene expression in diet - induced obese mice . DESIGN : Male C57BL / 6J mice were fed a high - fat diet ( HFD ) for 8 weeks to induce obesity , and then randomized to receive HFD + probiotic ( Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 , n = 9 ) or HFD + placebo ( n = 9 ) for another 10 weeks . Normal diet ( ND ) fed mice ( n = 9 ) served as non - obese controls . RESULTS : Diet - induced obese mice treated with probiotics showed reduced body weight gain and fat accumulation as well as lowered plasma insulin , leptin , total - cholesterol and liver toxicity biomarkers . A total of 151 , 061 pyrosequencing reads for fecal microbiota were analyzed with a mean of 6 , 564 , 5 , 274 and 4 , 464 reads for the ND , HFD + placebo and HFD + probiotic groups , respectively . Gut microbiota species were shared among the experimental groups despite the different diets and treatments . The diversity of the gut microbiota and its composition were significantly altered in the diet - induced obese mice and after probiotic treatment . We observed concurrent transcriptional changes in adipose tissue and the liver . In adipose tissue , pro - inflammatory genes ( TNFα , P05231 , IL1β and MCP1 ) were down - regulated in mice receiving probiotic treatment . In the liver , fatty acid oxidation - related genes ( PGC1α , CPT1 , P23786 and Q15067 ) were up - regulated in mice receiving probiotic treatment . CONCLUSIONS : The gut microbiota of diet - induced obese mice appears to be modulated in mice receiving probiotic treatment . Probiotic treatment might reduce diet - induced obesity and modulate genes associated with metabolism and inflammation in the liver and adipose tissue .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"Endothelial dihydrofolate reductase : critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase . Recent studies demonstrate that oxidative inactivation of tetrahydrobiopterin ( H4B ) may cause uncoupling of endothelial nitric oxide synthase ( P29474 ) to produce superoxide ( O2 *- ) . H4B was found recyclable from its oxidized form by dihydrofolate reductase ( P00374 ) in several cell types . Functionality of the endothelial P00374 , however , remains completely unknown . Here we present findings that specific inhibition of endothelial P00374 by RNA interference markedly reduced endothelial H4B and nitric oxide ( NO . ) bioavailability . Furthermore , angiotensin II ( 100 nmol / liter for 24 h ) caused a H4B deficiency that was mediated by H2O2 - dependent down - regulation of P00374 . This response was associated with a significant increase in endothelial O2 *- production , which was abolished by P29474 inhibitor N - nitro - L - arginine - methyl ester or H2O2 scavenger polyethylene glycol - conjugated catalase , strongly suggesting H2O2 - dependent P29474 uncoupling . Rapid and transient activation of endothelial NAD ( P ) H oxidases was responsible for the initial burst production of O2 * ( Rac1 inhibitor NSC 23766 but not an N - nitro - L - arginine - methyl ester - attenuated P03372 O2 *- signal at 30 min ) in response to angiotensin II , preceding a second peak in O2 *- production at 24 h that predominantly depended on uncoupled P29474 . Overexpression of P00374 restored NO . production and diminished P29474 production of O2 *- in angiotensin II - stimulated cells . In conclusion , these data represent evidence that P00374 is critical for H4B and NO . bioavailability in the endothelium . Endothelial NAD ( P ) H oxidase - derived H2O2 down - regulates P00374 expression in response to angiotensin II , resulting in H4B deficiency and uncoupling of P29474 . This signaling cascade may represent a universal mechanism underlying P29474 dysfunction under pathophysiological conditions associated with oxidant stress .",
"Q96NZ9 - sensitive P15309 - conjugated nanoparticles for multi - targeting therapy of brain glioma . Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways , and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory . Therefore , drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits . In the present study , we developed a multi - targeting drug delivery system modified with uPA - activated cell - penetrating peptide ( P15309 ) for the treatment of brain glioma ( P01160 ) . In vitro experiments demonstrated nanoparticles ( NP ) decorated with cell - penetrating peptide ( CPP ) or P15309 could significantly improve nanoparticles uptake by P13671 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel ( PTX ) was loaded . In vivo imaging experiment revealed that P01160 accumulated more specifically in brain glioma site than NP decorated with or without CPP . Brain slides further showed that P15309 contributed to more nanoparticles accumulation in glioma site , and P01160 could co - localize not only with glioma parenchyma cells , but also with stroma cells including neo - vascular cells and tumor associated macrophages . The pharmacodynamics results demonstrated P15309 could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice . In conclusion , the results suggested that nanoparticles modified with uPA - sensitive P15309 could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy .",
"Natriuretic peptides induce weak P50552 phosphorylation at DB00133 239 in platelets . Cyclic guanosine - 3 ', 5 '- monophoshate ( cGMP ) is the common second messenger for the cardiovascular effects of nitric oxide ( NO ) and natriuretic peptides ( NP ; e . g . atrial NP [ P01160 ] ) , which activate soluble and particulate guanylyl cyclases , respectively . The role of NO in regulating cGMP and platelet function is well documented , whereas there is little evidence supporting a role for NPs in regulating platelet reactivity . By studying platelet aggregation and secretion in response to a P25116 peptide , collagen and ADP , and phosphorylation of the cGMP - dependent protein kinase ( PKG ) substrate vasodilator - stimulated phosphoprotein ( P50552 ) at serine 239 , we evaluated the effects of NPs in the absence or presence of the non - selective cGMP and DB02527 phosphodiesterase ( PDE ) inhibitor , DB07954 ( DB07954 ) . Our results show that NPs , possibly through the clearance receptor ( natriuretic peptide receptor - C ) expressed on platelet membranes , increase P50552 phosphorylation but only following PDE inhibition , indicating a small , localised cGMP synthesis . As platelet aggregation and secretion measured under the same conditions were not affected , we conclude that the magnitude of PKG activation achieved by NPs in platelets per se is not sufficient to exert functional inhibition of platelet involvement in haemostasis .",
"DB00583 palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases . The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis . It has recently been reported that variations of the P23786 ( carnitine palmitoyl transferase II ) gene may be associated with fatal or severe cases of influenza - associated encephalopathy . In the present study , we examined the genotype of P23786 in cases of acute encephalopathy associated with various preceding infections . Twenty - nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion ( AESD ) or acute necrotizing encephalopathy ( ANE ) were studied . The frequency of F352C of P23786 exon 4 was significantly higher in patients than in controls . All patients who had allele C in F352C had allele I in V368I and allele M in M647V ( CIM haplotype ) , which reportedly decreases P23786 activity to one third of that with Q9UBW7 or FVM haplotype . The frequency of CIM haplotype was significantly different between patients and controls , but not between AESD and ANE . Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy , regardless of its antecedent infections .",
"Genes involved in carnitine synthesis and carnitine uptake are up - regulated in the liver of sows during lactation . BACKGROUND : Convincing evidence exist that carnitine synthesis and uptake of carnitine into cells is regulated by peroxisome proliferator - activated receptor α ( Q07869 ) , a transcription factor which is physiologically activated during fasting or energy deprivation . Sows are typically in a negative energy balance during peak lactation . We investigated the hypothesis that genes involved in carnitine synthesis and uptake in the liver of sows are up - regulated during peak lactation . FINDINGS : Transcript levels of several PPARα target genes involved in fatty acid uptake ( P15090 , O43772 ) , fatty acid oxidation ( Q15067 , CYP4A24 ) and ketogenesis ( P54868 , Q9NSA1 ) were elevated in the liver of lactating compared to non - lactating sows ( P < 0 . 05 ) . In addition , transcript levels of genes involved in carnitine synthesis ( P49189 , Q9NVH6 , O75936 ) and carnitine uptake ( O76082 ) in the liver were greater in lactating than in non - lactating sows ( P < 0 . 05 ) . DB00583 concentrations in liver and plasma were about 20 % and 50 % , respectively , lower in lactating than in non - lactating sows ( P < 0 . 05 ) , which is likely due to an increased loss of carnitine via the milk . CONCLUSIONS : The results of the present study show that PPARα is activated in the liver of sows during lactation which leads to an up - regulation of genes involved in carnitine synthesis and carnitine uptake . The PPARα mediated up - regulation of genes involved in carnitine synthesis and uptake in the liver of lactating sows may be regarded as an adaptive mechanism to maintain hepatic carnitine levels at a level sufficient to transport excessive amounts of fatty acids into the mitochondrion .",
"11β - Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid - induced insulin resistance and lipolysis in mouse abdominal adipose tissue . Long - term glucocorticoid exposure increases the risk for developing type 2 diabetes . Prereceptor activation of glucocorticoid availability in target tissue by 11β - hydroxysteroid dehydrogenase type 1 ( 11β - HSD1 ) coupled with hexose - 6 - phosphate dehydrogenase ( H6PDH ) is an important mediator of the metabolic syndrome . We explored whether the tissue - specific modulation of 11β - HSD1 and H6PDH in adipose tissue mediates glucocorticoid - induced insulin resistance and lipolysis and analyzed the effects of 11β - HSD1 inhibition on the key lipid metabolism genes and insulin - signaling cascade . We observed that corticosterone ( O00230 ) treatment increased expression of 11β - HSD1 and H6PDH and induced lipase Q05469 and Q96AD5 with suppression of p - DB00156 ( 172 ) AMPK in adipose tissue of C57BL / 6J mice . In contrast , O00230 induced adipose insulin resistance , as reflected by a marked decrease in IR and P35568 gene expression with a reduction in p - DB00156 ( 308 ) Akt / P31749 . Furthermore , 11β - HSD1 shRNA attenuated O00230 - induced 11β - HSD1 and lipase expression and improved insulin sensitivity with a concomitant stimulation of pThr ( 308 ) Akt / P31749 and p - DB00156 ( 172 ) AMPK within adipose tissue . Addition of O00230 to 3T3 - Q9NUQ9 adipocytes enhanced 11β - HSD1 and H6PDH and impaired p - DB00156 ( 308 ) Akt / P31749 , leading to lipolysis . Knockdown of 11β - HSD1 by shRNA attenuated O00230 - induced lipolysis and reversed O00230 - mediated inhibition of pThr ( 172 ) AMPK , which was accompanied by a parallel improvement of insulin signaling response in these cells . These findings suggest that elevated adipose 11β - HSD1 expression may contribute to glucocorticoid - induced insulin resistance and adipolysis .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"Mortality prediction using modern peptide biomarkers in hemodialysis patients -- a comparative analysis . BACKGROUND / AIMS : Determination of peptide biomarkers such as troponins , natriuretic peptides or the recently reported Q9GZV9 can be useful to identify hemodialysis patients with a high risk of mortality . However , it is desirable to focus on few robust parameters to warrant their routine application . METHODS : In a prospective cohort study with 239 prevalent hemodialysis patients we studied the prognostic significance of 10 simultaneously determined modern peptide biomarkers ( high sensitive troponin I and T , NT - pro - DB04899 , DB04899 , MR - pro - P01160 , MR - pro - P35318 , CT - pro - ET1 , copeptin , Q9GZV9 and a - Q9UEF7 ) and compared them with parameters traditionally associated with mortality ( PTH , Ca , Pi , albumin , CRP , cholesterol , AP ) . RESULTS : After a follow - up of 4 years , plasma concentration of troponins , natriuretic peptides , MR - pro - P35318 , Q9GZV9 as well as PTH , CRP , AP were significantly higher in deceased patients ( n = 95 ) . Hazard ratios from cox regression on a continuous scale ( doubling of plasma concentration ) or relative in tertiles were highest for high sensitive troponins , followed by natriuretic peptides and MR - pro - P35318 ( 1 . 6 - 2 . 0 and 2 . 3 - 5 . 5 , resp . ) . C - indices were also highest for troponins ( 0 . 708 - 0 . 746 ) , followed by natriuretic peptides ( 0 . 706 - 0 . 731 ) . Traditional parameters had low c - indices ( 0 . 598 - 0 . 655 ) . Stepwise cox regression revealed that among all parameters troponin I , NT - pro - DB04899 , PTH and CRP remained independent predictors of mortality and a composite score had the highest c - index ( 0 . 799 [ 0 . 740 - 0 . 849 ] ) . CONCLUSIONS : Among peptide biomarkers high sensitive troponins and to a lesser extent natriuretic peptides are strong predictors of mortality in asymptomatic hemodialysis patients , followed by markers of mineral - bone disease and inflammation .",
"Substrate specificity of human carnitine acetyltransferase : Implications for fatty acid and branched - chain amino acid metabolism . DB00583 acyltransferases catalyze the reversible conversion of acyl - CoAs into acylcarnitine esters . This family includes the mitochondrial enzymes carnitine palmitoyltransferase 2 ( P23786 ) and carnitine acetyltransferase ( P43155 ) . P23786 is part of the carnitine shuttle that is necessary to import fatty acids into mitochondria and catalyzes the conversion of acylcarnitines into acyl - CoAs . In addition , when mitochondrial fatty acid β - oxidation is impaired , P23786 is able to catalyze the reverse reaction and converts accumulating long - and medium - chain acyl - CoAs into acylcarnitines for export from the matrix to the cytosol . However , P23786 is inactive with short - chain acyl - CoAs and intermediates of the branched - chain amino acid oxidation pathway ( BCAAO ) . In order to explore the origin of short - chain and branched - chain acylcarnitines that may accumulate in various organic acidemias , we performed substrate specificity studies using purified recombinant human P43155 . Various saturated , unsaturated and branched - chain acyl - DB01992 esters were tested and the synthesized acylcarnitines were quantified by P19957 - MS / MS . We show that P43155 converts short - and medium - chain acyl - CoAs ( P06681 to Q99622 - DB01992 ) , whereas no activity was observed with long - chain species . Trans - 2 - enoyl - DB01992 intermediates were found to be poor substrates for this enzyme . Furthermore , P43155 turned out to be active towards some but not all the BCAAO intermediates tested and no activity was found with dicarboxylic acyl - DB01992 esters . This suggests the existence of another enzyme able to handle the acyl - CoAs that are not substrates for P43155 and P23786 , but for which the corresponding acylcarnitines are well recognized as diagnostic markers in inborn errors of metabolism .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK15___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Phospho - ΔNp63α / P36956 protein interactions : bridging cell metabolism and cisplatin chemoresistance . Tumor protein ( TP ) - p53 family members ( Q9H3D4 , Q9H3D4 and O15350 ) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment . DB00515 - induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels . We previously found that squamous cell carcinoma ( SCC ) cells exposed to cisplatin displayed the Q13315 - dependent phosphorylation of ΔNp63α ( p - ΔNp63α ) , which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells . However , SCC cells expressing non - p - ΔNp63α became more cisplatin - resistant . We also found that p - ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest , apoptosis , autophagy , RNA splicing and chromatin modifications . Here , we showed that p - ΔNp63α induced P05089 , P04406 , and P23786 gene transcription in cisplatin - sensitive SCC cells , while non - p - ΔNp63α increased a transcription of CAD , P11413 and P49327 genes in cisplatin - resistant SCC cells . We report that the p - ΔNp63α - dependent regulatory mechanisms implicated in the modulation of plethora of pathways , including amino acid , carbohydrate , lipid and nucleotide metabolisms , thereby affect tumor cell response to cisplatin - induced cell death , suggesting that the Q13315 - dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy .",
"Platelet - derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3 - kinase and sterol regulatory element - binding proteins . We analyzed the transcriptional program elicited by stimulation of normal human fibroblasts with platelet - derived growth factor ( PDGF ) using cDNA microarrays . 103 significantly regulated transcripts that had not been previously linked to PDGF signaling were identified . Among them , a cluster of genes involved in fatty acid and cholesterol biosynthesis , including stearoyl - DB01992 desaturase ( O00767 ) , fatty acid synthase , and hydroxymethylglutaryl - Q13057 ( Q01581 ) , was up - regulated by PDGF after 24 h of treatment , and their expression correlated with increased membrane lipid production . These genes are known to be controlled by sterol regulatory element - binding proteins ( SREBP ) . PDGF increased the amount of mature P36956 and regulated the promoters of O00767 and Q01581 in an SREBP - dependent manner . In line with these results , blocking SREBP processing by addition of 25 - hydroxycholesterol blunted the effects of PDGF on lipogenic enzymes . SREBP activation was dependent on the phosphatidylinositol 3 - kinase ( PI3K ) pathway , as judged from the effects of the inhibitor LY294002 and mutation of the PDGFbeta receptor tyrosines that bind the PI3K adaptor subunit p85 . Fibroblast growth factors ( P09038 and P08620 ) and other growth factors mimicked the effects of PDGF on NIH3T3 and human fibroblasts . In conclusion , our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK62___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Dietary L - carnitine supplementation increases lipid deposition in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) through changes in lipid metabolism . DB00583 has been reported to improve growth performance and reduce body lipid content in fish . Thus , we hypothesised that carnitine supplementation can improve growth performance and reduce lipid content in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) , a commonly cultured freshwater fish in inland China , and tested this hypothesis in the present study . Diets containing l - carnitine at three different concentrations of 47 mg / kg ( control , without extra carnitine addition ) , 331 mg / kg ( low carnitine ) and 3495 mg / kg ( high carnitine ) diet were fed to yellow catfish for 8 weeks . The low - carnitine diet significantly improved weight gain ( WG ) and reduced the feed conversion ratio ( FCR ) . In contrast , the high - carnitine diet did not affect WG and FCR . Compared with the control diet , the low - carnitine and high - carnitine diets increased lipid and carnitine contents in the liver and muscle . The increased lipid content in the liver could be attributed to the up - regulation of the mRNA levels of SREBP , PPARγ , fatty acid synthase ( FAS ) and ACCa and the increased activities of lipogenic enzymes ( such as FAS , glucose - 6 - phosphate dehydrogenase , 6 - phosphogluconate dehydrogenase and malic enzyme ) and to the down - regulation of the mRNA levels of the lipolytic gene P50416 . The increased lipid content in muscle could be attributed to the down - regulation of the mRNA levels of the lipolytic genes P50416 and Q96AD5 and the increased activity of lipoprotein lipase . In conclusion , in contrast to our hypothesis , dietary carnitine supplementation increased body lipid content in yellow catfish .",
"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK99___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .",
"Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation - deficient fibroblasts . DB00583 palmitoyl transferase 2 ( P23786 ) and very - long - chain Acyl - DB01992 dehydrogenase ( P49748 ) deficiencies are among the most common inborn mitochondrial fatty acid β - oxidation ( FAO ) disorders . Despite advances in their clinical and molecular characterizations , few therapeutic approaches exist for these diseases . DB02709 ( RSV ) is a natural polyphenol extensively studied for its potential health benefits . Indeed , it is presently thought that RSV could delay the onset of some cancers , and have protective effects against common aging disorders such as type II diabetes , cardiovascular or neurodegenerative diseases . Here , we show that exposure to RSV induces a dose - and time - dependant increase in FAO flux in human fibroblasts , and can restore normal FAO capacities in a panel of patients ' fibroblasts with the mild forms ( harboring various genotypes ) of P23786 or P49748 deficiency . The correction of FAO flux correlated with a marked increase in mutant P23786 or P49748 protein level , in cells treated by RSV . Inhibition of sirtuin 1 ( Q96EB6 ) by Sirtinol and the use of peroxisome proliferator - activated receptor gamma co - activator - 1 - alpha ( P20142 - 1α ) small interfering RNAs demonstrate that the RSV - induced stimulation of FAO requires the presence of P20142 - 1α and Q96EB6 . These results show , for the first time , that RSV markedly induces mitochondrial FAO capacities in human fibroblasts , and provides the initial proof - of - concept that RSV might be efficient for correction of inherited FAO disorders .",
"P01375 - alpha - induced cyclooxygenase - 2 expression via sequential activation of ceramide - dependent mitogen - activated protein kinases , and O15111 1 / 2 in human alveolar epithelial cells . The role of Q8TCB0 / 42 mitogen - activated protein kinase ( MAPK ) , p38 , and c - Jun NH ( 2 )- terminal kinase ( JNK ) in tumor necrosis factor ( P01375 ) - alpha - induced cyclooxygenase ( P36551 ) - 2 expression was studied in NCI - H292 epithelial cells . P01375 - mediated P35354 expression and P35354 promoter activity were inhibited by the MAPK kinase inhibitor PD98059 or the p38 inhibitor SB203580 . Treatment of cells for 10 min with P01375 resulted in activation of Q8TCB0 / 42 MAPK , p38 , and JNK . P06681 - ceramide ( a cell - permeable ceramide analog ) , bacterial neutral sphingomyelinase ( Smase ; an enzyme that degrades sphingomyelin to ceramide ) , and N - oleoylethanolamine ( a ceramidase inhibitor ) all induced activation of MAPKs , P35354 expression , nuclear factor ( NF ) - kappaB DNA - protein binding , and P35354 promoter activity . The inactive analog , dihydro - P06681 - ceramide , had no effect . SMase - or P06681 - ceramide - induced P35354 expression and P35354 promoter activity were also inhibited by PD98059 or SB203580 . Glutathione , a neutral SMase inhibitor , attenuated P01375 - or SMase - induced activation of MAPKs , P35354 expression , and P35354 promoter activity . P01375 - or P06681 - ceramide - induced P35354 promoter activity was inhibited by the dominant negative mutant of extracellular signal - regulated kinase 2 , p38 , JNK , O15111 ( IKK ) 1 , or O14920 . IKK activity was stimulated by either P01375 or P06681 - ceramide , and these effects were inhibited by PD98059 or SB203580 . All these results suggest that , in NCI - H292 epithelial cells , activation of MAPKs by ceramide contributes to the P01375 signaling that occurs downstream of neutral SMase activation and results in the stimulation of O15111 / 2 , and NF - kappaB in the P35354 promoter , followed by initiation of P35354 expression .",
"Prenatal diagnosis of carnitine palmitoyltransferase 2 deficiency in chorionic villi : a novel approach . DB00583 palmitoyltransferase 2 ( P23786 ) deficiency , the most common autosomal recessive inherited disease of the mitochondrial long - chain fatty acid ( LCFA ) beta - oxidation , may result in three distinct clinical phenotypes , namely , a mild adult muscular form , a severe infantile hepatocardiomuscular disease , and a neonatal form , which includes dysmorphic features in addition to hepatocardiomuscular symptoms . Both the latter forms are life - threatening diseases , and prenatal diagnosis ( P01160 ) can be offered to couples at a one - fourth risk of having an affected child . P01160 of P23786 deficiency hitherto relied mostly on mutation detection from fresh chorionic villi ( 10 weeks ' gestation ) , since P23786 activity could be assayed on cultured amniocytes only ( 16 - 17 weeks ' gestation ) . We devised a P23786 activity assay from 10 mg of chorionic villi sampling ( CVS ) . Combining this enzymatic assay to haplotype study using polymorphic markers linked to the P23786 gene , we were able to carry out within 2 days , P23786 deficiency P01160 , in two unrelated families , using a CVS performed at the 11th week of gestation .",
"A case of CPT deficiency , homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy . A 45 - year - old male patient had an episode of acute renal failure with myoglobinuria , myalgias , weakness , and markedly increased serum CK levels . Similar episodes had occurred in the past . DB00583 palmitoyl - transferase II ( P23786 ) deficiency was documented both biochemically and genetically . Interestingly , muscle biopsy also showed some ragged red fibers ( Q96E11 ) and complete mitochondrial DNA ( mtDNA ) sequence disclosed a homoplasmic T3394C point mutation . This mutation is described in Leber ' s hereditary optic neuropathy ( LHON ) or in patients with diabetes mellitus .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK24___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK97___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"Peroxisome proliferator - activated receptor ( Q07869 ) α and - γ regulate IFNγ and Q16552 production by human T cells in a sex - specific way . Women develop certain autoimmune diseases more often than men . It has been hypothesized that this may relate to the development of more robust T - helper ( Th ) 1 responses in women . To test whether women exhibit a Th1 bias , we isolated naïve cluster of differentiation ( CD ) 4 (+) T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti - CD3 and anti - P10747 . We observed that P01730 (+) T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male P01730 (+) T cells . Intriguingly , male P01730 (+) T cells instead had a predilection toward Q16552 production . This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss / Jackson Laboratory ( SJL ) mouse . Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T - cell expression of peroxisome proliferator activated receptor ( Q07869 ) α and PPARγ . Androgens increased PPARα and decreased PPARγ expression by human P01730 (+) T cells . PPARα siRNA - mediated knockdown had the effect of increasing IFNγ by male P01730 (+) T cells , while transfection of P01730 (+) T cells with PPARγ siRNAs increased Q16552 production uniquely by female T cells . Together , our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and Q16552 that may be driven by expressions of PPARα and PPARγ .",
"[ Exploration of exercise intolerance by 31P NMR spectroscopy of calf muscles coupled with Q9BWK5 and ergometry ] . One hundred patients presenting with exercise intolerance or rhabdomyolysis episodes have been examined successively by 31P Nuclear Magnetic Resonance Spectroscopy ( P59665 ) of leg plantar flexor muscles with exercise test . In all cases a muscle biopsy was performed . At the end of investigations , diagnosis of a metabolic myopathy was made in 33 patients : glycogenolysis or glycolysis deficiency in 8 cases , mitochondrial myopathy in 24 cases and P23786 deficiency in one case . Muscular dystrophy or congenital myopathy were diagnosed in 6 cases . No precise etiology could be found in 30 patients with either high CK levels or muscle biopsy abnormalities . Seven patients had rhabdomyolysis related to excessive physical activities . Twenty - four patients had functional symptoms . The principal P59665 parameters used for diagnosis were the values of intracellular pH at the end of exercise and the time constant of phosphocreatine resynthesis during recovery . Lack of acidosis after exercise was observed in all patients with blockade of glycogenolysis or glycolysis . A slowing in phosphocreatine resynthesis was found in 66 p . cent of patients with definite mitochondrial myopathy . The specificity of these parameters were respectively 92 . 4 p . cent and 85 . 5 p . cent for the two groups . In conclusion ( 31 ) P P59665 allows the detection of muscular glycogenoses with a sensitivity close to 100 p . cent . However , its sensitivity was lower for the detection of mitochondrial myopathies , as is also known for the other in vivo metabolic investigations , reflecting the heterogeneity of expression of mitochondrial abnormalities in a given muscle . The integration of imaging in the examination protocol may help to orientate towards the diagnostic of a dystrophy in some patients .",
"Use of a collagen biomatrix ( TissuDura ) for dura repair : a long - term neuroradiological and neuropathological evaluation . PURPOSE : The aim of this study was to evaluate the clinical , neuroradiological , and neuropathological outcomes of patients treated with equine collagen foil ( TissuDura ) as a dura mater substitute during cranial and spinal neurosurgical procedures . MATERIALS AND METHODS : All patients treated at the Department of Neurosurgery of the Second University of Naples with TissuDura between 2005 and 2009 were included . Dural reconstruction was performed using TissuDura , overlaid 1 cm over the dural defect with additional fixation using fibrin glue . No surgical sutures were used . Patients underwent postoperative contrast - enhanced magnetic resonance scans at 1 week , 1 month , and 1 year after surgery to detect any cerebrospinal fluid ( P04141 ) leaks , infections , inflammations , or P04141 circulation in the surgical region . RESULTS : Dural reconstruction was performed in 74 patients , including 50 patients with tumors , two with P06681 neurinoma , two with acoustic neurinoma , six with Chiari I malformation , two with severe head injury , and 12 requiring spinal surgery . Clinical and neuroradiological findings were normal and no signs of graft rejection or P04141 leaks at postoperative follow - up were observed . In two cases of atypical meningioma , re - operation of the dural reconstruction was performed after 1 year . No adherences between brain and neodura were detected , and histopathological investigations demonstrated dural regeneration . CONCLUSIONS : Following dural reconstructions with TissuDura without surgical sutures , no local toxicity or complications were observed for up to 1 year . TissuDura demonstrated elasticity , non - reactivity , and good adaptability . The overlay technique using fibrin glue was simple and fast . Future studies and longer follow - up are needed to confirm the efficacy of TissuDura .",
"DB00583 palmitoyltransferase 2 and carnitine / acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines . Acylcarnitines are commonly used in the diagnosis of mitochondrial fatty acid β - oxidation disorders ( mFAODs ) . It is generally assumed that this plasma acylcarnitine profile reflects the mitochondrial accumulation of acyl - CoAs . The identity of the enzymes and the mitochondrial and plasmalemmal transporters involved in the synthesis and export of these metabolites have remained undefined . We used lentiviral shRNA to knock down the expression of medium - chain acyl - DB01992 dehydrogenase ( P11310 ) in control and carnitine palmitoyltransferase 2 ( P23786 ) - , carnitine / acylcarnitine translocase ( O43772 ) - , and plasmalemmal carnitine transporter ( O76082 ) - deficient human fibroblasts . These cell lines , including mock - transduced controls , were loaded with decanoic acid and carnitine , followed by the measurement of the acylcarnitine profile in the extracellular medium . In control fibroblasts , P11310 knockdown markedly increased the production of octanoylcarnitine ( 3 - fold , P < 0 . 01 ) . O76082 - deficient cell lines also showed extracellular accumulation of octanoylcarnitine ( 2 . 8 - fold , P < 0 . 01 ) , suggesting that the cellular export of acylcarnitines does not depend on O76082 . In contrast , in P23786 - and O43772 - deficient cells , the accumulation of octanoylcarnitine in the medium did not significantly increase in the P11310 knockdown . Similar results were obtained using pharmacological inhibition of P23786 in fibroblasts from P11310 - deficient individuals . This shows that P23786 and O43772 are crucial for mitochondrial acylcarnitine formation and export to the extracellular fluids in mFAOD .",
"[ Improving the outcome of peritoneal dialysis in the long term : is it possible ? ] . Improving the results of peritoneal dialysis ( PD ) over time means reducing both the technique ' s drop out ( P48775 ) and mortality rates . The PD mortality rate has diminished over the years , due to greater experience in using the technique and the reduction in mortality due to peritonitis making it comparable with the hemodialysis ( HD ) mortality rate . Moreover , improved control of the hydrosaline balance through the use of ambulatory peritoneal dialysis ( APD ) and icodextrin could further improve the survival rate in the future . The adequacy targets needed to reduce the mortality rate still appear to be debatable , as their importance seems conditioned by the presence of Q96E11 and comorbidity . The P48775 is higher in PD than in HD because PD is a self - administered treatment that uses a biological membrane as a filter . The most frequent causes of P48775 are peritonitis ( 30 - 40 % ) , dialytic inadequacy ( 11 - 27 % ) , and subsequent inability and / or choice ( 10 - 32 % ) . Peritonitis is the cause that has seen the greatest reduction over time due to the introduction of the Y - Set , but a further reduction could result from the prevention of P19957 , and from improvements in the patient selection procedure designed to identify both clinical and psycho - social disposition peritonitis risk factors . Among the causes of P48775 due to dialytic inadequacy , insufficient ultrafiltration ( UF ) could benefit from the diffusion of APD and icodextrin , while insufficient depuration could be reduced by new targets and optimization of the prescription . Finally , P48775 due to social causes could be reduced by the use of APD , care support and appropriate patient selection .",
"[ Use of 2 - DE and MALDI - TOF - MS to screen differentially expressed serum proteins in patients with oral lichen planus before and after hydroxychloroquine treatment ] . PURPOSE : To establish 2 - dimensional gel electrophoresis images and compare the differences of serum proteins of oral lichen planus patients before and after hydroxychloroquine therapy . METHODS : The serum of oral lichen planus patients before and after hydroxychloroquine therapy were collected , and total protein were extracted . Differential proteome profiles were established and analysed by means of 2 - DE and MALDI - TOF - MS . The types and functions of protein were analyzed . SAS 9 . 12 software package was used for statistical analysis . RESULTS : Six proteins were well characterized including plasminogen precursor , Apo A - IV precursor , P0C0L4 / P0C0L5 complement , P06681 precursor , Vitamin D binding protein and hypothetical protein . The differences were statistically significant . CONCLUSIONS : P00747 precursor , Apo A - IV precursor , P0C0L4 / P0C0L5 complement , P06681 precursor , Vitamin D binding protein and hypothetical protein are differentially expressed in oral lichen planus patients before and after hydroxychloroquine therapy , but the results need to be validated by other biochemical technologies .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK34___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK34___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK34___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK34___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK34___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Three novel mutations in the carnitine - acylcarnitine translocase ( O43772 ) gene in patients with O43772 deficiency and in healthy individuals . DB00583 - acylcarnitine translocase ( O43772 ) and carnitine palmitoyltransferase II ( P23786 ) are key enzymes for transporting long - chain fatty acids into mitochondria . Deficiencies of these enzymes , which are clinically characterized by life - threatening non - ketotic hypoglycemia and rhabdomyolysis , can not be distinguished by acylcarnitine analysis performed using tandem mass spectrometry . We had previously reported the P23786 genetic structure and its role in P23786 deficiency . Here , we analyzed the O43772 gene in 2 patients diagnosed clinically with O43772 deficiency , 18 patients with non - traumatic rhabdomyolysis and 58 healthy individuals , all of whom were confirmed to have normal P23786 genotypes . To facilitate O43772 genotyping , we used heat - denaturing high - performance liquid chromatography ( DHPLC ) , which helped identify five distinct patterns . The abnormal heteroduplex fragments were subjected to O43772 - specific DNA sequencing . We found that one patient with O43772 deficiency , Case 1 , carried c . 576G > A and c . 199 - 10t > g mutations , whereas Case 2 was heterozygous for c . 106 - 2a > t and c . 576G > A . We also found that one patient with non - traumatic rhabdomyolysis and one healthy individual were heterozygous for c . 804delG and the synonymous mutation c . 516T > C , respectively . In summary , c . 576G > A , c . 106 - 2a > t and c . 516T > C are novel O43772 gene mutations . Among the five mutations identified , three were responsible for O43772 deficiency . We have also demonstrated the successful screening of O43772 mutations by DHPLC .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK44___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"DB00583 - palmitoyltransferase 2 deficiency : novel mutations and relevance of newborn screening . We report on a newborn male , born at term after an uneventful pregnancy presenting with a pathological acylcarnitine profile in routine newborn screening on the third day of life . The profile showed characteristic elevations of C14 : 0 - , C16 : 0 - , C16 : 1 - and C18 : 1 - acylcarnitines , while the ratio of ( C16 + C18 : 1 ) / P06681 was increased , suggesting P23786 - or carnitine - acylcarnitine - translocase - deficiency . The acylcarnitine profile in blood taken on day 9 was normal with breast milk feeding . No dicarboxylic aciduria was found . In fibroblasts , the activity of P23786 was decreased to 25 % , overall oxidation of the long - chain fatty acids was reduced to 10 % of control values . Sequence analysis of the P23786 gene showed heterozygosity for two previously undescribed mutations in exon 4 : c . 748 - 749delAA ( truncating ) , and c . 1436A > G ( p . Tyr479Cys ; missense ) mutations . The asymptomatic parents were found to be heterozygous , the mother carries the c . 748 - 749delAA and the father the c . 1436A > G mutation . The boy is now 2 . 5 years old ; no clinical symptoms associated with the marked impairment of long - chain fatty acid oxidation have occurred . Confirmation of mitochondrial fatty acid oxidation defects from an initial abnormal newborn - screening by tandem mass spectrometry should include enzyme and , if possible , molecular genetic analysis despite a normal 2nd screening . Biochemical testing of urine ( organic acids ) may be unrevealing .",
"An evaluation of molecular diagnostic tools for the detection and differentiation of human - pathogenic Cryptosporidium spp . The performance of 10 commonly used genotyping tools in the detection and differentiation of 7 human - pathogenic Cryptosporidium spp . ( C . hominis , C . parvum , C . meleagridis , C . felis , C . canis , C . muris and Cryptosporidium pig genotype 1 ) was evaluated . All 3 SU rRNA gene - based tools could amplify the DNA of 7 Cryptosporidium spp . efficiently . However , the tools based on the antigens TRAP - C1 , TRAP - P06681 and COWP genes , the housekeeping genes HSP70 and P00374 , or a genomic sequence , failed to detect the DNA of C . felis , C . canis , Cryptosporidium pig genotype I , and C . muris . With the exception of 1 tool based on the TRAP - P06681 gene , the PCR - RFLP or the PCR sequencing tools evaluated in this study could differentiate C . hominis , C . parvum and C . meleagridis from each other , and 2 SSU rRNA gene - based tools could differentiate all 7 Cryptosporidium spp . Thus , a thorough understanding of the strength and weakness of each technique is needed when using molecular diagnostic tool in epidemiological investigations of human cryptosporidiosis .",
"Developmental changes in carnitine palmitoyltransferases I and II gene expression in intestine and liver of suckling rats . DB00583 palmitoyltransferase ( CPT ) I is expressed in the intestine of suckling rats ; its mRNA increases very rapidly after birth , remains on a plateau until day 18 and decreases until weaning , when basal ( adult ) values are reached , which remain unchanged thereafter . P23786 mRNA values do not show any appreciable change in this period . CPT I and P23786 are expressed mainly in mucosa and , to a lesser extent , in the muscular part of the intestine . Intestinal expression of CPT I is maximal in duodenum and jejunum , whereas P23786 is expressed in a similar pattern throughout the whole intestine . Dam ' s milk may influence the intestinal expression of CPT I , since mRNA levels at birth are low but increase after the first lactation . Moreover , rats weaned at either day 18 or 21 decrease their mRNA levels . Apparently , P23786 gene expression is not influenced by the mother ' s milk . CPT I and P23786 are also expressed in the liver of suckling rats . Hepatic CPT I is maximal at day 3 , and levels of P23786 mRNA do not change , in a similar fashion to that in intestine . The profile of expression of CPT I in liver and intestine strongly resembles that previously reported for mitochondrial 3 - hydroxy - 3 - methyl - glutaryl - Q13057 .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"A novel O43772 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine - acylcarnitine translocase ( O43772 ) deficiency . DB00583 - acylcarnitine translocase ( O43772 ) deficiency is a rare disorder of fatty acid oxidation associated with high mortality . Two female newborns of different ethnic origin ( the first Anglo - Celtic and the second Palestinian Arab ) both died after sudden collapse on day 2 of life . Both had elevated bloodspot long - chain acylcarnitines consistent with either O43772 or carnitine palmitoyltransferase II ( P23786 ) deficiency ; the latter was excluded by demonstrating normal P23786 activity in fibroblasts . Direct sequencing of all O43772 ( O43772 ) gene exons and exon - intron boundaries revealed that Patient 1 was compound heterozygous for a novel c . 609 - 3c > g ( IVS6 - 3c > g ) mutation on the paternal allele and a previously described c . 326delG mutation on the maternal allele . Patient 2 was homozygous for the same , novel c . 609 - 3c > g mutation . Previously reported O43772 mutations have been almost exclusively confined to a single family or ethnic group . Analysis of fibroblast cDNA by RT - PCR , agarose gel electrophoresis and sequencing of extracted bands showed that both mutations produce aberrant splicing . c . 609 - 3C > G results in exon 7 skipping leading to a frameshift with premature termination seven amino acids downstream . c . 326delG was confirmed to produce skipping of exons 3 or 3 plus 4 . O43772 activity in both patients ' fibroblasts was near - zero . For both families , prenatal diagnosis of an unaffected fetus was performed by mutation analysis on CVS tissue in a subsequent pregnancy . Due to the urgency of prenatal diagnosis in the second family , molecular diagnosis was performed prior to demonstration of O43772 enzyme deficiency , illustrating that mutation analysis is a rapid and reliable approach to first - line diagnosis of O43772 deficiency .",
"Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK15___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .",
"L - carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow . BACKGROUND : In our model of a congenital heart defect ( Q8NE62 ) with increased pulmonary blood flow ( PBF ; shunt ) , we have recently shown a disruption in carnitine homeostasis , associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase ( P29474 ) / heat shock protein ( Hsp ) 90 interactions that contribute to P29474 uncoupling , increased superoxide levels , and decreased bioavailable nitric oxide ( NO ) . Therefore , we undertook this study to test the hypothesis that L - carnitine therapy would maintain mitochondrial function and NO signaling . METHODS : Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft . Immediately after delivery , lambs received daily treatment with oral L - carnitine or its vehicle . RESULTS : L - DB00583 - treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine : free carnitine ratio as compared with vehicle - treated shunt lambs . These changes correlated with increased carnitine acetyl transferase ( P43155 ) protein and enzyme activity and decreased levels of nitrated P43155 . The lactate : pyruvate ratio was also decreased in L - carnitine - treated lambs . Hsp70 protein levels were significantly decreased , and this correlated with increases in P29474 / Hsp90 interactions , NOS activity , and NOx levels , and a significant decrease in P29474 - derived superoxide . Furthermore , acetylcholine significantly decreased left pulmonary vascular resistance only in L - carnitine - treated lambs . CONCLUSION : L - DB00583 therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation .",
"Selective glycosylation of steroidal saponins by Arthrobacter nitroguajacolicus . In this study seven strains of the genus Arthrobacter were screened by biotransformation to discover glycosylating patterns on steroid saponins . A strain of Arthrobacter nitroguajacolicus ( CPCC 203516 ) was found to have the ability of fructosylation . Crude enzyme of the strain was extracted for the further study of conversion characteristics and patterns . DB02772 was used as a non - activated sugar donor , and fifteen steroidal saponins were involved . Nine furostan saponins of the substrates were converted , and ten products were isolated and identified . Based on the HR - P19957 - MS , 1D , and 2D NMR spectral data , one fructosyl was added to furostan saponins at P13671 - OH of 26 - O - β - D - glucopyranosyl by A . nitroguajacolicus for all nine products . One product was distinguished by an additional fructosyl at the position of P13671 - OH on the first added fructosyl . Spirostan saponins of the substrates could not be converted . Steroidal saponins embracing a fructosyl are quite rare according to other reports based on similar studies . This study successfully converted furostan saponins into new compounds .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK99___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK99___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"Docosahexaenoic acid inhibits insulin - induced activation of sterol regulatory - element binding protein 1 and cyclooxygenase - 2 expression through upregulation of Q96EB6 in human colon epithelial cells . Multiple lines of compelling evidence from clinical and population - based studies support that hyperinsulinemia often accompanying obesity - associated insulin insensitivity promotes colon carcinogenesis . P01308 can acetylate , thereby activating sterol regulator element - binding protein 1 ( P36956 ) , a prime transcription factor responsible for expression of genes involved in lipogenesis . Moreover , P36956 upregulates cyclooxygenase - 2 ( P35354 ) , a key player in inflammatory signaling . Docosahexaenoic acid ( DB01708 ) , a representative omega - 3 polyunsaturated fatty acid , has been known to negatively regulate P36956 , but the underlying molecular mechanism is not fully clarified yet . This prompted us to investigate whether DB01708 could inhibit insulin - induced activation of P36956 and P35354 expression in the context of its potential protective effect on obesity - induced inflammation and carcinogenesis . Q96EB6 , a NAD (+)- dependent histone / non - histone protein deacetylase , has been reported to inhibit intracellular signaling mediated by P36956 through deacetylation of this transcription factor . We found that DB01708 induced Q96EB6 expression in CCD841CoN human colon epithelial cells . DB01708 abrogated insulin - induced acetylation as well as expression of P36956 and P35354 upregulation . P01308 - induced stimulation of CCD841CoN cell migration was also inhibited by DB01708 . These effects mediated by DB01708 were attenuated by pharmacologic inhibition of Q96EB6 . Hyperinsulinemia or insulin resistance is considered to be associated with obesity - associated inflammation . Genetically obese ( ob / ob ) mice showed higher colonic expression levels of both P36956 and P35354 than did normal lean mice . Likewise , expression of P36956 and P35354 was elevated in human colon tumor specimens compared with surrounding normal tissues . In conclusion , DB01708 may protect against obesity - associated inflammation and colon carcinogenesis by suppressing insulin - induced activation of P36956 and expression of P35354 through up - regulation of Q96EB6 .",
"Hypogonadism on admission to acute rehabilitation is correlated with lower functional status at admission and discharge . PRIMARY OBJECTIVE : To investigate the association between hormone levels and functional status during acute TBI rehabilitation . RESEARCH DESIGN : Retrospective cohort study of 43 men with moderate - to - severe TBI admitted to an acute rehabilitation unit during a 1 year period . METHODS AND PROCEDURES : Labs were drawn on admission , including total and free testosterone ( T ) , prolactin , adrenocorticotropin hormone ( DB01285 ) , cortisol , thyroid stimulating hormone ( DB00024 ) , free thyroxine ( fT4 ) and insulin - like growth factor ( DB01277 ) . Functional Independence Measure ( Q9UBW7 ) scores were obtained at admission and discharge . MAIN OUTCOME AND RESULTS : Associations between admission hormone levels and the main outcomes , admission and discharge Q9UBW7 scores , were assessed using linear regression . Lower total and free T - levels at admission were associated with lower total Q9UBW7 scores at admission ( p < 0 . 038 ) and discharge ( p < 0 . 046 ) . Higher cortisol levels at admission were significantly associated with lower admission ( p = 0 . 012 ) and discharge ( p = 0 . 036 ) scores on the cognitive - Q9UBW7 . P01236 , DB00024 , fT4 and DB01277 were not correlated with functional status . CONCLUSIONS : In men , lower total and free T - levels at admission to acute rehabilitation correlate with lower admission and discharge Q9UBW7 scores . These data support the need for studies to investigate the impact of physiological testosterone therapy on outcomes during and post - rehabilitation .",
"Disorders of carnitine transport and the carnitine cycle . DB00583 plays an essential role in the transfer of long - chain fatty acids across the inner mitochondrial membrane . This transfer requires enzymes and transporters that accumulate carnitine within the cell ( O76082 carnitine transporter ) , conjugate it with long chain fatty acids ( carnitine palmitoyl transferase 1 , CPT1 ) , transfer the acylcarnitine across the inner plasma membrane ( carnitine - acylcarnitine translocase , O43772 ) , and conjugate the fatty acid back to DB01992 for subsequent beta oxidation ( carnitine palmitoyl transferase 2 , P23786 ) . Deficiency of the O76082 carnitine transporter causes primary carnitine deficiency , characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues . Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy , or with skeletal and cardiac myopathy . This disease responds to carnitine supplementation . Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia . The heart and the muscle , which express a genetically distinct form of CPT1 , are usually unaffected . These patients can have elevated levels of plasma carnitine . O43772 deficiency presents in most cases in the neonatal period with hypoglycemia , hyperammonemia , and cardiomyopathy with arrhythmia leading to cardiac arrest . Plasma carnitine levels are extremely low . Deficiency of P23786 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise . More severe variants of P23786 deficiency present in the neonatal period similarly to O43772 deficiency associated or not with multiple congenital anomalies . Treatment for deficiency of CPT1 , P23786 , and O43772 consists in a low - fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine , carnitine supplements , and avoidance of fasting and sustained exercise .",
"Q07869 - γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow . OBJECTIVE : DB00583 homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow ( Shunt ) . Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in Q07869 - γ expression in Shunt lambs . Thus , this study was carried out to determine if there is a causal link between loss of Q07869 - γ signaling and carnitine dysfunction , and whether the Q07869 - γ agonist , rosiglitazone preserves carnitine homeostasis in Shunt lambs . METHODS AND RESULTS : siRNA - mediated Q07869 - γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 ( CPT1 and 2 ) and carnitine acetyltransferase ( P43155 ) protein levels . This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction , as determined by a reduction in cellular DB00171 levels . In turn , the decrease in cellular DB00171 attenuated NO signaling through a reduction in P29474 / Hsp90 interactions and enhanced P29474 uncoupling . In vivo , rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining DB00171 levels . This in turn preserved P29474 / Hsp90 interactions and NO signaling . CONCLUSION : Our study indicates that Q07869 - γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo . Further , it identifies a new mechanism by which Q07869 - γ regulates NO signaling through Hsp90 . Thus , Q07869 - γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow .",
"Serum concentrations of growth factors in women with and without endometriosis : the action of anti - endometriosis medicines . Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis . Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis . Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease . In the present study , we investigate the soluble levels of vascular endothelial growth factor ( P15692 ) , epidermal growth factor - receptor ( P01133 - R ) , granulocyte / macrophage - colony stimulating factor ( GM - P04141 ) , P01308 - like growth factor - 1 ( DB01277 ) and interferon - gamma ( P01579 ) in the serum of 28 women with and 20 without endometriosis . We also compared these levels before , during and after treatment with danazol and leuprorelin acetate depot , the two therapeutic regiments of choice concerning this disease . We found that only sVEGF levels were higher in women with endometriosis in comparison to controls ( P < 0 . 001 ) while sEGF - R is not present . GM - P04141 , DB01277 and P01579 soluble levels are not affected in either healthy or endometriotic subjects . The 6 - month treatment with danazol decreased sVEGF levels ( P < 0 . 02 ) and increased sEGF - R levels ( P < 0 . 001 ) . These observations support the view that P15692 may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold . However , future studies will be focused on the anti - angiogenic control of the action of P15692 in patients with endometriosis .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK86___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Obesity and breast cancer : the roles of peroxisome proliferator - activated receptor - γ and plasminogen activator inhibitor - 1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high - fat diet and obesity . P00747 activator inhibitor - 1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 - γ and P05121 expression to high - fat diet and obesity in the risk of breast cancer .",
"P19957 - kinase is essential for ADP - stimulated integrin alpha ( IIb ) beta3 - mediated platelet calcium oscillation , implications for P2Y receptor pathways in integrin alpha ( IIb ) beta3 - initiated signaling cross - talks . Phosphatidylinositol 3 - kinase ( PI3K ) pathway is important for platelet activation . Recent studies showed that PI3K and oscillative calcium could cross talk to each other and positively regulate integrin alpha ( IIb ) beta3 - mediated outside - in signaling . However , the mechanism of this feedback regulation remains to be further characterized . Here we found that treatments of both PI3K inhibitor wortmannin and P47900 inhibitor A3P5P could inhibit granular secretion in platelets . Additionally , when RGD - substrate adherent platelets were treated with the ADP scavenger apyrase to deplete the granular - released ADP , their attachments in engaging with substrates became looser and the frequency of calcium oscillation decreased . Since it is known that ADP stimulates the PI3K and calcium signal primarily through Q9H244 and P47900 receptors respectively , our data indicated that integrin alpha ( IIb ) beta3 downstream PI3K and calcium activation might be not completely coupled to integrin associated signaling complex , but in part through feedback stimulation by granular released ADP . Our data indicates the important roles of PI3K and granular released ADP in coordinating the feedback regulations in integrin alpha ( IIb ) beta3 - mediated platelet activation ."
] |
[
"___MASK15___",
"___MASK21___",
"___MASK24___",
"___MASK34___",
"___MASK44___",
"___MASK62___",
"___MASK86___",
"___MASK97___",
"___MASK99___"
] |
___MASK86___
|
MH_train_301
|
interacts_with DB01235?
|
[
"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .",
"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"The post - ischemic administration of 3 -[ 2 -[ 4 -( 3 - chloro - 2 - methylphenyl )- 1 - piperazinyl ] ethyl ]- 5 , 6 - dimethoxy - 1 -( 4 - imidazolylmethyl )- 1H - indazole dihydrochloride 3 . 5 hydrate ( DY - 9760e ) , a novel calmodulin antagonist , prevents delayed neuronal death in gerbil hippocampus . The novel calmodulin ( P62158 ) antagonist DY - 9760e ( 3 -[ 2 -[ 4 -( 3 - chloro - 2 - methylphenyl )- 1 - piperazinyl ] ethyl ]- 5 , 6 - dimethoxy - 1 -( 4 - imidazolylmethyl )- 1H - indazole dihydrochloride 3 . 5 hydrate ) with an apparent neuroprotective effect in vivo preferentially inhibits neuronal nitric oxide synthase ( P29475 ) , Ca2 +/ P62158 - dependent protein kinase IIalpha ( CaMKIIalpha ) , and calcineurin in vitro . In the present study , we investigated the molecular mechanism underlying its neuroprotective effect with the gerbil transient forebrain ischemia model , by focusing on its inhibition of these Ca2 +/ P62158 - dependent enzymes . Post - ischemic DY - 9760e treatment ( 5 mg / kg , i . p . ) immediately after 5 - min ischemia significantly reduced the delayed neuronal death in the hippocampal P00915 region . CaMKIIalpha was transiently autophosphorylated immediately after reperfusion with concomitant sustained decrease in its total amounts in the Triton X - 100 - soluble fractions . Calcineurin activity , accessed by the phosphorylation state of dopamine - and DB02527 - regulated phosphoprotein of Mr 32 , 000 ( Q9UD71 ) at Thr34 , was elevated at 6 h after reperfusion . Post - treatment of DY - 9760e had no effects on both CaMKIIalpha and Q9UD71 phosphorylation at 6 h after reperfusion . However , DY - 9760e significantly inhibited nitrotyrosine formation , as a biomarker of NO , and in turn , peroxynitrite ( ONOO - ) production . These results suggest that DY - 9760e primarily inhibits Ca2 +/ P62158 - dependent neuronal NOS , without any effects on CaMKII and calcineurin , and the inhibition of NO production possibly accounts for its neuroprotective action in brain ischemic injury .",
"Gene expression profiles of adipose tissue of obese rats after central administration of neuropeptide Y - Q15761 antisense oligodeoxynucleotides by cDNA microarrays . To investigate the gene expression profiles of adipose tissue of obese rats after central administration of neuropeptide Y - Q15761 antisense oligodeoxynucleotides ( ODNs ) , Q15761 antisense , mismatched ODNs or vehicle was intracerebroventricularly injected and cDNA microarrays were undertaken . Central administration of Q15761 antisense ODNs decreased food intake , body weight and serum insulin compared with both vehicle and mismatched ODNs . The average area of adipocytes both at retroperitoneal and epididymal adipose tissue were fall in antisense group while only the weight of the retroperitoneal fat pats was reduced in antisense group . cDNA microarrays containing 18 , 000 genes / Ests were used to investigate gene expression of adipose tissue . Autoradiographic analysis showed that 404 , 81 , and 34 genes were differently expressed over twofold , threefold , and fivefold , respectively . The analysis of gene expression profiles indicated that 332 genes were up - regulated and 187 genes were down - regulated in response to Q15761 antisense ODNs treatment . Different clusters of genes associated with apoptosis , signal transduction , energy metabolism , lipid metabolism , etc . , such as P51114 , Q8WV24 , Q7L5Y9 , P27986 , P13598 , Q00169 , P62158 , Q13557 , P61925 , P14416 , O95258 , CKB , P22760 , P38571 , O15254 , O60427 , were concerned . Analysis of differentially expressed genes will help to understand the effects of Q15761 antisense ODNs therapy .",
"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .",
"Regulation of the natural killer cell response to interferon - alpha by biogenic amines . Monocytes , recovered from human peripheral blood by counter - current centrifugal elutriation ( CCE ) , suppressed baseline natural killer ( NK ) cell cytotoxicity ( NKCC ) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon - alpha ( IFN - alpha ) by a cell contact - dependent mechanism . Monocyte - induced suppression of resting and IFN - activated NK cells was abrogated by the biogenic amines histamine [ via H2 - type receptors ( P25021 ) ] and serotonin [ via P08908 - type receptors ( 5 - HT1AR ) ] . Our data are suggestive of a monocyte / NK cell interaction that is subject to regulation by biogenic amines .",
"___MASK19___ protects against 3 - nitropropionic acid neurotoxicity through the modulation of calpain , CREB , and P23560 . In this study we tested whether phosphodiesterase 5 ( O76074 ) inhibitors , sildenafil and vardenafil , would afford protection against 3 - nitropropionic acid ( 3NP ) , which produces striatal lesions that closely mimic some of the neuropathological features of Huntington ' s Disease ( HD ) . The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps . Animals treated with O76074 inhibitors ( sildenafil or vardenafil ) showed improved neurologic scores , reduced the loss of striatal Q9UD71 protein levels and lesion volumes , and decreased calpain activation produced by 3NP . This protective effect was independent of changes in 3NP - induced succinate dehydrogenase inhibition . Furthermore , striatal p - CREB levels along with the expression of P23560 were significantly increased in sildenafil - treated rats . In summary , O76074 inhibitors protected against 3NP - induced striatal degeneration by reducing calpain activation and by promoting survival pathways . These data encourage further evaluation of O76074 inhibitors in transgenic mouse models of HD .",
"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .",
"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Roles of protein kinase C and actin - binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor . P35462 ( D ( 3 ) R ) is expressed mainly in parts of the brain that control the emotional behaviors . It is believed that the improper regulation of D ( 3 ) R is involved in the etiology of schizophrenia . Desensitization of D ( 3 ) R is weakly associated with G protein - coupled receptor kinase ( GRK ) / beta - arrestin - directed internalization . This suggests that there might be an alternative pathway that regulates D ( 3 ) R signaling . This report shows that D ( 3 ) R undergoes robust protein kinase C ( PKC ) - dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling . PKC - dependent D ( 3 ) R sequestration , which was enhanced by P05771 or - delta , was dynamin dependent but independent of GRK , beta - arrestin , or caveolin 1 . Site - directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D ( 3 ) R identified serine residues at positions 229 and 257 as the critical amino acids responsible for phorbol - 12 - myristate - 13 - acetate ( PMA ) - induced D ( 3 ) R phosphorylation , sequestration , and desensitization . In addition , the LxxY endocytosis motif , which is located between residues 252 and 255 , was found to play accommodating roles for PMA - induced D ( 3 ) R sequestration . A continuous interaction with the actin - binding protein 280 ( filamin A ) , which was previously known to interact with D ( 3 ) R , is required for PMA - induced D ( 3 ) R sequestration . In conclusion , the PKC - dependent but GRK -/ beta - arrestin - independent phosphorylation of D ( 3 ) R is the main pathway responsible for the sequestration and desensitization of D ( 3 ) R . Filamin A is essential for both the efficient signaling and sequestration of D ( 3 ) R .",
"Profound conformational changes of Q15121 / PEA - 15 in P28482 complex revealed by NMR backbone dynamics . Q15121 / PEA - 15 is a small , non - catalytic , Q9NY61 containing protein that is widely expressed in different tissues and highly conserved among mammals . Q15121 / PEA - 15 has been found to interact with several protein targets in various pathways , including Q13158 and procaspase - 8 ( apoptosis ) , P27361 / 2 ( cell cycle entry ) , and Q13393 / 2 ( diabetes ) . In this research , we have studied the Q15121 / PEA - 15 in a complex with P28482 , a Q96HU1 kinase , using NMR spectroscopic techniques . Q96HU1 Kinase signaling pathways are involved in the regulation of many cellular functions , including cell proliferation , differentiation , apoptosis and survival . P27361 / 2 are activated by a variety of external stimuli , including growth factors , hormones and neurotransmitters . Inactivated P28482 is primarily found in the cytosol . Once the P29323 / MAPK cascade is initiated , P28482 is phosphorylated and stimulated , allowing it to redistribute in the cell nucleus and act as a transcription factor . Previous studies have shown that Q15121 / PEA - 15 complexes with P28482 in the cytoplasm and prevents redistribution into the nucleus . Although the NMR structure and dynamics of Q15121 / PEA - 15 in the free form have been documented recently , no detailed structural and dynamic information for the P28482 - bound form is available . Here we report NMR chemical shift perturbation and backbone dynamic studies at the fast ps - ns timescale of Q15121 / PEA - 15 , in its free form and in the complex with P28482 . These analyses characterize motions and conformational changes involved in P28482 recognition and binding that orchestrate the reorganization of the Q9NY61 and immobilization of the C - terminal tail . A new induced fit binding model for Q15121 / PEA - 15 is proposed .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK53___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Granulocyte macrophage - colony stimulating factor increases the expression of histamine and histamine receptors in monocytes / macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage - colony - stimulating factor ( GM - P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine - producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM - P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM - P04141 - induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC - expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM - P04141 was also detected in the lesions . In U937 cells , GM - P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM - P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM - P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis - related genes in monocytes and smooth muscle cells . The presence of histamine - producing macrophages and gene expression of histamine receptors and GM - P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM - P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM - P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression .",
"___MASK73___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK73___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"Dopamine - related genes and their relationships to monoamine metabolites in P04141 . Monoamine metabolite ( MM ) levels in lumbar cerebrospinal fluid ( P04141 ) are extensively used as indirect estimates of monoamine turnover in the brain . In this study we investigated genotypes for DNA polymorphisms in the D2 ( P14416 ) , D3 ( P35462 ) , and D4 ( P21917 ) dopamine receptor and tyrosine hydroxylase ( TH ) genes and their relationships to P04141 MM in healthy volunteers ( n = 66 ) . Concentrations of homovanillic acid ( HVA ) , 3 - methoxy - 4 - hydroxyphenylglycol ( MHPG ) , and 5 - hydroxyindoleacetic acid ( 5 - HIAA ) were corrected for back length , a confounding variable . Corrected MM levels were not related to age , gender , height , weight heredity , season or atmospheric pressure at sampling . Individuals with specific P14416 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations . P35462 homo - and heterozygotic genotypes had significantly different P04141 5 - HIAA levels . P21917 genotypes were not related to MM concentrations . The results suggest that specific P14416 , P35462 , and TH genotypes participate in the regulation of monoamine turnover in the central nervous system . Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in P04141 . The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain .",
"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK63___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells . Sorting nexin 5 ( Q9Y5X3 ) belongs to the P20073 family , which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins , receptors , and transporters . Q9Y5X3 is important in the resensitization of the dopamine D1 - like receptor ( D1R ) . D1R is uncoupled from its effector proteins in hypertension and diabetes , and treatment of diabetes restores D1R function and insulin receptor ( IR ) expression . We tested the hypothesis that the D1R and Q9Y5X3 regulate IR by studying the expression , distribution , dynamics , and functional consequences of their interaction in human renal proximal tubule cells ( hRPTCs ) . D1R , Q9Y5X3 , and IR were expressed and colocalized in the brush border of RPTs . P01308 promoted the colocalization of Q9Y5X3 and IR at the perinuclear area of hRPTCs . Unlike Q9Y5X3 , the D1R colocalized and coimmunoprecipitated with IR , and this interaction was enhanced by insulin . To evaluate the role of Q9Y5X3 and D1R on IR signaling , we silenced via RNA interference the endogenous expression of Q9Y5X3 or the D1R gene P21728 in hRPTCs . We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B , which are crucial components of the IR signal transduction pathway . Our data indicate that Q9Y5X3 and D1R are necessary for normal IR expression and activity . It is conceivable that D1R and Q9Y5X3 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling .",
"Neuron - specific alterations in signal transduction pathways associated with Alzheimer ' s disease . The hallmarks of sporadic Alzheimer ' s disease ( AD ) are extracellular amyloid deposits , intracellular neurofibrillary tangles ( NFTs ) , and neuronal death . Hyperphosphorylation of tau is a key factor in the generation of NFTs . Mitogen activated protein kinase 1 ( P28482 ) and protein kinase C beta ( P05771 ) are thought to play a role in hyperphosphorylation , and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction , and to trigger MAPK phosphorylation pathways . We performed single - cell analyses of neurons with different vulnerabilities to AD - related changes . Using quantitative PCR ( qPCR ) , we measured the levels of P28482 and P05771 transcript in P00915 ( high vulnerability ) , P00918 pyramidal cells from the hippocampus , granule cells from the cerebellum ( low vulnerability ) , and neurons from the brain stem ( nucleus tractus spinalis nervi trigemini , characterized by early neurophysiological deficits ) at progressive Braak stages compared to age - matched controls . The highly vulnerable P00915 pyramidal neurons were characterized by age - and disease - unrelated increases in PRCKB levels and by age - and disease - related increases in P28482 levels . In contrast , low P05771 levels were found in P00918 pyramidal neurons , and P28482 levels were elevated in controls and intermediate AD stages . Both P05771 and P28482 were increased in the late AD stages . P28482 and P05771 levels were low in the brainstem and cerebellum . We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region - specific manner . In addition , multiple signal transduction pathways need to be affected to result in AD instead of physiological aging .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK51___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK51___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK51___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK51___ among adults with ADHD .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK71___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"___MASK73___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"P10275 inactivation contributes to antitumor efficacy of 17 { alpha }- hydroxylase / 17 , 20 - lyase inhibitor 3beta - hydroxy - 17 -( 1H - benzimidazole - 1 - yl ) androsta - 5 , 16 - diene in prostate cancer . We previously reported that our novel compound 3beta - hydroxy - 17 -( 1H - benzimidazole - 1 - yl ) androsta - 5 , 16 - diene ( VN / 124 - 1 ) is a potent 17alpha - hydroxylase / 17 , 20 - lyase ( P05093 ) inhibitor / antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice . In this study , we report that VN / 124 - 1 and other novel P05093 inhibitors also cause down - regulation of androgen receptor ( AR ) protein expression in vitro and in vivo . This mechanism of action seems to contribute to their antitumor efficacy . We compared the in vivo antitumor efficacy of VN / 124 - 1 with that of castration and a clinically used antiandrogen , ___MASK63___ , and show that VN / 124 - 1 is more potent than castration in the LAPC4 xenograft model . Treatment with VN / 124 - 1 ( 0 . 13 mmol / kg twice daily ) was also very effective in preventing the formation of LAPC4 tumors ( 6 . 94 versus 2410 . 28 mm ( 3 ) in control group ) . VN / 124 - 1 ( 0 . 13 mmol / kg twice daily ) and VN / 124 - 1 ( 0 . 13 mmol / kg twice daily ) + castration induced regression of LAPC4 tumor xenografts by 26 . 55 % and 60 . 67 % , respectively . Treatments with ___MASK63___ ( 0 . 13 mmol / kg twice daily ) or castration caused significant tumor suppression compared with control . Furthermore , treatment with VN / 124 - 1 caused marked down - regulation of AR protein expression , in contrast to treatments with ___MASK63___ or castration that caused significant up - regulation of AR protein expression . The results suggest that VN / 124 - 1 acts by several mechanisms ( P05093 inhibition , competitive inhibition , and down - regulation of the AR ) . These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors . VN / 124 - 1 is more efficacious than castration in the LAPC4 xenograft model , suggesting that the compound has potential for the treatment of prostate cancer .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK10___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( ___MASK51___ ) reduces hyperactive - impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate ___MASK51___ effects in P51689 , as in typically developing children with attention - deficit / hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to ___MASK51___ during a 1 - week safety / tolerability lead - in phase and 58 who went on to be randomized to placebo and three doses of ___MASK51___ during a 4 - week blinded , crossover study . Outcome measures included the Clinical Global Impression - Improvement ( CGI - I ) scale and the Aberrant Behavior Checklist ( ABC - hyperactivity index ) . A total of 14 subjects discontinued the study because of ___MASK51___ side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty - nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P = 0 . 006 ) , P08913 ( P < 0 . 02 ) , P21964 ( P < 0 . 04 ) , P35462 ( P < 0 . 05 ) , P21917 ( P < 0 . 05 ) , Q01959 ( P < 0 . 05 ) and P31645 ( P < 0 . 05 ) genotypes were found for responders versus non - responders . Variants in P14416 ( P < 0 . 001 ) and P35462 ( P < 0 . 04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first ___MASK51___ pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in ___MASK51___ ' s efficacy and tolerability .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK71___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors . The neuregulin / ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations -- a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders . Because neuregulin - 1 ( Q99988 ) dramatically increases extracellular dopamine levels in the hippocampus , we investigated the relationship between DB04223 / ErbB and dopamine signaling in hippocampal γ oscillations . Using agonists for different D1 - and D2 - type dopamine receptors , we found that the D4 receptor ( D4R ) agonist PD168077 , but not D1 / D5 and D2 / D3 agonists , increases γ oscillation power , and its effect is blocked by the highly specific D4R antagonist L - 745 , 870 . Using double in situ hybridization and immunofluorescence histochemistry , we show that hippocampal D4R mRNA and protein are more highly expressed in Q99259 - positive GABAergic interneurons , many of which express the Q99988 receptor ErbB4 . Importantly , D4 and ErbB4 receptors are coexpressed in parvalbumin - positive basket cells that are critical for γ oscillations . Last , we report that D4R activation is essential for the effects of Q99988 on network activity because L - 745 , 870 and the atypical antipsychotic clozapine dramatically reduce the Q99988 - induced increase in γ oscillation power . This unique link between D4R and ErbB4 signaling on γ oscillation power , and their coexpression in parvalbumin - expressing interneurons , suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control . These findings are important given the association of a P21917 polymorphism with alterations in attention , working memory , and γ oscillations , and suggest potential benefits of D4R modulators for targeting cognitive deficits .",
"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK81___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK81___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK81___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK81___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK81___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK81___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK81___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK81___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK81___ in the treatment of changes in hypervigilance following severe stress .",
"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .",
"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .",
"Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .",
"The human interleukin 18 gene Q14116 maps to 11q22 . 2 - q22 . 3 , closely linked to the P14416 gene locus and distinct from mapped IDDM loci .",
"Heroin addiction in African Americans : a hypothesis - driven association study . Heroin addiction is a chronic complex disease with a substantial genetic contribution . This study was designed to identify gene variants associated with heroin addiction in African Americans . The emphasis was on genes involved in reward modulation , behavioral control , cognitive function , signal transduction and stress response . We have performed a case - control association analysis by screening with 1350 variants of 130 genes . The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse . Single nucleotide polymorphism ( SNP ) , haplotype and multi - SNP genotype pattern analyses were performed . Seventeen SNPs showed point - wise significant association with heroin addiction ( nominal P < 0 . 01 ) . These SNPs are from genes encoding several receptors : adrenergic ( ADRA1A ) , arginine vasopressin ( P37288 ) , cholinergic ( P08172 ) , dopamine ( P21728 ) , GABA - A ( P28472 ) , glutamate ( Q12879 ) and serotonin ( P46098 ) as well as alcohol dehydrogenase ( P40394 ) , glutamic acid decarboxylase ( Q99259 and Q05329 ) , the nucleoside transporter ( Q99808 ) and diazepam - binding inhibitor ( DBI ) . The most significant result of the analyses was obtained for the Q12879 haplotype G - A - T ( rs4587976 - rs1071502 - rs1366076 ) with protective effect ( P ( uncorrected ) = 9 . 6E - 05 , P ( corrected ) = 0 . 058 ) . This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction . Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability .",
"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .",
"Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Molecular and biochemical analysis of calmodulin interactions with the calmodulin - binding domain of plant glutamate decarboxylase . We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase ( Q99259 ) is a calmodulin ( P62158 ) - binding protein . Here , we studied the Q99259 P62158 - binding domain in detail . A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2 +/ P62158 with a 1 : 1 stoichiometry , and amino acid substitutions suggest that tryptophan - 485 has an indispensable role in P62158 binding . Chemical cross - linking revealed specific P62158 / Q99259 interactions even in the absence of Ca2 + . However , increasing KCI concentrations or deletion of two carboxy - terminal lysines abolished these interactions but had a mild effect on P62158 / Q99259 interactions in the presence of Ca2 + . We conclude that in the presence of Ca ( 2 +)- hydrophobic interactions involving tryptophan - 485 and electrostatic interactions involving the carboxy - terminal lysines mediate P62158 / Q99259 complex formation . By contrast , in the absence of Ca2 + , P62158 / Q99259 interactions are essentially electrostatic and involve the carboxy - terminal lysines . In addition , a tryptophan residue and carboxy - terminal lysines are present in the P62158 - binding domain of an Arabidopsis Q99259 . Finally , we demonstrate that petunia Q99259 activity is stimulated in vitro by Ca2 +/ P62158 . Our study provides a molecular basis for Ca ( 2 +)- dependent P62158 / Q99259 interactions and suggests the possible occurrence of Ca ( 2 +)- independent P62158 / Q99259 interactions .",
"Meta - analysis of six genes ( P23560 , P21728 , P35462 , P21917 , Q13224 and P21397 ) involved in neuroplasticity and the risk for alcohol dependence . BACKGROUND : DB00898 - related problems have a large impact on human health , accounting for around 4 % of deaths and 4 . 5 % of disability - adjusted life - years around the world . Genetic factors could explain a significant fraction of the risk for alcohol dependence ( AD ) . Recent meta - analyses have found significant pooled odds ratios ( ORs ) for variants in the P00325 , P00326 , P14416 and P28223 genes . METHODS : In the present study , we carried out a meta - analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity : P23560 , P21728 , P35462 , P21917 , Q13224 and P21397 . We carried out a systematic search for published association studies that analyzed the genes of interest . Relevant articles were retrieved and demographic and genetic data were extracted . Pooled ORs were calculated using a random - effects model using the Meta - Analyst program . Dominant , recessive and allelic models were tested and analyses were also stratified by ethnicity . RESULTS : Forty two published studies were included in the current meta - analysis : P23560 - rs6265 ( nine studies ) , P21728 - rs4532 ( four studies ) , P35462 - rs6280 ( eleven studies ) , P21917 - VNTR ( seven studies ) , Q13224 - rs1806201 ( three studies ) and P21397 - uVNTR ( eight studies ) . We did not find significant pooled ORs for any of the six genes , under different models and stratifying for ethnicity . CONCLUSIONS : In terms of the number of candidate genes included , this is one of the most comprehensive meta - analyses for genetics of AD . Pooled ORs did not support consistent associations with any of the six candidate genes tested . Future studies of novel genes of functional relevance and meta - analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD .",
"The additive effect of neurotransmitter genes in pathological gambling . As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling , known as pathological gambling . Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role . Polymorphisms at 31 different genes involved in dopamine , serotonin , norepinephrine , GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age , race , and sex - matched controls . Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable , and the 31 coded genes as the independent variables . Fifteen genes were included in the regression equation . The most significant were the P14416 , P21917 , Q01959 , P17752 , P18825 , NMDA1 , and P49768 genes . The r ( 2 ) or fraction of the variance was less than 0 . 02 for most genes . Dopamine , serotonin , and norepinephrine genes contributed approximately equally to the risk for pathological gambling . These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling . Multi - gene profiles in specific individuals may be of assistance in choosing the appropriate treatment .",
"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .",
"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .",
"Cell intrinsic roles of apoptosis - associated speck - like protein in regulating innate and adaptive immune responses . The role of apoptosis - associated speck - Like protein ( ASC ) in the assembly of the inflammasome complex within macrophages has been elucidated in several studies . In this particular role , ASC functions as an adaptor protein by linking nod - like receptors ( NLRs ) and procaspase - 1 , thereby leading to the activation of caspase - 1 to cleave inflammatory cytokines IL - 1β and Q14116 and inducing pyroptosis . It has been noted that ASC maintains inflammasome - independent roles , including but not limited to controlling the expression of Dock2 and mitogen - activated protein kinases ( MAPK / P28482 ) and regulating the NF - κB pathway . This paper will emphasize the major roles of ASC during pathogen infection , the mechanisms by which it mediates inflammation , and discuss its more recently discovered functions .",
"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .",
"Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease - related and genetic factors contribute to inter - individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four - point categorical scales . In stratified regression models including demographical and disease - related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter - individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0 . 01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini - Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .",
"Darpp - 32 : a novel antiapoptotic gene in upper gastrointestinal carcinomas . We show the molecular mechanisms involved in Darpp - 32 overexpression and its biological role in upper gastrointestinal adenocarcinomas ( UGC ) . A tumor tissue array of 377 samples was developed and used to detect Q9UD71 DNA amplification and protein overexpression , which occurred in 32 % and 60 % of UGCs , respectively . Concomitant overexpression of mRNA for Darpp - 32 and its truncated isoform t - Darpp was observed in 68 % of tumors ( P < 0 . 001 ) . When Darpp - 32 and t - Darpp were overexpressed in AGS and RKO gastrointestinal cells , up to a 4 - fold reduction in the apoptosis rate was observed ( terminal deoxynucleotidyl transferase - mediated nick - end labeling and P08758 assays ) in response to camptothecin , sodium butyrate , and ceramide . However , the introduction of mutations in phosphorylation sites abrogated this effect . Expression of Darpp - 32 and t - Darpp preserved the mitochondrial transmembrane potential and was associated with increased levels of Bcl2 protein . A reversal of Bcl2 protein level was obtained using small interfering RNAs for Darpp - 32 and t - Darpp . Luciferase assays using the p53 and P38936 reporter plasmids and probing of immunoblots with antibodies specific for p53 transcriptional targets , such as Q00987 and P38936 , indicated that neither Darpp - 32 nor t - Darpp interfere with p53 function . Altogether , we show more frequent mRNA and protein overexpression of Darpp - 32 than DNA amplification , suggesting that , in addition to amplification , transcriptional or posttranscriptional mechanisms may play an important role . The expression of Darpp - 32 and t - Darpp is associated with a potent antiapoptotic advantage for cancer cells through a p53 - independent mechanism that involves preservation of mitochondrial potential and increased Bcl2 levels .",
"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .",
"Cav1 . 2 L - type Ca² ⁺ channels mediate cocaine - induced P42261 trafficking in the nucleus accumbens , a long - term adaptation dependent on ventral tegmental area Ca ( v ) 1 . 3 channels . AMPA receptor ( AMPAR ) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine - induced behavioral responses ; however , the precise mechanism underlying these changes remains unknown . Utilizing cocaine psychomotor sensitization , we have examined phosphorylation of P42261 at key residues serine 845 ( S845 ) and S831 , as well as P42261 cell surface levels in the nucleus accumbens ( NAc ) of cocaine - preexposed mice and the role of brain - specific Ca ( v ) 1 . 2 and Ca ( v ) 1 . 3 L - type Ca² ⁺ channels ( LTCCs ) , therein . We found higher basal levels of S845 phospho - P42261 ( P - P42261 ) and cell surface P42261 in the NAc following protracted withdrawal from cocaine exposure , changes that occur independently of LTCCs . In contrast , we found that a cocaine challenge that elicits expression of the cocaine - sensitized response increases S831 P - P42261 that further increases surface P42261 beyond the higher basal levels . Intra - NAc pharmacological manipulations indicate that the Ca ( v ) 1 . 2 - activated P62158 kinase II ( CaMKII ) mediates cocaine - induced increase in S831 P - P42261 and that both Ca ( v ) 1 . 2 - activated CaMKII and extracellular signal - regulated kinase 2 ( P28482 ) mediate the increase in P42261 cell surface levels specific to the sensitized response . Experiments using adenoassociated viral vectors expressing Ca ( v ) 1 . 3 and P28482 siRNA further indicate that recruitment of the Ca ( v ) 1 . 2 pathway in the NAc is dependent on ventral tegmental area Ca ( v ) 1 . 3 LTCCs and P28482 . Together , these results identify candidate pathways that mediate cocaine - induced AMPAR plasticity in the NAc and provide a mechanism linking LTCCs and P42261 plasticity to cocaine - induced persistent behavioral changes .",
"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .",
"Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK19___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .",
"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .",
"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .",
"Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK27___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .",
"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse ."
] |
[
"___MASK10___",
"___MASK19___",
"___MASK27___",
"___MASK51___",
"___MASK53___",
"___MASK63___",
"___MASK71___",
"___MASK73___",
"___MASK81___"
] |
___MASK53___
|
MH_train_302
|
interacts_with DB00594?
|
[
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK55___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK55___ who were treated with a single dose of mifepristone .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"Transforming growth factor alpha - induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) - alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF - alpha rescues neurons from N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue - type plasminogen activator ( t - PA ) release was shown to potentiate DB01221 - induced excitotoxicity , we observed that TGF - alpha treatment reduced DB01221 - induced increase of t - PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF - alpha induces activation of the extracellular signal - regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF - alpha , by an P29323 - dependent mechanism , stimulates the astrocytic expression of P05121 , a t - PA inhibitor , which mediates the neuroprotective activity of TGF - alpha against DB01221 - mediated excitotoxic neuronal death . Taken together , we indicate that TGF - alpha rescues neurons from DB01221 - induced excitotoxicity in mixed cultures through inhibition of t - PA activity , involving P05121 overexpression by an P29323 - dependent pathway in astrocytes .",
"P01308 - like growth factor stimulation increases radiosensitivity of a pancreatic cancer cell line through endoplasmic reticulum stress under hypoxic conditions . Tumor hypoxia is an obstacle to radiotherapy . Radiosensitivity under hypoxic conditions is determined by molecular oxygen levels , as well as by various biological cellular responses . The insulin - like growth factor ( IGF ) signaling pathway is a widely recognized survival signal that confers radioresistance . However , under hypoxic conditions the role of IGF signaling in radiosensitivity is still poorly understood . Here , we demonstrate that P01344 stimulation decreases clonogenic survival under hypoxic conditions in the pancreatic cancer cell lines AsPC - 1 and Panc - 1 , and in the human breast cancer cell line MCF - 7 . IGF treatment under hypoxic conditions suppressed increased radiation sensitivity in these cell lines by pharmacologically inhibiting the phosphoinositide 3 - kinase - mammalian target of rapamycin pathway , a major IGF signal - transduction pathway . Meanwhile , P01344 induced the endoplasmic reticulum stress response under hypoxia , including increased protein levels of P35638 and P18848 , mRNA levels of P35638 , O75807 , and P11021 , as well as splicing levels of P17861 . The response was suppressed by inhibiting phosphoinositide 3 - kinase and mammalian target of rapamycin activity . Overexpression of P35638 in AsPC - 1 cells increased radiation sensitivity by P01344 simulation under hypoxic conditions , whereas suppression of P35638 expression levels with small hairpin RNA or a dominant negative form of a proline - rich extensin - like receptor protein kinase in hypoxia decreased IGF - induced radiosensitivity . IGF - induced endoplasmic reticulum stress contributed to radiosensitization independent of cell cycle status . Taken together , IGF stimulation increased radiosensitivity through the endoplasmic reticulum stress response under hypoxic conditions .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Apoptosis induction associated with the ER stress response through up - regulation of JNK in HeLa cells by gambogic acid . BACKGROUND : Gambogic acid ( GA ) was extracted from the dried yellow resin of gamboge ( Garcinia hanburyi ) which is traditionally used as a coloring material for painting and cloth dying . Gamboge has been also used as a folk medicine for an internal purgative and externally infected wound . We focused on the mechanisms of apoptosis induction by GA through the unfold protein response ( ER stress ) in HeLa cells . METHODS : The cytotoxic effect of GA against HeLa cells was determined by trypan blue exclusion assay . Markers of ER stress such as P17861 , P11021 , P35638 , O75807 and Q9UBS3 were analyzed by RT - PCR and Real - time RT - PCR . Cell morphological changes and apoptotic proteins were performed by Hoechst33342 staining and Western blotting technique . RESULTS : Our results indicated a time - and dose - dependent decrease of cell viability by GA . The ER stress induction is determined by the up - regulation of spliced P17861 mRNA and activated P11021 , P35638 , O75807 and Q9UBS3 expression . GA also induced cell morphological changes such as nuclear condensation , membrane blebbing and apoptotic body in Hela cells . Apoptosis cell death detected by increased DR5 , caspase - 8 , - 9 , and - 3 expression as well as increased cleaved - PARP , while decreased Bcl - 2 upon GA treatment . In addition , phosphorylated JNK was up - regulated but phosphorylated P29323 was down - regulated after exposure to GA . CONCLUSIONS : These results suggest that GA induce apoptosis associated with the ER stress response through up - regulation of p - JNK and down - regulation of p - P29323 in HeLa cells .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK80___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners . Mutations in the tumor suppressor genes Q92574 and P49815 , encoding hamartin and tuberin , respectively , cause the tumor syndrome tuberous sclerosis with similar phenotypes . Until now , over 50 proteins have been demonstrated to interact with hamartin and / or tuberin . Besides tuberin , the proteins Q96N67 , ezrin / radixin / moesin , Q8TDY2 , IKKbeta , Melted , P35240 , Q00994 ( p75NTR ) , P07196 , Plk1 and Q9P0N9 have been found to interact with hamartin . Whereas Plk1 and Q9P0N9 have been demonstrated not to bind to tuberin , for all the other hamartin - interacting proteins the question , whether they can also bind to tuberin , has not been studied . P49815 interacts with 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , AMPK , P62158 , Q9BUF7 / Q8NI35 , cyclin A , cyclins D1 , D2 , D3 , Dsh , ERalpha , Erk , FoxO1 , Q15751 , HPV16 E6 , HSCP - 70 , P0DMV8 , P49137 , Q96PY6 , p27KIP1 , Pam , PC1 , PP2Ac , Q15276 , Rheb , RxRalpha / P11473 and Q15796 / 3 . 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , Dsh , FoxO1 , Q15751 , p27KIP1 and PP2Ac are known not to bind to hamartin . For the other tuberin - interacting proteins this question remains elusive . The proteins axin , Cdk1 , cyclin B1 , O75807 , GSK3 , P42345 and Q15418 have been found to co - immunoprecipitate with both , hamartin and tuberin . The kinases Cdk1 and IKKbeta phosphorylate hamartin , Erk , Akt , P49137 , AMPK and Q15418 phosphorylate tuberin , and GSK3 phosphorylates both , hamartin and tuberin . This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin .",
"Acid - sensing ion channels promote the inflammation and migration of cultured rat microglia . Microglia , the major immune cells in central nervous system , act as the surveillance and scavenger of immune defense and inflammatory response . Previous studies suggest that there might be close relationship between acid - sensing ion channels ( ASICs ) and inflammation , however , the exact role of ASICs in microglia during inflammation remains elusive . In the present study , we identified the existence of ASICs in the primary cultured rat microglia and explored their functions . By using reverse transcriptase polymerase chain reaction ( RT - PCR ) , quantitative real - time PCR ( qPCR ) , western blotting , and immunofluorescence experiments , we demonstrated that P78348 , ASIC2a , and Q9UHC3 were existed in cultured and in situ rat microglia . After lipopolysaccharide ( LPS ) stimulation , the expressions of microglial P78348 and ASIC2a were upregulated . Meanwhile , ASIC - like currents and acid - induced elevation of intracellular calcium were increased , which could be inhibited by the nonspecific ASICs antagonist amiloride and specific homomeric ASIC1a blocker PcTx1 . In addition , both inhibitors reduced the expression of inflammatory cytokines , including inducible nitric oxide synthase and cyclooxygenase 2 stimulated by LPS . Furthermore , we also observed significant increase in the expression of P78348 and ASIC2a in scrape - stimulated microglial migration . DB00594 and PcTx1 prevented the migration by inhibiting P29323 phosphorylation . Taken together , these results suggest that ASICs participate in neuroinflammatory response , which will provide a novel therapeutic strategy for controlling the inflammation - relevant neuronal diseases .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Selective cyclooxygenase - 2 inhibitor rofecoxib ( Vioxx ) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer . Recent studies indicate that cyclooxygenase - 2 ( P35354 ) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer . A human pancreatic adenocarcinoma cell line , Mia PaCa - 2 , was incubated for 18 hours with 5 micromol / L of rofecoxib ( Vioxx ) , a selective P35354 inhibitor . Total RNA was isolated and gene expression analyzed by DNA microarray chips . In a separate experiment , athymic mice were orthotopically injected with 7 . 5 x 10 ( 5 ) Mia PaCa - 2 cells through a minilaparotomy . After 1 month , laparotomy was repeated to measure tumor size , and mice were randomized to receive reformulated rodent chow containing either 12 . 5 mg / kg / day of rofecoxib or no drug for 21 days . Tumor growth was assessed by comparing volume before and after treatment . In vitro , rofecoxib decreased gene expression of cyclin D1 / P24385 , a key component of cell cycle progression , while increasing expression of several cell cycle arrest genes , including P38936 / P38936 , p33 / ING , O75807 , and P24522 ( P < 0 . 05 ) . In vivo , tumor growth was significantly reduced in treated vs . control mice ( P < 0 . 05 ) . No systemic toxicity was observed in mice receiving rofecoxib . These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK70___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"An uncleavable Q03405 mutant allows dissection of signaling pathways in uPA - dependent cell migration . P00749 ( uPA ) binding to Q03405 induces migration , adhesion , and proliferation through multiple interactions with G proteins - coupled receptor P25090 , integrins , or the epidermal growth factor ( P01133 ) receptor ( P00533 ) . At least two forms of Q03405 are present on the cell surface : full - length and cleaved Q03405 , each specifically interacting with one or more transmembrane proteins . The connection between these interactions and the effects on the signaling pathways activation is not clear . We have exploited an Q03405 mutant ( hcr , human cleavage resistant ) to dissect the pathways involved in uPA - induced cell migration . This mutant is not cleaved by proteases , is glycosylphosphatidylinositol anchored , and binds uPA with a normal K ( d ) . Both wild - type ( wt ) and hcr - Q03405 are able to mediate uPA - induced migration , are constitutively associated with the P00533 , and associate with alpha3beta1 integrin upon uPA binding . However , they engage different pathways in response to uPA . wt - Q03405 requires both integrins and P25090 to mediate uPA - induced migration , and association of wt - Q03405 to alpha3beta1 results in Q03405 cleavage and extracellular signal - regulated kinase ( P29323 ) activation . On the contrary , hcr - Q03405 does not activate P29323 and does not engage P25090 or any other G protein - coupled receptor , but it activates an alternative pathway initiated by the formation of a triple complex ( Q03405 - alpha3beta1 - P00533 ) and resulting in the autotyrosine phosphorylation of P00533 .",
"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .",
"FTY720 , a fungus metabolite , inhibits in vivo growth of androgen - independent prostate cancer . FTY720 , a derivative of fungus , has demonstrated dramatic anticancer effect in several malignancies recently . Our study evaluates the therapeutic potential of FTY720 in the treatment of androgen - independent prostate cancer using a human prostate cancer xenograft in nude mice . CWR22R , an androgen - independent human prostate tumor xenograft was inoculated into castrated nude mice and the animals were administrated with either normal saline or FTY720 ( 10 mg / kg ) through intraperitoneal ( i . p . ) injection for 20 days . Body weight and tumor volume were recorded every 2 days , and serum prostate specific antigen ( PSA ) levels were also measured before and after the treatment . The effect of FTY720 on tumor cell proliferation was examined using antibodies against P12004 and Ki - 67 by immunohistochemical staining , MTT assay and colony forming assay , whereas apoptotic effect of FTY720 was evaluated by TUNEL assay and immunostaining using antibodies against cleaved caspase 3 and Bcl - 2 . In addition , the potential inhibitory effect of FTY720 on prostate cancer angiogenesis and metastasis was investigated by immunostaining of CD31 , P15692 , P12830 and beta - catenin . Our results showed that FTY720 treatment led to suppression of CWR22R tumor growth without causing any detectable side effects in nude mice . The FTY720 - induced tumor suppression was correlated with decreased serum PSA level as well as reduced proliferation rate , suppression of angiogenic factors , and restoration of P12830 and beta - catenin expression . In addition , the FTY720 - treated tumors showed increased apoptosis rate demonstrated by increased TUNEL - and cleaved caspase 3 - positive cells , and decreased Bcl - 2 expression . Our results suggest a potential novel agent in the suppression of androgen - independent prostate cancer .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Dexamethasone reverses adrenalectomy - induced neuronal de - differentiation in midbrain raphe - hippocampus axis . Differentiation leads to specific morphological and biochemical characteristics . We examined whether epigenetic factors ( e . g . , glucocorticoids ) are required to maintain neuronal differentiation in the adult brain . In the midbrain , adrenalectomy ( P10109 ) ( 1 - 2 wk ) reduced the size of tryptophan hydroxylase ( WH ) - immunoreactive ( IR ) neurons . P10109 rats exposed to short - term ( 24 - 72 - h ) dexamethasone ( ST - DEX ) in the drinking saline ( 10 mg / l ) showed an increase in WH protein , somal area and dendritic size of WH - IR neurons . In the hippocampus , P10109 for 2 - 3 mo ( long - term ; LT ) reduced Nissl staining , calbindin ( DB09061 ) - IR and P08908 receptor mRNA in the granular cell layer , and the size of the molecular layer and its DB09061 - IR dendrites . Small vimentin ( Vim ) - IR glial cells emerged in the granular layer . ST - DEX after LT - P10109 rapidly induced a recovery of P08908 mRNA , Nissl labeling and DB09061 - IR in the granule cell layer . In the molecular layer , there was an increase in the area and in the number of DB09061 - IR dendrites . Furthermore , the Vim - IR glial cells were enlarged in size and branching . The rate of cell proliferation was studied in these animals . Immunostaining with antibodies against proliferating cell nuclear antigen ( P12004 ) and use of bromouridine argue against enhanced neurogenesis after ST - DEX in LT - P10109 . We propose that glucocorticoids induce and maintain differentiation of serotonergic and DB09061 - IR neurons in the midbrain - hippocampal axis . A neuronotrophic role for the glial P08908 receptor is suggested .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK66___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Microarray study reveals that HIV - 1 induces rapid type - I interferon - dependent p53 mRNA up - regulation in human primary P01730 + T cells . BACKGROUND : Infection with HIV - 1 has been shown to alter expression of a large array of host cell genes . However , previous studies aimed at investigating the putative HIV - 1 - induced modulation of host gene expression have been mostly performed in established human cell lines . To better approximate natural conditions , we monitored gene expression changes in a cell population highly enriched in human primary P01730 + T lymphocytes exposed to HIV - 1 using commercial oligonucleotide microarrays from Affymetrix . RESULTS : We report here that HIV - 1 influences expression of genes related to many important biological processes such as DNA repair , cellular cycle , RNA metabolism and apoptosis . Notably , expression of the p53 tumor suppressor and genes involved in p53 homeostasis such as O75807 were up - regulated by HIV - 1 at the mRNA level . This observation is distinct from the previously reported p53 phosphorylation and stabilization at the protein level , which precedes HIV - 1 - induced apoptosis . We present evidence that the HIV - 1 - mediated increase in p53 gene expression is associated with virus - mediated induction of type - I interferon ( i . e . IFN - alpha and IFN - beta ) . CONCLUSION : These observations have important implications for our understanding of HIV - 1 pathogenesis , particularly in respect to the virus - induced depletion of P01730 + T cells .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK68___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism , cell proliferation and cell transformation . We explored , by cDNA mini - arrays , gene expression measurements of MVLN , a human breast carcinoma cell line derived from MCF - 7 , after 4 days of exposure to 17beta - estradiol ( E ( 2 ) ) treatment , in order to extend our understanding of the mechanism of the pharmacological action of estrogens . We focused on 22 genes involved in estrogen metabolism , cell proliferation regulation and cell transformation . The specificity of the E ( 2 ) response was reinforced by comparison with 4 - hydroxytamoxifen ( OH - Tam ) , DB00947 and E ( 2 )+ OH - Tam expression profiles . Real - time quantitative PCR ( RTQ - PCR ) confirmed the variation of expression of known ( P04155 , P15514 , P35568 , P22692 , P12004 , P04626 , P07339 , MYC ) as well as novel ( DLEU2 , P20248 , P22309 , O15438 , O15440 , O75410 , P20827 , NOV , P01040 , P51511 , O75362 ) genes . The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E ( 2 ) treatment and this allowed the identification of different time - course patterns . Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of O15438 and O15440 through dissimilar pathways , and secondly that protein synthesis was needed for modulation of the expression of the P20248 and O75410 genes by estrogens . Western blot analysis performed on P04155 , P35568 , P22692 , amphiregulin , P12004 , cyclin A2 , O75410 and O15440 proteins confirmed the mini - array and RTQ - PCR data , even for genes harboring low variations of mRNA expression . Our findings should enhance the understanding of changes induced by E ( 2 ) on the transcriptional program of human E ( 2 )- responsive cells and permit the identification of new potential diagnostic / prognostic tools for the monitoring of estrogen - related disease conditions such as breast cancer .",
"P00749 stimulates the Ras / Extracellular signal - regulated kinase ( P29323 ) signaling pathway and MCF - 7 cell migration by a mechanism that requires focal adhesion kinase , Src , and Shc . Rapid dissociation of P62993 / Sps - Shc complex is associated with the transient phosphorylation of P29323 in urokinase - treated cells . P00749 ( uPA ) stimulates MCF - 7 cell migration by binding to the Q96NZ9 receptor and activating the Ras - extracellular signal - regulated kinase ( Ras - P29323 ) signaling pathway . Studies presented here show that soluble uPA receptor and a peptide derived from the linker region between domains 1 and 2 of the uPA receptor also stimulate cellular migration via a mitogen - activated protein kinase / P29323 kinase ( MEK ) - dependent pathway . Signaling proteins that function upstream of Ras in uPA - stimulated cells remain undefined . To address this problem , we transfected MCF - 7 cells to express the noncatalytic carboxylterminal domain of focal adhesion kinase ( Q05397 ) , Q05397 ( Y397F ) , kinase - defective c - Src , or Shc FFF , all of which express dominant - negative activity . In each case , P29323 phosphorylation and cellular migration in response to uPA were blocked . Both activities were rescued by co - transfecting the cells to express constitutively active Q02750 , indicating that Q05397 , c - Src , and Shc are upstream of MEK . Shc was tyrosine - phosphorylated in uPA - treated cells . The level of phosphorylated Shc was increased within 1 min and remained increased for at least 30 min . Sos co - immunoprecipitated with Shc in cells that were treated with uPA for 1 - 2 . 5 min , probably reflecting the formation of Shc - Grb2 / Sos complex ; however , by 10 min , co - immunoprecipitation of Sos with Shc was no longer observed . Rapid dissociation of Sos from Shc represents a possible mechanism for the transient phosphorylation of P29323 in uPA - treated MCF - 7 cells .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK1___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"P12004 D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer . Cyclin D1 is an important regulator of cell cycle progression . Phosphorylation of cyclin D1 at Thr286 by GSK3β triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome . Cyclin D1 overexpression is a common event in various types of human cancers ; however , reports of mutations are extremely rare . We analyzed mutations of the cyclin D1 gene , P24385 , in 88 endometrial cancer tissue specimens and detected mutations in 2 cases ( 2 . 3 % ) . Both were unreported mutations with substitution of threonine to isoleucine at codon 286 ( T286I ) . These two tumors harbored coexisting mutations in K - ras , P42336 and / or P60484 and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry . Furthermore , we analyzed the functions of mutant cyclin D1 ( T286I ) by luciferase assays , immunofluorescence , western blotting and clonogenic cell survival assays in P29320 - 293T cells . We found that exogenous mutant cyclin D1 ( T286I ) accumulated in the nuclei in P29320 - 293T cells , and that it inhibited the expression of P06400 . Additionally , the number of colonies was increased by introduction of mutant cyclin D1 ( T286I ) compared to that of wild - type cyclin D1 . In conclusion , we identified an unreported P24385 mutation ( T286I ) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells .",
"Role of TGFbeta / Smad signaling in gremlin induction of human trabecular meshwork extracellular matrix proteins . PURPOSE : The bone morphogenic protein ( BMP ) antagonist gremlin is elevated in glaucomatous trabecular meshwork ( TM ) cells and tissues and elevates intraocular pressure ( IOP ) . Gremlin also blocks P12644 inhibition of transforming growth factor ( TGF ) - β2 induction of TM extracellular matrix ( Q13201 ) proteins . The purpose of this study was to determine whether Gremlin regulates Q13201 proteins in cultured human TM cells . METHODS : Human TM cells were treated with recombinant gremlin to determine the effects on Q13201 gene and protein expression . Expression of the Q13201 genes FN , COL1 , P05121 , and P15502 was examined in cultured human TM cells by quantitative RT - PCR and Western immunoblot analysis . TM cells were pretreated with TGFBR inhibitors ( LY364947 , SB431542 or P36897 / P61812 siRNAs ) , inhibitors of the Smad signaling pathway ( SIS3 or Q15796 / 3 / 4 siRNAs ) , or P29279 siRNA to identify the signaling pathway ( s ) involved in gremlin induction of Q13201 gene and protein expression . RESULTS : All Q13201 genes analyzed ( FN , COL1 , P05121 , and P15502 ) were induced by gremlin . This gremlin induction of Q13201 genes and protein expression was blocked by inhibitors of TGFBR and the canonical Q15796 / 3 / 4 and P29279 signaling pathways . CONCLUSIONS : Gremlin employs canonical TGFβ2 / Smad signaling to induce Q13201 genes and proteins in cultured human TM cells . Gremlin also induces both TGFβ2 and P29279 , which can act downstream to mediate some of these Q13201 changes in TM cells .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK60___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK60___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK60___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK60___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK60___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK60___ increased the protein expression of hepatic P05181 and ___MASK60___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK60___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK60___ and RFP - induced hepatotoxicity .",
"Receptor - bound uPA is reversibly protected from inhibition by low molecular weight inhibitors . P00749 ( uPA ) plays a ubiquitous role in cell migration and invasiveness . DB00594 , a competitive inhibitor of uPA , can inhibit endothelial cell ( EC ) outgrowth during angiogenesis . To address the question of whether amiloride blocked angiogenesis by inhibiting uPA , we undertook a study of uPA expression in sprouting EC in vitro and the effects of amiloride on both enzymatic and morphogenetic activity . As expected , amiloride inhibited soluble uPA ( suPA ) with an IC ( 50 ) of 45 - 85 microm , however , receptor - bound uPA ( rbuPA ) from the sprouting EC was insensitive to amiloride . Removal of uPA from its receptors confers sensitivity to inhibition by amiloride suggesting that a reversible conformational change may mediate the insensitivity of rbuPA to amiloride and its analogs . In summary , we found no evidence to support the hypothesis that amiloride blocks capillary outgrowth by inhibition of uPA , but were able to successfully demonstrate a functional difference between two physiological forms of this important matrix - degrading enzyme .",
"Molecular mechanisms involving prostate cancer racial disparity . African American ( AA ) men with prostate cancer ( PCa ) have worse disease , with a higher incidence , younger age and more advanced disease at diagnosis , and a worse prognosis , compared to Caucasian ( CA ) men . In addition to socioeconomic factors and lifestyle differences , molecular alterations contribute to this discrepancy . In this review , we summarize molecular genetics research results interrelated with the biology of PCa racial disparity . Androgen and androgen receptor ( AR ) pathways have long been associated with prostate growth . Racial differences have also been found among variants of the genes of the enzymes involved in androgen biosynthesis and metabolism , such as P31213 , P05093 , and P08684 . The levels of expression and CAG repeat length of AR also show racial divergence and may be critical molecular alterations for racial disparity . Growth factors and their receptors , which promote cancer cell growth , are another potential cause of the disparity ; both P00533 and P29323 , two of the most studied receptors , show interethnic differences . Differences have also been found among genes regulating cell apoptosis , such as P10415 , which is increased in PCa in the AA population . Recent developments in genetics , proteomics , and genomics , among other molecular biotechnologies , will greatly aid the advancement of translational research on PCa racial disparity , hopefully culminating in the discovery of novel mechanisms of disease , in addition to prognostic markers and novel therapeutic approaches .",
"Angiogenic alterations associated with circulating neoplastic DNA in ovarian carcinoma . OBJECTIVES : Forty percent of women with ovarian carcinoma have circulating free neoplastic DNA identified in plasma . Angiogenesis is critical in neoplastic growth and metastasis . We sought to determine whether circulating neoplastic DNA results from alterations in the balance of angiogenesis activators and inhibitors . METHODS : Sixty patients with invasive ovarian carcinomas with somatic P04637 mutations that had been characterized for circulating neoplastic DNA had carcinoma analyzed for microvessel density using immunohistochemistry with CD31 and for the expression of P15692 , Q15389 , O15123 , P35354 , P00749 , P07996 , P09603 , P42336 , Q16665 , P10145 , P08253 , and P14780 message by real - time quantitative polymerase chain reaction . The expression of each gene was calculated relative to P04406 expression for each neoplasm . Patient plasma had been tested for circulating neoplastic DNA using a ligase detection reaction . RESULTS : P08253 expression was significantly correlated with free plasma neoplastic DNA ( P = . 007 ) . Microvessel density was not correlated with plasma neoplastic DNA or P38398 / 2 mutation status . The expression pattern of other angiogenic factors did not correlate with plasma neoplastic DNA but correlated with each other . P38398 / 2 mutated carcinomas had significantly different expression profiles of angiogenesis activators and inhibitors in comparison to sporadic carcinomas . CONCLUSIONS : P08253 expression is associated with the presence of circulating neoplastic DNA in women with ovarian carcinoma . These data are consistent with the proinvasive properties of P08253 and suggest that the presence of circulating neoplastic DNA indicates a more aggressive malignant phenotype . Carcinomas with germ line P38398 / 2 mutations had a lower angiogenic profile than those without mutations .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK54___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK54___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"5 - Hydroxytryptamine induces cyclooxygenase - 2 in rat vascular smooth muscle cells : Mechanisms involving Src , PKC and MAPK activation [ corrected ] . Considering the importance of 5 - hydroxytryptamine ( 5 - HT ) and cyclooxygenase ( P36551 ) products in vascular pathology , we investigated the effects of 5 - HT on P36551 expression in rat vascular smooth muscle cells ( VSMCs ) , and to provide mechanistic insights into these effects . VSMCs were enzymatically isolated from aortic media of Wistar rats . Incubation of VSMCs with 5 - HT for 24h stimulated prostaglandin I ( 2 ) production , but this stimulation was completely suppressed by NS - 398 , a selective P35354 inhibitor . 5 - HT induced transient P35354 , but not P23219 , protein and mRNA expression in concentration - and time - dependent manners . This effect of 5 - HT was completely inhibited by sarpogrelate , a 5 - HT ( 2A ) receptor antagonist . 5 - HT - induced P35354 expression was markedly blunted by Ca ( 2 +) depletion ; GF 109203X , a protein kinase C ( PKC ) inhibitor ; Q99463 , an inhibitor of Src - family tyrosine kinase ( Src ) ; PD 98059 , an inhibitor of extracellular signal - regulated kinase ( P29323 ) activation ; SB 203580 , an inhibitor of p38 mitogen - activated protein kinase ( MAPK ) ; and SP 600125 , an inhibitor of c - Jun N - terminal kinase ( JNK ) . 5 - HT activated P29323 and p38 MAPK , followed by JNK activation . Q99463 inhibited these activations , while GF 109203X inhibited only JNK activation . Furthermore , PD 98059 inhibited JNK activation . These results suggest that 5 - HT induces P35354 expression in rat VSMCs , and that PKC , Src , and MAPK activation are each essential for the full expression of P35354 pathways .",
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"[ DB00594 attenuates hypoxia - induced proliferation of rats pulmonary artery smooth muscle cells by suppressing Na +/ H + exchanger - 1 ] . AIM : To study the influence of Na +/ H + exchange inhibitor amiloride on hypoxia - induced proliferation in rats pulmonary artery smooth muscle cells ( PASMCs ) , also observe the change of Na +/ H + exchanger - 1 ( P19634 ) activity and expression . METHODS : Rats PASMGs were cultured in normoxia ( 21 % O2 ) or hypoxia ( 2 % O2 ) for 24 hours , as well as administered amiloride with various concentrations , cultured for 24 hours , then determined MTT OD values and rates of P12004 positive cells to investigate cells proliferation , moreover intracellular pH was determined by interactive Laser Cytometer , and Na +/ H + exchanger - 1 mRNA expression was determined by RT - PCR . RESULTS : Hypoxic exposure heightened intracellular pH and mRNA expression of P19634 in PASMCs , however , 3 . 123 - 50 micromol / L amiloride depressed them gradually . Additionally , hypoxic exposure raised MTT OD value and rates of P12004 positive cells , similarly , the above two indexes descended gradually with presence of 3 . 125 - 50 micromol / L amiloride . CONCLUSION : Na +/ H + exchange inhibitor amiloride can suppress hypoxia - induced proliferation in pulmonary artery smooth muscle cells , which is due to depress activity and expression of P19634 .",
"The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress . DB00398 is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells . Recently , we demonstrated that sorafenib diminishes Mcl - 1 protein expression by inhibiting translation through a Q02750 / 2 - P27361 / 2 signaling - independent mechanism and that this phenomenon plays a key functional role in sorafenib - mediated lethality . Here , we report that inducible expression of constitutively active Q02750 fails to protect cells from sorafenib - mediated lethality , indicating that sorafenib - induced cell death is unrelated to Q02750 / 2 - P27361 / 2 pathway inactivation . Notably , treatment with sorafenib induced endoplasmic reticulum ( ER ) stress in human leukemia cells ( U937 ) manifested by immediate cytosolic - calcium mobilization , P35638 and O75807 protein induction , P19525 - like ER kinase ( Q9NZJ5 ) and eukaryotic initiation factor 2alpha ( eIF2alpha ) phosphorylation , P17861 splicing , and a general reduction in protein synthesis as assessed by [ 35S ] methionine incorporation . These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic - calcium mobilization and a significant decline in P11021 / Bip protein levels . Interestingly , enforced expression of IRE1alpha markedly reduced sorafenib - mediated apoptosis , whereas knockdown of IRE1alpha or P17861 , disruption of Q9NZJ5 activity , or inhibition of eIF2alpha phosphorylation enhanced sorafenib - mediated lethality . Finally , downregulation of caspase - 2 or caspase - 4 by small interfering RNA significantly diminished apoptosis induced by sorafenib . Together , these findings demonstrate that ER stress represents a central component of a Q02750 / 2 - P27361 / 2 - independent cell death program triggered by sorafenib .",
"HSV type 2 infection increases HIV DNA detection in vaginal tissue of mice expressing human P01730 and P51681 . The goal of this study was to develop an in vivo murine model that can be used to study the influence of HSV - 2 on HIV infection . Mice expressing transgenes for human P01730 , P51681 , and P12004 T1 were infected intravaginally with HSV - 2 and 3 - 7 days later infected with HIV . HIV DNA was detected by real - time PCR . The frequency of detection of HIV DNA was significantly higher ( 65 % ) in vaginal tissue of HSV - 2 - infected mice compared to mock - infected mice ( 35 % ) when HIV was given 3 days after HSV - 2 . HSV - 2 - infected mice also had significantly higher levels of HIV DNA in vaginal tissue . HIV DNA was not detected in vaginal tissue of mice lacking human P01730 . Longer periods ( 5 or 7 days ) between infection with HSV - 2 and HIV did not increase the frequency of detection or the amount of HIV DNA detected . HIV DNA was also detected in lymph nodes from some of the mice that were infected intravaginally with HSV - 2 and HIV . Flow cytometric and mRNA analysis of human P01730 in vaginal tissue suggested that HSV - 2 infection increased the number of T cells expressing human P01730 in vaginal tissue . This study provides evidence that HIV infection of cells occurs in the vagina of mice expressing human P01730 , P51681 , and P12004 T1 and that HSV - 2 infection increases HIV infection . These findings demonstrate that this model can be used to study the mechanisms responsible for increased susceptibility to HIV in HSV - 2 - infected persons and for testing preventative treatments .",
"Loss of the mu opioid receptor on different genetic backgrounds leads to increased bromodeoxyuridine labeling in the dentate gyrus only after repeated injection . The endogenous opioid system is involved in various physiological processes , including neurogenesis in the dentate gyrus ( DG ) of the hippocampus . In the current study , we investigated the role of the mu opioid receptor ( P35372 ) on DG neurogenesis and measured glucocorticoid levels following several injection paradigms to supplement the neurogenesis experiments . P35372 knockout ( KO ) mice on C57BL / 6 and 129S6 backgrounds were injected with bromodeoxyuridine ( BrdU ) using either a single injection or two different repeated injection protocols and then sacrificed at different time points . The total number of BrdU and proliferating cell nuclear antigen ( P12004 ) positive cells in the DG is significantly increased in P35372 KO mice compared with wild type ( WT ) on both strains after repeated injection , but not after a single injection . Plasma corticosterone ( O00230 ) levels increased similarly in P35372 KO and WT mice following both single and repeated injection , indicating that the stress response is activated following any injection protocol , but that the mechanism responsible for the increase in BrdU labeling in P35372 KO mice is O00230 - level independent . Finally , WT 129S6 mice , independent of genotype , showed higher levels of plasma O00230 compared with WT C57BL / 6 mice in both noninjected controls and following injection at two separate time points ; these levels were inversely correlated with low numbers of BrdU cells in the DG in 129S6 mice compared with C57BL / 6 mice . In summary , these data demonstrate that loss of P35372 increases BrdU labeling in the DG independent of O00230 levels , but only following a repeated injection , illustrating the capability of injection paradigms to influence cell - proliferative responses in a genotype - dependent manner .",
"Involvement of urokinase in cigarette smoke extract - induced epithelial - mesenchymal transition in human small airway epithelial cells . P00749 ( uPA ) augments inflammation and tissue remodeling during lung injury and repair . The uPA expression in small airway epithelium of chronic obstructive pulmonary disease ( P48444 ) increases . Epithelial - mesenchymal transition ( EMT ) is important in the small airway fibrosis of P48444 . This study shows the uPA regulation in cigarette smoke extract ( CSE ) - induced EMT in human small airway epithelial cell lines ( HSAEpiCs ). uPA is overexpressed in the small airway epithelium of P48444 patients and CSE - treated cell lines . Furthermore , uPA expression correlated with vimentin expression in the small airway epithelium of P48444 patients . uPA inhibition blocks CSE - induced EMT by reversing P12830 and α - catenin expression and retarding the induction of P19022 and vimentin , resulting in reduction in migration . uPA overexpression in HSAEpiC cells also promotes EMT and migration . EMT is partly reversed in uPA - overexpressing HSAEpiC cells through the silencing expression of uPA receptor . In conclusion , this study provides new insights into the contribution of uPA upregulation to EMT associated with small airway remodeling in P48444 .",
"Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .",
"P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .",
"Amelioration of experimental colitis by Na - H exchanger - 1 inhibitor amiloride is associated with reversal of IL - 1ss and P29323 mitogen - activated protein kinase . OBJECTIVE : Na - H exchanger - 1 ( P19634 ) is induced in experimental colitis . It has not yet been established whether its inhibition ameliorates colitis . The effects of amiloride , an inhibitor of P19634 , on colitis were examined in this study . Levels of mitogen - activated protein ( Q96HU1 ) kinases P29323 , p38 and interleukin 1ss which participate in intestinal inflammation were also examined in the colonic smooth muscle of rats with colitis . MATERIAL AND METHODS : Colitis was induced in Sprague - Dawley male rats by intrarectal administration of trinitrobenzenesulphonic acid ( TNBS ) and treated daily with amiloride ( 3 , 5 , and 10 mg / kg b . w . ( body - weight ) , orally ) starting 1 h before induction of colitis . The animals were sacrificed on day 5 post - TNBS . Controls received phosphate buffered saline in a similar manner . RESULTS : The highest dose of amiloride ( 10 mg / kg ) was lethal . The lowest dose ( 3 mg / kg ) was tolerated and was used in this study . DB00594 significantly reversed the colitis - reduced contractility and induction of P05164 activity , P19634 , IL - 1ss and P29323 , but not of p38 in inflamed colonic smooth muscle . Splenomegaly , increased colonic mass and decreased sodium pump activity were significantly reversed by amiloride treatment . There was no recovery of b . w . loss in the treated colitic animals . Urine output was increased , whereas food and water intake remained unchanged following amiloride treatment . CONCLUSIONS : These findings suggest that the beneficial effects of P19634 inhibition in experimental colitis are mediated through IL - 1ss and P29323 Q96HU1 kinase .",
"P00749 and plasminogen activator inhibitor type - 1 mRNA assessment in breast cancer by means of NASBA : correlation with protein expression . DB00013 plasminogen activator ( uPA ) and its main inhibitor , plasminogen activator inhibitor type - 1 ( P05121 ) determined in tumor tissue by means of enzyme - linked immunosorbent assay ( ELISA ) can discriminate patients with primary breast cancer at high risk vs low risk for recurrence . The aim of this study was to analyze uPA and P05121 messenger RNA ( mRNA ) expression by means of quantitative nucleic acid sequence - based amplification ( NASBA ) on 77 primary breast tumor samples and to correlate this expression with the uPA and P05121 protein content . We observed that the 2 markers were significantly overexpressed ( uPA , P < . 0001 ; P05121 , P = . 0042 ) in mRNA in the ELISA + group . The receiver operating characteristic ( ROC ) curves demonstrated high concordance between NASBA and ELISA ( area under the ROC curve of 0 . 84 and 0 . 70 for uPA and P05121 , respectively ) and showed that uPA and P05121 status could be predicted by using the molecular assay with sensitivity and specificity values of 80 . 8 % and 82 . 4 % and sensitivity and specificity values of 66 . 7 % and 74 . 0 % , respectively .",
"Immunohistochemical detection of alpha1E voltage - gated Ca ( 2 +) channel isoforms in cerebellum , P01308 - 1 cells , and neuroendocrine cells of the digestive system . Polyclonal antibodies were raised against a common and a specific epitope present only in longer alpha1E isoforms of voltage - gated Ca ( 2 +) channels , yielding an \" anti - E - com \" and an \" anti - E - spec \" serum , respectively . The specificity of both sera was established by immunocytochemistry and immunoblotting using stably transfected P29320 - 293 cells or membrane proteins derived from them . Cells from the insulinoma cell line P01308 - 1 , tissue sections from cerebellum , and representative regions of gastrointestinal tract were stained immunocytochemically . P01308 - 1 cells expressed an alpha1E splice variant with a longer carboxy terminus , the so - called alpha1Ee isoform . Similarily , in rat cerebellum , which was used as a reference system , the anti - E - spec serum stained somata and dendrites of Purkinje cells . Only faint staining was seen throughout the cerebellar granule cell layer . After prolonged incubation times , neurons of the molecular layer were stained by anti - E - com , suggesting that a shorter alpha1E isoform is expressed at a lower protein density . In human gastrointestinal tract , endocrine cells of the antral mucosa ( stomach ) , small and large intestine , and islets of Langerhans were stained by the anti - E - spec serum . In addition , staining by the anti - E - spec serum was observed in Paneth cells and in the smooth muscle cell layer of the lamina muscularis mucosae . We conclude that the longer alpha1Ee isoform is expressed in neuroendocrine cells of the digestive system and that , in pancreas , alpha1Ee expression is restricted to the neuroendocrine part , the islets of Langerhans . alpha1E therefore appears to be a common voltage - gated Ca ( 2 +) channel linked to neuroendocrine and related systems of the body .",
"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .",
"Growth associated proteins in tumor cells and stroma related to disease progression of colon cancer accounting for tumor tissue DB00917 content . Connections among specific proteins ( Bax , Bcl - 2 , P09038 , P23219 , P35354 , E - cad , p15 , p53 , P12004 , TGFbeta3 , TUNEL , P04275 ) in control of cell proliferation , apoptosis , cell adhesion , tumor vascularity and DB00917 content were evaluated in colon cancer as related to disease progression and survival . Tumor tissue and adjacent normal colon mucosa were obtained at curative resection in 22 patients . DB00917 concentrations were assessed in tumor tissue and tumor derived blood , splanchnic blood , peripheral venous blood and urine . Host inflammation was determined ( CRP , P03372 ) in relationship to tumor differentiation and stage . Patients survived as expected according to Dukes A - D staging . Growth - related proteins correlated between tumor cells and stroma as well as between protein factors within tumor cells and tumor stroma . P35354 predicted tumor tissue content of DB00917 ( p < 0 . 002 ) , without reflection in tumor derived blood . Systemic inflammation was predicted by p15 , TGFbeta3 and Bcl - 2 in tumor tissue ( p < 0 . 001 ) . p15 and P04275 predicted reduced survival in ungrouped patients ( p < 0 . 02 ) , while p15 , P12004 , TGFbeta3 and P04275 predicted reduced survival ( p < 0 . 0001 ) when patient grouping accounted for high tumor content of DB00917 . Our results connect systemic inflammation and survival to P35354 staining and increased DB00917 in colon cancer . Thus , it seems important to understand proximal signals behind upregulation of P35354 and subsequent DB00917 production in certain tumor cells in colon cancer .",
"Differential role for phospholipase D1 and phospholipase D2 in 12 - O - tetradecanoyl - 13 - phorbol acetate - stimulated MAPK activation , Cox - 2 and P10145 expression . Phospholipase D ( PLD ) is expressed in many tissues and stimulated by growth factors and cytokines . However , the role of PLD in signal transduction is still not well - understood . Human embryonic kidney ( P29320 - 293 ) cells exhibit low levels of both Q13393 and O14939 mRNA , however , only Q13393 protein was detected by Western blot . When either isoform of PLD was stably expressed in P29320 - 293 cells , we observed an increased PLD activity in a cell - free system and a 12 - O - tetradecanoyl - 13 - phorbol acetate ( TPA ) - stimulated increase in PLD activity in intact cells . This system was then used to elucidate the effects of PLD activity on TPA - stimulated signaling pathways . Two such pathways , the mitogen - activated protein kinases ( MAPK ) , extracellular regulated protein kinase ( P29323 ) and p38 are activated by growth factors and cellular stress , respectively . We found that TPA stimulated P29323 phosphorylation regardless of the expression status of PLD . In contrast to P29323 kinase , P29320 - 293 cells were unable to induce p38 phosphorylation by TPA stimulation . When P29320 - 293 cells expressed either Q13393 or O14939 , we observed elevated p38 phosphorylation in response to TPA stimulation . The P29323 and p38 MAPKs can also stimulate the expression of both cyclooxygenase - 2 ( Cox - 2 ) and interleukin - 8 ( P10145 ) . We used this system to differentiate the effect of Q13393 or O14939 activity on the expression of Cox - 2 and P10145 . Increased Cox - 2 and P10145 expression was found only in P29320 - 293 cells expressing Q13393 . These data identify a novel role for the Q13393 isoform in the induction of gene expression and provide new insight into the differential role of Q13393 and O14939 in cells .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK71___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Differential involvement of Galpha16 in CC chemokine - induced stimulation of phospholipase Cbeta , P29323 , and chemotaxis . Chemokines are known to regulate the chemotaxis of leukocytes and play an important role in immunological processes . Chemokine receptors are widely distributed in hematopoietic cells and are often co - localized with the hematopoietic - specific G ( 16 ) and its close relative , G ( 14 ) . Yet , many chemokine receptors utilize pertussis toxin - sensitive G ( i ) proteins for signaling . Given that both G ( 16 ) and G ( 14 ) are capable of linking G ( i )- coupled receptors to the stimulation of phospholipase Cbeta , we examined the capacity of six CC chemokine receptors ( P32246 , CCR2a , CCR2b , P51677 , P51681 and P32248 ) to interact with G ( 14 ) and G ( 16 ) in a heterologous expression system . Among the CC chemokine receptors tested , P32246 , CCR2b , and P51677 were capable of mediating chemokine - induced stimulation of phospholipase Cbeta via either G ( 14 ) or G ( 16 ) . The G ( 14 )/ G ( 16 )- mediated responses exhibited CC chemokine dose - dependency and were resistant to pertussis toxin ( PTX ) treatment . In contrast , CCR2a , P51681 and P32248 were unable to interact with G ( 14 ) and G ( 16 ) . Under identical experimental conditions , all six CC chemokine receptors were fully capable of inhibiting adenylyl cyclase via G ( i ) as well as stimulating phospholipase Cbeta via 16z44 , a G ( 16 / z ) chimera that possesses increased promiscuity toward G ( i )- coupled receptors . Moreover , P32246 - mediated P27361 / 2 phosphorylation was largely PTX - insensitive in THP - 1 monocytic cells that endogenously express Galpha ( 16 ) . In addition , P32246 agonist was less efficacious in mediating chemotaxis of THP - 1 cells following the knockdown of Galpha ( 16 ) by overexpressing siRNA , indicating the participation of Galpha ( 16 ) in P32246 - induced cell migration . These results show that different CC chemokine receptors can discriminate against G ( 14 ) and G ( 16 ) for signal transduction .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"DB00594 derivatives induce apoptosis by depleting ER Ca ( 2 +) stores in vascular endothelial cells . BACKGROUND AND PURPOSE : DB00594 derivatives are blockers of the Na (+)/ H (+) exchanger ( NHE ) and at micromolar concentrations have protective effects on cardiac and brain ischaemia / reperfusion injury but at higher concentrations also induce apoptosis . Here , we aimed to elucidate the mechanism related to this cytotoxic action . EXPERIMENTAL APPROACH : We quantified the expression of genes associated with endoplasmic reticulum ( ER ) stress and measured changes in luminal ER Ca ( 2 +) concentration ( [ Ca ( 2 +)]( ER ) ) with a ' cameleon ' indicator , D1ER . KEY RESULTS : DB00594 derivatives induced apoptosis in vascular endothelial cells , an effect that increased at alkaline extracellular pH . The potency order for cytotoxicity was 5 -( N , N - hexamethylene )- amiloride ( HMA ) > 5 -( N - methyl - N - isobutyl ) amiloride > 5 -( N - ethyl - N - isopropyl ) amiloride ( EIPA ) >> amiloride . HMA dose - dependently increased the transcription of the ER stress genes P35638 and O75807 and rapidly depleted [ Ca ( 2 +)]( ER ) , mimicking the effects of the sarco / endoplasmic reticulum ATPase ( SERCA ) inhibitor thapsigargin . The P19634 - specific inhibitor HOE 694 inhibited NHE activity by 87 % but did not alter [ Ca ( 2 +)]( ER ) . The decrease in [ Ca ( 2 +)]( ER ) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca ( 2 +) concentration . CONCLUSIONS AND IMPLICATIONS : DB00594 derivatives disrupt ER and cytosolic Ca ( 2 +) homeostasis by a mechanism unrelated to NHE inhibition , most likely by interfering with the activity of SERCA . We propose that ER Ca ( 2 +) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives .",
"Inhibition of the MEK / P29323 signaling pathway by the novel antimetastatic agent NAMI - A down regulates c - myc gene expression and endothelial cell proliferation . Imidazolium trans - imidazoledimethyl sulfoxide - tetrachlororuthenate ( NAMI - A ) is a novel ruthenium - containing experimental antimetastatic agent . Compelling evidence ascribes a pivotal role to endothelial cells in the orchestration of tumor angiogenesis and metastatic growth , suggesting antiangiogenic therapy as an attractive approach for anticancer treatment . In this context , activation of the mitogen - activated protein kinase ( MAPK ) / extracellular signal - regulated kinase ( P29323 ) signaling pathway has been found fundamental in transducing extracellular stimuli that modulate a number of cellular process including cell proliferation , migration and invasion . Here we show that exposure of the transformed endothelial cell line ECV304 to NAMI - A significantly inhibited DNA synthesis , as well as the expression of the proliferating cell nuclear antigene ( P12004 ) . These responses were associated with a marked down - regulation of P29323 phosphorylation in serum - cultured cells . In addition , NAMI - A markedly reduced serum stimulated - and completely suppressed phorbol 12 - myristate 13 - acetate ( PMA ) - triggered MAPK / P29323 kinase activity . NAMI - A was also able to inhibit the phosphorylation of MEK , the upstream activator of P29323 , and , similar to both the protein kinase C ( PKC ) inhibitor GF109203X and the MAPK / P29323 ( MEK ) inhibitor PD98059 , it completely counteracted PMA - induced P29323 phosphorylation . Finally , NAMI - A and PD98059 down regulated c - myc gene expression to the same extent in serum - cultured cells and dose - dependently counteracted , and ultimately abolished , the increase in c - myc gene expression elicited by PMA in serum - free cells . These results suggest that inhibition of MEK / P29323 signaling by NAMI - A may have an important role in modulating c - myc gene expression and ECV304 proliferation ."
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MH_train_303
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interacts_with DB09074?
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"Triple negative breast cancer : therapeutic and prognostic implications . Triple negative breast cancers ( TNBC ) lack oestrogen receptor ( ER ) , progesterone receptor ( PR ) , nor over - express human epidermal growth factor receptor 2 ( P04626 ) . Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinic - pathologic features and risk factors when compared to women with other subtypes of breast cancer . They are associated with poor prognosis , as defined by low five - year survival . To date many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings . Targeted therapy options involving P09874 and P00533 inhibition , are currently in different phases of development and will hopefully change the paradigm of how patients with TNBC are treated . The present commentary aims to summarize the latest findings on chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents .",
"Redox regulation of Q96EB6 in inflammation and cellular senescence . Sirtuin 1 ( Q96EB6 ) regulates inflammation , aging ( life span and health span ) , calorie restriction / energetics , mitochondrial biogenesis , stress resistance , cellular senescence , endothelial functions , apoptosis / autophagy , and circadian rhythms through deacetylation of transcription factors and histones . Q96EB6 level and activity are decreased in chronic inflammatory conditions and aging , in which oxidative stress occurs . Q96EB6 is regulated by a NAD (+)- dependent DNA repair enzyme , poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , and subsequent NAD (+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence . Q96EB6 has been shown to undergo covalent oxidative modifications by cigarette smoke - derived oxidants / aldehydes , leading to posttranslational modifications , inactivation , and protein degradation . Furthermore , oxidant / carbonyl stress - mediated reduction of Q96EB6 leads to the loss of its control on acetylation of target proteins including p53 , RelA / p65 , and O43524 , thereby enhancing the inflammatory , prosenescent , and apoptotic responses , as well as endothelial dysfunction . In this review , the mechanisms of cigarette smoke / oxidant - mediated redox posttranslational modifications of Q96EB6 and its roles in P09874 and NF - κB activation , and O43524 and P29474 regulation , as well as chromatin remodeling / histone modifications during inflammaging , are discussed . Furthermore , we have also discussed various novel ways to activate Q96EB6 either directly or indirectly , which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases .",
"Antagonism by salvianolic acid B of lipopolysaccharide - induced disseminated intravascular coagulation in rabbits . The aim of the present study was to investigate the effects of salvianolic acid B on lipopolysaccharide ( LPS ) - induced disseminated intravascular coagulation ( DIC ) in rabbits . Continuous infusion of LPS was used to induce a DIC model in rabbits . Treatment with salvianolic acid B ( 1 , 3 or 6 mg / kg ) was started simultaneously with LPS infusion ( 0 . 5 mg / kg LPS in 60 mL saline ; 10 mL / h over a period of 6 h ) through the contralateral marginal ear vein . Activated partial thromboplastin time ( APTT ) , prothrombin time ( PT ) , platelet count and fibrinogen concentration were determined , as were plasma levels of fibrin - fibrinogen degradation products ( Q9NRC9 ) , alanine aminotransferase ( ALT ) , blood urea nitrogen ( BUN ) , protein C activity , antithrombin III ( P01008 ) and tumour necrosis factor ( P01375 ) - α concentration . The gradual impairment of haemostatic parameters was induced by continuous infusion of LPS . There were marked increases in APTT , PT , BUN , ALT and plasma P01375 - α and marked decreases in the platelet count , fibrinogen , Q9NRC9 , protein C and P01008 . The intravenous administration of 1 , 3 or 6 mg / kg salvianolic acid B attenuated the increases in APTT , PT , BUN , ALT and plasma P01375 - α and the decreases in fibrinogen , platelet , Q9NRC9 , protein C and P01008 induced by LPS infusion . These observations indicate that salvianolic acid B has an effect against LPS - induced DIC in rabbits .",
"Antitumor activity of Ru ( III ) complexes carrying beta - diketonato ligands in vitro and in vivo . PURPOSE : To investigate the antitumor activity of two newly synthesized ruthenium ( III ) [ Ru ( III ) ] compounds carrying bidentate ligands : ( acac )- acetylacetonate , [ Ru ( acac ) 3 ) , and ( tfac )- trifluoroacetylacetonate [ Ru ( tfac ) 3 ] . MATERIALS AND METHODS : The activity of ruthenium ( III ) analogues was evaluated on HeLa , B16 , and Femx cell lines for cytotoxicity in vitro using MTT assay , and inhibition on tumor invading ability in vitro using cell migration and invasion assays , whereas inhibition of tumor growth in vivo was estimated on advanced B16 murine melanoma model . Both compounds were also investigated in combinations with cisplatin , oxaliplatin , or poly ADP - ribose polymerase - 1 ( P09874 ) inhibitor , in order to determine the pattern of mutual interactions . RESULTS : Applied as single drugs , Ru ( tfac ) 3 showed high cytotoxic activity against HeLa and Femx cell lines , while Ru ( acac ) 3 did not reach the IC50 on any of the cell lines tested . In combinations , Ru ( acac ) 3 with cisplatin gained synergistic interaction , antagonistic with oxaliplatin , and of different kind with ( P09874 ) inhibitor in concentration - and cell line - dependent manner . Ru ( acac ) 3 exhibited inhibition of HeLa cell migration and gelatinolytic activity of P08253 and P14780 . Ru ( tfac ) 3 complexes did not induce significant reduction of melanoma growth in vivo , whereas Ru ( acac ) 3 did , but the latter failed to contribute in lifespan improvement . CONCLUSION : The investigated ruthenium complexes showed different levels of antitumor activity in vitro and in vivo , implicating on different mechanisms of their action as well as diverse perspectives in cancer treatment .",
"A Phase I , dose - finding and pharmacokinetic study of olaparib ( AZD2281 ) in Japanese patients with advanced solid tumors . DB09074 ( AZD2281 ) is an orally active Poly ( ADP - ribose ) polymerase ( PARP ) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with P38398 / 2 mutations in Western ( USA and European ) studies . This Phase I dose - finding study evaluated the tolerability , pharmacokinetics , PARP inhibitory activity , and antitumor activity of olaparib in Japanese patients with solid tumors . DB09074 was administered as a single - dose on day 1 , followed by twice - daily dosing for 28 days from 48 h after a single dose . Doses were escalated from 100 mg b . i . d . in successive cohorts , up to a maximum of 400 mg b . i . d . The present study enrolled 12 patients ( n = 3 , 3 , and 6 in 100 , 200 and 400 - mg b . i . d . levels , respectively ) . The most common adverse events were nausea , increased blood creatinine , decreased hematocrit , leukopenia and lymphopenia ; dose - limiting toxicities were not observed up to and including the 400 - mg b . i . d . dose level . Following twice - daily dosing , olaparib showed no marked increase in exposure at steady state over that expected from the single - dose pharmacokinetics . P09874 inhibition was observed from the 100 - mg b . i . d . dose level in peripheral blood mononuclear cells from 6 h post - dose on day 1 during the multiple - dosing period . A patient with metastatic breast cancer ( 100 mg b . i . d . ) had a partial response for 13 months and four patients ( two each in the 200 and 400 - mg b . i . d . levels ) had stable disease > 8 weeks . DB09074 was well tolerated up to the 400 - mg b . i . d . dose in Japanese patients with solid tumors . Preliminary evidence of antitumor activity was observed .",
"DB09074 , P09874 inhibitor in ovarian cancer . INTRODUCTION : Ovarian cancer is the most important cause of gynecological cancer - related mortality . Conventional treatments for advanced or recurrent disease offer limited results in terms of long - term responses and survival . Researches have recently focused on target therapies , which represent a new , promising , therapeutic approach , able to maximizing tumor kill and minimizing toxicity . The family of polyadenosine diphosphate - ribose polymerase ( PARP ) inhibitors is currently one of the most hopeful and investigated alternatives . AREAS COVERED : Preclinical and clinical studies of DB09074 , the most investigated PARP inhibitor in ovarian cancer , are analyzed and discussed . Data were obtained by searching for all English peer - reviewed articles on Medline , on Cochrane Database and all on - going Phase I and II studies registered on National Cancer Institute Clinical Trials ; also any related abstracts recently presented on DB09074 at major international congresses will be included . EXPERT OPINION : Bad prognosis and drug resistance usually affect ovarian cancer . Recent trends toward the knowledge of molecular - specific pathways have produced new target drugs . PARP inhibition mediated by DB09074 in P38398 ( breast cancer 1 ) and P51587 ( breast cancer 2 ) - mutated and in sporadic ovarian cancer represents a promising field of investigation . Further studies are needed to confirm initial exciting results .",
"Inhibition of P09874 - dependent end - joining contributes to DB09074 - mediated radiosensitization in tumor cells . Poly - ADP - ribose - polymerase inhibitors ( PARPi ) are considered to be optimal tools for specifically enhancing radiosensitivity . This effect has been shown to be replication - dependent and more profound in HR - deficient tumors . Here , we present a new mode of PARPi - mediated radiosensitization which was observed in four out of six HR - proficient tumor cell lines ( responders ) investigated , but not in normal cells . This effect is replication - independent , as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin . We showed that responders are radiosensitized by DB09074 because their DSB - repair is switched to P09874 - dependent end - joining ( P09874 - EJ ) , as evident by ( i ) the significant increase in the number of residual γ P16104 foci following irradiation with 3Gy and treatment with DB09074 , ( ii ) the enhanced enrichment of P09874 at the chromatin after 3Gy and ( iii ) the inhibition of end - joining activity measured by a specific reporter substrate upon DB09074 treatment . This is the first study which directly demonstrates the switch to P09874 - EJ in tumor cells and its contribution to the response to DB09074 as a radiosensitizer , findings which could widen the scope of application of PARPi in tumor therapy .",
"O75791 plays an important role in glucolipotoxicity - induced apoptosis in P01308 - 1 cells . OBJECTIVES : The mechanism underlying the regulation of glucolipotoxicity - induced apoptosis by MAPKs was examined in P01308 - 1 cells . METHODS : The rat insulinoma cell line P01308 - 1 was cotreated with glucose ( 30 mM ) and palmitic acid ( 0 . 2 mM ) ( GLU + PA ) . Apoptosis was assessed by cell morphology and detection of PARP cleavage . The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK , P27361 / 2 , and O75791 . RESULTS : ( 1 ) Live cell imaging studies showed that treatment with GLU + PA for 72 h induced significant cell death , concomitant with P09874 cleavage and caspase - 3 activation , which peaked at 96 h of treatment . ( 2 ) Western blot analysis of the activation of MAPKs during GLU + PA - induced P01308 - 1 cell apoptosis showed that phosphorylation of O75791 increased gradually and reached a peak at 96 h , which coincided with P09874 cleavage . A transient increase of P29323 activation was followed by a rapid decline at 96 h , whereas JNK phosphorylation status remained unchanged in response to GLU + PA . ( 3 ) Phosphorylation of insulin receptor substrate ( P41252 ) - 2 at 48 h of treatment triggered its degradation , which coincided with O75791 activation . ( 4 ) Inhibition of O75791 , but not JNK or P29323 , blocked GLU + PA - induced P01308 - 1 cell apoptosis . CONCLUSIONS : O75791 may be involved in the regulation of glucolipotoxicity - induced apoptosis through the phosphorylation of Q9Y4H2 .",
"Development and validation of a high - performance liquid chromatography - tandem mass spectrometry assay quantifying olaparib in human plasma . DB09074 is an inhibitor of poly ADP ribose polymerase 1 ( P09874 ) . Phase I and II trials showed promising results of olaparib against tumours in BRCA mutation carriers . Currently an increasing number of clinical trials with olaparib in combination with other compounds or radiotherapy are conducted . To support these clinical trials an LC - MS / MS method was developed and validated for the quantification of olaparib in human plasma . Human plasma samples were collected in the clinic and stored at nominally - 20 ° C . DB09074 was isolated from plasma by liquid - liquid extraction , separated on a C18 column with gradient elution and analyzed with triple quadrupole mass spectrometry in positive ion mode . A deuterated isotope was used as internal standard for the quantification . The assay , ranging from 10 to 5000ng / mL , was linear with correlation coefficients ( r ( 2 ) ) of 0 . 9994 or better . The assay was accurate and precise , with inter - assay and intra - assay accuracies within ± 7 . 6 % of nominal and inter - assay and intra - assay precision ≤ 9 . 3 % at the lower limit of quantification and ≤ 5 . 7 % at the other concentration levels tested . All results were within the acceptance criteria of the US FDA and the latest P15941 guidelines for method validation . A quantitative method was developed and validated for the quantification of olaparib in human plasma . The method could successfully be applied for the pharmacokinetic quantification of olaparib in cancer patients treated with olaparib .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK2___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2 / M arrest and γ - P16104 foci formation in colorectal cancer . BACKGROUND : Poly ( ADP - ribose ) polymerase 1 ( P09874 ) has an important role in homologous recombination repair . The purpose of this study was to investigate the effect of P09874 inhibitor on oxaliplatin treatment for colorectal cancer ( CRC ) . METHODS : A cell counting kit - 8 assay was used to determine the sensitivity of CRC cells to olaparib and / or oxaliplatin . The gene and protein expressions of P09874 and the gamma histone variant P16104 ( γ P16104 ) were measured by real - time quantitative polymerase chain reaction and western blotting , respectively . The γ P16104 foci formation assay was used to investigate the influence of treatments on cells . Flow cytometry was used to examine the changes in cell cycle distribution . Finally , we investigated the combination of olaparib and oxaliplatin in the CRC tumor model . RESULTS : DB09074 changed the expression of γ P16104 and P09874 , and increased the sensitivity of CRC cells to oxaliplatin . The γ P16104 foci assay showed that olaparib did not induce double - strand breaks ( DSBs ) alone , but it enhanced the induction of DSBs by oxaliplatin . The flow cytometry results showed that cells exposed to combination treatment had more G2 / M - phase cells than control . Additionally , tumor xenograft studies suggested that combined treatment inhibited the growth of CRC . CONCLUSION : CRC cells are sensitized to combined treatment with olaparib and oxaliplatin , and this could be a promising strategy for clinical chemotherapy in CRC .",
"Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK42___ GITS , Diaprel MR ) . One daily dose of ___MASK42___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"Desmopressin ( ___MASK73___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK73___ ) also has strong vasodilatory effects . ___MASK73___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK73___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK73___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK73___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK73___ - induced vasodilation .",
"Novel targeted therapeutics : inhibitors of Q00987 , Q9UM73 and PARP . We reviewed preclinical data and clinical development of Q00987 ( murine double minute 2 ) , Q9UM73 ( anaplastic lymphoma kinase ) and PARP ( poly [ ADP - ribose ] polymerase ) inhibitors . Q00987 binds to p53 , and promotes degradation of p53 through ubiquitin - proteasome degradation . JNJ - 26854165 and RO5045337 are 2 small - molecule inhibitors of Q00987 in clinical development . Q9UM73 is a transmembrane protein and a member of the insulin receptor tyrosine kinases . Q9HC35 - Q9UM73 fusion gene is identified in approximately 3 - 13 % of non - small cell lung cancer ( NSCLC ) . Early - phase clinical studies with DB08865 , an Q9UM73 inhibitor , in NSCLC harboring Q9HC35 - Q9UM73 have demonstrated promising activity with high response rate and prolonged progression - free survival . PARPs are a family of nuclear enzymes that regulates the repair of DNA single - strand breaks through the base excision repair pathway . Randomized phase II study has shown adding P09874 inhibitor BSI - 201 to cytotoxic chemotherapy improves clinical outcome in patients with triple - negative breast cancer . DB09074 , another oral small - molecule PARP inhibitor , demonstrated encouraging single - agent activity in patients with advanced breast or ovarian cancer . There are 5 other PARP inhibitors currently under active clinical investigation .",
"Inhibition of poly ( ADP - ribose ) polymerase interferes with Trypanosoma cruzi infection and proliferation of the parasite . Poly ( ADP - ribosylation ) is a post - translational covalent modification of proteins catalyzed by a family of enzymes termed poly ( ADP - ribose ) polymerases ( PARPs ) . In the human genome , 17 different genes have been identified that encode members of the PARP superfamily . Poly ( ADP - ribose ) metabolism plays a role in a wide range of biological processes . In Trypanosoma cruzi , PARP enzyme appears to play a role in DNA repair mechanisms and may also be involved in controlling the different phases of cell growth . Here we describe the identification of potent inhibitors for T . cruzi PARP with a fluorescence - based activity assay . The inhibitors were also tested on T . cruzi epimastigotes , showing that they reduced ADP - ribose polymer formation in vivo . Notably , the identified inhibitors are able to reduce the growth rate of T . cruzi epimastigotes . The best inhibitor , DB09074 , is effective at nanomolar concentrations , making it an efficient chemical tool for chacterization of ADP - ribose metabolism in T . cruzi . PARP inhibition also decreases drastically the amount of amastigotes but interestingly has no effect on the amount of trypomastigotes in the cell culture . Knocking down human P09874 decreases both the amount of amastigotes and trypomastigotes in cell culture , indicating that the effect would be mainly due to inhibition of human P09874 . The result suggests that the inhibition of PARP could be a potential way to interfere with T . cruzi infection .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK48___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Isothiocyanate iberin modulates phase II enzymes , posttranslational modification of histones and inhibits growth of Caco - 2 cells by inducing apoptosis . The aim of presented study was to further investigate the concentration - dependent changes induced by isothiocyanate iberin ( IBN ) in human colon carcinoma Caco - 2 cells . The concentrations of IBN below IC ( 50 ) value ( 18 microM , 72 h ) triggered the augmentation of mRNA levels for phase II detoxification P08263 and P22309 enzymes and antioxidant thioredoxin reductase 1 gene in cells treated for 24 h . In addition a significant increase of acetylated H4 histone was detected . The mRNA induction peaked at IC ( 50 ) value and returned to level of control cells at 40 microM concentration of IBN . The cell cycle changes , gamma - P16104 stainability and the increase of phospho - H3 mitotic marker were induced at concentrations above IC ( 50 ) value . Appearance of P08758 positive apoptotic cells and sub - P55008 fragmented DNA as well as decrease of mitochondrial transmembrane potential confirmed cytotoxic effect of IBN observed in MTT assay . The predominance of necrotic cells and profound positivity of gamma - P16104 took place at the highest concentration of IBN . Thus , IBN represents the effective member of natural chemopreventive isothiocyanate family with which apoptotic potential can by employed to eliminate tumor cells .",
"Chronic myeloid leukemic cells trigger poly ( ADP - ribose ) polymerase - dependent inactivation and cell death in lymphocytes . NK cells and T cells are commonly dysfunctional in CML , and their status may determine the course of disease . We aimed to define the molecular mechanisms of leukemia - induced immunosuppression with focus on the role of ROS and the P09874 pathway of cell death . Malignant granulocytes from patients with P11274 - P00519 - positive CML expressed the oxygen radical - producing enzyme NOX , produced large amounts of ROS , and triggered extensive cell death in NK cells . Inhibition of P09874 maintained NK cell viability in cocultures with suppressive leukemic cells . Under conditions of oxidative stress , P09874 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells , in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells . Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML .",
"PARP inhibitor , olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice . We have previously shown that P09874 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury . DB09074 is a potent new generation PARP inhibitor that has been approved for human testing . The present work was designed to evaluate its beneficial potential against LPS - induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice . Administration of olaparib at different doses , 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg / kg b . wt . reduced the total number of inflammatory cells particularly neutrophils in the lungs . This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially . DB09074 provided strong protection against LPS - mediated secondary kidney injury as reflected by restoration of serum levels of urea , creatinine , and uric acid toward normal . The drug restored the LPS - mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and DB00143 levels . Finally , RT - PCR data revealed that olaparib downregulates the LPS - induced expression of NF - κB - dependent genes namely P01375 - α , IL - 1β , and P19320 in the lungs without altering the expression of total p65NF - κB . Overall , the data suggest that olaparib has a strong potential to protect against LPS - induced lung injury and associated dysfunctioning of kidney in mice . Given the fact that olaparib is approved by FDA for human testing , our findings can pave the way for testing of the drug on humans inflicted with acute lung injury .",
"Src and P61073 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib . ___MASK48___ is a dual P00533 and ErbB - 2 tyrosine kinase inhibitor that has significantly improved the clinical outcome of ErbB - 2 - overexpressing breast cancer patients . However , patients inexorably develop mechanisms of resistance that limit the efficacy of the drug . In order to identify potential targets for therapeutic intervention in lapatinib - resistant patients , we isolated , from ErbB - 2 - overexpressing SK - Br - 3 breast cancer cells , the SK - Br - 3 Lap - R - resistant subclone , which is able to routinely grow in 1 µM lapatinib . Resistant cells have a more aggressive phenotype compared with parental cells , as they show a higher ability to invade through a matrigel - coated membrane . ___MASK48___ - resistant cells have an increased Src kinase activity and persistent levels of activation of P27361 / 2 and AKT compared with parental cells . Treatment with the Src inhibitor saracatinib in combination with lapatinib reduces AKT and P27361 / 2 phosphorylation and restores the sensitivity of resistant cells to lapatinib . SK - Br - 3 Lap - R cells also show levels of expression of P61073 that are higher compared with parental cells and are not affected by Src inhibition . Treatment with saracatinib or a specific P61073 antibody reduces the invasive ability of SK - Br - 3 Lap - R cells , with the two drugs showing cooperative effects . Finally , blockade of Src signaling significantly increases P50591 - induced cell death in SK - Br - 3 Lap - R cells . Taken together , our results demonstrate that breast cancer cells with acquired resistance to lapatinib have a more aggressive phenotype compared with their parental counterpart , and that Src signaling and P61073 play an important role in this phenomenon , thus representing potential targets for therapeutic intervention in lapatinib - resistant breast cancer patients .",
"P38398 , P09874 and γ P16104 in acute myeloid leukemia : Role as biomarkers of response to the PARP inhibitor olaparib . DB09074 ( AZD - 2281 , Ku - 0059436 ) is an orally bioavailable and well - tolerated poly ( ADP - ribose ) polymerase ( PARP ) inhibitor currently under investigation in patients with solid tumors . To study the clinical potential of olaparib as a single - agent for the treatment of acute myeloid leukemia ( AML ) patients , we analyzed the in vitro sensitivity of AML cell lines and primary blasts . Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples ( 88 % ) and tested cell lines . At these concentrations , olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and P28906 - enriched peripheral blood cells obtained from healthy donors . Most primary AML analyzed were characterized by low P38398 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib . Noteworthy , while P09874 over - expression was detected in blasts not responsive to olaparib , phosphorylation of the histone P16104 ( γ P16104 ) was associated with drug sensitivity . As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion . The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and / or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy .",
"Comparative antiproliferative effects of iniparib and olaparib on a panel of triple - negative and non - triple - negative breast cancer cell lines . PARP inhibitors , both as monotherapy and in combination with cytotoxic drugs , are currently undergoing clinical trials in several different cancer types . In this investigation , we compared the antiproliferative activity of two PARP / putative PARP inhibitors , i . e . , olaparib and iniparib , in a panel of 14 breast cancer cell lines ( seven tripe - negative and seven non - triple - negative ) . In almost all cell lines investigated , olaparib was a more potent inhibitor of cell growth than iniparib . Inhibition by both drugs was cell line - dependent and independent of the molecular subtype status of the cells , i . e . , whether cells were triple - negative or non - triple negative . Although the primary target of PARP inhibitors is P09874 , no significant association was found between baseline levels of P09874 activity and inhibition with either agent . Similarly , no significant correlation was evident between sensitivity and levels of P06493 , P38398 or miR - 182 . Combined addition of olaparib and either the P06493 inhibitor , RO - 3306 or a pan HER inhibitor ( neratinib , afatinib ) resulted in superior growth inhibition to that obtained with olaparib alone . We conclude that olaparib , in contrast to iniparib , is a strong inhibitor of breast cancer cell growth and may have efficacy in breast cancer irrespective of its molecular subtype , i . e . , whether P04626 - positive , estrogen receptor ( ER ) - positive or triple - negative . DB09074 , in combination with a selective P06493 inhibitor or a pan HER inhibitor , is a potential new approach for treating breast cancer .",
"___MASK95___ : evaluation and analysis of its role in chronic myeloid leukemia . ___MASK95___ , formally known as AMN107 , is a second - generation tyrosine kinase inhibitor , rationally designed from its revolutionary parent compound imatinib , to produce a 30 - 40 - fold enhancement in the inhibition of the P11274 - P00519 - derived oncoprotein associated with chronic myeloid leukemia . In clinical trials , nilotinib has proven to be a useful agent in the treatment of imatinib - refractory disease and was initially approved by both the US FDA and P15941 in 2007 for use in adults as a second - line therapy . More recently , data from the first randomized controlled trials of the front - line use of nilotinib in newly diagnosed patients with chronic phase chronic myeloid leukemia have demonstrated superiority in the rates of major molecular responses at 12 months over the gold standard - imatinib 400 mg . As such , in June 2010 , the FDA granted accelerated approval for its use in newly diagnosed Philadelphia chromosome - positive chronic myeloid leukemia . ___MASK95___ is well tolerated , with a favorable side - effect profile . With the emergence of supportive trial data , it is likely to have a leading role both in the front - line management of newly presenting patients and in the second - line treatment of patients resistant to or intolerant of imatinib and other second - line agents .",
"7 - Azaindole - 1 - carboxamides as a new class of P09874 inhibitors . 7 - Azaindole - 1 - carboxamides were designed as a new class of P09874 inhibitors . The compounds displayed a variable pattern of target inhibition profile that , in part , paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects . A selected compound ( 1l ; ST7710AA1 ) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp . In antitumor activity studies against the P20591 human breast carcinoma growth in nude mice , the compound exhibited an effect similar to that of DB09074 in terms of tumor volume inhibition when used at a lower dose than the reference compound . Treatment was well tolerated , as no deaths or significant weight losses were observed among the treated animals .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Cytokines and P11274 - P00519 mediate suppression of P50591 - induced apoptosis through inhibition of forkhead FOXO3a transcription factor . Cytokine - provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl - 2 family members . Here we show that in hematopoietic cells , cytokines also regulate death receptor - mediated pathways . We demonstrate that hematopoietic cytokines such as P08700 and erythropoietin in normal cells , as well as P11274 - P00519 oncoprotein in transformed cells , inhibit transcription of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) . Using small interfering RNAs , we show that the inhibition of P50591 function is sufficient to partially rescue cytokine - deprived cells from apoptosis . Finally , we demonstrate that cytokine and P11274 - P00519 suppression of P50591 transcription is mediated through phosphorylation and inhibition of the forkhead FOXO3a transcription factor . P11274 - P00519 - induced inhibition of P50591 transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia .",
"Anti - allergic effects of nilotinib on mast cell - mediated anaphylaxis like reactions . ___MASK95___ is a new orally bioavailable potent tyrosine kinase inhibitor that is used for the treatment of P11274 - P00519 - positive chronic myelogenous leukemia . However , its effect on mast cell - mediated anaphylactic reaction is still not known . The present study aimed to investigate the effect of nilotinib on the anaphylactic allergic reaction and study its possible mechanism ( s ) of action . ___MASK95___ administration prevented systemic anaphylaxis in mice , mediated by compound 48 / 80 , in a dose - and time - dependent manner . Also , nilotinib significantly inhibited ( P < 0 . 05 ) allergic paw edema in rats . Furthermore , nilotinib significantly decreased ( P < 0 . 05 ) the IgE - mediated passive cutaneous anaphylaxis in a dose dependent manner . In addition , nilotinib dose - dependently reduced histamine release from the rat peritoneal mast cells activated either by compound 48 / 80 or by ovalbumin . Moreover , nilotinib attenuated the secretion of pro - inflammatory cytokine , tumor necrosis factor ( P01375 ) - α expression in the rat peritoneal mast cells . These findings provide evidence that nilotinib inhibits mast cell - derived immediate - type allergic reactions and so it could be a candidate as an anti - allergic agent .",
"PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma . BACKGROUND : Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma ( GBM ) . We show that targeting PARP by the small molecule inhibitors , DB09074 ( AZD - 2281 ) or PJ34 , reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo . METHODS : The sensitizing effects of PARP inhibition on P50591 - mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines , low - passage neurospheres and astrocytes in vitro . Molecular analyses included western blots and gene silencing . In vivo , effects on tumor growth were examined in a murine subcutaneous xenograft model . RESULTS : The combination treatment of PARP inhibitors and P50591 led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single - agent treatment . Mechanistically , pharmacological PARP inhibition elicited a nuclear stress response with up - regulation of down - stream DNA - stress response proteins , e . g . , CCAAT enhancer binding protein ( C / EBP ) homology protein ( P35638 ) . Furthermore , DB09074 and PJ34 increased protein levels of DR5 in a concentration and time - dependent manner . In turn , siRNA - mediated suppression of DR5 mitigated the effects of P50591 / PARP inhibitor - mediated apoptosis . In addition , suppression of P09874 levels enhanced P50591 - mediated apoptosis in malignant glioma cells . Treatment of human astrocytes with the combination of P50591 / PARP inhibitors did not cause toxicity . Finally , the combination treatment of P50591 and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone . CONCLUSIONS : PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM .",
"Pharmacological approach to acute pancreatitis . The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis ( AP ) based on experimental animal models and clinical trials . Somatostatin ( SS ) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis ( PEP ) . The protease inhibitor gabexate mesilate ( GM ) is used routinely as treatment to AP in some countries , but randomized clinical trials and a meta - analysis do not support this practice . Nitroglycerin ( P04626 ) is a nitrogen oxide ( NO ) donor , which relaxes the sphincter of Oddi . Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted . Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials . The non - steroidal anti - inflammatory drugs ( NSAID ) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP . Interleukin 10 ( P22301 ) is a cytokine with anti - inflammatory properties but two trials testing P22301 as prophylaxis to PEP have returned conflicting results . Antibodies against tumor necrosis factor - alpha ( P01375 ) have a potential as rescue therapy but no clinical trials are currently being conducted . The antibiotics beta - lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis . Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti - inflammatory drugs are warranted .",
"___MASK49___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"Effects and expression of P50591 and its apoptosis - promoting receptors in human pancreatic cancer . Pancreatic cancer cells are usually resistant to apoptosis mediated by tumor necrosis factor ( P01375 ) - alpha or P48023 , and their toxicity towards normal cells hampers their application for therapeutic use . P50591 ( P50591 ) , a novel member of the P01375 family , triggers apoptosis in a variety of malignant cells , but exhibits less cytotoxicity in normal cells . To investigate the therapeutic potential of P50591 , we analyzed the expression of P50591 and its apoptosis - inducing receptors ( DR4 and DR5 ) in the normal and cancerous human pancreas , and the sensitivity of pancreatic cancer cells to P50591 cytotoxicity . P50591 , DR4 and DR5 mRNA levels were concomitantly increased in pancreatic cancers compared with normal controls ( P < 0 . 01 ) , and there were positive correlations between the expression levels of P50591 and DR4 , P50591 and DR5 and between DR4 and DR5 mRNA ( r = 0 . 85 , r = 0 . 87 , r = 0 . 91 ; P < 0 . 01 ) . Immunostaining revealed the presence of the corresponding proteins frequently within the same cancer cells . In five pancreatic cancer cell lines , P50591 , DR4 and DR5 mRNA expression was detectable at various levels . However , independent of the presence of DR4 and DR5 , P50591 cytotoxicity assays revealed that pancreatic cancer cells showed a significantly lower sensitivity ( LD ( 50 ) > 85 ng / ml ) to P50591 treatment than Jurkat T lymphoma cells ( LD ( 50 )= 7 . 2 ng / ml ) . These findings show that pancreatic cancers are insensitive towards P50591 - mediated apoptosis despite expression of P50591 and its receptors , suggesting the presence of mediators which inhibit the P50591 cell - death - inducing pathway in pancreatic cancer cells .",
"Bacterial translocation in cirrhotic rats stimulates P29474 - derived NO production and impairs mesenteric vascular contractility . DB00435 ( NO ) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis . Bacteria , potent activators of NO and P01375 synthesis , are found in the mesenteric lymph nodes ( MLNs ) of ascitic cirrhotic rats . Here , we investigated the impact of bacterial translocation ( BT ) to MLNs on P01375 production , vascular NO release , and contractility in the mesenteric vasculature of ascitic cirrhotic rats . Vascular response to the alpha - adrenoagonist methoxamine , which is diminished in the superior mesenteric arterial beds of cirrhotic rats , is further blunted in the presence of BT . BT promoted vascular NO release in cirrhotic rats , an effect that depended on pressure - induced shear stress and was blocked by the NO inhibitor N ( omega )- nitro - L - arginine . Removing the endothelium had the same effect . Endothelial NO synthase ( P29474 ) , but not the inducible isoform ( P35228 ) , was present in mesenteric vasculature of cirrhotic rats with and without BT , and its expression was enhanced compared with controls . P01375 was induced in MLNs by BT and accumulated in parallel in the serum . This P01375 production was associated with elevated levels of tetrahydrobiopterin ( BH ( 4 ) ) , a P01375 - stimulated cofactor and enhancer of P29474 - derived NO biosynthesis and NOS activity in mesenteric vasculature . These findings establish a link between BT to MLNs and increased P01375 production and elevated BH ( 4 ) levels enhancing P29474 - derived NO overproduction , further impairing contractility in the cirrhotic mesenteric vasculature .",
"___MASK84___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK84___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .",
"Antitumor efficacy of piperine in the treatment of human P04626 - overexpressing breast cancer cells . Piperine is a bioactive component of black pepper , Piper nigrum Linn , commonly used for daily consumption and in traditional medicine . Here , the molecular mechanisms by which piperine exerts antitumor effects in P04626 - overexpressing breast cancer cells was investigated . The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase - 3 activation and PARP cleavage . Furthermore , piperine inhibited P04626 gene expression at the transcriptional level . Blockade of P27361 / 2 signaling by piperine significantly reduced P36956 and FAS expression . Piperine strongly suppressed P01133 - induced P14780 expression through inhibition of AP - 1 and NF - κB activation by interfering with P27361 / 2 , p38 MAPK , and Akt signaling pathways resulting in a reduction in migration . Finally , piperine pretreatment enhanced sensitization to paclitaxel killing in P04626 - overexpressing breast cancer cells . Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with P04626 overexpression .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK42___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Attenuation of the progression of adjuvant - induced arthritis by 3 - aminobenzamide treatment . Rheumatoid arthritis ( RA ) is a disease that is still insufficiently controlled by current treatments . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors ameliorate immune - mediated diseases in several experimental models , including RA , colitis , experimental autoimmune encephalomyelitis and allergy . Together these findings showed that ADP - ribosylating enzymes , in particular P09874 , play a pivotal role in the regulation of immune responses and may represent a noble target for new therapeutic approaches in immune - mediated diseases . The effect of 3 - aminobenzamide ( 3 - AB ) , an inhibitor of poly ( ADP - ribose ) synthetase activity , was evaluated in a mouse model of adjuvant - induced arthritis ( AIA ) on pro - inflammatory cytokines , adhesion molecules , inflammatory mediators and chemokine production / expression in serum and knee joint . Histopathological examination was also done on joint section . Our data demonstrates that 3 - AB , 10mg / kg , intraperitoneally ( i . p . ) significantly reduces pro - inflammatory cytokine ( Q16552 , P01375 - α and P60568 ) and chemokine ( P13500 and MIP - 2 ) production / expression , accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores and was associated with a significant reduction of P19320 and P05362 expression in the knee joint . Moreover , the expression of inflammatory mediators ( P35228 , P35354 , P08253 , P14780 ) and joint histological inflammatory damage was also markedly decreased . The results of this study suggest that P09874 inhibitor may play a role in the inflammatory arthritic process after administration of 3 - AB may be a beneficial therapeutic approach .",
"Charcot - Marie - Tooth neuropathy related to chromosome 1 . One family with documented male - to - male transmission of Charcot - Marie - Tooth ( CMT ) neuropathy was studied clinically and by genetic linkage . Patients had progressive distal weakness and atrophy , areflexia , and distal sensory loss , but early onset ( before age 3 years ) in all 5 cases , and phrenic nerve involvement in the propositus ( a 39 - year - old woman ) requiring Q9HC77 ventilator support during the night . Motor - nerve conduction velocities ( MNCVs ) were significantly slow , consistent with severe demyelinating neuropathy . Electromyography ( EMG ) data were normal . Two - point and multipoint linkage analyses strongly suggested the presence of a CMT gene on chromosome 1q . A maximum multipoint lod score of 2 . 70 was obtained at P15941 ( theta = 0 ) , with the locus order centromere - P15941 - P02549 - Fc gamma RII - P01008 - telomere . Multipoint linkage analysis excluded the CMT locus from chromosome 17 markers in this family .",
"Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism , cell proliferation and cell transformation . We explored , by cDNA mini - arrays , gene expression measurements of MVLN , a human breast carcinoma cell line derived from MCF - 7 , after 4 days of exposure to 17beta - estradiol ( E ( 2 ) ) treatment , in order to extend our understanding of the mechanism of the pharmacological action of estrogens . We focused on 22 genes involved in estrogen metabolism , cell proliferation regulation and cell transformation . The specificity of the E ( 2 ) response was reinforced by comparison with 4 - hydroxytamoxifen ( OH - Tam ) , DB00947 and E ( 2 )+ OH - Tam expression profiles . Real - time quantitative PCR ( RTQ - PCR ) confirmed the variation of expression of known ( P04155 , P15514 , P35568 , P22692 , P12004 , P04626 , P07339 , MYC ) as well as novel ( DLEU2 , P20248 , P22309 , O15438 , O15440 , O75410 , P20827 , NOV , P01040 , P51511 , O75362 ) genes . The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E ( 2 ) treatment and this allowed the identification of different time - course patterns . Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of O15438 and O15440 through dissimilar pathways , and secondly that protein synthesis was needed for modulation of the expression of the P20248 and O75410 genes by estrogens . Western blot analysis performed on P04155 , P35568 , P22692 , amphiregulin , P12004 , cyclin A2 , O75410 and O15440 proteins confirmed the mini - array and RTQ - PCR data , even for genes harboring low variations of mRNA expression . Our findings should enhance the understanding of changes induced by E ( 2 ) on the transcriptional program of human E ( 2 )- responsive cells and permit the identification of new potential diagnostic / prognostic tools for the monitoring of estrogen - related disease conditions such as breast cancer .",
"Poly ( ADP - ribose ) polymerase - 1 mediates angiotensin II - induced expression of plasminogen activator inhibitor - 1 and fibronectin in rat mesangial cells . OBJECTIVE : To investigate the effects of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) on angiotensin II ( Ang II ) - induced plasminogen activator inhibitor - 1 ( P05121 ) and fibronectin ( FN ) in rat mesangial cells ( RMCs ) . METHODS : Followed by serum starvation for 16 h , RMCs were exposed to Ang II for an indicated time to examine the protein expression of P09874 . The cells were treated with or without Ang II for 12 - 24 h in the presence or absence of an inhibitor of PARP , N -( 6 - oxo - 5 , 6 - dihydrophenanthridin - 2 - yl )- N , N - dimethylacetamide hydrochloride ( PJ34 ) or small interfering RNA ( siRNA ) duplexes targeting P09874 . The mRNA and protein expressions of P09874 , P05121 and FN were determined by real - time RT - PCR and Western blot , respectively . The activity of P09874 was examined by colorimetric assay . RESULTS : Ang II did not only significantly induce P09874 expression and activity , but also increased P05121 and FN expression in RMCs . All these responses induced by Ang II were significantly inhibited by both the PARP inhibitor PJ34 and downregulating P09874 with the siRNA technique . CONCLUSIONS : Our data suggest that P09874 mediates Ang II - induced P05121 and FN in RMCs and may thus represent a potential therapeutic target in the treatment of glomerular disease .",
"P35354 regulates the proliferation of glioma stem like cells . Cancer stem - like cells ( CSCs ) possessing features of neural precursor cells ( NPC ) influence initiation , recurrence and chemoresistance of glioblastoma multiforme ( GBM ) . As inflammation is crucial for glioblastoma progression we investigated the effect of chronic IL - 1β treatment on CSCs derived from glioblastoma cell line U87MG . Exposure to IL - 1β for 10 days increased ( i ) accumulation of 8 - OHdG - a key biomarker of oxidative DNA damage ; ( ii ) DNA damage response ( DDR ) indicators γ P16104 , Q13315 and DNA - PK ; ( iii ) nuclear and cytoplasmic p53 and P35354 levels and ( iv ) interaction between P35354 and p53 . Despite upregulating p53 expression IL - 1β had no effect on cell cycle progression , apoptosis or self renewal capacity of CSCs . P35354 inhibitor Celecoxib reduced self renewal capacity and increased apoptosis of both control and IL - 1β treated CSCs . Therefore the ability of P35354 to regulate proliferation of CSCs irrespective of exposure to IL - 1β , warrants further investigation of P35354 as a potential anti - glioma target .",
"Potential role of P50591 in the management of autoimmune diabetes mellitus . Type 1 diabetes mellitus ( T1DM ) is an autoimmune disease , due to the immune - mediated destruction of pancreatic β - cells , whose incidence has been steadily increasing during the last decades . P01308 replacement therapy can treat T1DM , which , however , is still associated with substantial morbidity and mortality . For this reason , great effort is being put into developing strategies that could eventually prevent and / or cure this disease . These strategies are mainly focused on blocking the immune system from attacking β - cells together with functional islet restoration either by regeneration or transplantation . Recent experimental evidences suggest that TNFrelated apoptosis - inducing ligand ( P50591 ) , which is an immune system modulator protein , could represent an interesting candidate for the cure for T1DM and / or its complications . Here we review the evidences on the potential role of P50591 in the management of T1DM .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"P50591 deficiency contributes to diabetic nephropathy in fat - fed ApoE -/- mice . BACKGROUND : We recently demonstrated that P50591 ( P50591 ) is protective of diet - induced diabetes in mice . While P50591 has been implicated in chronic kidney disease , its role in vivo in diabetic nephropathy is not clear . The present study investigated the role of P50591 in the pathogenesis of diabetic nephropathy using P50591 (-/-) ApoE (-/-) mice . METHODS : P50591 (-/-) ApoE (-/-) and ApoE (-/-) mice were fed a high fat diet for 20 w . Plasma glucose and insulin levels were assessed over 0 , 5 , 8 and 20 w . At 20 w , markers of kidney function including creatinine , phosphate , calcium and cystatin C were measured . Changes in mRNA expression of MMPs , P01033 , IL - 1β and Q14116 were assessed in the kidney . Functional and histological changes in kidneys were examined . DB09341 and insulin tolerance tests were performed . RESULTS : P50591 (-/-) ApoE (-/-) mice had significantly increased urine protein , urine protein : creatinine ratio , plasma phosphorous , and plasma cystatin C , with accelerated nephropathy . Histologically , increased extracellular matrix , mesangial expansion and mesangial cell proliferation in the glomeruli were observed . Moreover , P50591 (-/-) ApoE (-/-) kidneys displayed loss of the brush border and disorganisation of tubular epithelium , with increased fibrosis . P50591 - deficient kidneys also had increased expression of MMPs , P01033 , P05121 , IL - 1β and Q14116 , markers of renal injury and inflammation . Compared with ApoE (-/-) mice , P50591 -/- ApoE -/- mice displayed insulin resistance and type - 2 diabetic features with reduced renal insulin - receptor expression . CONCLUSIONS : Here , we show that P50591 - deficiency in ApoE (-/-) mice exacerbates nephropathy and insulin resistance . Understanding P50591 signalling in kidney disease and diabetes , may therefore lead to novel strategies for the treatment of diabetic nephropathy .",
"Long - term safety and anti - tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast , ovarian or fallopian tube cancer . BACKGROUND : DB09074 ( AZD2281 ) , a P09874 / 2 inhibitor , has been extensively investigated in clinical trials . However , limited clinical data are available about its long - term safety and anti - tumour activity . METHODS : Patients had first participated in a phase I study of olaparib combined with carboplatin and / or paclitaxel . They continued with olaparib monotherapy in their best interest if they failed to tolerate the combination due to the treatment - related adverse events ( TRAEs ) . Safety data were collected by physical examination and regular laboratory evaluations . Disease evaluations were performed by CT scan . RESULTS : At data cutoff , 21 patients were included ; 10 with breast , 9 with ovarian and 2 with fallopian tube cancer of whom 16 patients had a BRCA mutation ( 13 P38398 ; 3 P51587 ) . TRAEs were mostly haematological and most prominent shortly after switching from combination to monotherapy , probably due to carry - over effects of chemotherapy . Over time , both severity and frequency of TRAEs decreased . Responses to olaparib were durable with a median treatment duration of 52 ( range 7 - 183 ) weeks . In total , nine ( 43 % ) patients were still on study at data cutoff . CONCLUSION : Continued long - term daily olaparib was found to be safe and tolerable . Encouragingly , patients who showed a favourable response on earlier combination therapy maintained this response on olaparib monotherapy .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK58___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK58___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK58___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK58___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK58___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK58___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK58___ .",
"Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice . BACKGROUND : We previously reported that enhanced nuclear factor kappa B ( NFκB ) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice . METHODS : In this study , we aimed to determine whether augmented NFκB activity also impairs conductance artery ( thoracic aorta ) function in type 2 diabetic mice . We treated type 2 diabetic ( db (-) / db (-) ) and control ( db (-) / db (+) ) mice with two NFκB inhibitors ( dehydroxymethylepoxyquinomicin , 6 mg / kg , twice a week and IKK - NBD peptide , 500 µg / kg / day ) for 4 weeks . RESULTS : As expected , the NFκB inhibition did not affect blood glucose level and body weight . Thoracic aorta vascular endothelium - dependent relaxation ( EDR ) , determined by the wire myograph , was impaired in diabetic mice compared with control and was significantly improved after NFκB inhibition . Interestingly , thoracic EDR was also rescued in db (-) / db (- p50NFκB -/-) and db (-) / db (- P09874 -/-) double knockout mice compared with db (-) / db (-) mice . Similarly , the acute in vitro down regulation of NFκB - p65 using p65 shRNA lentiviral particles in arteries from db (-) / db (-) mice also improved thoracic aorta EDR . Western blot analysis showed that the p65NFκB phosphorylation , cleaved P09874 and P35354 expression were increased in thoracic aorta from diabetic mice , which were restored after NFκB inhibition and in db (-) / db (- p - 50NFκB -/-) and db (-) / db (- P09874 -/-) mice . CONCLUSIONS : The present results indicate that in male type 2 diabetic mice , the augmented NFκB activity also impairs conductance artery function through P09874 and P35354 - dependent mechanisms .",
"___MASK67___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK67___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK95___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Inhibition of Q00987 by nilotinib contributes to cytotoxicity in both Philadelphia - positive and negative acute lymphoblastic leukemia . ___MASK95___ is a selective P11274 - P00519 tyrosine kinase inhibitor related to imatinib that is more potent than imatinib . ___MASK95___ is widely used to treat chronic myelogenous leukemia ( CML ) and Philadelphia - positive ( Ph + ) acute lymphoblastic leukemia ( ALL ) . The present study identifies Mouse double minute 2 homolog ( Q00987 ) as a target of nilotinib . In studying ALL cell lines , we found that the expression of Q00987 in both Philadelphia positive ( Ph + ) and Philadelphia negative ( Ph - ) ALL cells was remarkably inhibited by nilotinib , in a dose - and time - dependent manner . Further studies demonstrated that nilotinib inhibited Q00987 at the post - translational level by inducing Q00987 self - ubiquitination and degradation . ___MASK95___ - mediated Q00987 downregulation did not result in accumulation and activation of p53 . Inhibition of Q00987 in nilotinib - treated ALL cells led to downregulation of the anti - apoptotic protein P98170 ( P98170 ) , a translational target of Q00987 , resulting in activation of caspases . Inhibition of P98170 following nilotinib - mediated downregulation of Q00987 resulted in apoptosis of Q00987 - expressing ALL ; however , similar nilotinib treatment induced stronger apoptosis in Ph +/ Q00987 + ALL than in Ph -/ Q00987 + or Ph +/ Q00987 - ALL . The ALL cells that were Ph -/ Q00987 - were totally resistant to nilotinib . These results suggested that nilotinib can inhibit Q00987 and induce a p53 - independent apoptosis pathway by downregulating P98170 ; thus , nilotinib can treat not only Ph + , but also Ph - ALL patients whose cancer cells overexpress Q00987 .",
"Differential effects of poly ( ADP - ribose ) polymerase inhibition on DNA break repair in human cells are revealed with Epstein - Barr virus . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors can generate synthetic lethality in cancer cells defective in homologous recombination . However , the mechanism ( s ) by which they affect DNA repair has not been established . Here we directly determined the effects of PARP inhibition and P09874 depletion on the repair of ionizing radiation - induced single - and double - strand breaks ( SSBs and DSBs ) in human lymphoid cell lines . To do this , we developed an in vivo repair assay based on large endogenous Epstein - Barr virus ( EBV ) circular episomes . The EBV break assay provides the opportunity to assess quantitatively and simultaneously the induction and repair of SSBs and DSBs in human cells . Repair was efficient in P55008 and G2 cells and was not dependent on functional p53 . shRNA - mediated knockdown of P09874 demonstrated that the P09874 protein was not essential for P05455 repair . Among 10 widely used PARP inhibitors , none affected DSB repair , although an inhibitor of DNA - dependent protein kinase was highly effective at reducing DSB repair . Only DB09074 and Iniparib , which are in clinical cancer therapy trials , as well as 4 - AN inhibited P05455 repair . However , a decrease in P09874 expression reversed the ability of Iniparib to reduce P05455 repair . Because Iniparib disrupts P09874 - DNA binding , the mechanism of inhibition does not appear to involve trapping PARP at SSBs .",
"PARP inhibition sensitizes childhood high grade glioma , medulloblastoma and ependymoma to radiation . Poly ADP - ribose polymerase ( PARP ) is a protein involved in single strand break repair . Recently , PARP inhibitors have shown considerable promise in the treatment of several cancers , both in monotherapy and in combination with cytotoxic agents . Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways . In addition , PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents , including radiotherapy . Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor DB09074 in childhood medulloblastoma , ependymoma and high grade glioma ( HGG ) . Increased P09874 expression was observed in medulloblastoma , ependymoma and HGG , as compared to non - neoplastic brain tissue . Pediatric high grade glioma , medulloblastoma and ependymoma gene expression profiling revealed that high P09874 expression is associated with poor prognosis . Cell growth inhibition assays with DB09074 resulted in differential sensitivity , with IC50 values ranging from 1 . 4 to 8 . 4 µM , irrespective of tumor type and P09874 protein expression . Sensitization to radiation was observed in medulloblastoma , ependymoma and HGG cell lines with subcytotoxic concentrations of DB09074 , which coincided with persistence of double strand breaks . Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome .",
"Personalized medicine : factors influencing reimbursement . OBJECTIVES : Personalized medicine ( PM ) has attracted tremendous interest , but yielded few marketed products . We examined factors influencing the reimbursement of existing PM technologies . METHODS : We conducted six case studies of the following paired genetic tests and treatments : P04626 / neu with trastuzumab ( Herceptin ) ; hepatitis C genotyping with ribavirin / pegylated interferon ; Oncotype DX with chemotherapy ; P22309 with irinotecan ( Camptosar ) ; Q9BQB6 / P11712 with warfarin ; P38398 / 2 with prophylactic surgical measures ; and Oncotype DX with chemotherapy . We developed a framework for categorizing PM technology , and assessed factors influencing reimbursement , including quality of evidence , type of regulatory oversight , presence of clinical guidelines , and cost - effectiveness . RESULTS : PM is not a monolithic concept , but rather encompasses different types of technology . The strength of evidence available for existing PM technology varies widely and , along with endorsement of clinical guidelines , appears to be the strongest predictor of reimbursement . In the absence of reimbursement , direct - to - consumer marketing has continued for some PM technology . The type of regulatory oversight and the results of cost - effectiveness analysis do not appear to be associated with reimbursement to date . CONCLUSIONS : To date , the promise and hype of PM has outpaced its evidentiary support . In order to achieve favorable coverage and reimbursement and to support premium prices for PM , manufacturers will need to bring better clinical evidence to the marketplace and better establish the value of their products ."
] |
[
"___MASK2___",
"___MASK42___",
"___MASK48___",
"___MASK49___",
"___MASK58___",
"___MASK67___",
"___MASK73___",
"___MASK84___",
"___MASK95___"
] |
___MASK95___
|
MH_train_304
|
interacts_with DB00796?
|
[
"P30556 overexpression defines a subset of breast cancer and confers sensitivity to losartan , an P30556 antagonist . Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations . To identify additional opportunities for targeted therapy , we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3 , 200 microarray experiments . In addition to prioritizing P04626 , we found P30556 , the angiotensin II receptor type I , to be markedly overexpressed in 10 - 20 % of breast cancer cases across multiple independent patient cohorts . Validation experiments confirmed that P30556 is highly overexpressed , in several cases more than 100 - fold . P30556 overexpression was restricted to estrogen receptor - positive tumors and was mutually exclusive with P04626 overexpression across all samples . Ectopic overexpression of P30556 in primary mammary epithelial cells , combined with angiotensin II stimulation , led to a highly invasive phenotype that was attenuated by the P30556 antagonist losartan . Similarly , losartan reduced tumor growth by 30 % in P30556 - positive breast cancer xenografts . Taken together , these observations indicate that marked P30556 overexpression defines a subpopulation of ER - positive , P04626 - negative breast cancer that may benefit from targeted therapy with P30556 antagonists , such as losartan .",
"DAPk1 inhibits NF - κB activation through P01375 - α and P27352 - γ - induced apoptosis . Recent studies have shown DAPk as a molecular modulator induced by the second messenger , responsible for controlling cell destiny decisions , but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 - α and P27352 - γ on DAPk1 in human ovarian carcinoma cell lines , OVCAR - 3 . Both P01375 - α and P27352 - γ significantly induce DAPk1 levels in a time - dependent manner . At the same time , they both arrested cell cycle progression in the G ( 0 )- G ( 1 ) and G2 / M phase , down - regulated cyclin D1 , P11802 and NF - κB expression , while also up - regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk1 was investigated . In the presence of DAPk1 , P01375 - α or P27352 - γ - induced apoptosis was additively increased , while P01375 - α or P27352 - γ - induced NF - κB activity was inhibited . Conversely , P01375 - α or P27352 - γ - dependent NF - κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA . The activity of NF - κB was dependent on the level of DAPk1 , indicating the requirement of DAPk1 for the activation of NF - κB . Low levels of DAPk1 expression were frequently observed in different human patient ' s tissue and cancer cell lines compared to normal samples . In addition , over - expression of DAPk1 from either P01375 - α or P27352 - γ - treatment cells suppressed the anti - apoptosis protein P98170 as well as P35354 and P05362 , more than control . Taken together , our data findings suggest that DAPk1 can mediate the pro - apoptotic activity of P01375 - α and P27352 - γ via the NF - κB signaling pathways .",
"Role for macrophage migration inhibitory factor in acute respiratory distress syndrome . The critical role of macrophage migration inhibitory factor ( MIF ) in mediating inflammatory lung injury in acute respiratory distress syndrome ( ARDS ) has been raised recently . The present study has identified enhanced MIF protein expression in alveolar capillary endothelium and infiltrating macrophages in lung tissues from ARDS patients . The possibility that MIF up - regulates its synthesis in an autocrine fashion in ARDS was tested using cultured endothelial cells stimulated with MIF and a murine model of lipopolysaccharide ( LPS ) - induced acute lung injury . MIF induced significant MIF and tumour necrosis factor ( P01375 ) - alpha synthesis in cultured endothelial cells and the effect was blocked by neutralizing anti - MIF antibody . A similar blocking effect was observed when MIF - stimulated endothelial cells were pretreated with neutralizing anti - P01375 antibody or glucocorticoid , supporting the notion that MIF induced P01375 production via an amplifying pro - inflammatory loop . Treatment with anti - MIF or glucocorticoid effectively attenuated pulmonary pathology and the synthesis of MIF or P01375 in mice with LPS - induced acute lung injury . Mildly augmented expression of aquaporin 1 ( P29972 ) was also detected in alveolar capillary endothelium in ARDS . In vitro studies revealed that both MIF and P01375 induced a small increase of P29972 synthesis in cultured endothelial cells . These findings suggest that MIF plays a crucial pathological role leading to alveolar inflammation in ARDS . Anti - MIF and early glucocorticoid therapy may represent a novel therapeutic approach for reducing alveolar inflammation in ARDS .",
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"DB00796 inhibits Toll - like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll - like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT ( 1 ) R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti - inflammatory effects . Thus , we investigated whether an ARB exerts anti - inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0 . 05 vs . control ) along with decrease in the activity of NF - kappaB and the expression of IL - 1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti - inflammatory effects .",
"P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist DB00834 , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .",
"DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK58___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK58___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .",
"A - type natriuretic peptide level in angiotensin II type 1a receptor knockout mice . A - type ( atrial ) natriuretic peptide ( P01160 ) levels in the heart and plasma were examined by immunohistochemistry , electron microscopy , and radioimmunoassay ( RIA ) in angiotensin II type 1a receptor knockout ( Agtr1a KO ) mice . Additionally , the P01160 mRNA level in the heart was measured using a real - time polymerase chain reaction ( PCR ) assay . The blood pressure in Agtr1a KO mice was significantly lower than that in wild - type ( WT ) mice . The number of P01160 granules and P01160 immunoreactivity in the auricular cardiocytes were significantly lower in Agtr1a KO mice than in WT mice . Ultrastructurally , the ventricular cardiocytes in Agtr1a KO mice occasionally had P01160 - like granules , which were not present in WT mice . The plasma , auricular , and ventricular P01160 and plasma cyclic guanosine monophosphate ( cGMP ) concentrations were significantly higher in Agtr1a KO mice than in WT mice . The P01160 mRNA levels of the auricular and ventricular cardiocytes in the Agtr1a KO mice were almost twice as large as those in WT mice . The present data suggest that a notable increase in the P01160 biosynthesis and release in the heart of Agtr1a KO mice may account for the reduction in blood pressure together with the lack of an P30556 receptor in this model .",
"[ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin - converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin - converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy - proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non - nephrotic proteinuria ( protein , 0 . 5 to 3 . 5 g / day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8 - week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0 . 05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type - IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type - IV collagen excretion was recognized in patients with chronic glomerulonephritis .",
"___MASK77___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .",
"Regulation of angiotensin type 2 receptor in bovine granulosa cells . Angiotensin II ( AngII ) is best known for its role in blood pressure regulation , but it also has documented actions in the reproductive system . There are two AngII receptors , type 1 ( P30556 ) and type 2 ( P50052 ) . P50052 mediates the noncardiovascular effects of AngII and is expressed in the granulosa cell layer in rodents and is associated with follicle atresia . In contrast , expression of P50052 is reported to occur only in theca cells in cattle . The objective of the present study was to determine whether AngII also plays a role in follicle atresia in cattle . RT - PCR demonstrated P50052 mRNA in both granulosa and theca cells of bovine follicles . The presence of P50052 protein was confirmed by immunofluorescence . Abundance of P50052 mRNA in granulosa cells was higher in healthy compared with atretic follicles , whereas in theca cells , it did not change . Granulosa cells were cultured in serum - free medium , and treatment with hormones that increase estradiol secretion ( DB00094 , P05019 , and bone morphogenetic protein - 7 ) increased P50052 mRNA and protein levels , whereas fibroblast growth factors inhibited estradiol secretion and P50052 protein levels . The addition of AngII or an P50052 - specific agonist to granulosa cells in culture did not affect estradiol secretion or cell proliferation but inhibited abundance of mRNA encoding serine protease inhibitor E2 , a protein involved in tissue remodeling . Because estradiol secretion is a major marker of nonatretic granulosa cells , these data suggest that AngII is not associated with follicle atresia in cattle but may have other specific roles during follicle growth .",
"Effect of matrine on the expression of DB05875 receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts . Matrine is a kind of alkaloid found in certain Sophora plants , which has been extensively used in China for the treatment of viral hepatitis , cancer , cardiac diseases and skin diseases ( such as atopic dermatitis and eczema ) . It also has been confirmed that DB05875 ( SP ) and its receptor ( neurokinin - 1 receptor , P25103 ) are involved in the pathogenesis of inflammatory skin disorders . So the present study was designed to investigate the effect of matrine on the expression of P25103 and cytokines production induced by SP in HaCaT cells ( a human epidermal keratinocyte cell line ) and dermal fibroblasts . In addition , cell viability was also evaluated . The results showed that matrine inhibited the expression of P25103 in HaCaT cells and fibroblasts . SP induced the production of interleukin ( IL ) - 1beta , P10145 , interferon ( IFN ) - gamma , and monocyte chemotactic protein ( MCP ) - 1 in both cell types . Matrine 5 - 100 microg / mL had little effect on cell viability . It inhibited SP - induced IL - 1beta , P10145 and P13500 production in HaCaT cells and fibroblasts , while it increased the production of P01579 in HaCaT cells . Both SP and matrine had no effect on the secretion of P05231 . These findings suggest that matrine may have potential treatment function on SP related cutaneous inflammation by inhibition of the expression of DB05875 receptor and regulation of the production of inflammatory cytokines .",
"Global gene expression profiles of subcutaneous adipose and muscle from glucose - tolerant , insulin - sensitive , and insulin - resistant individuals matched for BMI . OBJECTIVE : To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic , insulin - resistant individuals compared with insulin - sensitive individuals matched for BMI . RESEARCH DESIGN AND METHODS : A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity ( 31 insulin - resistant and 31 insulin - sensitive subjects ; 40 were European American and 22 were African American ) and matched for age and obesity measures . Global gene expression profiles were determined and compared between ethnic groups and between insulin - resistant and insulin - sensitive participants individually and using gene - set enrichment analysis . RESULTS : African American and European American subjects differed in 58 muscle and 140 adipose genes , including many inflammatory and metabolically important genes . Peroxisome proliferator - activated receptor γ cofactor 1A ( Q9UBK2 ) was 1 . 75 - fold reduced with insulin resistance in muscle , and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated . Unexpected categories included ubiquitination , citrullination , and protein degradation . In adipose , highly represented categories included lipid and fatty acid metabolism , insulin action , and cell - cycle regulation . Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene - set enrichment analysis . O60427 , P15692 , P26045 , Q9UIH9 , P56645 , Q687X5 , and P30556 were among genes expressed differentially in both adipose and muscle . CONCLUSIONS : Adipose tissue gene expression showed more differences between insulin - resistant versus insulin - sensitive groups than the expression of genes in muscle . We confirm the role of Q9UBK2 in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues .",
"___MASK72___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK72___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK72___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK72___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .",
"___MASK72___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK72___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK36___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"The potential role of PD0332991 ( ___MASK90___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK90___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Methylation of promoter regions of genes of the human intrauterine P00797 Angiotensin system and their expression . The intrauterine renin angiotensin system ( DB01367 ) is implicated in placentation and labour onset . Here we investigate whether promoter methylation of DB01367 genes changes with gestation or labour and if it affects gene expression . Early gestation amnion and placenta were studied , as were term amnion , decidua , and placenta collected before labour ( at elective caesarean section ) or after spontaneous labour and delivery . The expression and degree of methylation of the prorenin receptor ( O75787 ) , angiotensin converting enzyme ( P12821 ) , angiotensin II type 1 receptor ( P30556 ) , and two proteases that can activate prorenin ( kallikrein , P06870 , and cathepsin D , P07339 ) were measured by qPCR and a DNA methylation array . There was no effect of gestation or labour on the methylation of DB01367 genes and P07339 . Amnion and decidua displayed strong correlations between the percent hypermethylation of DB01367 genes and P07339 , suggestive of global methylation . There were no correlations between the degree of methylation and mRNA abundance of any genes studied . P06870 was the most methylated gene and the proportion of hypermethylated P06870 alleles was lower in placenta than decidua . The presence of intermediate methylated alleles of P06870 in early gestation placenta and in amnion after labour suggests that P06870 methylation is uniquely dynamic in these tissues .",
"Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK77___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK77___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK77___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK77___ - induced liver damage in the future .",
"Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome . The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease ( CKD ) in Japanese individuals with metabolic syndrome . The study population comprised 2150 Japanese individuals with metabolic syndrome , including 411 subjects with CKD [ estimated glomerular filtration rate ( eGFR ) < 50 mL / min / 1 . 73m ( 2 ) ] and 1739 controls ( eGFR >/= 60 mL / min / 1 . 73m ( 2 ) ) . The genotypes for 100 polymorphisms of 80 candidate genes were determined . The chi - square test , multivariable logistic regression analysis with adjustment for covariates , as well as a stepwise forward selection procedure revealed that nine polymorphisms of P02649 , O95477 , P23219 , P01375 , Q96IY4 , P30556 , Q8NGZ3 , and P16520 were associated ( P < 0 . 05 ) with the prevalence of CKD . Among these polymorphisms , the - 219G --> T polymorphism of P02649 ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome .",
"___MASK80___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK80___ is the first of a new class of antihypertensive agents . ___MASK80___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK80___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK12___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"___MASK90___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK90___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .",
"___MASK47___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK47___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"[ Moclobemide ( ___MASK3___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK80___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK80___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK58___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes ."
] |
[
"___MASK12___",
"___MASK36___",
"___MASK3___",
"___MASK47___",
"___MASK58___",
"___MASK72___",
"___MASK77___",
"___MASK80___",
"___MASK90___"
] |
___MASK80___
|
MH_train_305
|
interacts_with DB05239?
|
[
"P35367 activation stimulates mitogenesis in human astrocytoma U373 MG cells . In human astrocytoma U373 MG cells that express histamine H1 receptors ( 180 +/- 6 fmol / mg protein ) but not H2 or H3 receptors , histamine stimulated mitogenesis as assessed by [ 3H ] - thymidine incorporation ( 173 +/- 2 % of basal ; EC50 , 2 . 5 +/- 0 . 4 microM ) . The effect of 100 microM histamine was fully blocked by the selective H1 antagonist mepyramine ( 1 microM ) and was markedly reduced ( 93 +/- 4 % inhibition ) by the phospholipase C inhibitor U73122 ( 10 microM ) . The activator of protein kinase C ( PKC ) phorbol 12 - tetradecanoyl - 13 - acetate ( TPA , 100nM ) stimulated [ 3H ] - thymidine incorporation ( 270 +/- 8 % of basal ) , and this response was not additive with that to 100 microM histamine . The incorporation of [ 3H ] - thymidine induced by 100 microM histamine was partially reduced by the PKC inhibitor Ro 31 - 8220 ( 57 +/- 7 % inhibition at 300 nM ) and by the compound PD 098 , 059 ( 30 microM , 62 +/- 14 % inhibition ) , an inhibitor of the mitogen - activated kinase ( MAPK ) kinases Q02750 / P36507 . These results show that histamine H1 receptor activation stimulates the proliferation of human astrocytoma U373 MG cells . The action of histamine appears to be partially mediated by PKC stimulation and MAPK activation .",
"DB04335 strongly enhances proliferation of human Q9UBR5 melanoma cells through P98160 - PKC - Q02750 / 2 - P27361 / 2 and PI3K pathways . Malignant melanoma is the most deadly type of skin cancer . The lack of effective pharmacological approaches for this tumour can be related to the incomplete understanding of the pathophysiological mechanisms involved in melanoma cell proliferation . DB00640 has growth - promoting and growth inhibitory effects on tumour cells . We aimed to investigate effects of adenosine and its metabolic product , inosine , on human Q9UBR5 melanoma cells and the signalling pathways involved . The 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ( MTT ) reduction and bromodeoxyuridine ( BrdU ) proliferation assays were used to evaluate adenosine , adenosine deaminase and inosine effects , in the absence or presence of adenosine receptor ( AR ) , A3 AR and P47900 R antagonists and P98160 , PKC , Q02750 / 2 and PI3K inhibitors . P27361 / 2 levels were determined using an ELISA kit . DB00640 and inosine levels were quantified using an enzyme - coupled assay . DB00640 caused cell proliferation through AR activation . DB00640 deaminase increased inosine levels ( nanomolar concentrations ) on the extracellular space , in a time - dependent manner , inducing proliferation through A3 AR activation . Micromolar concentrations of inosine enhanced proliferation through A3 AR activation , causing an increase in P27361 / 2 levels , and P47900 R activation via ENT - dependent mechanisms . We propose the simultaneous activation of P98160 - PKC - Q02750 / 2 - P27361 / 2 and PI3K pathways as the main mechanism responsible for the proliferative effect elicited by inosine and its significant role in melanoma cancer progression .",
"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK67___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .",
"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK82___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK82___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK82___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .",
"P62158 as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells . DB04115 is an isoquinoline alkaloid that has drawn extensive attention because it possesses various biological activities . Several mechanisms have been proposed to interpret the anticancer activity of berberine . However , these explanations are mostly based on its downstream - regulated genes or proteins ; information on the direct target proteins that mediate the antiproliferative action of berberine remains unclear . In this study , a computational pipeline based on a ligand - protein inverse docking program and mining of the ' Connectivity Q96HU1 ' data was adopted to explore the potential target proteins for berberine . The results showed that four proteins , that is calmodulin , cytochrome P450 3A4 , sex hormone - binding globulin , and carbonic anhydrase II , were suggested to be the potential targets of berberine . The anticalmodulin property of berberine was demonstrated with an in vitro phosphodiesterase activity assay . Flow cytometric analysis found that P55008 cell cycle arrest induced by berberine in Bel7402 cells was enhanced by cotreatment with calmodulin inhibitors . Western blotting results indicated that berberine treatment decreased phosphorylation of calmodulin kinase II and blocked subsequent Q02750 activation as well as p27 protein degradation . These results suggested that calmodulin might play crucial roles in berberine - induced cell cycle arrest in cancer cells .",
"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK30___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK30___ is in clinical development as an orally active agent .",
"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK1___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK1___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK1___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .",
"Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .",
"Modulatory effect of phytoglycoprotein ( 38 kDa ) on cyclin D1 / P11802 in BNL CL . 2 cells induced by N - methyl - N '- nitro - N - nitrosoguanidine . In the developmental stages of cancer , cell transformation occurs after the promotion stage and is a marker of cancer progression . This cell transformation is related to abnormal proliferation during the cancer initiation stage . The purpose of this study was to evaluate the effect of Styrax japonica Siebold et al . Zuccarin ( SJSZ ) glycoprotein on cell transformation in murine embryonic liver cells ( BNL CL . 2 ) following N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) treatment . To determine abnormal proliferation during the initiation stage , intracellular reactive oxygen species ( ROS ) , phosphorylation of extracellular signal - regulated kinase ( P29323 ) , p38 mitogen - activated protein kinase ( MAPK ) , activities of cell cycle - related factors [ cyclin D1 / cyclin dependent kinase ( CDK ) 4 ] , cell cycle inhibitors ( p53 , P38936 , and p27 ) , nuclear factor ( NF ) - κB , and proliferating cell nuclear antigen ( P12004 ) were evaluated using Western blot analysis and real - time PCR . Our study demonstrated that SJSZ glycoprotein ( 50 μg / ml ) reduces foci formation with combined treatment [ MNNG and 12 - O - tetradecanoyl phorbol - 13 - acetate ] of BNL CL . 2 cells . With regard to proliferation - related signals , our finding indicated that SJSZ glycoprotein ( 50 μg / ml ) diminished the production of intracellular ROS , activity of phosphorylated P29323 , p38 MAPK , NF - κB ( p50 and p65 ) , P12004 , and cyclin D1 / P11802 in MNNG - induced BNL CL . 2 cells . Taken together , these results lead us to speculate that SJSZ glycoprotein can inhibit abnormal cell proliferation at the initiation stage of hepatocarcinogenesis .",
"Wnt1 and Q02750 cooperate to promote cyclin D1 accumulation and cellular transformation . Members of the Wnt family of signal transducers regulate cellular differentiation / reorganization and cellular proliferation . However , few pro - proliferative targets of Wnt have been identified . We now show that cyclin D1 , a critical mediator of cell cycle progression , is a downstream target of Wnt - dependent signaling . NIH - 3T3 cell lines engineered to overexpress Wnt1 displayed reduced glycogen synthase kinase - 3beta activity . Wnt1 - dependent glycogen synthase kinase - 3beta inhibition corresponded with decreased cyclin D1 proteolysis and , thus , hyperaccumulation of active cyclin D1 . P11802 ( cyclin - dependent kinase 4 ) kinase . However , in the absence of serum - derived growth factors , Wnt - 1 was not sufficient to drive cyclin D1 accumulation or S - phase entry . In contrast , cells engineered to co - express Wnt1 and activated Q02750 accumulated high levels of cyclin D1 and entered the DNA synthetic phase in the absence of serum - derived growth factors , a characteristic of neoplastic transformation . The ability of a dominant - negative cyclin D1 mutant , D1 - T156A , to inhibit Wnt1 / Q02750 - dependent S - phase entry suggests that cyclin D1 is a critical downstream target for Wnt1 - and Q02750 - dependent cellular proliferation .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Exposure to an organophosphate ( ___MASK82___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK82___ ( ___MASK82___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK82___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK82___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK82___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"Absolute bioavailability and effect of formulation change , food , or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects . DB05239 is a potent and highly selective inhibitor of Q02750 / 2 . Since cobimetinib exhibited absorption variability in cancer patients , a series of single - dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation , food , and elevated gastric pH on cobimetinib bioavailability . Three crossover trials were performed with a 20 mg cobimetinib oral dose : absolute bioavailability using a 2 mg intravenous infusion ( n = 13 ) , relative bioavailability of tablets versus capsules and food effect ( n = 20 ) , and drug interaction with a proton pump inhibitor ( 20 mg of rabeprazole daily for 5 days prior to cobimetinib administration ; n = 20 ) . Absolute bioavailability of cobimetinib was 46 . 2 % ( 24 . 2 , CV % ) , likely due to metabolism rather than incomplete absorption . The mean systemic clearance of cobimetinib was low ( 11 . 7 L / h [ 28 . 2 , CV % ] ) . Administration of cobimetinib tablets with a high - fat meal delayed drug absorption ( prolonged tmax ) but had no statistically significant effect on cobimetinib exposure ( Cmax and AUC0 -∞ ) . Tablet and capsule formulations of cobimetinib showed comparable exposures . DB05239 exhibited delayed absorption ( tmax ) in the presence of rabeprazole , with no statistically significant effects on drug exposure ( Cmax and AUC0 -∞ ) in the fasted state . In conclusion , cobimetinib oral absorption was not affected by change in formulation , food , or elevated gastric pH .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK20___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK30___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK84___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"MEK - P29323 signaling dictates DNA - repair gene P16455 expression and temozolomide resistance of stem - like glioblastoma cells via the Q00987 - p53 axis . Overcoming the resistance of glioblastoma cells against temozolomide , the first - line chemotherapeutic agent of choice for newly diagnosed glioblastoma , is a major therapeutic challenge in the management of this deadly brain tumor . The gene encoding O ( 6 ) - methylguanine DNA methyltransferase ( P16455 ) , which removes the methyl group attached by temozolomide , is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide . However , to date , signaling pathways regulating P16455 in P16455 - expressing glioblastoma cells have been poorly delineated . Here in this study , we provide lines of evidence that the mitogen - activated protein / extracellular signal - regulated kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 ) - murine double minute 2 ( Q00987 ) - p53 pathway plays a critical role in the regulation of P16455 expression , using stem - like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum , which not only possess stem - like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived . We show that , in stem - like glioblastoma cells , MEK inhibition reduced Q00987 expression and that inhibition of either MEK or Q00987 resulted in p53 activation accompanied by p53 - dependent downregulation of P16455 expression . MEK inhibition rendered otherwise resistant stem - like glioblastoma cells sensitive to temozolomide , and combination of MEK inhibitor and temozolomide treatments effectively deprived stem - like glioblastoma cells of their tumorigenic potential . Our findings suggest that targeting of the MEK - P29323 - Q00987 - p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma .",
"miR - 181b modulates glioma cell sensitivity to temozolomide by targeting Q02750 . PURPOSE : Recent studies have reported that miR - 181b contributes to chemoresistance in several cancer types and functions as a tumor suppressor in glioma . This study aimed to explore whether miR - 181b could enhance the chemotherapeutic effect of temozolomide in glioma cells and sought to identify the candidate target genes which mediated the effect . METHODS : Using 48 frozen samples from patients with glioma who had received in vitro chemosensitivity assay , we measured P16455 promoter methylation status by methylation - specific PCR and miR - 181b expression by qRT - PCR . Then , miR - 181b expression level was correlated with temozolomide IC₅₀ and P16455 promoter methylation status . To investigate the mechanism of miR - 181b - induced chemosensitivity , assays were performed using stable miR - 181b - expressing transfectants of glioma cell lines created by a lentiviral system . RESULTS : Glioma cells rich in miR - 181b were more sensitive to temozolomide . miR - 181b expression was not correlated with P16455 promoter methylation status . miR - 181b combined with temozolomide enhanced glioma cell sensitivity and apoptosis . The effects were through posttranscriptional repression of Q02750 . We demonstrated that miR - 181b bound directly to the 3 ' untranslated regions of Q02750 , thus reducing both the mRNA and protein levels of Q02750 . Additionally , knockdown of Q02750 using small interfering RNA resulted in effects similar to ectopic miR - 181b expression , whereas enforced expression of Q02750 lacking the 3 ' untranslated regions abrogated the effects . Finally , inverse correlation between miR - 181b and Q02750 was established in glioma specimens . CONCLUSION : miR - 181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via Q02750 downregulation . A combination of miR - 181b and temozolomide may be an effective therapeutic strategy for gliomas .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK42___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK66___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK66___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Molecular mechanisms of gastrin - dependent gene regulation . The peptide hormone gastrin is the key regulator of gastric acid secretion . P01350 exerts its effects as acid secretagogue through functional activation of gastric enterochromaffin - like ( ECL ) cells , which control acid secretion through biosynthesis and release of histamine . In ECL cells , concerted activation of histidine decarboxylase ( HDC ) , vesicular monoamine transporter 2 ( Q05940 ) , and chromogranin A ( P10645 ) genes by gastrin is a prerequisite for proper acid control . To elucidate the molecular pathways underlying gastrin - dependent control of ECL cell genes , we recently analyzed the signaling cascades , regulatory promoter elements , and transcription factors mediating the transcriptional effects of gastrin . Our studies identified the Raf > Q02750 > P29323 1 /- 2 kinase module as the common signaling pathway mediating gastrin - dependent ECL cell gene transcription . In contrast to this uniform signaling cascade , pronounced heterogeneity was detected between cis - and trans - activating regulatory factors conferring gastrin responsiveness . The molecular diversity of transcription factors and regulatory enhancer elements transmitting gastrin - triggered gene transcription offers the molecular basis for synergistic , but differential , regulation of HDC , Q05940 , and P10645 genes during a secretory challenge of ECL cells by gastrin and possibly other acid secretagogues .",
"P08908 receptor - mediated regulation of mitogen - activated protein kinase phosphorylation in rat brain . Mitogen - activated protein kinases ( MAPKs ) , a family of signal transduction mediators important in a host of cellular activities , include the extracellular signal - regulated kinases Erk1 and Erk2 . We determined whether 5 - HT ( 1A ) receptors activate Erk1 / 2 in rat brain in vivo , as they do in recombinant cell lines . In contrast to the effect in cells , the 5 - HT ( 1A ) receptor agonist 8 - hydroxy - N , N - diproylaminotetralin ( 8 - OH - DPAT ) dose - and time - dependently decreased basal levels of phosphorylated Erk1 / 2 ( phospho - Erk1 / 2 ) in rat hippocampus ( ED ( 50 ) approximately 0 . 1 mg / kg , maximum approximately 90 % ) without altering total Erk1 / 2 . The effects were kinase - specific , as 8 - OH - DPAT did not modify phosphorylated or total levels of the MAPKs c - Jun - N - terminal kinase / stress - activated protein kinase ( JNK / SAPK ) and p38 MAPK . Moreover , 8 - OH - DPAT did not modify phospho - Erk1 / 2 in striatum or frontal cortex . The effect of 8 - OH - DPAT was blocked by pretreatment with the selective 5 - HT ( 1A ) receptor antagonists N -[ 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N - 2 - pyridinylcyclohexanecarboxamide ( WAY 100635 ) , 1 -( 2 - methoxyphenyl )- 4 -( 4 -[ 2 - phthalimido ] butyl ) piperazine ( NAN - 190 ) and 4 - fluoro - N -( 2 -[ 4 -( 2 - methoxyphenyl ) 1 - piperazinyl ] ethyl )- N -( 2 - pyridinyl ) benzamide dihydrochloride ( p - MPPF ) , but not by the weak partial agonist / antagonist 8 -( 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl )- 8 - azaspiro ( 4 . 5 ) decane - 7 , 9 - dione dihydrochloride ( BMY 7378 ) . Other 5 - HT ( 1A ) receptor agonists ( buspirone , gepirone and ipsapirone ) also reduced phospho - Erk1 / 2 levels in hippocampus . 8 - OH - DPAT also reduced the levels of the upstream activator of Erk1 / 2 , phosphorylated extracellular signal - regulated kinase kinase ( phospho - Q02750 / 2 ) , and at least one potential downstream target , the nuclear transcription factor phospho - Elk - 1 . The region - and kinase - specific effects suggest that the Erk1 / 2 signal transduction cascade is likely an important differential mediator of 5 - HT ( 1A ) receptor - regulated events in the central nervous system .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"The potential role of PD0332991 ( ___MASK69___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK69___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK67___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .",
"Determination of cobimetinib in human plasma using protein precipitation extraction and high - performance liquid chromatography coupled to mass spectrometry . Inhibition of Q96HU1 / P29323 kinase ( MEK ) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway . DB05239 ( P16260 - 0973 ) ( S ) -[ 3 , 4 - Difluoro - 2 -( 2 - fluoro - 4 - iodo - phenylamino )- phenyl ]- ( ( S ) - 3 - hydroxy - 3 - piperidin - 2 - yl - azetidin - 1 - yl ) - methanone ) inhibits proliferation of a variety of human tumor cell lines by inhibiting Q02750 and P36507 . A specific high performance liquid chromatography - mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma . The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54 . 1 % . The calibration curve was ranged from 0 . 20 to 100ng / mL . The LLOQ was sensitive enough to detect terminal phase concentrations of the drug . The intra - and inter - assay precision ( % CV ) was within 10 . 3 % and 9 . 5 % for cobimetinib . The assay accuracy ( % RE ) was within ± 13 . 7 % of the nominal concentration values for cobimetinib with the normal analytical QCs . The developed assay was successfully used to analyze the human plasma samples ( for pharmacokinetic analysis ) from clinical trials ."
] |
[
"___MASK1___",
"___MASK20___",
"___MASK30___",
"___MASK42___",
"___MASK66___",
"___MASK67___",
"___MASK69___",
"___MASK82___",
"___MASK84___"
] |
___MASK69___
|
MH_train_306
|
interacts_with DB01427?
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[
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK23___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774 . 1 macrophages . The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes . Increases in intracellular cyclic AMP ( DB02527 ) and / or cyclic GMP ( cGMP ) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response . DB01427 is a clinically used positive inotropic agent which elevates intracellular DB02527 and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme . In the current study , we investigated the effect of various concentrations ( 1 - 300 microM ) of amrinone on lipopolysaccharide - induced production of pro - and anti - inflammatory cytokines and of nitric oxide ( NO ) in vitro . In cultured murine J774 . 1 macrophages , 1 ng / ml - 10 microg / ml of lipopolysaccharide from Escherichia coli O55 : P46977 induced production of tumor necrosis factor - alpha ( P01375 ) , interleukin - 10 , and nitrite ( breakdown product of NO ) . Pretreatment of cells with amrinone caused a dose - dependent suppression of P01375 production in the concentration range of 1 - 100 microM . Furthermore , this drug suppressed NO production in the range of 30 - 300 microM . Similarly to the results in the J774 . 1 cells , amrinone also inhibited P01375 and NO production in the range of 10 - 100 microM in primary rat peritoneal macrophages . At 300 microM , but not at lower concentrations , amrinone inhibited interleukin - 10 production in lipopolysaccharide - treated J774 . 1 macrophages . Pretreatment of the macrophages with 100 and 300 microM amrinone increased the lipopolysaccharide - elicited translocation of nuclear factor - kappa B . Taken together , our results indicate that the phosphodiesterase III inhibitor amrinone modulates the activation / production of many pro - and anti - inflammatory factors in endotoxin - stimulated cells . It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent .",
"Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast - mediated collagen gel degradation induced by tumor necrosis factor - alpha and neutrophil elastase . Tissue destruction , resulting in emphysema , can be a consequence of several pathologic processes . The current study evaluated the effects of the phosphodiesterase ( PDE ) 4 inhibitor , cilomilast , and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix . Using the three - dimensional collagen gel culture system , fibroblasts ( HFL - 1 ) were cultured with tumor necrosis factor ( P01375 ) - alpha , known to induce matrix metalloproteinase ( MMP ) release , and / or neutrophil elastase ( NE ) , which can induce MMP activation . On Day 4 , gels containing P01375 and NE were significantly degraded ( 20 . 8 +/- 2 . 9 % of original collagen content ) . DB03849 ( 10 micro M ) inhibited this degradation ( 84 . 4 +/- 8 . 4 % ) . DB01427 , a PDE3 inhibitor , and zaprinast , a O76074 inhibitor , had no effect . Gelatin zymography and immunoblotting revealed that fibroblasts cultured with P01375 released increased amounts of latent P03956 and - 9 . The addition of NE resulted in the conversion of P03956 and - 9 to their active forms , indicative of collagen degradation . DB03849 inhibited the release of P03956 and - 9 , as well as conversion of P03956 to its active form . Using real - time PCR analysis , cilomilast ' s effect on P03956 release was not associated with the proteinase ' s mRNA expression , suggesting that the inhibition of release is regulated at the post - transcriptional level . These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction , such as emphysema .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"MicroRNA - 155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting O15524 . MicroRNA ( miR ) - 155 is a critical player in both innate and adaptive immune responses . It can influence P01730 (+) T cell lineage choice . To clarify the role of miR - 155 in P01730 (+) CD25 (+) regulatory T ( Treg ) / T helper ( Th ) 17 cell differentiation and function , as well as the mechanism involved , we performed gain - and loss - of - function analysis by transfection pre - miR - 155 and anti - miR - 155 into purified P01730 (+) T cells . The results showed that miR - 155 positively regulated both Treg and Th17 cell differentiation . It also induced the release of interleukin ( IL ) - 17A by Th17 cells , but not the release of P22301 and transforming growth factor ( TGF ) - β1 by Treg cells . Furthermore , we found that miR - 155 reacted through regulating Janus kinase / signal transducer and activator of transcription ( JAK / P35610 ) rather than TGF - β / mothers against decapentaplegic homolog ( SMAD ) signaling pathway in the process of Treg and Th17 cells differentiation . This may because suppressors of cytokine signaling ( Q9NSE2 ) 1 , the important negative regulator of JAK / P35610 signaling pathway , was the direct target of miR - 155 in this process , but Q15796 and Q99717 were not . Therefore , we demonstrated that miR - 155 enhanced Treg and Th17 cells differentiation and Q16552 production by targeting O15524 .",
"Generation and characterization of a human monoclonal IgM antibody that recognizes a conserved epitope shared by lipopolysaccharides of different gram - negative bacteria . A hybridoma cell line secreting a human monoclonal antibody ( humab ) directed to an epitope in the lipid A region of lipopolysaccharides of Gram - negative bacteria was isolated . Peripheral blood lymphocytes ( PBL ) obtained from a healthy volunteer were immortalized by Epstein - Barr virus ( EBV ) transformation . Lymphoblastoid cell lines ( LCL ) secreting antibodies to the lipopolysaccharides of Gram - negative bacteria were determined by an enzyme - linked immunosorbent assay ( ELISA ) and subsequently fused with the human - mouse heteromyeloma cell line CB - P08709 by polyethylenglycol ( PEG ) - mediated fusion . A hybridoma line producing a humab ( LPD5H4 ) , of the IgM / lambda isotype , which strongly reacted with the lipid A portion of Salmonella and E . coli spp . in ELISA , was established . The antibody was purified by hydrophobic interaction chromatography and gel filtration . Immunoblotting experiments showed a strong reactivity of the humab LPD5H4 with the lower molecular species of different rough and smooth lipopolysaccharide ( LPS ) types of the bacteria species Salmonella , E . coli , Klebsiella , and Neisseria meningitidis , whereas those of Pseudomonas spp . were negative . Binding of humab LPD5H4 to solid phase bound lipid A and different rough mutants of LPS could be inhibited by the corresponding antigens in solution . Competition assays with a murine monoclonal antibody to lipid A and with polymyxin B indicate that humab LPD5H4 recognizes its epitope in this extremely conserved part of the LPS molecule . In vitro tests demonstrated that the MAb is able to partially inhibit the LPS - induced release of P01375 using isolated peripheral blood mononuclear cells ( PBMC ) .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK75___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Gene expression by PBMC in primary sclerosing cholangitis : evidence for dysregulation of immune mediated genes . Primary sclerosing cholangitis ( PSC ) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis . The precise role of the immune system in the pathogenesis of PSC remains unknown . We used RNA microarray analysis to identify immune - related genes and pathways that are differentially expressed in PSC . Messenger RNA ( mRNA ) from peripheral blood mononuclear cells ( PBMC ) was isolated from both patients with PSC and age and sex matched healthy controls . Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data , relevant genes were chosen for confirmation by RT - PCR in 10 PSC patients and 10 controls . Using unsupervised hierarchical clustering , gene expression in PSC was statistically different from our control population . Interestingly , genes within the P60568 receptor beta , P05231 and Q96HU1 Kinase pathways were found to be differently expressed in patients with PSC compared to controls . Further , individual genes , P01375 induced protein 6 ( TNFaip6 ) and membrane - spanning 4 - domains , subfamily A ( ms4a ) were found to be upregulated in PSC while similar to Q99717 ( Q99717 ) was downregulated . In conclusion , several immune - related pathways and genes were differentially expressed in PSC compared to control patients , giving further evidence that this disease is systemic and immune - mediated .",
"Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors . Phosphodiesterase ( PDE ) inhibitors are used as therapeutic agents for management of congestive heart failure . PDE inhibitors are potent inotropic and vasodilator drugs , which have also been shown to inhibit tumor necrosis factor alpha ( P01375 ) production . P01375 is a pleiotropic cytokine that has the ability to produce cardiac depressant and other cardiovascular effects in many disease conditions . P01375 levels are elevated in patients with chronic congestive heart failure , and it is possible that P01375 may play a role in this condition . The effects of PDE inhibitors on P01375 secretion from rat heart were evaluated in this study . Rat left ventricle was minced and incubated for 4 hr with various PDE inhibitors , and the amount of P01375 secretion was evaluated by cytotoxicity assay . Ro - 20 , 1724 , etazolate , amrinone , milrinone and pentoxifylline inhibited unstimulated P01375 production , with IC50 values of 1 . 87 , 2 . 07 , 13 . 9 , 153 and 201 microM , respectively . Lipopolysaccharide - induced P01375 secretion from rat left ventricle was also evaluated in this study . DB01427 , milrinone and pentoxifylline inhibited lipopolysaccharide - induced P01375 secretion , with IC50 values of 14 . 8 , 81 . 6 and 748 microM , respectively , whereas Ro - 2D , 1724 and etazolate had no effect on lipopolysaccharide - induced P01375 secretion . These results demonstrated that P01375 was secreted from rat left ventricle after 4 hr and different pharmacological manipulations were able to inhibit the secretion of P01375 from left ventricle . These initial pharmacological results may provide an important tool for further investigation into the beneficial effects of PDE inhibitors in congestive heart failure or other conditions where P01375 levels are elevated .",
"P49841 inhibitor suppresses Porphyromonas gingivalis lipopolysaccharide - induced P25942 expression by inhibiting nuclear factor - kappa B activation in mouse osteoblasts . Bone - forming osteoblasts have been recently reported capable of expressing the critical co - stimulatory molecule P25942 upon exposure to bacterial infection , which supports the unappreciated role of osteoblasts in modulating bone inflammation . Recent studies highlight the anti - inflammatory potential of glycogen synthase kinase - 3β ( GSK - 3β ) inhibitors ; however , their effect on osteoblasts remains largely unclear . In the present study , we showed that treatment with SB216763 , a highly specific GSK - 3β inhibitor , resulted in a dose - dependent decrease in the mRNA and protein expression of P25942 , as well as production of pro - inflammatory cytokines P05231 , P01375 - α and IL - 1β , in the Porphyromonas gingivalis - lipopolysaccharide ( LPS ) - stimulated murine osteoblastic - like MC3T3 - E1 cells . Furthermore , inhibition of GSK - 3β remarkably represses the LPS - induced activation of the nuclear factor kappa B ( NF - κB ) signaling pathway by suppressing IκBα phosphorylation , NF - κBp65 nuclear translocation , and NF - κBp65 DNA binding activity . Closer investigation by immunoprecipitation assay revealed that β - catenin can physically interact with NF - κBp65 . The negative regulation effect of GSK - 3β inhibitor on P25942 expression is mediated through β - catenin , for siRNA of β - catenin attenuated the GSK - 3β inhibitor - induced repression of NF - κB activation and , consequently , the expression of P25942 and production of pro - inflammatory cytokines in LPS - stimulated MC3T3 - E1 cells . Thus our results elucidate the molecular mechanisms whereby GSK - 3β inhibitor prevents the LPS - induced P25942 expression on osteoblasts and provide supportive evidence of the potential role of GSK - 3β inhibitors in suppressing the immune function of osteoblasts in inflammatory bone diseases .",
"Establishment of a double Philadelphia chromosome - positive acute lymphoblastic leukemia - derived cell line , TMD5 : effects of cytokines and differentiation inducers on growth of the cells . A double Philadelphia chromosome ( Ph ) - positive leukemia cell line with common - B cell phenotype , designated TMD5 , was established from the blast cells of a patient with double Ph - positive acute lymphoblastic leukemia . TMD5 cells expressed 190 kDa P11274 / P00519 chimeric protein and 145 kDa P00519 protein . The cells proliferated without added growth factors . Autocrine growth mechanism was not recognized . The addition of growth factors such as DB00099 , GM - P04141 , P08700 , P05231 , or Stem Cell Factor did not affect the growth . Herbimycin A suppressed the growth of TMD5 cells at the low concentration that did not affect Ph - negative cells . It suppressed tyrosine phosphorylation of intracellular proteins in TMD5 cells . Dexamethasone and dibutyryl cyclic AMP also suppressed the growth . They , however , did not affect the phosphorylation significantly . Neither all - trans retinoic acid nor interferon - alpha affected the growth . TMD5 cells , characterized minutely here and rare in that they have double Ph chromosomes , will be a useful tool for the study of Ph - positive leukemia .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK66___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK66___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Toll - like receptor signaling is impaired in dendritic cells from patients with X - linked agammaglobulinemia . Bruton ' s tyrosine kinase ( Q06187 ) , which is defective in patients with X - linked agammaglobulinemia ( XLA ) , is expressed not only in B cells but also in monocytes and dendritic cells ( DCs ) . DCs play a crucial role in the innate immune response against infections by sensing pathogens through Toll - like receptors ( TLRs ) . However , it is not known whether Q06187 deficiency in XLA might impair TLR - mediated signaling in DCs , which are susceptible to various infections . The phenotypic maturation and cytokine production mediated by TLRs were examined in monocyte - derived DC from XLA patients and normal controls . The TLR expression in DCs was analyzed by flow cytometry . TLR - mediated signaling in DCs was evaluated for the phenotypic maturation based on Q01151 expression and production of cytokines , such as P01375 , P05231 and IL - 12p70 . TLR levels in DCs were similar between XLA and controls . O60603 , O00206 and Q9NYK1 / 8 ligands elicited less phenotypic maturation of DCs from XLA patients than normal controls based on Q01151 expression . Stimulation with O60603 , O00206 and Q9NYK1 / 8 ligands , as well as O15455 ligand , resulted in significantly lower production of P01375 , but neither P05231 nor IL - 12p70 , by DCs from XLA patients in comparison to normal controls . These findings suggest that Q06187 may thus be required for TLR signaling in DCs . The impaired TLR signaling in DCs may therefore be partly responsible for the occurrence of severe infections with bacteria and some viruses in XLA patients .",
"Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury . Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia , related in part to implantation injury . The cell - specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells ( EC ) and medial smooth muscle cells ( SMC ) from canine vein grafts , 2 hours ( H ) to 30 days ( D ) following surgery . Our results demonstrate a robust genomic response beginning at 2 H , peaking at 12 - 24 H , declining by 7 D , and resolving by 30 D . Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses , apoptosis , mitosis , and extracellular matrix reorganization in both cell types . Through backpropagation an integrated network was built , starting with genes differentially expressed at 30 D , followed by adding upstream interactive genes from each prior time - point . This identified significant enrichment of P05231 , P10145 , NF - κB , dendritic cell maturation , glucocorticoid receptor , and Triggering Receptor Expressed on Myeloid Cells ( Q9NP99 ) signaling , as well as PPARα activation pathways in graft EC and SMC . Interactive network - based analyses identified P05231 , P10145 , IL - 1α , and P01308 Receptor ( P06213 ) as focus hub genes within these pathways . Real - time PCR was used for the validation of two of these genes : P05231 and P10145 , in addition to Collagen 11A1 ( P12107 ) , a cornerstone of the backpropagation . In conclusion , these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury , and identifying novel targets for its prevention .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK69___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"The role of P01375 in insulin resistance . P01308 resistance is an important component of the metabolic syndrome associated with obesity . Early - stage insulin - resistance and related mild glucose intolerance may be compensated by increased insulin secretion . When combined with impaired insulin secretion , insulin resistance plays an important role in type 2 diabetes ( 1 ) . P01308 - resistance is also associated with a variety of pathological conditions , including trauma , infection , and cancer . Obesity and type 2 diabetes are the most common metabolic diseases in Western societies , together affecting as much as half of the adult population ( 2 ) . The prevalence of these conditions is not only high , but continues to increase . We have only recently come to appreciate the role of fat , especially visceral fat , as an endocrine organ . Visceral fat is the source of a number of substances which might play a role in the development of insulin resistance . Among the latter are tumor necrosis factor - alpha ( P01375 ) , adiponectin , P05231 , resistin and free fatty acids . This review will discuss the regulation of insulin responses by P01375 and evidence supporting the hypothesis that over expression of P01375 plays a role in the pathophysiology of insulin resistance .",
"The use of cytokine inhibitors . A new therapeutic insight into heart failure . Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure . Elevated levels of circulating cytokines have been reported in patients with heart failure , and various cytokines have been shown to depress myocardial contractility in vitro and in vivo . We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival . DB01427 , pimobendan and vesnarinone , phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits , inhibited P01375 production . Differential modulation of the production of IL - 1beta and P05231 was observed ; amrinone and pimobendan enhanced the production of IL - 1beta , whereas vesnarinone did not . As inotropic agents differentially modulate cytokine production , these agents may interfere with induction of inducible nitric oxide ( NO ) synthase through an inhibition of cytokine formation . Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure , further study is necessary to reach this conclusion . We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro . The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO . As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure , it should be possible to design better and more targeted pharmacological agents . Furthermore , the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents .",
"Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK17___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .",
"Inhibitors of P11274 signalling interrupt the survival signal mediated by the micro - environment in mantle cell lymphoma . Several studies provide evidences for mantle cell lymphoma ( Q8WXI8 ) cell survival relying on B - cell receptor ( P11274 ) - mediated signalling pathways , whereas the nature of this activation is unknown . Significant progress in Q8WXI8 treatment is achieved through therapies targeting P11274 - associated kinases , i . e . , ___MASK17___ and Fostamatinib , inhibitors of Q06187 and P43405 , respectively . Our study addresses survival signals emanating from the P11274 or the tumour environment and how inhibiting P11274 signalling effectors might impact these survival signals . We found that Q06187 was constitutively activated and that P43405 phosphorylation was highly increased and sustained upon P11274 activation of primary Q8WXI8 cells . Moreover , Q8WXI8 cells from leukaemic patients secreted high amount of IL - 1β , P05231 , P10145 and P13501 . Activation of the P11274 induced ( i ) cell survival , ( ii ) P40763 activation and ( iii ) increased autocrine secretion of IL - 1β , P05231 , P10145 , P13501 , P22301 , TNFα and P15692 . Specific inhibition of Q06187 by ___MASK17___ or P43405 by Fostamatinib ( R406 ) reversed these protective effects and decreased both basal and P11274 - induced autocrine cytokine secretions associated with P40763 phosphorylation . Interestingly , targeting Q06187 and P43405 prevented and inhibited P11274 - induced Q8WXI8 cell adhesion to human bone marrow stromal cells ( HMSCs ) in short - and long - term co - culture . We demonstrated that P11274 - induced survival relies on autocrine secretion of IL - 1β , TNFα and P13501 that might facilitate adhesion of Q8WXI8 cells to HMSC . Treatment with ___MASK17___ or Fostamatinib blocked the chemotactic signal thus increasing apoptosis .",
"___MASK63___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK63___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK13___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Myocardial tumor necrosis factor - alpha secretion in hypertensive and heart failure - prone rats . Acute increases in blood pressure ( BP ) increase myocardial tumor necrosis factor ( P01375 ) - alpha production , but it is not known whether chronic hypertensive stress elevates myocardial P01375 production , possibly contributing to cardiac remodeling , decreased cardiac function , and faster progression to heart failure . BP , cardiac function , and size were evaluated in normotensive [ Sprague - Dawley ( SD ) ] , spontaneously hypertensive ( SHR ) , and spontaneously hypertensive heart failure - prone ( SHHF ) rats at 6 , 12 , 15 , and 18 mo of age and in failing SHHF . Left ventricular tissues were evaluated for secretion of bioactive P01375 and inhibition of P01375 secretion by phosphodiesterase inhibitors . All ventricles secreted bioactive and immunoreactive P01375 , but secretion decreased with age . SHR and SHHF rats secreted more P01375 than SD rats at 6 mo of age , but only failing SHHF rats secreted significantly more P01375 at 18 mo . DB01427 inhibited P01375 secretion in all rats and was less potent but more efficacious than RO - 201724 in all strains . P01375 secretion correlated with BP and left ventricular mass in 6 - mo - old rats , but this relationship disappeared with age . Results suggest that hypertension and / or cardiac remodeling is associated with elevated myocardial P01375 , and , although hypertension , per se , did not maintain elevated cardiac P01375 levels , SHHF rats increase P01375 production during the end stages of failure .",
"DB01427 and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice . Intracellular cyclic nucleotide levels play an important role in the regulation of several immunological processes . Since elevation of intracellular cyclic adenosine monophosphate and / or cyclic guanosine monophosphate concentration by inhibition of phosphodiesterase ( PDE ) is known to modulate the inflammatory response , we compared the effect of amrinone , an inhibitor of the PDE III isoenzyme , and of theophylline , a nonspecific PDE inhibitor , on the plasma tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , interleukin - 10 ( P22301 ) , and nitric oxide response in mice to intraperitoneal injection of bacterial lipopolysaccharide ( LPS ) . Intraperitoneal treatment of animals with amrinone ( 100 mg / kg ) 30 min before LPS administration decreased both plasma P05231 and P22301 concentrations in the first phase of the response , but enhanced plasma levels of these cytokines in the second part . In contrast , pretreatment of the animals with theophylline ( 100 mg / kg ) enhanced LPS - induced plasma P05231 and P22301 levels during the whole response . However , pretreatment with both PDE inhibitors resulted in a marked inhibition of LPS - evoked plasma concentrations of P01375 and nitrite / nitrate ( breakdown products of nitric oxide ) throughout the response . This study demonstrates for the first time that amrinone and theophylline possess differential , but primarily anti - inflammatory , properties during LPS - induced systemic inflammation in the mouse .",
"[ The role of glycogen synthase kinase - 3 beta in the pathogenesis of liver ischemia reperfusion injury ] . OBJECTIVE : To investigate the role of the key intracellular signaling molecule glycogen synthase kinase - 3 beta in the mechanism of liver ischemia reperfusion ( IR ) . METHODS : C57BL / 6 mice were subjected to 90 min warm liver cephalad lobe ischemia , followed by various length of reperfusion . Experiment groups included sham control group , liver IRI model group and glycogen synthase kinase - 3 beta inhibitor - treated group ( SB216763 in DB01093 , 25 g / kg , i . p , 2 hour prior to the onset of liver ischemia ) . The expression of glycogen synthase kinase - 3 beta protein was analysed by Western blotting . The serum ALT levels were determined to reflect the function of liver . The affected liver lobes were harvested for histology analysis . The inflammatory gene expression was detected by Quantitative PCR . RESULTS : By western blot analysis , we found that ischemia itself activated glycogen synthase kinase - 3 beta by a significant decrease of its phosphorylation . P49841 inhibitor SB216763 - pretreatment ameliorated the liver damages significantly as compared to the controls ( sALT : 2046 +/- 513 U / L vs 5809 +/- 1689 U / L , P = 0 . 0153 ) , and suppressed the gene expressions of IL - 12 , TNFa , IL - 1b and P05231 . CONCLUSIONS : This study demonstrated that the ischemia process modulated liver innate immune activation via a GSK - 3 - dependent mechanism which favored the development of a pro - inflammation response and lead to liver tissue damages . GSK - 3b may be a new therapeutic target to ameliorate liver IRI in transplant patients .",
"DB01427 suppresses the synthesis of tumor necrosis factor - alpha in human mononuclear cells . P01375 - alpha ( P01375 ) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock . Elevated circulating levels of P01375 have also been reported in patients with severe chronic heart failure . We studied the effect of amrinone , a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure , on the synthesis of P01375 in vitro . Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone . P01375 production is suppressed in a dose - dependent manner to a minimum of 9 % of controls with 1000 microM of amrinone , reaching half - maximal inhibition at 80 microM amrinone . This effect appears to be mediated via DB02527 , which accumulated nearly twofold in the presence of amrinone . Suppression of P01375 synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK33___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK33___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"___MASK95___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation ."
] |
[
"___MASK13___",
"___MASK17___",
"___MASK23___",
"___MASK33___",
"___MASK63___",
"___MASK66___",
"___MASK69___",
"___MASK75___",
"___MASK95___"
] |
___MASK75___
|
MH_train_307
|
interacts_with DB00862?
|
[
"Interaction between Q9Y6W8 - O75144 and P33681 - P10747 costimulatory pathways in alloimmune responses in vivo . The P33681 - P10747 pathway is one of the foremost costimulatory pathways involved in T - cell activation . Recently , a number of additional costimulatory pathways have been described and preliminary data suggest that they play important roles in alloimmunity . However , the interactions between these different pathways are not well understood . We studied the effect of targeting O75144 , O75144 , in a rat cardiac transplant model , with and without concomitant blockade of the P33681 pathway using ___MASK91___ . In a fully mismatched WF to LEW vascularized cardiac allograft model , without therapy , grafts were acutely rejected ( MST 10 . 8 +/- 1 . 6 days ) . Early ( day of transplant ) O75144 blockade with ICOSIg alone had little effect on graft survival and rather than being additive with P33681 blockade , ICOSIg abrogated the prolonged graft survival induced by ___MASK91___ treatment . By contrast , delayed ( day 2 post - transplant ) blockade of O75144 did not have such an effect . These findings were not related to cytokine deviation but may be in part related to the pattern of down - regulation of P33681 . 2 expression following early O75144 blockade . This is the first report describing the complex interactions between Q9Y6W8 - O75144 and P33681 - P10747 costimulatory pathways in alloimmunity in vivo .",
"___MASK36___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"___MASK73___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK73___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK73___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK73___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK73___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"O60674 - P40763 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells . P05231 - mediated P40763 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis . To investigate the molecular mechanism underlying the antirheumatic effects and T cell regulatory effects of P40763 inhibition , we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell / regulatory T cell ( Treg ) balance and osteoclastogenesis . AG490 was administered to mice with collagen - induced arthritis ( CIA ) via i . p . injection , and its in vivo effects were determined . Differential expression of proinflammatory cytokines , including Q16552 , IL - 1β , and P05231 , was analyzed by immunohistochemistry . Levels of phosphorylated P40763 and P42229 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining . In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real - time PCR . AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3 (+) Tregs . In contrast , the proportion of Q16552 - producing T cells and levels of inflammatory markers were reduced in AG490 - treated mice . Numbers of p - P40763 (+) P01730 (+) T cells and p - P42229 (+) P01730 (+) T cells were reduced and elevated , respectively , after treatment with AG490 . Furthermore , AG490 markedly increased the expression of molecules associated with Treg development ( Q9Y6W8 , programmed cell death protein 1 , P05362 , and CD103 ) . The development and function of osteoclasts were suppressed by AG490 treatment . Our results suggest that AG490 , specifically regulating the O60674 / P40763 pathway , may be a promising treatment for rheumatoid arthritis .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK8___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .",
"Murine lupus susceptibility locus Sle1a controls regulatory T cell number and function through multiple mechanisms . The Sle1 locus is a key determinant of lupus susceptibility in the NZM2410 mouse model . Within Sle1 , we have previously shown that Sle1a expression enhances activation levels and effector functions of P01730 (+) T cells and reduces the size of the P01730 (+) CD25 (+) Foxp3 (+) regulatory T cell subset , leading to the production of autoreactive T cells that provide help to chromatin - specific B cells . In this study , we show that Sle1a P01730 (+) T cells express high levels of Q9Y6W8 , which is consistent with their increased ability to help autoreactive B cells . Furthermore , Sle1a P01730 (+) CD25 (+) T cells express low levels of Foxp3 . Mixed bone marrow chimeras demonstrated that these phenotypes require Sle1a to be expressed in the affected P01730 (+) T cells . Expression of other markers generally associated with regulatory T cells ( Tregs ) was similar regardless of Sle1a expression in Foxp3 (+) cells . This result , along with in vitro and in vivo suppression studies , suggests that Sle1a controls the number of Tregs rather than their function on a per cell basis . Both in vitro and in vivo suppression assays also showed that Sle1a expression induced effector T cells to be resistant to Treg suppression , as well as dendritic cells to overproduce P05231 , which inhibits Treg suppression . Overall , these results show that Sle1a controls both Treg number and function by multiple mechanisms , directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells .",
"Emerging oral drugs for erectile dysfunction . Erectile dysfunction ( ED ) is a common medical condition that affects the sexual life of millions of men worldwide . Many drugs are now available for the treatment of ED , with oral pharmacotherapy representing the first - line option for most patients . DB00203 citrate , an inhibitor of the enzyme phosphodiesterase type 5 ( O76074 ) , is the most widely prescribed oral agent and has a very satisfactory efficacy - safety profile in all patient categories . DB00820 ( DB00820 ; Eli Lilly & Co . , Q9Y6W8 ) and vardenafil ( DB00862 ; Bayer Pharmaceuticals , GlaxoSmithKline ) are new O76074 inhibitors that have recently been approved worldwide . Both have been associated with significant positive efficacy - safety profiles . DB00714 sublingual is a dopamine D1 and D2 receptor agonist , which has been approved for marketing in Europe . It is best selected for treating patients with mild - to - moderate ED , but it is seldom used in clinical practice due to its limited efficacy and side effects , particularly nausea . Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy . The efficacy of second - line treatment is high , but the attrition rate remains significant . For the purpose of this review , clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy , including O76074 inhibitors and sublingual apomorphine .",
"High biochemical selectivity of tadalafil , sildenafil and vardenafil for human phosphodiesterase 5A1 ( O76074 ) over PDE11A4 suggests the absence of PDE11A4 cross - reaction in patients . The physiological role of phosphodiesterase ( PDE ) 11 is unknown and its biochemical characteristics are poorly understood . We have expressed human DB00117 - tagged PDE11A4 and purified the enzyme to apparent homogeneity . PDE11A4 displays K ( m ) values of 0 . 97 microM for cGMP and 2 . 4 microM for DB02527 , and maximal velocities were 4 - to 10 - fold higher for DB02527 than for cGMP . Given the homology between PDE11 and O76074 , we have compared the biochemical potencies of tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , vardenafil ( DB00862 , Bayer - GSK ) , and sildenafil ( Viagra , Pfizer Inc . ) for PDE11A4 and PDE5A1 . PDE5A1 / PDE11A4 selectivities are 40 - , 9300 - , and 1000 - fold for tadalafil , vardenafil , and sildenafil , respectively . This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients .",
"Characterization of intratumoral follicular helper T cells in follicular lymphoma : role in the survival of malignant B cells . Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma ( FL ) has a key role in both lymphomagenesis and patient outcome . Malignant FL B cells are found admixed to specific stromal and immune cell subsets , in particular P01730 ( pos ) T cells displaying phenotypic features of follicular helper T cells ( T ( FH ) ) . The goal of our study was to functionally characterize intratumoral P01730 ( pos ) T cells . We showed that P32302 ( hi ) Q9Y6W8 ( hi ) P01730 ( pos ) T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features : ( i ) CD25 ( pos ) follicular regulatory T cells ( T ( FR ) ) , and ( ii ) CD25 ( neg ) T ( FH ) displaying a FL - B cell supportive activity without regulatory functions . Furthermore , despite their strong similarities with tonsil - derived T ( FH ) , purified FL - derived T ( FH ) displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis , in particular P01375 , P01374 , P05112 or P29965 . Interestingly , we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab - induced apoptosis . Altogether , our study demonstrates that tumor - infiltrating P01730 ( pos ) T cells are more heterogeneous than previously presumed , and underlines for the first time the crucial role of T ( FH ) in the complex set of cellular interactions within FL microenvironment .",
"Primary B cell immunodeficiencies : comparisons and contrasts . Sophisticated genetic tools have made possible the identification of the genes responsible for most well - described immunodeficiencies in the past 15 years . Mutations in Btk , components of the pre - B cell and B cell receptor ( lambda5 , Igalpha , Igbeta ) , or the scaffold protein Q8WV28 account for approximately 90 % of patients with defects in early B cell development . Hyper - IgM syndromes result from mutations in P29965 , P25942 , Q9GZX7 , or P13051 in 70 - 80 % of affected patients . Rare defects in Q9Y6W8 or P15391 can result in a clinical picture that is consistent with common variable immunodeficiency , and as many as 10 % of patients with this disorder have heterozygous amino acid substitutions in O14836 . For all these disorders , there is considerable clinical heterogeneity in patients with the same mutation . Identifying the genetic and environmental factors that influence the clinical phenotype may enhance patient care and our understanding of normal B cell development .",
"Multiorgan infiltration by CD8 + T cells and 1p ; 16p translocation in a patient with hypogammaglobulinemia and a reduced number of B cells . Common variable immunodeficiency ( CVID ) disorders are the most common form of clinically significant primary immunodeficiencies found in adults . There is now clear evidence that CVID includes a group of clinically and genetically heterogeneous conditions . In addition to recurrent infections , some patients are highly prone to granulomatous lesions . Rarely , CVID may be characterized by an increased number of circulating CD8 + T cells with tissue infiltration . We report a unique case of CVID associated with a sarcoidosis - like disease and polyclonal CD8 + T cell expansion with multiple tissue infiltration occurring in a subject with the chromosome translocation t ( 1 ; 16 ) . No sequence variant in O14836 , APRIL , Q9Y275 , Q9Y6W8 or Q06187 genes was discovered . Cytometric analysis showed that the chemokine receptors expressed on peripheral and tissue CD8 + T cells are responsible for the tissue homing of the cells . Moreover , CD8 + T cells produced high amounts of IFN - γ , but not P05112 and Q16552 , with regular expression of the transcription factor Vav1 . Genes coding for P24001 and P42345 , both involved in the regulation of memory T cell differentiation , are located in the translocation breakpoint . This suggests that a chromosomal abnormality plays a role in the clinical features of this phenotypic variant of CVID .",
"Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway . OBJECTIVE : Inducible costimulator ( Q9Y6W8 ) is a member of the P10747 family . Although inflammation is an essential pathological feature of myocarditis , the role of Q9Y6W8 in myocarditis remains unclear . METHODS AND RESULTS : Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis ( EAM ) . Flow cytometry was used to examine expression of Q9Y6W8 on myocardial infiltrating cells . Anti - Q9Y6W8 antibody or Q9Y6W8 - immunoglobulin ( ICOSIg ) was administered intravenously , and rats were killed on day 14 or 21 to study effects of Q9Y6W8 / Q9Y6W8 - ligand ( O75144 ) pathway blockade during the antigen priming phase ( days 0 - 14 ) or immune response phase ( days 14 - 21 ) , respectively . The heart weight to body weight ratio was determined , and histological examination and echocardiogram were performed to evaluate the severity of the disease . Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed . Flow cytometry revealed that the majority of infiltrating cells , especially P01730 - positive cells , expressed Q9Y6W8 . Blockade of the Q9Y6W8 / O75144 pathway during the immune response phase attenuated EAM development . However , blockade of the Q9Y6W8 / O75144 pathway during the antigen priming phase did not attenuate and exacerbate EAM . Blockade of T cell activation through Q9Y6W8 suppressed expression of cytokines including P27352 - gamma , P05112 , P05231 , P22301 , P01584 , and P01375 and inhibited T cell proliferation in vitro . CONCLUSIONS : Blockade of T cell activation through Q9Y6W8 during the immune response phase regulates development of EAM , and therefore , Q9Y6W8 may be an effective target for treating myocarditis .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK63___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Repair of U / G and U / A in DNA by UNG2 - associated repair complexes takes place predominantly by short - patch repair both in proliferating and growth - arrested cells . Nuclear uracil - DNA glycosylase UNG2 has an established role in repair of U / A pairs resulting from misincorporation of DB03800 during replication . In antigen - stimulated B - lymphocytes UNG2 removes uracil from U / G mispairs as part of somatic hypermutation and class switch recombination processes . Using antibodies specific for the N - terminal non - catalytic domain of UNG2 , we isolated UNG2 - associated repair complexes ( UNG2 - ARC ) that carry out short - patch and long - patch base excision repair ( BER ) . These complexes contain proteins required for both types of BER , including UNG2 , P27695 , POLbeta , POLdelta , P18887 , P12004 and DNA ligase , the latter detected as activity . Short - patch repair was the predominant mechanism both in extracts and UNG2 - ARC from proliferating and less BER - proficient growth - arrested cells . Repair of U / G mispairs and U / A pairs was completely inhibited by neutralizing P13051 - antibodies , but whereas added recombinant Q53HV7 could partially restore repair of U / G mispairs , it was unable to restore repair of U / A pairs in UNG2 - ARC . Neutralizing antibodies to P27695 and POLbeta , and depletion of P18887 strongly reduced short - patch BER , and a fraction of long - patch repair was POLbeta dependent . In conclusion , UNG2 is present in preassembled complexes proficient in BER . Furthermore , UNG2 is the major enzyme initiating BER of deaminated cytosine ( U / G ) , and possibly the sole enzyme initiating BER of misincorporated uracil ( U / A ) .",
"Identification of Mycobacterium tuberculosis - specific Th1 , Th17 and Th22 cells using the expression of P29965 in tuberculous pleurisy . Important advances have been made in the immunodiagnosis of tuberculosis ( TB ) based on the detection of Mycobacterium tuberculosis ( MTB ) - specific T cells . However , the sensitivity and specificity of the immunological approach are relatively low because there are no specific markers for antigen - specific Th cells , and some of the Th cells that do not produce cytokines can be overlooked using this approach . In this study , we found that MTB - specific peptides of ESAT - 6 / P27918 - 10 can stimulate the expression of P29965 specifically in P01730 (+) T cells but not other cells from pleural fluid cells ( PFCs ) in patients with tuberculous pleurisy ( P20226 ) . P01730 (+) P29965 (+) but not P01730 (+) P29965 (-) T cells express IFN - γ , P60568 , P01375 - α , Q16552 or Q9GZX6 after stimulation with MTB - specific peptides . In addition , P01730 (+) P29965 (+) T cells were found to be mostly polyfunctional T cells that simultaneously produce IFN - γ , P60568 and P01375 - α and display an effector or effector memory phenotype ( CD45RA (-) CD45RO (+) P32248 (-) CD62L (-) Q9Y6W8 (-) ) . To determine the specificity of P01730 (+) P29965 (+) T cells , we incubated PFCs with ESTA - 6 / P27918 - 10 peptides and sorted live P01730 (+) P29965 (+) and P01730 (+) P29965 (-) T cells by flow cytometry . We further demonstrated that sorted P01730 (+) P29965 (+) , but not P01730 (+) P29965 (-) fractions , principally produced IFN - γ , P60568 , P01375 - α , Q16552 and Q9GZX6 following restimulation with ESTA - 6 / P27918 - 10 peptides . Taken together , our data indicate that the expression of P29965 on MTB - specific P01730 (+) T cells could be a good marker for the evaluation and isolation of MTB - specific Th cells and might also be useful in the diagnosis of TB .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK51___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Activating AMP - activated protein kinase ( AMPK ) slows renal cystogenesis . Renal cyst development and expansion in autosomal dominant polycystic kidney disease ( ADPKD ) involves both fluid secretion and abnormal proliferation of cyst - lining epithelial cells . The chloride channel of the cystic fibrosis transmembrane conductance regulator ( P13569 ) participates in secretion of cyst fluid , and the mammalian target of rapamycin ( P42345 ) pathway may drive proliferation of cyst epithelial cells . P13569 and P42345 are both negatively regulated by AMP - activated protein kinase ( AMPK ) . Metformin , a drug in wide clinical use , is a pharmacological activator of AMPK . We find that metformin stimulates AMPK , resulting in inhibition of both P13569 and the P42345 pathways . Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis . In addition , metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD . Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD .",
"DB06268 ( Q9Y6W8 - Texas Biotechnology ) . Q9Y6W8 - Texas Biotechnology is developing the endothelin A ( P25101 ) receptor antagonist , sitaxsentan , for the potential treatment of pulmonary hypertension , congestive heart failure ( CHF ) , chronic obstructive pulmonary disease and subarachnoid hemorrhage [ 205713 ] , [ 302200 ] . The compound is in phase IIa trials as an iv formulation for CHF and has completed phase I safety trials as an oral formulation [ 272071 ] . Phase II / III trials for pulmonary hypertension are planned for the first quarter of 2001 [ 3945711 ] . In June 2000 , Q9Y6W8 and Texas Biotechnology established a joint venture to develop and commercialize endothelin antagonists [ 370007 ] . US - 05591761 was issued to Texas in January 1997 , covering TBC - 11251 and several related isomers [ 2309301 .",
"Radiolabeled ligand binding to the catalytic or allosteric sites of O76074 and PDE11 . Cyclic nucleotide phosphodiesterases ( PDEs ) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes . Phosphodiesterase - 5 ( O76074 ) , which is highly specific for guanosine 3 '- 5 '- cyclic - monophosphate ( cGMP ) at both its catalytic site and its allosteric sites , has generated particular interest because it is potently and specifically inhibited by three drugs : sildenafil ( Viagra , Pfizer ) , tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , and vardenafil ( DB00862 , Bayer GSK ) . Previously , we have used [( 3 ) H ] cGMP to directly study the interaction of cGMP with the allosteric sites of O76074 , but because cGMP binds with relatively low affinity to the catalytic site , it has been difficult to devise a binding assay for this particular binding reaction . This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme . We now use a similar approach to study the characteristics of high - affinity [( 3 ) H ] inhibitor binding to the O76074 catalytic domain . For these studies , we have prepared [( 3 ) H ] sildenafil and [( 3 ) H ] tadalafil , two structurally different competitive inhibitors of O76074 . The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of O76074 . We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on O76074 . These techniques have also been successfully applied to the study of binding of radiolabeled O76074 inhibitors to PDE11 , suggesting that these methods are applicable to the study of other PDEs , and perhaps other enzyme families .",
"Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone - induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( ___MASK82___ ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 +] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 +] i were significantly attenuated in cells pretreated with ___MASK82___ in a dose - dependent manner . P06401 antagonists prevented the attenuated Ca2 + transients induced by ___MASK82___ . P25101 and ETB receptor subtypes were expressed in myometrial cells , and treatment with ___MASK82___ resulted in significant downregulation of P25101 and ETB receptor binding . ___MASK82___ did not alter ionomycin - stimulated increases in [ Ca2 +] i and had no effect on inositol trisphosphate - dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone - induced modification of receptor - mediated increases in [ Ca2 +] i .",
"DB09280 - ___MASK62___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK27___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system ."
] |
[
"___MASK27___",
"___MASK36___",
"___MASK51___",
"___MASK62___",
"___MASK63___",
"___MASK73___",
"___MASK82___",
"___MASK8___",
"___MASK91___"
] |
___MASK62___
|
MH_train_308
|
interacts_with DB01184?
|
[
"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK98___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK42___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high - fat diet induced obese mice . Calorie restriction is the most effective way of expanding life - span and decreasing morbidity . It improves insulin sensitivity and delays the age - related loss of dopamine receptor D ( 2 ) ( P14416 ) expression in the brain . Conversely , high - fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild - type C57Bl6 male mice was restricted to 60 % of ad lib . intake while they were treated with the P14416 antagonist haloperidol or vehicle using s . c . implanted pellets . Mice with ad lib . access to food receiving vehicle treatment served as controls . All mice received high - fat food throughout the experiment . After 10 weeks , an i . p . glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie - restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . ___MASK2___ completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high - fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"___MASK16___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK16___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK59___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK59___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Imatinib has the potential to exert its antileukemia effects by down - regulating Q12809 K + channels in chronic myelogenous leukemia . Imatinib is a powerful protein tyrosine kinase ( PTK ) inhibitor that specifically targets P11274 - P00519 , P10721 , and P09619 kinases , has become the current first - line therapy for all newly diagnosed chronic myeloid leukemia ( CML ) . Beside PTKs , PTK inhibitors alter the activity of a large number of voltage - dependent ion channels . Q12809 K (+) channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis . The present study explored a possible regulatory effect of imatinib upon Q12809 K (+) channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML . The results demonstrated that Q12809 was highly detected in K562 cells and primary CML cells , and down - regulated by imatinib at mRNA and protein levels . Furthermore , imatinib markedly reduced hERG currents in HEK293T - hERG cells , this effect was accompanied by inhibition of CML cell proliferation and apoptosis , as well as suppression of vascular endothelial growth factor ( P15692 ) secretion . Moreover , these antileukemia effects of imatinib were potentiated by E - 4031 , a specific Q12809 inhibitor . Together , these results provide evidence of a novel potential molecular mechanism of antileukemic activities by imatinib which , independent of targeting tyrosine kinase , highlight Q12809 K (+) channels as a therapeutic target for CML treatment .",
"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .",
"The role of Q12809 K + channels and a functional link between Q12809 K + channels and P48061 in acute leukemic cell migration . Stromal cell - derived factor - 1 ( P48061 ) and its unique receptor , P61073 , regulate stem / progenitor cell migration and retention in the bone marrow and are required for hematopoiesis . Recent studies found that Q12809 K (+) channels were important regulators of tumor cell migration . In this study , we investigated whether P48061 induced acute leukemic cell migration associated with Q12809 K (+) channels . Our results showed that E - 4031 , a specific Q12809 K (+) channels inhibitor , significantly blocked P48061 - induced migration of leukemic cell lines , primary acute leukemic cells , leukemic stem cells and HEK293T cells transfected with herg - pEGFP . The migration of phenotypically recognizable subsets gave the indication that lymphoblastic leukemic cells were inhibited more than myeloid cells while in the presence of E - 4031 which maybe associated with herg expression . P48061 increased Q12809 K (+) current expressed in oocytes and HEK293T cells transfected with herg - pEGFP . There were no significant changes of P61073 expression on both HL - 60 cells and primary leukemic cells regardless if untreated or treated with E - 4031 for 24 h ( P > 0 . 05 ) . The Q12809 K (+) current increased by P48061 might contribute to the mechanism of P48061 - induced leukemic cell migration . The data suggested that Q12809 K (+) channels functionally linked to cell migration induced by P48061 .",
"[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .",
"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .",
"___MASK95___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK95___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK5___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Antineoplastic chemotherapy induced QTc prolongation . Anticancer drugs are sometimes associated with QT prolongation . Classical , new and candidate agents to treat cancer may affect ventricular repolarization through a set of different mechanisms . Interference on human ether - a - go - go - related gene potassium ion channels ( Q12809 K + ) seems to be a common mechanism for many of these drugs . Anthracycline chemotherapy is associated with electrocardiographic alterations including prolongation of QT interval , development of ventricular late potentials and various arrhythmias . The effects of the interaction of anthracyclines with the monoclonal antibody against P04626 / neu ( Erb - 2 ) trastuzumab could potentiate the cardiotoxic effects . Electrocardiographic changes have been also reported with the use of 5 - fluorouracil . QTc alterations have also been reported with some platinum compounds . Taxanes ( paclitaxel and docetaxel ) have also been associated with cardiotoxicity , promoting both bradi - and tachyarrhythmias and other cardiac disturbances . Among the newest compounds , symptomatic or asymptomatic QTc aberrations were reported with multitargeted tyrosine - kinase inhibitors , anti HERG2 , anti - P15692 , vascular disruption agents and histone deacetylase inhibitors . Patients with cancer are at increased risk of sudden death due to severe cardiac arrhythmias because of the high prevalence of predisposing risk factors such as electrolytic abnormalities , starvation and concomitant medications . The use of specific anticancer drug that may prolong the QT interval need to be properly evaluated in each case to reduce this risk .",
"[ ___MASK27___ sodium ( Photofrin - II ) ] . ___MASK27___ sodium ( ___MASK27___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK27___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"___MASK17___ binding to human and rat dopamine and 5 - HT receptors . ___MASK17___ ( ___MASK17___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK17___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK17___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK17___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds ."
] |
[
"___MASK16___",
"___MASK17___",
"___MASK27___",
"___MASK2___",
"___MASK42___",
"___MASK59___",
"___MASK5___",
"___MASK95___",
"___MASK98___"
] |
___MASK59___
|
MH_train_309
|
interacts_with DB01268?
|
[
"Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival . BACKGROUND : Lymphatics are important for their conduit functions of transporting antigen , immune cells , and inflammatory mediators to draining lymph nodes and to the general circulation . Lymphangiogenesis is involved in many pathologic processes ; however , the roles for lymphatic responses in transplantation have not been thoroughly investigated . METHODS : Mice were made diabetic by a single high dose of streptozotocin and then received islet allografts . Animals were treated with three different lymphatic inhibitors . FTY720 , an analog of sphingosine 1 - phosphate , inhibited lymphocyte migration into afferent and efferent lymphatics . DB01268 , a kinase inhibitor , blocked several receptors , including vascular endothelial growth factor receptor 3 ( P35916 ) , the major growth factor receptor for lymphatic endothelial cells . Anti - P35916 monoclonal antibody specifically inhibited P35916 . Diabetes was determined by daily monitoring of blood glucose levels . Inflammation within islet grafts was assessed by immunohistochemistry for insulin , T cells ( CD3 ) , and lymphatics ( Q9Y5Y7 ) . RESULTS : After transplantation , lymphangiogenesis occurred in islet allografts and in draining lymph nodes . FTY720 , sunitinib , and anti - P35916 each inhibited lymphangiogenesis in the islets and significantly prolonged allograft survival . Immunofluorescent staining demonstrated that administration of each of the lymphatic inhibitors resulted in preservation of islets and β - cells along with a markedly reduced infiltration of T cells into the grafts . CONCLUSION : Lymphangiogenesis occurs in islet allografts in response to inflammation and plays a key role in the islet inflammation in alloimmunity . Interfering with lymphatic function leads to inhibition of lymphangiogenesis and prolonged or indefinite allograft survival . These observations suggest new therapeutic targets for rejection and tolerance .",
"Peroxisome proliferator - activated receptor - gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells . Vascular endothelial growth factor ( P15692 ) , expressed in a variety of mesenchymal cells including vascular smooth muscle cells ( VSMC ) , is a potent mitogen for endothelial cells , and is used clinically applied for ischemic disease of peripheral vessels . To determine whether peroxisome proliferator - activated receptor gamma ( PPARgamma ) regulates P15692 production in VSMC , we examined P15692 secretion from VSMC treated with Q07869 agonists . DB00197 increased P15692 secretion in a time - and dose - dependent manner ( 261 +/- 35 % with 25 mM of troglitazone for 24 h ) , and also increased levels of P15692 mRNA . P15692 secretion was also increased by other PPARgamma agonists , pioglitazone , LY171883 , and 15d - PGJ2 ( 224 +/- 17 . 1 % , 247 +/- 36 . 8 % and 171 +/- 7 . 8 % , respectively ) , but not the PPARgamma agonists bezafibrate and Wy14643 ( 85 . 2 +/- 1 . 5 % , 94 . 6 +/- 3 . 2 , respectively ) . Our findings suggest that thiazolidinediones might be useful for the therapeutic angiogenesis for ischemic artery disease .",
"Second line therapies for the treatment of gastrointestinal stromal tumor . PURPOSE OF REVIEW : Most gastrointestinal stromal tumors eventually acquire resistance to imatinib mesylate . This review focuses on recent progress on management of patients whose disease progresses on the standard dose of imatinib . RECENT FINDINGS : Approximately 30 % of patients failing standard - dose imatinib achieve disease stabilization with high - dose imatinib , but objective responses are few and the clinical benefit usually short - lived . Patients receiving enzyme - inducing drugs may need high imatinib doses to achieve therapeutic blood concentrations . Surgical excision of a single growing metastasis leads to a median progression - free survival time of 7 - 11 months . DB01268 malate is effective following imatinib failure . The median time to disease progression is approximately 6 months with sunitinib therapy versus 6 weeks with placebo following discontinuation of imatinib , but few ( 5 % ) patients achieve objective response . Patients with gastrointestinal stromal tumor with P10721 exon 9 mutation may benefit more from sunitinib than those with exon 11 mutation . DB01268 frequently causes abnormal thyroid function . SUMMARY : DB01268 is now the approved second line therapy following imatinib failure and for patients intolerant to imatinib . The clinical benefit is only moderate , and thyroid function monitoring is required . Several investigational agents are being evaluated for imatinib - resistant gastrointestinal stromal tumor . Palliative procedures , such as hepatic arterial embolization , also require study .",
"In vitro and in vivo activity of ___MASK54___ , a novel Src - Abl inhibitor , against imatinib - resistant Bcr - Abl + neoplastic cells . Resistance to imatinib represents an important scientific and clinical issue in chronic myelogenous leukemia . In the present study , the effects of the novel inhibitor ___MASK54___ on various models of resistance to imatinib were studied . ___MASK54___ proved to be an active inhibitor of Bcr - Abl in several chronic myelogenous leukemia cell lines and transfectants , with IC ( 50 ) values in the low nanomolar range , 1 to 2 logs lower than those obtained with imatinib . Cells expressing activated forms of P10721 or platelet - derived growth factor receptor ( P09619 ) , two additional targets of imatinib , were unaffected by ___MASK54___ , whereas activity was found against Q9P1W9 . ___MASK54___ retained activity in cells where resistance to imatinib was caused by P11274 - P00519 gene amplification and in three of four Bcr - Abl point mutants tested . In vivo experiments confirmed ___MASK54___ activity in models where resistance was not caused by mutations as well as in cells carrying the Y253F , E255K , and D276G mutations . Modeling considerations attribute the superior activity of ___MASK54___ to its ability to bind a conformation of Bcr - Abl different from imatinib .",
"A decade of tyrosine kinase inhibitor therapy : Historical and current perspectives on targeted therapy for GIST . The introduction of molecularly targeted therapies has ushered in a considerable transformation in the management of gastrointestinal stromal tumors ( GIST ) that currently defines the paradigm of targeted therapy for solid tumors . Indeed , in the past decade the management of GIST has evolved from a disease only effectively treatable by surgery to the archetype of a tumor treatable with a molecularly targeted therapy . Better understanding of the molecular and genetic characteristics that underlie the aberrant behavior of GIST has increased the accuracy of its diagnosis and allowed for the identification of distinct genetic hallmarks , prognostic groups , and treatment strategies . Collectively , this has resulted in the development of the targeted tyrosine kinase inhibitors ( TKIs ) imatinib and sunitinib , and continues to prompt studies of novel agents in this disease . Since approval in 2002 , imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST , including a median progression - free survival ( PFS ) of 2 years and median overall survival approaching 5 years , with some patients progression - free after 10 years of treatment . Imatinib is now also approved in adult patients following resection of P10721 - positive GIST . In 2006 , sunitinib was approved for the treatment of advanced GIST after failure of imatinib . DB01268 provides significant benefit in this setting , with a median PFS close to 6 months after imatinib failure . Following progression on these agents , patients have limited treatment options . This critical unmet need is being addressed by the development of new TKIs and the use of novel regimens with approved agents .",
"Response of hemopoiesis in dogs to continuous low dose rate total body irradiation . Among the cytotoxic agents which particularly cause damage to cell renewal systems , ionizing radiation is one of the most effective ones since it leads to inactivation of all types of proliferating cells including resting stem cells . It is the aim of this paper to present the effects of continuous low dose rate total body irradiation ( TBI ) on hemopoiesis in dogs . The animals were exposed to gamma - rays from a 60 - Co source , receiving a daily radiation dose of 0 . 0188 Gy for indefinite times . Sequential hematological studies performed included determinations of peripheral blood cell counts and of total cell numbers in standardized bone marrow samples , assessments of progenitor cells GM - Q15814 in the blood and bone marrow , and of colony - stimulating activity ( Q13216 ) in the serum . The lymphocytes , the thrombocytes and neutrophilic granulocytes uniformly showed early decreases within the first 200 to 500 days corresponding to cumulative radiation doses in the range up to 3 . 8 to 9 Gy , but remained stable at subnormal levels in the period up to 1 , 700 days of exposure . The GM - Q15814 numbers in bone marrow samples from the rib clearly showed a strong decrease within the first 150 days of exposure preceding the changes in the blood granulocyte concentration . A transient partial recovery of the GM - Q15814 was observed at later times between 700 and 1 , 200 days of exposure , followed by another decrease to extremely low values at cumulative doses in the range of 32 Gy . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"DB01268 synergizes the antitumor effect of cisplatin via modulation of P07992 expression in models of gastric cancer . We evaluated the effects of sunitinib monotherapy and in combination with cisplatin in human gastric cancer cell lines . DB01268 showed antiproliferative effect in gastric cancer cells line with high P16234 expression . Knockdown of P16234 showed that sunitinib sensitivity was correlated with the basal expression of P16234 . Synergistic growth inhibitory activity in combination with cisplatin was identified . We further explored how sunitinib potentiated the activity of cisplatin . We found that sunitinib treatment resulted in the down - regulation of P07992 expression via the modulation of P16234 expression in gastric cancer cells . The effect was verified via SNU484 xenograft model . Our data support the rationale of clinical trial using sunitinib in combination of cisplatin in gastric cancer .",
"Biomarkers to predict response to sunitinib therapy and prognosis in metastatic renal cell cancer . DB01268 is an orally - administered , multitargeted tyrosine kinase inhibitor . The main targets are vascular endothelial growth factor receptor ( VEGFR ) - 1 , P35968 , P35916 , platelet - derived growth factor receptor ( P09619 ) - α , and P09619 - β . Among therapeutic targeting agents , it is the best available in the USA for patients with metastatic renal cell cancer ( RCC ) . Well - constructed clinical trials have led to the worldwide approval of various agents for RCC . However , in clinical practice , it remains difficult to determine the best treatment strategy with these agents . Therefore , the identification of biomarkers to predict response and side - effects and to select optimal dosages is urgently needed . Potential mechanisms of action and resistance need to be understood in order to make accurate predictions . This article briefly reviews candidate biomarkers of sunitinib therapy in terms of clinical variables , genetic factors , and circulating proteins and endothelial cells . Although further validation and implementation is necessary , if validated , biomarkers will help measure the therapeutic response in individual patients and establish treatment strategies for metastatic RCC .",
"Interleukin 2 receptor traffic in a murine cytolytic T cell line . We have analyzed different parameters of the interleukin 2 receptor ( IL2R ) traffic in a murine P60568 - dependent T cell line , B6 . 1 . These cells express about 10 ( 5 ) IL2R , of which approximately 10 % are of high affinity ( Q9Y5Y7 ) . About 90 % of all mature immunoprecipitable receptor molecules in the cell are on the cell surface . Measurements of the half life and of the rate of receptor synthesis indicate that these cells produce approximately 500 receptor molecules per cell and min . P60568 deprival for less than 6 h does not affect this rate . B6 . 1 cells internalize P60568 via their Q9Y5Y7 only , with a maximal rate of about 500 molecules per cell and min . Among the receptors present at a given time on the cell surface , about 15 % are internalized within 30 min . Receptor internalization is independent of P60568 . The data obtained argue against rapid recycling of the Q9Y5Y7 . The rate of receptor synthesis can be reconciled with the rate of P60568 internalization and the observation that internalization occurs only via Q9Y5Y7 by assuming that cell surface low - affinity receptors can be transformed into Q9Y5Y7 by associating with other molecules .",
"Molecular diagnostics of thyroid tumors . CONTEXT : Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing . Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance . OBJECTIVE : To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility . DATA SOURCES : PubMed ( US National Library of Medicine ) - available review articles , peer - reviewed original articles , and experience of the author . CONCLUSIONS : The most common molecular alterations in thyroid cancer include P15056 and DB01367 point mutations and P07949 / PTC and Q06710 / Q07869 γ rearrangements . These nonoverlapping genetic alterations are found in more than 70 % of papillary and follicular thyroid carcinomas . These molecular alterations can be detected in surgically resected samples and fine - needle aspiration samples from thyroid nodules and can be of significant diagnostic use . The diagnostic role of P15056 mutations has been studied most extensively , and recent studies also demonstrated a significant diagnostic utility of DB01367 , P07949 / PTC , and Q06710 / Q07869 γ mutations , particularly in thyroid fine - needle aspiration samples with indeterminate cytology . In addition to the diagnostic use , P15056 V600E mutation can also be used for tumor prognostication , as this mutation is associated with higher rate of tumor recurrence and tumor - related mortality . The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer .",
"Gastrointestinal stromal tumors : a review of case reports , diagnosis , treatment , and future directions . Gastrointestinal stromal tumor ( GIST ) is a nonepithelial , mesenchymal tumor first described by Mazur and Clark in 1983 . Since then , its molecular biology has been studied in great detail . Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research . Mutation in c - kit exons 9 , 11 , 13 , 17 and P16234 mutation in exons 12 , 14 , 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth . However , 5 to 15 % of GISTs does not harbor these mutations , which raises additional questions in another alternate signaling pathway mutation yet to be discovered . Diagnosis of GISTs relies heavily on P10721 / CD117 immunohistochemical staining , which can detect most GISTs except for a few 3 % to 5 % that harbors P16234 mutation . Newer staining against PKC theta and DOG - 1 genes showed promising results but are not readily available . Clinical manifestation of GISTs is broad and highly dependent on tumor size . Surgery still remains the first - line treatment for GISTs . The advancement of molecular biology has revolutionized the availability of newer drugs , Imatinib and DB01268 . Together with its advancement is the occurrence of Imatinib / DB01268 drug resistance . With this , newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs .",
"Heterogeneous expression of cyclooxygenase - 2 and inducible nitric oxide synthase within colorectal tumors : correlation with tumor angiogenesis . BACKGROUND : Recent studies have shown that the cyclooxygenase ( P36551 ) and the inducible nitric oxide synthase ( P35228 ) pathways are involved in the development of tumor angiogenesis in human cancers . AIMS : To investigate whether a different pattern of P35354 and P35228 expression / activity exists within different areas of colorectal tumors and to analyze the relationship between these two enzymes and tumor angiogenesis . METHODS : Microvessel density ( P53602 ) and P35354 , P35228 , vascular endothelial growth factor ( P15692 ) and P15692 receptor - 2 ( P35968 ) protein expression were evaluated at both the invasive front ( IF ) and the tumor center ( TC ) in 46 human colorectal cancer specimens . We also investigated the concentration of DB00917 and NO at the same sites . RESULTS : P35354 and P35228 protein expression and activity were significantly higher within the IF than the TC of the tumor specimens . Similarly , P53602 and P15692 / P35968 expression significantly increased from the TC to the IF . Only P35354 expression was significantly correlated with P53602 and P15692 / P35968 expression at both the TC and the IF . CONCLUSION : Our study shows a heterogeneous expression of P35354 and P35228 in colorectal cancer . The up - regulation of P35354 at the IF parallels an increase in vessel density and P15692 / P35968 expression , thus supporting the hypothesis that the tumor periphery is the most aggressive portion of a colorectal tumor .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK75___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK75___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK75___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK75___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK75___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"___MASK90___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK90___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"Combination of rapamycin and protein tyrosine kinase ( PTK ) inhibitors for the treatment of leukemias caused by oncogenic PTKs . Abnormal protein tyrosine kinases ( PTKs ) cause many human leukemias . For example , P11274 / P00519 causes chronic myelogenous leukemia ( CML ) , whereas P36888 mutations contribute to the pathogenesis of acute myelogenous leukemia . The P00519 inhibitor Imatinib ( Gleevec , STI571 ) has remarkable efficacy for treating chronic phase CML , and P36888 inhibitors ( e . g . , PKC412 ) show similar promise in preclinical studies . However , resistance to PTK inhibitors is a major emerging problem that may limit long - term therapeutic efficacy . Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders . Here , we report that the P42345 inhibitor rapamycin synergizes with Imatinib against P11274 / P00519 - transformed myeloid and lymphoid cells and increases survival in a murine CML model . ___MASK94___ / Imatinib combinations also inhibit Imatinib - resistant mutants of P11274 / P00519 , and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412 - sensitive or - resistant leukemogenic P36888 mutants . Biochemical analyses raise the possibility that inhibition of Q13541 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor / rapamycin combinations . Addition of a mitogen - activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy . Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and / or acute myelogenous leukemia caused by P36888 mutations . Similar strategies may be useful for treating solid tumors associated with mutant and / or overexpressed PTKs .",
"DB01268 malate . Recently , there has been a growing interest in understanding the role of receptor tyrosine kinases ( RTK ) , such as vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) , stem cell factor receptor ( P10721 ) , and fms - like tyrosine kinase 3 ( P36888 ) , in promoting tumor angiogenesis , tumor growth and metastasis . DB01268 ( sunitinib malate ; SU11248 ; SUTENT ; Pfizer Inc , New York , NY , USA ) is a novel , orally bio - available , oxindole , multi - targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and P09619 which has shown anti - tumor and anti - angiogenic activities . This drug recently received approval from the US Food and Administration ( FDA ) in two indications simultaneously : advanced renal cell carcinoma ( adRCC ) and gastrointestinal stromal tumors ( GIST ) , in patients who are resistant or intolerant to the treatment with imatinib . The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology .",
"DB01268 . DB01268 is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) alpha and beta , c - kit , and other receptors . These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma ( RCC ) and unresectable gastrointestinal stromal tumors ( GIST ) . Most side effects , including hypertension , hand - foot syndrome , and diarrhea are generally well manageable . Clinical trials are underway to determine the efficacy of sunitinib in other tumor types including metastatic breast , colorectal , and lung cancers . This chapter will detail the preclinical data leading to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in metastatic RCC and advanced GIST .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"Imatinib and nilotinib inhibit hematopoietic progenitor cell growth , but do not prevent adhesion , migration and engraftment of human cord blood P28906 + cells . BACKGROUND : The availability of tyrosine kinase inhibitors ( TKIs ) has considerably changed the management of Philadelphia chromosome positive leukemia . The P11274 - P00519 inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor , c - Kit . DB04868 is 30 times more potent than imatinib towards P11274 - P00519 in vitro . Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib . The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation , differentiation , adhesion , migration and engraftment capacities of human cord blood P28906 (+) cells . DESIGN AND METHODS : After a 48 - hour cell culture with or without TKIs , Q15814 , LTC - IC , migration , adhesion and cell cycle analysis were performed . In a second time , the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD / SCID / IL - 2Rγ ( null ) mice . RESULTS : TKIs did not affect LTC - IC frequencies despite in vitro inhibition of Q15814 formation due to inhibition of P28906 (+) cell cycle entry . Adhesion of P28906 (+) cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations . Migration through a SDF - 1α gradient was not changed by cell culture in the presence of TKIs . Finally , bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model . No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for P10721 . CONCLUSIONS : These data suggest that combining non - myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe .",
"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .",
"New perspectives : role of sunitinib in breast cancer . DB01268 malate ( SU11248 ) is a multitarget oral tyrosine kinase receptor ( RTKs ) inhibitor which was approved by FDA in renal cells carcinoma ( RCC ) and imatinib - resistant or imatinib - intollerant gastrointestinal stromal tumour ( GIST ) . DB01268 is able to inhibit RTKs such as receptors for platelet - derived growth factor ( PDGF - R alpha and beta ) and for vascular endothelial growth factor ( VEGFRs ) . It is able to inhibit P10721 receptor , colony stimulating factor type 1 receptor ( P04141 - 1R ) , glial cell line neutrophic factor receptor ( P07949 ) , fms - like tyrosine kinase receptor - 3 ( P36888 or P36888 ) , signal transducer and activator of transcription 3 ( P40763 ) and AKT ( protein kinase B ) in tumour cells . Many sunitinib targets play important roles in growth and survival of human breast cancer ( BC ) . The \" rationale \" of sunitinib in BC ( with or without others antiagiogenetic therapy ) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals . We overviewed the most relevant studies concerning sunitinib in metastatic BC .",
"P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .",
"Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .",
"Pharmacological management of gastrointestinal stromal tumours : an update on the role of sunitinib . The efficacy and tolerability of the receptor tyrosine kinase inhibitor , sunitinib malate , have been demonstrated in phase I - III clinical trials of patients with imatinib - resistant or imatinib - intolerant gastrointestinal stromal tumours ( GIST ) as well as in a worldwide expanded - access study and in a continuous daily dosing ( CDD ) trial . Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib - resistant GIST . DB01268 activity was observed across different GIST genotypes and particularly in patients with wild - type and P10721 exon 9 mutations ( all relatively resistant to standard - dose imatinib ) and in patients with secondary P10721 exons 13 and 14 mutations . Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction , dose interruption or standard supportive measures . Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary . The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy , including dose adjustments based on blood testing to ensure optimal drug exposure , and the use of the alternative CDD regimen to avoid treatment interruption .",
"Growth factor receptor profile of P28906 + cells in AML and B - lineage ALL and in their normal bone marrow counterparts . Leukaemic cells show a low clonogenic activity and a heterogeneous proliferative response to growth factors . We investigated whether this could be due to an altered expression of growth factor receptors on the leukaemic precursors . Receptors for DB00099 , stem cell factor ( P21583 ) , P08700 , P05231 and P13232 were detected on P28906 + cells in AML and B - lineage ALL with monoclonal antibodies and flow cytometry . The expression was compared with that on myeloid and B - lymphoid P28906 + cells in normal bone marrow . Leukaemic P28906 + cells expressed the same receptors as their normal counterparts . AML and B - lineage ALL could be distinguished by the growth factor receptor profile of their P28906 + cells . P10721 , G - CSFR and IL - 6Ralpha were found in AML , IL - 7R in B - lineage ALL and IL - 3Ralpha in both . IL - 3Ralpha was upregulated in AML and B - lineage ALL P28906 + cells , while samples with low or high expression were present for the other receptors . This variable expression could correlate with the heterogeneous response of leukaemic cells to growth factors . Functional studies on isolated P28906 + cells are needed to investigate this further .",
"Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia . The dual Src / Abl kinase inhibitor bosutinib ( ___MASK54___ ) targets the tyrosine kinase brc - abl , the key enzyme in the development of chronic myeloid leukemia ( CML ) . In clinical trials , bosutinib yielded promising results with regard to efficacy , tolerability and toxicity in first - , second - and third - line therapy of CML patients . Remarkably , bosutinib is able to overcome most imatinib - resistant P11274 - P00519 - 1 mutations except V299L and T315I . Mostly , low - to - moderate grade gastrointestinal toxicitis are the most common treatment - emergent adverse events observed under bosutinib . Unlike other tyrosine kinase inhibitors approved for CML treatment to date , bosutinib shows only minimal inhibitory activity against c - P10721 and the PDGF receptor . This may be causative for its favorable hematologic toxicity profile . In this review , the authors give an overview on the mechanism of action and currently available preclinical and clinical data for bosutinib in CML .",
"The molecular biology of the human anaplastic thyroid carcinoma cell . In the present investigation we show data from our studies of anaplastic human thyroid carcinoma cell lines . The cell lines employed in the study were HTh 7 , HTh 74 , C 643 and SW 1736 , all derived from tumours diagnosed as anaplastic thyroid carcinomas . Northern blot analysis with four different thyroid specific cDNA probes showed a varying pattern of expression . Thyroglobulin mRNA was found in three of the carcinoma cell lines , although the signal was very weak compared to the expression in tissue from a toxic goitre , used as positive control . Interestingly , two of the cell lines expressed the receptor for thyrotropin , but none of them contained thyroperoxidase mRNA . Three of the cell lines expressed mRNA for receptors platelet - derived growth factor , P16234 and / or P09619 type . Messenger RNA of a thyroid specific transcription factor , Q15669 - 1 , known to regulate the normal function of thyrocytes , was found in the toxic goitre but not in the anaplastic thyroid carcinoma cell lines . Lack of expression of Q15669 - 1 might the immediate cause of the anaplastic phenotype , considering the possibility that Q15669 - 1 functions as a master regulatory gene in thyroid cell differentiation .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK48___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"DB01268 treatment in pediatric patients with advanced GIST following failure of imatinib . BACKGROUND : DB01268 inhibits P10721 and other members of the split - kinase - domain family of receptor tyrosine kinases . DB01268 prolongs survival in adult patients with imatinib - resistant gastrointestinal stromal tumor ( GIST ) . We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib . PROCEDURE : DB01268 therapy was provided through a treatment - use protocol . Patients were 10 - 17 years old at enrollment . All patients had GIST resistant to imatinib therapy . DB01268 was administered daily for 4 weeks in 6 - week treatment cycles . P10721 and platelet - derived growth factor receptor alpha ( P16234 ) genotyping of tumor tissue were performed . RESULTS : One patient achieved a partial response , five patients had stable disease and one patient had progressive disease on sunitinib . The duration of disease stabilization was between 7 and 21 + months , with a mean of 15 months . Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients . Two patients experienced grade 3 adverse events . All other adverse events were grade 1 - 2 . None of the five patients tested had mutations in P10721 or P16234 . CONCLUSION : DB01268 treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib - resistant GIST .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK33___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Class I histone deacetylase activity is required for proliferation of renal epithelial cells . The process of renal regeneration after acute kidney injury is thought to recapitulate renal development , and proliferation of renal proximal tubular cells ( RPTCs ) is a critical step in the regenerative response . Recent studies indicate that class I histone deacetylases ( HDACs ) are required for embryonic kidney gene expression , growth , and differentiation . The role and underlying mechanisms of class I HDAC activation in RPTC proliferation , however , remain unclear . In this study , we used cultured RPTCs to examine this issue since four class I HDAC isoforms ( 1 , 2 , 3 , and 8 ) are abundantly expressed in this cell type . Blocking class I HDAC activity with a highly selective inhibitor , MS - 275 , induced global histone H3 hyperacetylation , reduced RPTC proliferation , and diminished expression of cyclin D1 and proliferating cell nuclear antigen . Silencing Q13547 , 3 , or 8 with small interfering RNA resulted in similar biological effects . Activation of epidermal growth factor receptor ( P00533 ) and signal transducers and activators of transcription 3 ( P40763 ) was required for RPTC proliferation , and P40763 functioned downstream of P00533 . Treatment with MS - 275 or knockdown of Q13547 , 3 , or 8 suppressed P00533 expression and phosphorylation , and silencing Q13547 and 3 also reduced P40763 phosphorylation . However , Q92769 downregulation did not affect RPTC proliferation and phosphorylation of P00533 and P40763 . Collectively , these data reveal a critical role of class I HDACs in mediating proliferation of renal epithelial cells through activation of the P00533 / P40763 signaling pathway .",
"Platelets promote osteosarcoma cell growth through activation of the platelet - derived growth factor receptor - Akt signaling axis . The interactions of tumor cells with platelets contribute to the progression of tumor malignancy , and the expression levels of platelet aggregation - inducing factors positively correlate with the metastatic potential of osteosarcoma cells . However , it is unclear how tumor - platelet interaction contributes to the proliferation of osteosarcomas . We report here that osteosarcoma - platelet interactions induce the release of platelet - derived growth factor ( PDGF ) from platelets , which promotes the proliferation of osteosarcomas . Co - culture of platelets with MG63 or Q9UKB1 osteosarcoma cells , which could induce platelet aggregation , enhanced the proliferation of each cell line in vitro . Analysis of phospho - antibody arrays revealed that co - culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor ( P09619 ) and Akt . The addition of supernatants of osteosarcoma - platelet reactants also increased the growth of MG63 and Q9UKB1 cells as well as the level of phosphorylated - P09619 and - Akt . DB01268 or LY294002 , but not erlotinib , significantly inhibited the platelet - induced proliferation of osteosarcoma cells , indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the P09619 and then Akt . Our results suggest that inhibitors that specifically target osteosarcoma - platelet interactions may eradicate osteosarcomas .",
"Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502 - 3ins mutation : an in vitro mutagenesis screen for drug resistance . PURPOSE : Although tyrosine kinase inhibitors have improved survival in advanced gastrointestinal stromal tumor ( GIST ) , complete response is rare and most patients eventually fail the first - line treatment with imatinib . DB01268 malate is the only approved second - line therapy for patients with imatinib - resistant or imatinib - intolerant GIST . The clinical benefit of sunitinib is genotype - dependent in regards to both primary and secondary mutations , with GIST patients harboring the P10721 ( AY502 - 3ins ) exon 9 mutation being the most sensitive . EXPERIMENTAL DESIGN : As sunitinib resistance is now emerging , our goal was to investigate mechanisms of progression and to test the efficacy of novel tyrosine kinase inhibitor on these resistant mutants in vitro . N - ethyl - N - nitrosourea mutagenesis of Ba / P13726 cells expressing the P10721 ( AY502 - 3ins ) mutant was used to investigate novel patterns of resistant mutations evolving in the presence of sunitinib . RESULTS : Tumors from patients who developed sunitinib resistance after at least 1 year of radiographic response were analyzed , showing similar findings of a primary P10721 ( AY502 - 3ins ) mutation and a secondary mutation in the P10721 activation loop . Ba / P13726 cells expressing these sunitinib - resistant double mutants showed sensitivity to both dasatinib and nilotinib . CONCLUSIONS : DB01268 resistance in GIST shares similar pathogenetic mechanisms identified in imatinib failure , with acquisition of secondary mutations in the activation domain after an extended initial response to the drug . Moreover , in vitro mutagenesis with or without N - ethyl - N - nitrosourea of Ba / P13726 cells expressing P10721 ( AY502 - 3ins ) showed acquisition of secondary mutations restricted to the second kinase domain of P10721 . In contrast , in vitro resistance to imatinib produces a broader spectrum of secondary mutations including mutations in both P10721 kinase domains .",
"___MASK45___ : kinetic and dynamic profile in the treatment of pain . ___MASK45___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK45___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK45___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK45___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first - line therapy for chronic myelogenous leukemia . The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 non - receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 receptor kinase , AMN107 ( DB04868 ) and INNO - 406 ( NS - 187 ) specific for c - P10721 kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK787 / ZK 222584 ) , DB00398 ( Bay 43 - 9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .",
"Optimal use of targeted agents for advanced gastrointestinal stromal tumours . Imatinib is the recommended 1st - line treatment for a P10721 - positive unresectable and / or metastatic gastrointestinal stromal tumour ( GIST ) . However , some patients experience intolerance to imatinib and most patients will eventually experience disease progression while on imatinib treatment . DB01268 is approved for treatment of a GIST after disease progression on , or intolerance to , imatinib therapy . Progression may occur early or later on , in treatment and is determined by factors including initial GIST genotype and mutational status . GISTs with P10721 exon 11 mutations appear to be sensitive to standard dose imatinib , and patients with GISTs exhibiting P10721 exon 9 mutations whose disease has progressed on imatinib 400 mg / day have been shown to respond to imatinib 800 mg / day , albeit with a higher incidence of adverse events . DB01268 has shown clinical benefit in all major GIST mutational subtypes , particularly in patients with wild - type or P10721 exon 9 genotype and against GISTs with secondary P10721 exon 13 or 14 mutations . The choice between higher - dose imatinib and sunitinib after progression on standard dose imatinib is unclear , and apart from the GIST primary resistance genotype and mutational status , individual patient factors such as tumour characteristics , drug pharmacokinetics , and other clinical factors may affect response to treatment . Individualisation of therapy may help to maximise clinical benefit of therapy in these patients .",
"Sarcomatoid carcinoma of the lung presenting as a cutaneous metastasis . The author reports a very rare case of cutaneous metastasis of sarcomatoid carcinoma of the lung . The skin metastasis was an initial presentation . A 67 - year - old man consulted our hospital because of left chest skin mass . An excisional biopsy was performed , and it showed proliferation of malignant sarcomatoid spindle and polygonal cells in the deep dermis and subcutis remote from the epidermis and appendages . Immunohistochemically , the tumor cells were positive for pancytokeratins , cytokeratin ( CK ) 7 , CK 18 , vimentin , p53 , Ki - 67 ( 95 % ) and P16234 . They were negative for high molecular weight CK , CK 5 / 6 , CK 14 , CK 19 , CK 20 , epithelial membrane antigen , Q15669 - 1 , P06731 , desmin , S100 protein , alpha - smooth muscle actin , p63 , P28906 , surfactant apoprotein A , chromogranin , synaptophysin , neuron - specific enolase , P34810 , CD56 , D2 - 40 , calretinin and P10721 . A pathological diagnosis of metastatic sarcomatoid carcinoma probably originating from the lung was made . Then , the patient was admitted to our hospital , and imaging modalities including computed tomography ( CT ) and magnetic resonance imaging ( Q9BWK5 ) revealed a tumor in the left lung . No other tumors were detected in the imaging techniques . Lung biopsy was planned , but the patient suddenly died ; the cause of death was unclear . Autopsy was not performed . The present report suggests that sarcomatoid carcinoma of the lung should be considered in cutaneous metastatic lesions .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"The antitumor effects of sunitinib ( formerly SU11248 ) against a variety of human hematologic malignancies : enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling . We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib ( formerly SU11248 ) against a variety of hematologic malignancies including the following leukemias : eosinophilic ( EOL - 1 ) , acute myeloid ( THP - 1 , U937 , Kasumi - 1 ) , biphenotypic ( MV4 - 11 ) , acute lymphoblastic ( NALL - 1 , Jurkat , BALL - 2 , PALL - 1 , PALL - 2 ) , blast crisis of chronic myeloid ( KU812 , Kcl - 22 , K562 ) , and adult T - cell ( Q9BT22 , P02795 , P47944 ) , as well as non - Hodgkin ' s lymphoma ( KS - 1 , Dauji , Akata ) and multiple myeloma ( U266 ) . DB04485 uptake studies showed that sunitinib was active against EOL - 1 , MV4 - 11 , and Kasumi - 1 cells , which possessed activating mutations of the PDGFRalpha , P36888 , and c - P10721 genes , respectively , with IC ( 50 ) s of < 30 nmol / L . In addition , sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in P36888 gene . P08758 staining showed that sunitinib induced apoptosis of these cells . DB01268 inhibited phosphorylation of P36888 and PDGFRalpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4 - 11 and EOL - 1 cells , respectively . Interestingly , rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down - regulate levels of mammalian target of rapamycin effectors P08133 S6 kinase and eukaryotic initiation factor 4E - binding protein 1 in these cells . Taken together , sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase , and the combination of sunitinib and RAD001 represents a promising novel treatment strategy .",
"Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK71___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK71___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK71___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .",
"New perspectives : role of DB01268 in breast cancer . DB01268 malate ( SU11248 ) is a multitarget oral tyrosine kinase receptor ( RTKs ) inhibitor which was approved by FDA in renal cells carcinoma ( RCC ) and imatinib - resistant or imatinib - intollerant gastro - intestinal stromal tumour ( GIST ) . DB01268 is able to inhibit RTKs such as receptors for platelet - derived growth factor ( PDGF - Rα and β ) and for vascular endothelial growth factor ( VEGFRs ) . It is able to inhibit P10721 receptor , colony stimulating factor type 1 receptor ( P07333 ) , glial cell line neutrophic factor receptor ( P07949 ) , fms - like tyrosine kinase receptor - 3 ( P36888 or P36888 ) , signal transducer and activator of transcription 3 ( P40763 ) and AKT ( protein kinase B ) in tumour cells . Many DB01268 targets play important roles in growth and survival of human breast cancer ( BC ) . The \" rationale \" of DB01268 in BC ( with or without others antiagiogenetic therapy ) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals . We overviewed the most relevant studies concerning DB01268 in metastatic BC .",
"Role of P0DMC3 region in auto - activation of mutant P10721 receptor : a molecular dynamics simulation insight . P10721 receptor is the prime target in gastrointestinal stromal tumor ( GISTs ) therapy . Second generation inhibitor , DB01268 , binds to an inactivated conformation of P10721 receptor and stabilizes it in order to prevent tumor formation . Here , we investigated the dynamic behavior of wild type and mutant D816H P10721 receptor , and emphasized the extended A - loop ( EAL ) region ( 805 - 850 ) by conducting molecular dynamics simulation ( ∼ 100 ns ) . We analyzed different properties such as root mean square cutoff or deviation , root mean square fluctuation , radius of gyration , solvent - accessible surface area , hydrogen bonding network analysis , and essential dynamics . Apart from this , clustering and cross - correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of P10721 receptor . Molecular dynamics analysis indicated that mutation ( D816H ) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region . Moreover , flexible secondary elements , specially , coil and turns were dominated in EAL region of mutant P10721 receptor during simulation . This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation . Our atomic investigation of mutant P10721 receptor which emphasized on EAL region provided a better insight into the understanding of DB01268 resistance mechanism of P10721 receptor and would help to discover new therapeutics for P10721 - based resistant tumor cells in GIST therapy .",
"P42345 inhibition enhances DB00238 - AUY922 - induced autophagy - mediated P10721 degradation and cytotoxicity in imatinib - resistant gastrointestinal stromal tumors . Our previous study demonstrated DB00238 - AUY922 , a P07900 inhibitor , could enhance mutant P10721 degradation in gastrointestinal stromal tumor ( GIST ) cells through both proteasome - and autophagy - mediated pathways . Herein , we showed rapamycin , a P42345 inhibitor and autophagy inducer , could reduce total and phospho - P10721 expression levels and enhance apoptosis in imatinib - resistant GIST cells . The involvement of autophagy in rapamycin - induced P10721 downregulation was further confirmed by co - localization of P10721 and autophagosome , and partial recovery of P10721 expression level by either siRNA - mediated Q14457 and Q9H1Y0 silencing or autophagy inhibitors after rapamycin . ___MASK94___ and DB00238 - AUY922 synergistically inhibited GIST cells growth in vitro . The combination of low - dose DB00238 - AUY922 with rapamycin had comparable effects on reducing P10721 expression , increasing Q9GZQ8 puncta and tumor necrosis , and inhibiting tumor growth as high - dose DB00238 - AUY922 did in GIST430 xenograft model . Our results suggest the addition of a P42345 inhibitor may reduce DB00238 - AUY922 dose requirement and potentially improve its therapeutic index in mutant P10721 - expressing GISTs .",
"Thymoma patients treated in a phase I clinic at MD Anderson Cancer Center : responses to P42345 inhibitors and molecular analyses . BACKGROUND : Thymomas and thymic carcinoma are rare tumors with no approved therapies . Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy ( Phase I Clinic ) . METHODS : We retrospectively reviewed the medical records of consecutive referred patients with advanced / metastatic thymoma or thymic carcinoma RESULTS : Twenty - one patients were identified ( median age 52 years ; 10 women ; median number of prior systemic therapies = 2 ) . Six of 10 patients ( 60 % ) treated with P42345 inhibitor combination regimens achieved stable disease ( SD ) ≥ 12 months or a partial response ( PR ) . For patients treated on P42345 inhibitor regimens ( N = 10 ) , median time to treatment failure ( Q15669 ) was 11 . 6 months versus 2 . 3 months on last conventional regimen prior to referral ( p = 0 . 024 ) . Molecular analyses ( performed by next generation sequencing in seven patients and single polymerase chain reaction ( PCR ) - based assays in an additional six patients ) showed diverse actionable mutations : P42336 ( 1 of 12 tested ; 8 % ) ; P00533 ( 1 of 13 ; 8 % ) ; P07949 ( 1 of 7 ; 14 % ) ; and P31749 ( 1 of 7 ; 14 % ) . Of two patients with P42336 or P31749 mutations , one was treated with an P42345 inhibitor - based regimen and achieved 26 % regression with a Q15669 of 17 months . CONCLUSION : Patients with advanced / metastatic thymoma or thymic carcinoma demonstrated prolonged Q15669 on P42345 inhibitor - based therapy as compared to prior conventional treatment . Heterogeneity in actionable molecular aberrations was observed , suggesting that multi - assay molecular profiling and individualizing treatment merits investigation .",
"In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model . Neuroblastoma ( NB ) is one of the most common pediatric solid tumors originating from the neural crest lineage . Despite intensive treatment protocols including megatherapy with hematopoietic stem cell transplantation , the prognosis of NB patients remains poor . More effective therapeutics are required . High vascularity has been described as a feature of aggressive , widely disseminated NB . Our previous work demonstrated the overexpression of vascular endothelial growth factor ( P15692 ) in NB , and we showed that an anti - P15692 receptor ( P35968 ) antibody could induce sustained NB tumor suppression and regression . DB01268 is a kinase inhibitor targeting platelet - derived growth factor receptors and VEGFRs and , therefore , a promising antiangiogenic agent . In this study , we investigated the antitumor activity of sunitinib and its synergistic cytotoxicity with conventional ( cyclophosphamide ) and novel ( rapamycin ) therapies . Both NB cell lines and tumor - initiating cells from patient tumor samples were used in our in vitro and in vivo models for these drug testing . We show that sunitinib inhibits tumor cell proliferation and phosphorylation of VEGFRs . It also inhibits tumor growth , angiogenesis , and metastasis in tumor xenograft models . Low - dose sunitinib ( 20 mg / kg ) demonstrates synergistic cytotoxicity with an P42345 inhibitor , rapamycin , which is more effective than the traditional chemotherapeutic drug , cyclophosphamide . These preclinical studies provide the evidence of antitumor activity of sunitinib both in the early stage of tumor formation and in the progressive metastatic disease . These studies also provide the framework for clinical trial of sunitinib , alone and in combination with conventional and novel therapies to increase efficacy and improve patient outcome in NB .",
"DB01268 targets PDGF - receptor and Flt3 and reduces survival and migration of human meningioma cells . The multitargeted tyrosine - kinase inhibitor sunitinib is a highly effective anti - angiogenic and cytostatic agent in the therapy of various tumours . While malignant gliomas have been shown to be responsive to sunitinib , detailed studies analysing human meningiomas are missing . We therefore analysed the effects of sunitinib in two benign ( BenMen - 1 , HBL52 ) and two malignant ( IOMM - Lee , KT21MG ) human meningioma cell lines and found that DNA synthesis was significantly ( p ≤ 0 . 001 ) inhibited following 1 , 2 or 5 μM sunitinib , with IC ( 50 ) values between 2 and 5 μM in all cell lines . This effect was associated with a G ( 2 ) M - arrest at 10 μM for BenMen - 1 , HBL52 and IOMM - Lee , and 20 μM in KT21MG cells . Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10 μM or higher . Corresponding , cell viability assays showed a significant ( p ≤ 0 . 001 ) short term decrease of viable cells ( 24h ) only for high sunitinib concentrations with IC ( 50 )- values between 10 and 20 μM . However , pre - irradiated meningioma cells ( 5 Gy ) showed a sensitivity shift towards IC ( 50 )- values around 5 μM sunitinib . We also found that 5 μM strongly reduced meningioma cell migration in vitro . Western blot analyses showed abolished platelet derived growth factor receptor ( P09619 ) - autophosphorylation after sunitinib . Interestingly , the drug also inhibited the autophosphorylation of the receptor tyrosine kinase fms - like tyrosine kinase 3 ( Flt3 ) in a dose - dependent manner . Taken together , the present data show that micromolar sunitinib has strong cytostatic and anti - migratory effects on human meningioma cells .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK88___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"The effects of human P36888 ligand on in vitro human megakaryocytopoiesis . The human homolog of the murine flt3 / flk2 gene product is a tyrosine kinase receptor that plays a role in regulating the proliferation and differentiation of cells in the hematopoietic system . Using a plasma - clot clonal assay and a long - term bone marrow culture ( LTBMC ) system , we studied the effects of the recently cloned human flt3 ligand ( FL ) alone and in combination with granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) , interleukin - 3 ( P08700 ) , or stem cell factor ( c - kit ligand [ KL ] ) on human megakaryocytopoiesis . The effects of FL on the primitive megakaryocyte ( MK ) progenitor cell , the burst - forming unit - megakaryocyte ( BFU - MK ) , and the more differentiated colony - forming unit - megakaryocyte ( CFU - MK ) were determined . FL alone had no megakaryocytic colony - stimulating activity ( MK - Q13216 ) , but was capable of augmenting the MK - Q13216 of both GM - P04141 and P08700 . FL synergized with P08700 at the level of both CFU - MK and BFU - MK and with GM - P04141 and KL at the level of CFU - MK . Although FL alone exhibited a limited potential in sustaining long - term megakaryocytopoiesis in vitro , it synergistically augmented the ability of P08700 and KL , alone or in association , to promote long - term megakaryocytopoiesis . These data indicate that multiple cytokines are necessary to optimally stimulate the proliferation of both classes of MK progenitor cells and that FL plays a significant role in this process by amplifying the MK - Q13216 of GM - P04141 , P08700 , and KL .",
"The potential role of sunitinib in gastrointestinal cancers other than GIST . Gastrointestinal tumors are the most frequent and lethal malignancies worldwide . The deeper knowledge in molecular biology mechanisms involved in carcinogenesis has allowed the design of new targeted drugs mainly directed against the epidermal growth factor receptor ( P00533 ) , the vascular endothelial growth factor ( P15692 ) and its receptors ( VEGFRs ) . DB01268 is an oral multitargeted inhibitor of the P15692 , platelet - derived growth factor ( PDGF ) , and c - P10721 , among others , tyrosine kinase receptors . Therefore , sunitinib acts in a dual mode as antiangiogenic agent and as antitumoral drug . The aim of this review is to gather the preclinical rationale behind the clinical use of sunitinib in gastrointestinal malignancies other than gastrointestinal stromal tumors ( GIST ) and to summarize the clinical data from phase I to III trials currently available .",
"Semen characteristics and infertility in aging . A study was initiated to compare the spermiograms according to age in 570 consecutive men with a history of infertility . The semen was evaluated by computer - assisted semen analysis ( Q13216 ) and by the hyposmotic swelling test ( Q9UKB1 ) . A statistical difference was seen between men over 50 years of age compared with younger men , but only for the Q9UKB1 scores and velocity . No statistical differences were found on any of the other parameters . Since most semen parameters were similar even in the men over age 50 , a definite decline in fertility potential with increasing age could not be determined by this study .",
"Immunohistochemical expression of P12830 does not distinguish canine cutaneous histiocytoma from other canine round cell tumors . Immunohistochemistry for P12830 ( ECAD ) has been used to distinguish canine cutaneous histiocytoma from other leukocytic neoplasms ( \" round cell tumors \" ) . To determine the specificity of this test , 5 types of canine cutaneous round cell tumors were evaluated for immunohistochemical expression of ECAD . Tumors of all 5 types had variable cytoplasmic , plasma membrane , and / or paranuclear ECAD expression : All 13 cutaneous histiocytomas were ECAD + ; all but 1 of 14 mast cell tumors expressed ECAD ; 10 of 12 epitheliotropic lymphomas reacted with P12830 antibody ; of 72 plasmacytomas , 54 were ECAD + ; and 5 of 5 histiocytic sarcomas were positive . Conclusions based on these results include the following : First , immunoreactivity for ECAD is not limited to leukocytes of cutaneous histiocytoma ; second , antibody to ECAD also labels neoplastic cells in most mast cell tumors , plasmacytomas , cutaneous histiocytic sarcomas , and epitheliotropic lymphomas ; third , although most histiocytomas have membranous ECAD expression , the immunoreactivity varies among round cell tumors and is frequently concurrent in different cellular compartments ; fourth , the distinctively paranuclear ECAD expression pattern in epitheliotropic lymphomas might distinguish them from other round cell tumors ; and , fifth , ECAD should be used with other markers ( eg , MUM1 for plasmacytomas , P10721 for mast cell tumors , CD3 and CD79a for lymphomas ) to distinguish among canine round cell tumors .",
"DB01268 : bridging present and future cancer treatment . Tyrosine kinase receptors ( RTKs ) are a heterogeneous group of transmembrane proteins involved in signal transduction . These receptors are expressed in many different cells and regulate cellular growth , differentiation and angiogenesis . Overexpression and / or the structural alteration of different RTKs classes are generally associated to cancer and , when RTKs - mediated signal transduction pathways are abnormally activated , generate cancer growth , angiogenesis and metastatization . Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies . DB01268 malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs , which has both direct anticancer and antiangiogenetic activity . DB01268 targets selectively vascular endothelial growth factor , P10721 , Flt3 and platelet - derived growth factor receptors and the receptor encoded by the ret proto - oncogene . This drug is used in the treatment of gastrointestinal stromal cancer ( GIST ) resistant to imatinib and metastatic renal cell carcinoma ( RCC ) . In this review , we report preclinical data of sunitinib , even about synergism with chemotherapy and radiotherapy , data relative to phase III trials of sunitinib in the treatment of GIST and RCC , and we try to plan what will be future applications of sunitinib in different types of cancer , even in association to chemotherapy , radiotherapy and monoclonal antibodies ."
] |
[
"___MASK33___",
"___MASK45___",
"___MASK48___",
"___MASK54___",
"___MASK71___",
"___MASK75___",
"___MASK88___",
"___MASK90___",
"___MASK94___"
] |
___MASK54___
|
MH_train_310
|
interacts_with DB06168?
|
[
"Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK2___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK2___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .",
"Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor - 1 in cultured human endothelial cells : their possible mechanism of action . P00747 activator inhibitor - 1 ( P05121 ) is a primary endogenous inhibitor of tissue - type plasminogen activator ( t - PA ) . In this study , we examined the effects of oversulfated fucoidan ( OSF ) derivatives and heparin on lipopolysaccharide ( LPS ) - induced release of P05121 antigen from cultured human umbilical vein endothelial cells ( HUVEC ) . Addition of LPS ( 10 micrograms / ml ) enhanced the release of P05121 by HUVEC but not of t - PA antigen . At 18 h , a 2 . 4 - fold increase in the extracellular P05121 level was observed . The increased P05121 level was reduced to control level by the simultaneous addition of 10 micrograms / ml of OSF or heparin . The suppressive effect of native fucoidan was negligible . We also examined the molecular size effect of OSF , using 10 - 20 , 20 - 40 , and 40 - 60 kDa fragments . The result indicated that these fragments were effective as well as the 100 - 130 kDa form of OSF , hence suggesting an important role of the degree of sulfation . P01584 ( P01584 ) is a potent inducer of P05121 in cultured HUVEC . DB01109 , OSF , and its fragments did not suppress the P01584 - induced release of P05121 antigen . Treatment of HUVEC with heparitinase or monoclonal antibody against heparin sulfate proteoglycan ( HSPG ) resulted in a complete loss of its ability to enhance P05121 release in response to LPS stimulation , while the chondroitinase ABC treatment hardly affected the P05121 production . These results suggest that HSPG is involved in the initial binding of LPS to HUVEC . The suppressive effects of OSF and heparin on LPS - induced P05121 release may result from the inhibition of LPS binding to the cell surface HSPG .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK99___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK75___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK75___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK75___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Cytokines regulate L - arginine - dependent cyclic GMP production in rat glial cells . We have previously demonstrated that primary astrocyte cultures from neonatal rat cortex and P13671 glioma cells express a calcium - independent nitric oxide synthase ( NOS ) on induction with bacterial endotoxin ( lipopolysaccharide , LPS ) . One hypothesis regarding the mechanism of the LPS induction is that it causes release of cytokines from these cells which then induce the enzyme directly . Such cytokine induction of NOS has been demonstrated in many extraneural cell types . L - DB00125 - dependent increases in cyclic GMP correlate with smaller increases in accumulation of nitrite , the major oxidation product of nitric oxide , and hence can serve as a more sensitive measure of nitric oxide production . Here we provide evidence that interferon - gamma ( P01579 ) , interleukin ( IL ) - 1 beta and tumour necrosis factor - alpha induce L - arginine - dependent cyclic GMP synthesis in P13671 cells and that a combination of P01579 and P01584 induce L - arginine - dependent cyclic GMP synthesis in astrocyte cultures , indicating that these cytokines induce NOS . In both cell types the induction by cytokines was less sensitive to inhibition by dexamethasone , P22301 and P05112 than was induction by LPS . These data suggest that cytokines can also induce a NOS in glial cells and that the mechanism of this induction may be more direct than that of LPS , since it is less sensitive to modulation by immunosuppressors . Due to the close associations of astrocytes with neurons and microvasculature , cytokine - induced NOS could have potentially important pathophysiological effects in the central nervous system .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK23___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK61___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK98___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"P01584 and other cytokines stimulate adrenocorticotropin release from cultured pituitary cells of patients with Cushing ' s disease . Interleukin - 1 ( IL - 1 ) is a cytokine that is secreted by macrophages and monocytes which stimulates rodent hypothalamic P06850 release and possibly pituitary ___MASK27___ secretion . We studied the effect of P01584 and other cytokines ( gamma - interferon , thymosin fraction - 5 , and granulocyte colony - stimulating factor ) on ___MASK27___ release from corticotroph adenoma tissue obtained from two patients with Cushing ' s disease . P01584 ( 0 . 001 - 10 mumol / L ) increased ___MASK27___ release 3 - fold . Thymosin fraction - 5 ( 10 mumol / L ) , gamma - interferon ( 1 mumol / L ) , and granulocyte colony - stimulating factor ( 1 mumol / L ) also stimulated ___MASK27___ release . These cultured cells secreted little or no GH , PRL , DB00024 , LH , and DB00094 , and their release was not stimulated by any cytokine . These results suggest that ___MASK27___ release in patients with Cushing ' s disease may be responsive to stimulation by various cytokines .",
"P33681 - 1 expression of Langerhans cells is up - regulated by proinflammatory cytokines , and is down - regulated by interferon - gamma or by interleukin - 10 . Langerhans cells ( LC ) act as potent antigen - presenting cells ( P25054 ) for primary and secondary T cell - dependent immune responses . LC express several costimulatory and / or adhesion molecules such as P33681 / BB1 , which has been implicated as one of the important determinants for professional P25054 . Recent studies have shown that P33681 / BB1 antigens comprise three distinct molecules termed P33681 - 1 , P33681 - 2 , and P33681 - 3 . We have examined the regulatory properties of P33681 - 1 expression in LC using various cytokines including interleukin ( IL ) - 1 alpha , P01584 , P60568 , P08700 , P05112 , P05113 , P05231 , P13232 , P22301 , interferon ( IFN ) - gamma , granulocyte / macrophage colony - stimulating factor ( GM - P04141 ) , and tumor necrosis factor ( P01375 ) - alpha . We have demonstrated : 1 ) that the P33681 - 1 expression of LC is reproducibly up - regulated by either GM - P04141 , P01375 , P01583 , P01584 , or P05112 in a dose - and time - dependent manner , 2 ) that GM - P04141 exhibits the most active effect on P33681 - 1 up - regulation in each experiment , 3 ) that P01579 or P22301 profoundly inhibits the P33681 - 1 expression of LC in a dose - and time - dependent manner , and 4 ) that the down - regulatory ability of P01579 or P22301 neutralizes the activity of up - regulatory cytokines . The enhancing or inhibitory action of these cytokines on P33681 - 1 expression occurs selectively because none of the cytokines consistently affects I - A expression of LC . These data suggest that the P33681 - 1 expression of LC may be dynamically regulated by these up - and down - regulatory cytokines in normal and inflammatory epidermal microenvironment .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK45___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"Cardiovascular system related peptides and hypothalamic neurons . The hypothalamus is known to be an integrative site of cardiovascular , endocrine and autonomic functions . Our previous studies , using extracellular , intracellular and / or whole cell patch - clamp recordings in rat hypothalamic slice preparations , revealed that cardiovascular related peptides such as atrial natriuretic polypeptides ( P01160 ) , B - type polypeptides ( DB04899 ) , endothelin ( ET ) , angiotensin II ( AII ) and interleukin - 1 beta ( P01584 ) influence the hypothalamic neurons . P01160 modulated the firing rates in the supraoptic nucleus ( P18583 ) . DB04899 inhibited the P18583 neurons and these effects were mediated through cGMP and cGMP - dependent protein kinase . ET also inhibited approximately 60 % of P18583 neurons . By using slice patch - clamp techniques , AII inhibited the transient outward potassium current in the P18583 neurons . P01584 increased the firing rate and depolarized the membrane of the most P18583 neurons . A new type of transmitter , nitric oxide ( NO ) , identified as an endothelial - derived relaxing factor ( EDRF ) , modulated the glutaminergic inputs of the P18583 neurons . The results suggest that cardiovascular related peptides and NO modulate the neuronal activity of neurosecretory cells in the P18583 .",
"Role of protein tyrosine kinase in P01584 induced activation of mitogen - activated protein kinase in fibroblast - like synoviocytes of rheumatoid arthritis . OBJECTIVES : To study mitogen - activated protein kinase ( MAPKs ) activation in fibroblast - like synoviocytes ( FLS ) of rheumatoid arthritis ( RA ) under the stimulation of P01584 , and to elucidate the role of protein tyrosine kinase ( PTK ) in the activation of MAPKs . METHODS : Primary cultures of RA FLS were used . Western blot was applied to examine transient changes in protein tyrosine phosphorylation status and MAPKs activation in RA FLS stimulated with P01584 at various doses , and over different periods . DB01645 , the specific PTK inhibitor , was used to evaluate the inhibitory role in activation of MAPKs by P01584 . RESULTS : P01584 transiently increased protein tyrosine phosphorylation , and activated the MAPKs cascades ( mainly P28482 , P45984 and O75791 ) in RA FLS . There was no obvious difference in MAPKs activation among different doses of P01584 ( 1 IU / ml , 10 IU / ml , 100 IU / ml ) , but the peak activation of P28482 , P45984 and O75791 took place at 5 min , 15 min and 1 min , respectively , after stimulation with P01584 . The activation of P28482 was inhibited by genistein , but the inhibitory role on that of JNK and O75791 was relatively weak . CONCLUSIONS : During signal transduction of P01584 in RA FLS , tyrosine phosphorylation was increased transiently , the MAPKs cascade was activated in a few minutes , and there was heterogenicity in the activation among three subfamily members . PTK had a role in the activation of P29323 , but had weak effects on that of JNK and O75791 .",
"Influence of polymorphisms and P01375 and IL1β serum concentration on the infliximab response in Crohn ' s disease and ulcerative colitis . AIM : Inflammatory bowel diseases ( Q9UKU7 ) , such as Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) , are partially attributable to an increased secretion of proinflamatory cytokines , such as tumour necrosis factor ( P01375 ) and interleukin - 1β ( IL1β ) , which play essential roles in the disease pathogenesis and are target molecules for specific therapy . Given the inter - individual variability in the response to the anti - P01375 monoclonal antibody infliximab , the aim of our study was to explore the predictive value of P01375 and / or IL1β as surrogate markers of infliximab response . METHODS : Serial serum concentrations of P01375 and IL1β and P01375 promoter region and P01584 polymorphisms were determined in 47 patients ( 29 CD and 18 UC ) receiving infliximab and correlated with treatment response . RESULTS : Baseline serum concentrations of P01375 and IL1β were higher in UC patients than in CD patients ( p = 0 . 0097 and 0 . 0024 , respectively ) . CD patients showing < 0 . 64 pg / ml IL1β at baseline were more frequently responders than non - responders ( p = 0 . 036 ) , and the C allele of the P01584 polymorphism was associated with higher IL1β serum concentrations ( p = 0 . 026 ) and with poorer clinical remission after 14 weeks of infliximab treatment . No significant association was found between serum P01375 concentration or P01375 polymorphism and patient response to infliximab . CONCLUSION : This is the first study evaluating the pharmacogenetic role of the rs1143634 polymorphism of P01584 and P01375 polymorphisms in infliximab - treated Q9UKU7 patients . We found an association between the rs1143634 C allele and higher serum IL1β concentrations and a lower response to infliximab treatment in CD patients that warrants the interest of future studies in larger and independent series .",
"___MASK78___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK78___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK78___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK78___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .",
"Methodological challenges in monitoring new treatments for rare diseases : lessons from the cryopyrin - associated periodic syndrome registry . BACKGROUND : The Q96P20 - Associated Periodic Syndromes ( CAPS ) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome ( FCAS ) , Muckle - Wells Syndrome ( MWS ) , and Neonatal Onset Multisystem Inflammatory Disease ( NOMID ) . DB06168 is a monoclonal antibody directed against P01584 and approved for CAPS patients but requires post - approval monitoring due to low and short exposures during the licensing process . Creative approaches to observational methodology are needed , harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring . METHODS : A web - based registry was set up to collect information on long - term safety and effectiveness of canakinumab for CAPS . RESULTS : Starting in November 2009 , this registry enrolled 241 patients in 43 centers and 13 countries by December 31 , 2012 . One - third of the enrolled population was aged < 18 ; the overall population is evenly divided by gender . Enrolment is ongoing for children . CONCLUSIONS : Innovative therapies in orphan diseases require post - approval structures to enable in depth understanding of safety and natural history of disease . The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow - up . Broad international practice - based recruitment and web - based data collection are practical .",
"DNA polymorphism in cytokine genes based on length variation in simple - sequence tandem repeats . The possibility of the involvement of cytokines in the genetic predisposition to various diseases has been suggested by a large variety of studies . However , the study of potential disease linkage of cytokine genes has been hampered by a lack of sufficiently polymorphic markers at the restriction fragment length polymorphism ( RFLP ) level . We have investigated the distribution , the length polymorphism , the informativeness , and the efficiency of analysis , of simple - sequence tandem repeats in the mouse cytokine genes . Highly polymorphic sequences have been identified in the P01584 , IL - 1ra , P60568 , P05112 , P05113 , P05231 , P13232 , and P01579 genes . The utility and the value of these sequences as gene markers is exemplified by mapping the P13232 gene to mouse chromosome 3 close to pgk - 1ps3 and Car - 2 loci and the P01579 gene to chromosome 10 near the pg locus . Advantages of short tandemly repeated sequences as genetic markers are discussed in comparison with RFLPs ."
] |
[
"___MASK23___",
"___MASK27___",
"___MASK2___",
"___MASK45___",
"___MASK61___",
"___MASK75___",
"___MASK78___",
"___MASK98___",
"___MASK99___"
] |
___MASK23___
|
MH_train_311
|
interacts_with DB01257?
|
[
"P14416 agonists : an analysis of indirect models . To evaluate a previously suggested \" dopamine ( DA ) D2 receptor agonist pharmacophore model \" the N - propyl derivatives ( 1S , 2S ) - 5 - hydroxy - 1 - methyl - 2 - propylaminotetralin [ ( 1S , 2S ) - 3 ) ] and trans -(+/-)- 5 - hydroxy - 3 - methyl - 2 - propylaminotetralin [ (+/-)- 4 ] were synthesized and their conformational preferences were studied by molecular mechanics calculations . The new compounds were evaluated for affinity to striatal DA D2 receptors labelled by [ 3H ] spiroperidol and [ 3H ] N - propylnorapomorphine . In comparison to the corresponding N , N - dipropyl derivatives , compounds ( 1S , 2S ) - 3 and (+/-)- 4 more readily adopt pharmacophore conformations and have higher affinity for DA D2 receptors . Thus , the pharmacophore model for P01031 - oxygenated 2 - aminotetralins appears to be accurate . The DA D2 receptor binding affinities of a series of C1 - or P01024 - methyl substituted 5 - or 7 - hydroxy - 2 - dipropylaminotetralin derivatives were also determined to enable a comparison of three different modes of superposition , of 7 - and 5 - hydroxylated 2 - aminotetralin derivatives . The results show that the relative spatial positions of the C1 - and P01024 - methyl groups resulting from the various superpositions of 5 - and 7 - hydroxylated regioisomers differ and the fact that the bulk of a methyl group may be readily accepted by the receptor does not necessarily indicate that additional bulk may be tolerated . Consequently , a definitive choice of mode of superposition of 5 - and 7 - hydroxylated regioisomers can not be made at present and has to wait until the binding site itself has been better defined .",
"Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a P08603 mutation . Kidney transplant in patients with atypical hemolytic uremic syndrome ( aHUS ) is associated with a poor outcome because of recurrent disease , especially in patients known to have a factor H mutation . Long - term prophylactic plasma exchange and combined liver - kidney transplant have prevented graft loss caused by recurrence . However , the mortality associated with liver transplant is not negligible , and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma . DB01257 is a high - affinity humanized monoclonal antibody that binds to P01031 and thus prevents generation of C5a and the membrane attack complex . We report the case of a 17 - year - old girl with aHUS associated with a mutation in the gene for complement factor H ( P08603 ; c . 3572C > T , Ser1191Leu ) who was highly dependent on plasma exchange . Because of severe allergic reactions to plasma after the third renal graft , eculizumab was introduced in place of plasma exchange without problems . This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled .",
"A randomized , double - blind , placebo - controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis . INTRODUCTION : Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis ( MG ) . DB01257 , a humanized monoclonal antibody , blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 ( P01031 ) . METHODS : This study was a randomized , double - blind , placebo - controlled , crossover trial involving 14 patients with severe , refractory generalized MG ( gMG ) . RESULTS : Six of 7 patients treated with eculizumab for 16 weeks ( 86 % ) achieved the primary endpoint of a 3 - point reduction in the quantitative myasthenia gravis ( QMG ) score . Examining both treatment periods , the overall change in mean QMG total score was significantly different between eculizumab and placebo ( P = 0 . 0144 ) . After assessing data obtained from all visits , the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo ( P < 0 . 0001 ) . DB01257 was well tolerated . CONCLUSION : The data suggest that eculizumab may have a role in treating severe , refractory MG .",
"Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL - 1β . There is a tight interaction of the bone and the immune system . However , little is known about the relevance of the complement system , an important part of innate immunity and a crucial trigger for inflammation . The aim of this study was , therefore , to investigate the presence and function of complement in bone cells including osteoblasts , DB05914 ( O60682 ) , and osteoclasts . qRT - PCR and immunostaining revealed that the central complement receptors C3aR and P21730 , complement P01024 and P01031 , and membrane - bound regulatory proteins P15529 , P08174 , and P13987 were expressed in human O60682 , osteoblasts , and osteoclasts . Furthermore , osteoblasts and particularly osteoclasts were able to activate complement by cleaving P01031 to its active form C5a as measured by ELISA . Both C3a and C5a alone were unable to trigger the release of inflammatory cytokines interleukin ( IL ) - 6 and P10145 from osteoblasts . However , co - stimulation with the pro - inflammatory cytokine IL - 1β significantly induced P05231 and P10145 expression as well as the expression of receptor activator of nuclear factor - kappaB ligand ( O14788 ) and osteoprotegerin ( O00300 ) indicating that complement may modulate the inflammatory response of osteoblastic cells in a pro - inflammatory environment as well as osteoblast - osteoclast interaction . While C3a and C5a did not affect osteogenic differentiation , osteoclastogenesis was significantly induced even in the absence of O14788 and macrophage - colony stimulating factor ( P09603 ) suggesting that complement could directly regulate osteoclast formation . It can therefore be proposed that complement may enhance the inflammatory response of osteoblasts and increase osteoclast formation , particularly in a pro - inflammatory environment , for example , during bone healing or in inflammatory bone disorders .",
"Fatty acids and expression of adipokines . Adipose tissue has been recognised as the quantitatively most important energy store of the human body for many years , in addition to its functions as mechanical and thermic insulator . In mammals , the adipose organ is localised in several depots including white as well as brown adipose tissues . The largest depots are found subcutaneously and in the abdominal region . Several secretory proteins are synthesised in adipose tissue including leptin , resistin , adiponectin , tumor necrosis factor ( TNFalpha ) , angiotensinogen , adipsin , acylation - stimulating protein , retinol - binding protein ( P02753 ) , interleukin ( IL ) - 1b , P05231 , P10145 , P22301 , plasminogen activator inhibitor - 1 ( P05121 ) , fasting - induced adipose factor , fibrinogen - angiopoietin - related protein , metallothionein , tissue factor ( TF ) , complement P01024 , fibronectin , haptoglobin , entactin / nidogen , collagen VI alpha 3 , pigment epithelium - derived factor ( P36955 ) , hippocampal cholinergic neurostimulating peptide ( Q9HCS7 ) , neutrophil gelatinase - associated lipocalin ( P80188 ) and adiponutrin . Fatty acids may influence the expression of adipokines like leptin , resistin or adiponectin directly by interaction with transcription factors , or indirectly via unknown mechanisms possibly linked to fatty acid oxidation , synthesis or storage . Because fatty acids are the main components of adipose tissue , it is of essential interest to clarify the biological effects of different types of fatty acids on the expression of relevant adipokines .",
"[ P01031 : eculizumab ] . DB01257 is a recombinant humanized monoclonal antibody that specifically binds to a P01031 terminal complement and inhibits the cleavage of P01031 to C5a and C5b through complement activation . DB01257 has been used clinically for paroxysmal nocturnal hemoglobinuria . Clinical studies have been initiated for neurological disorders , such as , optic neuromyelitis and myasthenia gravis , mediated by the complement system . In addition , eculizumab is expected to be useful for the treatment of intractable neurological diseases .",
"Efficacy of eculizumab in a patient with factor - H - associated atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , chronic , life - threatening disease due to complement dysregulation . The use of early - onset plasma therapy is recommended , but optimal long - term treatment regimen is not well defined . DB01257 , a monoclonal humanized anti - P01031 antibody , has shown success in patients with aHUS . We report a 7 - year - old girl with aHUS associated with factor H mutations successfully treated with eculizumab . Weekly plasma infusion ( PI ) of 25 - 30 ml / kg with short - term intensified PI during aHUS exacerbations was effective for 4 . 3 years . Progressive mild renal failure ( stage 2 ) was attributed to chronic glomerular lesions . Subsequently , she exhibited aHUS exacerbation unresponsive to intensified PI . DB01257 was initiated at 600 mg , resulting in immediate and complete inhibition of terminal complement activation . During the week following treatment , we observed a complete reversal of aHUS activity . She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months . She had no aHUS exacerbation , and serum creatinine level returned to normal . In this patient , eculizumab led to control of PI - resistant aHUS exacerbation and chronic microangiopathic hemolytic activity . Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS .",
"Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria . BACKGROUND : Paroxysmal nocturnal hemoglobinuria ( PNH ) arises from a somatic mutation of the P37287 gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system . We tested the clinical efficacy of eculizumab , a humanized antibody that inhibits the activation of terminal complement components , in patients with PNH . METHODS : Eleven transfusion - dependent patients with PNH received infusions of eculizumab ( 600 mg ) every week for four weeks , followed one week later by a 900 - mg dose and then by 900 mg every other week through week 12 . Clinical and biochemical indicators of hemolysis were measured throughout the trial . RESULTS : Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment ( P = 0 . 002 ) . The mean percentage of PNH type III erythrocytes increased from 36 . 7 percent of the total erythrocyte population to 59 . 2 percent ( P = 0 . 005 ) . The mean and median transfusion rates decreased from 2 . 1 and 1 . 8 units per patient per month to 0 . 6 and 0 . 0 units per patient per month , respectively ( P = 0 . 003 for the comparison of the median rates ) . Episodes of hemoglobinuria were reduced by 96 percent ( P < 0 . 001 ) , and measurements of the quality of life improved significantly . CONCLUSIONS : DB01257 is safe and well tolerated in patients with PNH . This antibody against terminal complement protein P01031 reduces intravascular hemolysis , hemoglobinuria , and the need for transfusion , with an associated improvement in the quality of life in patients with PNH .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK45___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Fine needle aspiration cytology of benign breast disease . Markers of apoptosis and proliferation . Aim of the study was to compare the fine needle aspiration cytology findings of benign breast lesions with incidence of proliferation markers and apoptosis . This study included 37 patients with palpable breast lumps , referred for USG guided FNA . FNAC were prospectively classified as P06681 - benign , C4 - suspicious of malignancy , and P01031 - malignant . The specimens were simultaneously stained for Ki - 67 , MPM2 , Bcl2 and P04637 . The diagnoses in group - P06681 were following : simple cyst , multiple cysts , simple cyst with apocrine metaplasia , inflammatory cyst , benign dysplasia ( BD ) and benign solid tumors . The final diagnoses , after histopathological verification , in cases of primary classification as C4 and P01031 were as follow : proliferative fibroadenoma ( FAp ) and breas cancer , respectively . Great majority of P06681 / BD aspirates were negative for proliferative antigens Ki - 67 and P12004 . These antigens were detected in part of benign solid tumors , as anticipated in suspicious solid tumor , and in all of cancer aspirates . Bcl - 2 immunopositive cells were detected approximately in one quarter of P06681 / BD , nearly in half of P06681 solid tumors and in one C4 / FAp . Most of diagnosed specimens were P04637 - negative . Immunocytodetection of Ki67 , MPM2 , Bcl2 , P04637 might be promising , supportive method in the classification of benign breast lesions . FNAC increases the reliability of diagnosis when complemented by immunocytochemical staining . It could be helpful procedure of establishing more accurately the biology of these lesions and possibly serve as an essential factor in clinical follow - up . Nevertheless , further study on larger group of patients comparing cytological and histopathological diagnosis is required to estimate reliability of its predictive value .",
"Role of monoclonal antibodies in the treatment of immune - mediated glomerular diseases . Non - specific immunosuppressants have represented for decades the only therapies for patients with immune - mediated glomerular diseases . These treatments , however , are associated with high rates of no - response and are burdened by toxicities that frequently offset the benefits of proteinuria reduction . Monoclonal antibodies targeting selective cell populations or mediators implicated in the pathophysiology of glomerular diseases have recently become available . DB00073 , a chimeric monoclonal antibody against the P11836 antigen on B cells , safely reduced proteinuria in patients with nephrotic syndrome secondary to membranous nephropathy , minimal change disease , or focal segmental glomerulosclerosis . Its ability to reduce auto - antibody formation has been instrumental to treat also ANCA - associated vasculitis , lupus nephritis , and mixed cryoglobulinemia . Many reports have also documented the efficacy of the anti - P01031 humanized monoclonal antibody DB01257 to treat atypical hemolytic uremic syndrome , P01024 nephropathy , and membranoproliferative glomerulonephritis . Thanks to these encouraging findings , monoclonals are becoming very helpful tools to treat patients with glomerular diseases . Moreover , thanks to their specific mechanism of action , these and other monoclonal antibodies are important in improving our understanding of the pathophysiology of glomerular diseases . Their still high costs , however , might represent a major hurdle for their widespread implementation for all patients in need .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK47___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria : the AEGIS clinical trial . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a progressive and life - threatening disease characterized by complement - mediated chronic hemolysis , resulting in serious life - threatening complications and early mortality . DB01257 , a humanized anti - P01031 monoclonal antibody that inhibits terminal complement activation , has been shown to reduce hemolysis in PNH patients . The pivotal open - label , 12 - week phase II registration study ( AEGIS ) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH . This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance . Twenty - seven of the 29 patients responded to eculizumab treatment , resulting in an 87 % reduction in hemolysis ( P < 0 . 0001 ) and subsequent improvement in anemia ( P = 0 . 0003 ) despite reduction in transfusion requirements ( P = 0 . 006 ) . Fatigue and dyspnea significantly improved within 1 - 2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin . Chronic kidney disease ( CKD ) was common ( 66 % ) and eculizumab treatment improved CKD in 41 % of patients at 12 weeks ( P < 0 . 001 ) . Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized D : - dimer levels in 45 % of patients with elevated D : - dimers at baseline ( P < 0 . 001 ) . The AEGIS results demonstrate that eculizumab is effective , safe and well tolerated in Japanese patients with PNH .",
"Pathology after eculizumab in dense deposit disease and P01024 GN . DB01257 might benefit P01024 glomerulopathies mediated by dysregulation of the alternative complement pathway . Here , we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with P01024 GN . All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for P01024 without significant Ig . After 1 year of therapy , there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients , consistent with effective P01031 blockade , which prevents production of chemotactin C5a . One individual with mild mesangial disease had no significant change in activity or chronicity . One patient exhibited persistent activity and worsening chronicity despite therapy . Immunofluorescence showed no significant reduction in P01024 or C5b - 9 , and electron microscopy revealed persistent deposits in all cases , suggesting a long t ( 1 / 2 ) of C5b - 9 in extracellular matrix . Normal renal biopsies stained positive for C5b - 9 in glomeruli , tubular basement membranes , and vessel walls , albeit at lower intensity than in P01024 glomerulopathy . This indication of physiologic levels of C5b - 9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway . All post - treatment biopsies showed de novo monoclonal staining for IgG - κ in the same distribution as P01024 and C5b - 9 , mimicking monoclonal Ig deposition disease ( MIDD ) . Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses , suggesting the binding of monoclonal eculizumab to P01031 in renal tissues . The long - term effects of this apparent drug - tissue interaction are unknown .",
"Hyperhemolysis syndrome in anemia of chronic disease . BACKGROUND : Occasional cases of delayed hemolytic transfusion reaction ( P10275 ) demonstrate severe and persistent hemolysis and are referred to as hyperhemolysis syndrome . This syndrome usually occurs in patients with sickle cell disease and possibly thalassemia who receive multiple transfusions . There are few such clinical reports in patients without hemoglobinopathies . CASE REPORT : A 67 - year - old woman with anemia and a history of four previous transfusions was admitted with shortness of breath and a hematocrit ( Hct ) level of 27 percent . The patient was group O with a negative antibody screen . She received 1 unit of electronically cross - matched red blood cells ( RBCs ) and was discharged . Thirteen days later she returned to hospital with weakness and a Hct level of 23 percent . The antibody screen now demonstrated anti - K alloantibody . The direct antigloblulin test ( Q01959 ) was positive with both anti - immunoglobulin G and anti - complement ( P01024 ) . Anti - K was recovered in the eluate . The previously transfused RBC unit was positive for presence of the K antigen . The patient ' s RBCs were negative for the presence of K antigen . Other laboratory data confirmed ongoing hemolysis , and a diagnosis of P10275 was made . She continued to display findings of active hemolysis for 9 more weeks requiring 19 units of RBCs . Thirty - four days after the original transfusion , her Q01959 remained positive and both the plasma sample and a RBC eluate demonstrated anti - K . CONCLUSION : The delayed hemolytic transfusion reaction with hyperhemolysis can occur among patients without hemoglobinopathies .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Learnings from over 25 years of PNH experience : the era of targeted complement inhibition . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a progressive and life - threatening disease that causes thrombosis , end organ damage and impaired quality of life . Chronic uncontrolled complement activation leads to chronic haemolysis , causing progressive morbidities and early mortality . Hence , early diagnosis is essential for improved patient management and prognosis . DB01257 ( SOLIRIS ® ) specifically inhibits chronic , uncontrolled complement activation and is the first - in - class , humanised , monoclonal antibody targeting P01031 within the terminal complement pathway . DB01257 is the first and only approved treatment for PNH in adults and children .",
"DB01257 in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvement . BACKGROUND : Atypical haemolytic uraemic syndrome ( aHUS ) is a rare disorder usually caused by dysregulation of the alternative complement pathway . Uncontrolled complement activation results in systemic complement - mediated thrombotic microangiopathy ( TMA ) and subsequent multi - organ damage . The two most common extrarenal complications comprise neurological and cardiovascular involvement . DB01257 , a humanised anti - P01031 monoclonal antibody , has recently been introduced as a therapy for this condition . CASE - DIAGNOSIS / TREATMENT : A 19 - month - old child suffering from aHUS with severe neurological involvement , dilated cardiomyopathy and renal impairment requiring dialysis received eculizumab as first - line treatment , initiated within 12 h of admission , resulting in significant improvements in her neurological state and normalisation of cardiac and renal function . These positive outcomes have been sustained with fortnightly eculizumab therapy ( at the time of writing , on - going for 1 year ) . No further complications of TMA have occurred . CONCLUSION : Severe cardiac involvement in a child with aHUS is an important indication for prompt , first - line treatment with eculizumab , resulting in rapid normalisation of cardiac function .",
"Inhibition of complement activity by humanized anti - P01031 antibody and single - chain Fv . Activation of the complement system contributes significantly to the pathogenesis of numerous acute and chronic diseases . Recently , a monoclonal antibody ( DB01257 ) that recognizes the human complement protein P01031 , has been shown to effectively block P01031 cleavage , thereby preventing the generation of the pro - inflammatory complement components C5a and C5b - 9 . Humanized DB01257 antibody , Fab and scFv molecules have been produced by grafting the complementarity determining regions of DB01257 on to human framework regions . Competitive ELISA analysis indicated that no framework changes were required in the humanized variable regions for retention of high affinity binding to P01031 , even at framework positions predicted by computer modeling to influence CDR canonical structure . The humanized Fab and scFv molecules blocked complement - mediated lysis of chicken erythrocytes and porcine aortic endothelial cells in a dose - dependent fashion , with complete complement inhibition occurring at a three - fold molar excess , relative to the human P01031 concentration . In contrast to a previously characterized anti - P01031 scFv molecule , the humanized h5G1 . 1 scFv also effectively blocked C5a generation . Finally , an intact humanized h5G1 . 1 antibody blocked human complement lytic activity at concentrations identical to the original murine monoclonal antibody . These results demonstrate that humanized h5G1 . 1 and its recombinant derivatives retain both the affinity and blocking functions of the murine DB01257 antibody , and suggest that these molecules may serve as potent inhibitors of complement - mediated pathology in human inflammatory diseases .",
"[ ___MASK28___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK28___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Laboratory tests for paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematological disorder that is often suspected in a patient presenting with non - immune hemolytic anemia associated with pancytopenia or venous thrombosis . This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A ( P37287 ) gene in the hematopoietic stem cells ( P19526 ) of patients . The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol - anchored cell surface proteins , making red blood cells derived from the clone more sensitive to complement mediated hemolysis . The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies . The latest generation of tests allow for detection of very small populations of PNH cells , for following the natural course and response to therapy of the disease , and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein P01031 ( DB01257 ) , anticoagulation , and in some cases allogeneic P19526 transplant . In this article , we review the different diagnostic tests available to clinicians for PNH diagnosis .",
"Multilocus analysis of age - related macular degeneration . Age - related macular degeneration ( AMD ) is a late onset vision disorder . Recent studies demonstrate that alterations in complement cascade genes are associated with AMD . Of the three identified complement loci , variants in complement factor H ( P08603 ) have the highest impact as does an independent locus at 10q26 . Our matched case - control study using the Age - Related Eye Disease Study ( AREDS ) cohort confirms and extends the associations in these loci . Subjects were genotyped for single nucleotide polymorphisms ( SNPs ) from P08603 , complement component 2 ( P06681 ) , complement component 3 ( P01024 ) , complement factor B ( P00751 ) , age - related maculopathy susceptibility ( P0C7Q2 ) , HtrA serine peptidase 1 ( Q92743 ) , and apolipoprotein E ( P02649 ) . Individual SNPs , and haplotypes showed risk trends consistent with those seen in other population studies for P08603 , P01024 , P06681 , and P00751 . SNP rs10490924 on chromosome 10 in exon 1 of the P0C7Q2 gene showed a highly significant association with an odds ratio ( OR ) of 3 . 2 ( 95 % CI 2 . 4 - 4 . 2 ) for the risk allele and rs11200638 located in the proximal promoter region of Q92743 showed a higher significant association with an OR of 3 . 4 ( 95 % CI 2 . 5 - 4 . 6 ) with our AMD cases . We found that P02649 haplotypes were not significantly associated with disease status . Adjustments for other risk factors did not significantly alter the observed associations . This study validates the complement pathway ' s involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease . These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD .",
"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK43___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK43___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .",
"DB01257 reduces complement activation , inflammation , endothelial damage , thrombosis , and renal injury markers in aHUS . Atypical hemolytic uremic syndrome ( aHUS ) is a genetic , life - threatening disease characterized by uncontrolled complement activation , systemic thrombotic microangiopathy ( TMA ) , and vital organ damage . We evaluated the effect of terminal complement blockade with the anti - P01031 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally , during up to 1 year of treatment , compared with in healthy volunteers . Biomarker levels were elevated at baseline in most patients , regardless of mutational status , plasma exchange / infusion use , platelet count , or lactate dehydrogenase or haptoglobin levels . DB01257 reduced terminal complement activation ( C5a and sC5b - 9 ) and renal injury markers ( clusterin , cystatin - C , β2 - microglobulin , and liver fatty acid binding protein - 1 ) to healthy volunteer levels and reduced inflammation ( soluble tumor necrosis factor receptor - 1 ) , coagulation ( prothrombin fragment F1 + 2 and d - dimer ) , and endothelial damage ( thrombomodulin ) markers to near - normal levels . Alternative pathway activation ( Ba ) and endothelial activation markers ( soluble vascular cell adhesion molecule - 1 ) decreased but remained elevated , reflecting ongoing complement activation in aHUS despite complete terminal complement blockade . These results highlight links between terminal complement activation and inflammation , endothelial damage , thrombosis , and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage . Further research regarding underlying complement dysregulation is warranted . This trial was registered at www . clinicaltrials . gov as # NCT01194973 .",
"The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab . Paroxysmal nocturnal hemoglobinuria is a rare disorder of hemopoietic stem cells . Affected individuals have a triad of clinical associations - intravascular hemolysis , an increased risk of thromboembolism , and bone marrow failure . Most of the symptoms experienced in this disease occur due to the absence of complement regulatory proteins on the surface of the red blood cells . Complement activation is thus not checked and causes destruction of these cells . DB01257 is a monoclonal antibody treatment which specifically binds to the complement protein P01031 , preventing its cleavage , and so halts the complement cascade and prevents the formation of the terminal complement proteins . DB01257 prevents intravascular hemolysis , stabilizes hemoglobin levels , reduces or stops the need for blood transfusions , and improves fatigue and patient quality of life as well as reducing pulmonary hypertension , decreasing the risk of thrombosis and protecting against worsening renal function . It is not a curative therapy but has a great benefit on those with this rare debilitating condition .",
"Complement inhibitor eculizumab in atypical hemolytic uremic syndrome . BACKGROUND AND OBJECTIVES : Atypical hemolytic uremic syndrome ( aHUS ) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage . DB01257 , a humanized mAb against complement protein P01031 , inhibits activation of the terminal complement pathway . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS : We report an adolescent with relapsing unclassified aHUS . On admission , a high plasma creatinine level indicated a poor prognosis , and hemodialysis had to be started . Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk . Subsequently , plasma exchanges ( three times per week ) failed to prevent ongoing aHUS activity and progressive renal failure . After 12 wk , aHUS treatment was switched to eculizumab . RESULTS : DB01257 was effective in terminating the microangiopathic hemolytic process in two aHUS relapses ; however , after normalization of complement activity , aHUS recurred and ultimately led to anuric end - stage renal failure . CONCLUSIONS : In this patient , complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity . Nevertheless , renal damage as a result of preceding and subsequent aHUS activity resulted in end - stage renal failure ; therefore , therapeutic success may depend on early administration of eculizumab . The optimal duration of treatment may be variable and remains to be determined .",
"Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare clonal stem cell disorder , which affects women of child - bearing age . PNH is associated with thrombotic complications , which are the main causes of morbidity and mortality . Management of a pregnant woman with PNH remains a challenge due to high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy . PNH is associated with an increased rate of premature labor and fetal loss . DB01257 , a humanized monoclonal antibody directed against the terminal complement protein P01031 , has revolutionized treatment of PNH . However , the role of eculizumab in pregnancy is unclear . We review the current strategies for the management of pregnant women with PNH , underline the controversies and present our recommendations .",
"Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) in childhood is a rare disease associated with high morbidity and mortality . Most cases progress to end - stage renal failure . In approximately 50 % of affected patients , mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway . This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells , particularly in the kidneys . P08603 ( FH ) heterozygosity induces unregulated activation of the membrane attack complex ( MAC ) C5b - 9 . Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis . Unfortunately , kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post - transplantation HUS recurrence , particularly in patients with FH mutation . Combined liver - kidney transplantation is also associated with poor outcome , mostly as a result of premature liver failure secondary to uncontrolled complement activation . DB01257 is a complement P01031 antibody that inhibits complement factor 5a ( C5a ) and the formation of the MAC . Thus , this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation . We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation .",
"___MASK43___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK43___ , in the USA in 2003 .",
"Gene expression profile in response to doxorubicin - rapamycin combined treatment of HER - 2 - overexpressing human mammary epithelial cell lines . HER - 2 - positive breast cancers frequently sustain elevated AKT / P42345 signaling , which has been associated with resistance to doxorubicin treatment . Here , we investigated whether rapamycin , an P42345 inhibitor , increased the sensitivity to doxorubicin therapy in two HER - 2 - overexpressing cell lines : P01031 . 2 , which was derived from the parental HB4a by transfection with HER - 2 and SKBR3 , which exhibits HER - 2 amplification . The epithelial mammary cell line HB4a was also analyzed . The combined treatment using 20 nmol / L of rapamycin and 30 nmol / L of doxorubicin arrested HB4a and P01031 . 2 cells in S to G ( 2 )- M , whereas SKBR3 cells showed an increase in the G ( 0 )- G ( 1 ) phase . DB00877 increased the sensitivity to doxorubicin in HER - 2 - overexpressing cells by approximately 2 - fold , suggesting that the combination displayed a more effective antiproliferative action . Gene expression profiling showed that these results might reflect alterations in genes involved in canonical pathways related to purine metabolism , oxidative phosphorylation , protein ubiquitination , and mitochondrial dysfunction . A set of 122 genes modulated by the combined treatment and specifically related to HER - 2 overexpression was determined by finding genes commonly regulated in both P01031 . 2 and SKBR3 that were not affected in HB4a cells . Network analysis of this particular set showed a smaller subgroup of genes in which coexpression pattern in HB4a cells was disrupted in P01031 . 2 and SKBR3 . Altogether , our data showed a subset of genes that might be more robust than individual markers in predicting the response of HER - 2 - overexpressing breast cancers to doxorubicin and rapamycin combination .",
"Successful management of obstructive jaundice due to gallstones with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) makes patients susceptible to intravascular hemolysis and thrombosis , and it can be life - threatening in stressful situations . DB01257 , a humanized monoclonal antibody that inhibits the complement protein P01031 , has been evaluated as a novel therapy for PNH . We herein describe the case of a 59 - year - old Japanese woman with classic PNH , who had been successfully treated with eculizumab , but who later developed acute cholecystitis / cholangitis from gallstones . Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated , critical intravascular hemolysis and thrombosis were not observed . Therefore , utilizing eculizumab during the peri - operative management of PNH patients should be carefully taken into consideration .",
"DB01257 : safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic - uremic syndrome : case report . In a recent study , eculizumab , a humanized monoclonal antibody which targets complement factor P01031 , appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome . We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation . After 17 months of eculizumab treatment , and without concomitant plasma therapy , renal function was maintained , the need for blood transfusions reduced , and acute thrombotic microangiopathy and hemolysis controlled . These data suggested that eculizumab should be considered to be a permanent treatment for this patient .",
"N - aryl - N '- benzylpiperazines as potential antipsychotic agents . N1 -( 2 - Alkoxyphenyl ) piperazines additionally containing an N4 - benzyl group bearing alcohol , amide , imide , or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response ( CAR ) test predictive of clinical antipsychotic activity and in in vitro receptor - binding assays . Certain of the compounds display high affinity for the D2 , P08908 , and alpha 1 - adrenergic receptors . Structures bearing acyclic amide , lactam , and imide functionalities display good biological activity , with a preference for the 1 , 3 - disubstituted phenyl ring relative to the 1 , 4 - and 1 , 2 - congeners ( 7 vs 10 and 12 ) . Every possible position of hydantoin attachment was investigated ( e . g . , substitution at N1 , N3 , and P01031 ) . The hydantoin involving attachment to N1 ( 24 ) was found to have good biological activity , whereas those hydantoins with attachment to N3 or P01031 ( 22 , 23 , and 25 ) were inactive . Several of the smaller acetylated derivatives ( 30 and 33 ) have fair in vivo activity , which was lost in the case of the larger benzoyl analog 31 . DB03419 congener 34 had modest affinity for the D2 receptor ( 65 nM ) as well as excellent in vivo activity . Benzylamino compounds display ( viz . 27 and 35 - 38 ) moderate CAR activity but have surprising receptor affinity , often greater than those of comparable structures bearing a carbonyl ( 36 vs 7 ) . Benzyl and benzhydryl alcohol compounds 40 - 48 are more active than amino structures 27 and 35 - 38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and P08908 receptor binding .",
"Peripheral gangrene in children with atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a thrombotic microangiopathy with severe clinical manifestation , frequent recurrence , and poor long - term prognosis . It is usually caused by abnormalities in complement regulation . We report 2 cases of children affected by a catastrophic extrarenal complication . A 4 - year - old Indian girl developed gangrene of the finger tips 2 days after initial presentation of aHUS . Factor H autoantibodies were identified . Renal function continued to decline despite daily plasma exchanges , and she was started on peritoneal dialysis 5 days after admission . The distal tips of the left hand remained gangrenous with a line of demarcation . Three weeks later , she did not return for follow - up and died at home because of dialysis - related complications . An Arabic girl developed end - stage renal disease due to aHUS in the fourth month after birth . A de novo activating P01024 mutation was found . At age 9 months , she suddenly developed ischemic changes in fingers of both hands and several toes . The lesions progressed , and several finger tips became gangrenous despite intense plasma exchange therapy . The decision was made to administer complement blocking therapy with the P01031 antibody eculizumab . All nonnecrotic digits rapidly regained perfusion . The 3 already gangrenous fingers healed with loss of the end phalanges . During maintenance , eculizumab aHUS activity subsided completely and some late recovery of renal function was observed . aHUS may present by thrombotic macroangiopathy of small peripheral arteries . DB01257 appears effective in preserving tissue viability if administered before gangrene occurs and should be considered as first - line rescue therapy in such cases .",
"DB01257 for the treatment of preeclampsia / HELLP syndrome . Severe preeclampsia with hemolysis , elevated liver enzymes and low platelets ( HELLP ) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide . Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives : delivery as definitive therapy for maternal health vs . prolongation of pregnancy to avoid prematurity and associated morbidities . We describe a patient presenting with severe preeclampsia / HELLP syndrome at 26 weeks gestation that was treated with DB01257 , a targeted inhibitor of complement protein P01031 , which resulted in marked clinical improvement and complete normalization of lab parameters . Pregnancy was prolonged 17 days , likely resulting in a reduction of neonatal morbidity with its associated short and long - term health care costs . Successful use of DB01257 in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia / HELLP syndrome .",
"DB01257 for atypical hemolytic uremic syndrome recurrence in renal transplantation . DB01257 ( anti - P01031 ) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome ( aHUS ) . However , the lack of series precludes any firm conclusion about the optimal use of anti - P01031 for preventing or treating aHUS posttransplant aHUS recurrence . We thoroughly studied 22 renal transplant recipients with aHUS who received off - label therapy with anti - P01031 , including 12 cases , which have not been reported yet . Nine patients , all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence , received prophylactic anti - P01031 therapy to prevent posttransplant recurrence . Eight of them had a successful recurrence - free posttransplant course and achieved a satisfactory graft function , while the remaining patient experienced early arterial thrombosis of the graft . Thirteen renal transplant recipients were given anti - P01031 for posttransplant aHUS recurrence . A complete reversal of aHUS activity was obtained in all of them . Importantly , the delay of anti - P01031 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement . Three patients in whom anti - P01031 was subsequently stopped experienced a relapse . Altogether these data suggest that long - term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence . Our study also indicates that anti - P01031 should be promptly started if a recurrence occurs .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"Complement in lupus nephritis : the good , the bad , and the unknown . The complement system consists of 3 pathways and more than 30 proteins , including those with biological activity that directly or indirectly mediate the effects of this system , plus a set of regulatory proteins necessary to prevent injudicious complement activation on host tissue . The role for complement in the pathogenesis of systemic lupus erythematosus ( SLE ) is paradoxic . On one hand , the complement system appears to have protective features in that hereditary homozygous deficiencies of classic pathway components are associated with an increased risk for SLE . On the other hand , immune complex - mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathologic features that are logical consequences of complement activation . By using accurate mouse models of SLE , we have gained remarkable insights into pathogenic features likely relevant to the human disease , and the ability to test potential therapies , some of which have made it to standard clinical use . Studies in genetically altered mice and using recombinant protein inhibitors of complement have confirmed what was believed but unproven - early complement proteins C1q and C4 are protective whereas complement activation later in the pathways is proinflammatory and deleterious . Two complement inhibitors , soluble complement receptor 1 ( TP10 , Avant Immunotherapeutics , Needham , MA ) and a monoclonal anti - P01031 antibody ( DB01257 , Alexion Pharmaceuticals , Inc . , Cheshire , CT ) have been shown to inhibit complement safely and now are being investigated in a variety of clinical conditions . Although these and others earlier in their clinical development hold promise to be used therapeutically in lupus nephritis , this optimism must be tempered by the fact that the clinical trials to prove this remain fraught with obstacles .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK73___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"12 - O - retinoylphorbol - 13 - acetate ( RPA ) behaves like a retinoid - derivative in binding to retinol - binding - protein : a correlation with its specific action as an incomplete tumor promoter ? 12 - O - retinoylphorbol - 13 - acetate ( RPA ) , an incomplete tumor promoter of the phorbol ester type and protein kinase C ( PKC ) activator , consists of two characteristic structural elements : the phorbol body and the retinoyl ester chain . Therefore , possible binding of the incomplete tumor promoter RPA to the human transport protein retinol - binding - protein ( P02753 ) has been examined by molecular modeling methods and experimental binding studies . The calculated prediction of binding properties was primarily based on a comparative geometrical approach . It was shown that the beta - ionone - ring of RPA was not altered within the binding pocket of P02753 ( molecular modeling ) compared to retinoic acid ( X - ray crystallographic data ) . The torsion angle P01031 '- P13671 '- P10643 '- Q99618 ' , determining the conformation of the P02753 - beta - ionone - ring relative to the isoprene tail , is rotated by 42 degrees for RPA compared to retinol and to retinoic acid , respectively . Combining all the results from force field calculations , MD simulations and geometrical comparisons , the conclusion could be drawn that RPA should be able to bind to P02753 . This interaction should be less strong than that with its natural ligand retinol or with retinoic acid . This prediction was proven experimentally . RPA was able to compete with retinoic acid for binding at P02753 in human plasma . The binding properties were investigated using 3H - labeled retinoic acid in homologous and heterologous competition studies in a one - dimensional native polyacrylamide gel electrophoresis system . An approximately 2000 - fold weaker binding of RPA to P02753 as compared to retinoic acid was determined experimentally , confirming the prediction of the molecular modeling approach . The characteristic behaviour of RPA as an incomplete promoter , due to possible binding to PKC and P02753 , is discussed .",
"Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare , life - threatening and debilitating clonal blood disorder caused by an acquired mutation in the phosphatidylinositol glycan ( PIG ) - A gene . In pluripotent hematopoietic stem cells , this leads to a deficiency of glycosylphosphatidylinositol ( P06744 ) - anchors and P06744 - anchored proteins , including the complement regulators P08174 and P13987 , on the surface of affected blood cells . PNH red blood cells are highly vulnerable to activation of complement and the formation of the membrane attack complex ( MAC ) . The resulting chronic intravascular hemolysis is the underlying cause of PNH morbidities and mortality . Until recently , the treatment of PNH has been largely empirical and symptomatic with blood transfusions , anticoagulation , and supplementation with folic acid or iron . The only potentially curative treatment is allogeneic stem cell transplantation , but this has severe complications and high mortality and morbidity rates . A new targeted and disease - modifying treatment strategy is the inhibition of the terminal complement cascade with the humanized monoclonal anti - P01031 antibody , eculizumab . This effectively inhibits MAC formation and intravascular hemolysis . DB01257 has shown significant efficacy in controlled studies , with a marked decrease in anemia , fatigue , transfusion requirements , renal impairment , pulmonary hypertension , and risk of severe thromboembolic events , ultimately resulting in improving quality of life and survival .",
"P10275 - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti - tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR - target genes , mediating androgen - induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .",
"___MASK83___ for joints and bones . ___MASK83___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK83___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK83___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"DB01257 treatment of acute antibody - mediated rejection in renal transplantation : case reports . The occurrence of acute antibody - mediated rejection ( AMR ) , especially in more severe cases , continues to be associated with a poor prognosis for implant survival . Here , we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation . We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses , plasmapheresis , intravenous immunoglobulin , and rituximab . In both cases , the clinical course was favorable . DB01257 , a monoclonal antibody with a high affinity for complement protein P01031 , prevents generation of the final membrane attack complex , blocking this cascade . To date , there are a few reports of the usefulness of eculizumab in AMR . DB01257 can help to stop endothelial damage , especially in severe cases that show a risk of progression to cortical necrosis , by providing a therapeutic window until the other modalities begin to control the immune response . In our experience , the use of eculizumab can be beneficial in the treatment of AMR .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK72___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Osteoclast - derived complement component 3a stimulates osteoblast differentiation . Bone remodeling is regulated by a coupling of resorption to subsequent formation ; however , the \" coupling factor \" and underlying mechanism are not fully understood . Here , we found that the condition medium ( CM ) of mature osteoclasts contains a humoral factor that stimulates the differentiation of primary osteoblasts , as determined by alkaline phosphatase ( ALP ) activity . We purified osteoblastogenesis - stimulating activity from 3 L of osteoclast CM through successive ion exchange chromatographies by monitoring the ALP activity of osteoblasts and identified complement component 3 ( P01024 ) . Expression of the P01024 gene increased during osteoclastogenesis , and the cleavage product C3a was detected by ELISA in the CM of osteoclasts but not in that of bone marrow macrophages . The osteoblastogenesis - stimulating activity present in osteoclast CM was inhibited by a specific antagonist of the C3a receptor ( C3aR ) , SB290157 . Conversely , the retroviral expression of C3a as well as treatment with the C3aR agonist , benzeneacetamide , stimulated osteoblast differentiation . P01024 gene expression in bone was increased in the high bone turnover states of ovariectomy ( OVX ) or a receptor activator of NF - κB ligand ( O14788 ) injection , and blocking the action of C3a with the daily administration of SB290157 resulted in the attenuation of bone formation elevated by OVX and the exacerbation of bone loss . These results suggest that osteoclast - derived C3a functions in the relay from bone resorption to formation and may be a candidate for a coupling factor .",
"Severe atypical HUS caused by P08603 S1191L -- case presentation and review of treatment options . Atypical hemolytic uremic syndrome ( aHUS ) has been associated with defective regulation of the alternative complement pathway . Although the use of plasma therapy is recommended , there is little consensus on the optimal treatment regimen . The outcome in many cases remains poor despite an improvement in our understanding of the pathology of aHUS . We have followed a female patient with aHUS associated with heterozygous complement Factor H ( P08603 ) mutation ( S1191L ) over a period of 15 years . She has been plasma dependent since infancy and has subsequently progressed to end stage kidney disease ( ESKD ) requiring dialysis treatment . Despite ESKD she still depends on regular plasma infusions to prevent thrombocytopenia . The long - term treatment plan for this patient is challenging . Renal transplantation in patients with the S1191L mutation of the P08603 gene carries a high risk of failure due to recurrence of aHUS in the renal graft . Thus , the only available curative treatment seems to be combined liver - kidney transplantation , covered by intensive plasma therapy , which comes with a high risk of morbidity and mortality . Antibodies against key activating components of the complement cascade may provide a promising alternative therapeutic strategy in the future . DB01257 , a monoclonal humanized anti - P01031 antibody , has recently been shown to be effective and well - tolerated in patients with paroxysmal nocturnal hemoglobinuria by preventing complement - mediated lysis of affected erythrocytes . Treatment of our patient with eculizumab is supported by recent reports on its successful use in two ( pediatric and adult ) patients with complement - based aHUS .",
"DB01257 in anti - factor h antibodies associated with atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a life - threatening multisystemic condition often leading to end - stage renal failure . It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them . DB01257 is a monoclonal antibody directed against complement component P01031 and inhibiting the activation of the effector limb of the complement system . Its efficacy has already been demonstrated in aHUS . The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti - complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms . Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms . It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life - threatening complications and to reduce the risk of chronic disabilities . To obtain a complete inhibition of the effector limb activation , the advised dosage must be respected . After this initial therapy in the autoimmune aHUS form , a long - term immunosuppressive treatment should be considered , to prevent relapses by reducing anti - complement Factor H autoantibody plasma levels .",
"Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd - Chiari syndrome , with complement inhibitor eculizumab : Case Report . Background . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells . Erythrocytes have increased susceptibility to complement - mediated haemolysis . Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis . DB01257 , a monoclonal antibody blocking activation of complement P01031 is currently used in the treatment of PNH . Recent results demonstrated that eculizumab effectively reduces thrombosis . Description of case . We present a 30 - year - old male patient admitted with abdominal and lumbar pain . Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly . Imaging findings were compatible with a Budd - Chiari syndrome . Flow cytometry confirmed the PNH diagnosis . Due to refractory ascites he underwent a transjugular intrahepatic portal - systemic shunt ( TIPS ) and eculizumab administration was started . Results . He has already completed three years of eculizumab treatment and he is transfusion independent . There is also a significant reduction in fatigue with improvement in his quality of life . Doppler scans of his TIPS persistently show it to be patent . Conclusions . Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage . For these patients , eculizumab is a reasonable therapeutic option , expecting that by decreasing the risk for thrombosis , life expectancy may be increased .",
"Update on hemolytic uremic syndrome : Diagnostic and therapeutic recommendations . Hemolytic uremic syndrome ( HUS ) is a rare disease . In this work the authors review the recent findings on HUS , considering the different etiologic and pathogenetic classifications . New findings in genetics and , in particular , mutations of genes that encode the complement - regulatory proteins have improved our understanding of atypical HUS . Similarly , the complement proteins are clearly involved in all types of thrombotic microangiopathy : typical HUS , atypical HUS and thrombotic thrombocytopenic purpura ( TTP ) . Furthermore , several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients . The authors highlight the therapeutic aspects of this rare disease , examining both \" traditional therapy \" ( including plasma therapy , kidney and kidney - liver transplantation ) and \" new therapies \" . The latter include anti - Shiga - toxin antibodies and anti - P01031 monoclonal antibody \" eculizumab \" . DB01257 has been recently launched for the treatment of the atypical HUS , but it appears to be effective in the treatment of typical HUS and in TTP . Future therapies are in phases I and II . They include anti - P01031 antibodies , which are more purified , less immunogenic and absorbed orally and , anti - P01024 antibodies , which are more powerful , but potentially less safe . Additionally , infusions of recombinant complement - regulatory proteins are a potential future therapy .",
"Timing of eculizumab therapy for P01024 glomerulonephritis . DB01257 is an anti - P01031 antibody that inhibits P01031 cleavage and prevents the generation of the terminal complement complex C5b - 9 . DB01257 is licensed to treat paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome ( aHUS ) . Clinical trials are ongoing for P01024 glomerulopathy . Given the unfamiliarity of physicians with these rare diseases and the variability of clinical presentation , a delayed initiation of eculizumab therapy is common . Thus , the question arises as to what extent improvement of kidney function may be expected when patients have been dialysis dependent for weeks or months already when eculizumab is initiated . Furthermore , given the high cost and potential adverse effects of eculizumab , the question arises of when to stop therapy because of futility when patients with kidney - only manifestations remain dialysis dependent . In literature reports , eculizumab was stopped as early as after 3 weeks because the patient remained dialysis dependent . In this issue of CKJ , Inman et al . report on eculizumab - induced reversal of dialysis - dependent kidney failure from P01024 glomerulonephritis , illustrating both the potential benefit of eculizumab for this complement - mediated disease and the need for lengthy therapy - dialysis independency was reached after 5 months of eculizumab . Indeed , there are reports of renal function recovery when eculizumab was initiated after 4 months on dialysis and of recovery of renal function 2 . 0 - 3 . 5 months after initiation of eculizumab in dialysis - dependent patients with P01024 glomerulopathy or aHUS .",
"Investigation of plasma biomarkers in HIV - 1 / HCV mono - and coinfected individuals by multiplex iTRAQ quantitative proteomics . The analysis of plasma samples from HIV - 1 / HCV mono - and coinfected individuals by quantitative proteomics is an efficient strategy to investigate changes in protein abundances and to characterize the proteins that are the effectors of cellular functions involved in viral pathogenesis . In this study , the infected and healthy plasma samples ( in triplicate ) were treated with ProteoMiner beads to equalize protein concentrations and subjected to 4 - plex iTRAQ labeling and liquid chromatography / mass spectrometry ( LC - MS / MS ) analysis . A total of 70 proteins were identified with high confidence in the triplicate analysis of plasma proteins and 65 % of the proteins were found to be common among the three replicates . Apolipoproteins and complement proteins are the two major classes of proteins that exhibited differential regulation . The results of quantitative analysis revealed that P02652 , P02655 , P02649 , P01024 , P04196 proteins were upregulated in the plasma of all the three HIV - 1 mono - , HCV mono - , and coinfected patient samples compared to healthy control samples . Ingenuity pathway analysis ( IPA ) of the upregulated proteins revealed that they are implicated in the hepatic lipid metabolism , inflammation , and acute - phase response signaling pathways . Thus , we identified several differentially regulated proteins in HIV - 1 / HCV mono and coinfected plasma samples that may be potential biomarkers for liver disease .",
"DB01257 for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas - kidney transplantation -- a case report . A 34 - year - old female recipient of a simultaneous pancreas - kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction , thrombocytopenia , and microangiopathic hemolytic anemia . Renal biopsy revealed acute antibody - mediated rejection ( AMR ) and acute thrombotic microangiopathy ( TMA ) . Clinical and laboratory manifestations , which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin , resolved rapidly and completely to eculizumab ( Soliris , Alexion Pharmaceuticals , Inc . , Cheshire , Conn ) , a complement factor P01031 antibody . De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases . This is the first report of successful treatment of de novo TMA with eculizumab , which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR . Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA , especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease .",
"Increased interleukin 21 and follicular helper T - like cells and reduced interleukin 10 + B cells in patients with new - onset systemic lupus erythematosus . OBJECTIVE : To elucidate the potential role of follicular helper T cells ( TFH ) and interleukin 10 ( P22301 )+ B cells in the development of systemic lupus erythematosus ( SLE ) . METHODS : The numbers of peripheral blood P26842 + , P28907 + , P42081 + , CD95 + , P22301 + B cells , and inducible T cell costimulator ( Q9Y6W8 )+ , programmed death - 1 ( P18621 )+ , Q9HBE4 + , P32302 + P01730 + TFH - like cells were examined in 23 patients with new onset SLE and 20 healthy controls ( HC ) . RESULTS : In comparison with HC , significantly reduced numbers of P15391 + and P22301 + B cells , but increased numbers of P26842 ( high ) , P42081 + , CD95 + B cells , P32302 + P01730 + , Q9Y6W8 + , P18621 + , and Q9HBE4 + TFH - like cells were detected , which were accompanied by higher levels of serum Q9HBE4 , but lower levels of P22301 in the patients . Treatment with anti - SLE therapy modulated the imbalance of different subsets of B and TFH - like cells . The levels of serum Q9HBE4 and P22301 were positively correlated with the numbers of P01730 + P32302 + TFH - like and P15391 + P06127 + CD1d + B cells in the patients , respectively . The numbers of P26842 ( high ) B cells were correlated positively with Q9HBE4 + TFH - like cells , but negatively with P22301 + B cells . The values of SLE Disease Activity Index , P01024 , and erythrocyte sedimentation rate were correlated positively with serum Q9HBE4 , but negatively with P22301 in those patients . CONCLUSION : Our data indicate that the imbalance of Q9HBE4 + TFH - like , P26842 ( high ) , and P22301 + B cells may be associated with the pathogenesis of SLE , and levels of serum Q9HBE4 and P22301 may be valuable for evaluating disease activity in SLE .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK62___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK62___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Lack of association of variants previously associated with anti - P01375 medication response in rheumatoid arthritis patients : results from a homogeneous Greek population . Treatment strategies blocking tumor necrosis factor ( anti - P01375 ) have proven very successful in patients with rheumatoid arthritis ( RA ) , showing beneficial effects in approximately 50 - 60 % of the patients . However , a significant subset of patients does not respond to anti - P01375 agents , for reasons that are still unknown . The aim of this study was to validate five single nucleotide polymorphisms ( SNPs ) of P08575 , Q15762 , P51826 , MyD88 and O15111 gene loci that have previously been reported to predict anti - P01375 outcome . In addition , two markers of RA susceptibility , namely Q13077 / P01031 and Q14765 were assessed , in a cohort of anti - P01375 - treated RA patients , from the homogeneous Greek island of Crete , Greece . The RA patient cohort consisted of 183 patients treated with either of 3 anti - P01375 biologic agents ( infliximab , adalimumab and etanercept ) from the Clinic of Rheumatology of the University Hospital of Crete . The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms ( RFLPs ) approach . Disease activity score in 28 joints ( DAS28 ) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP . None of the 7 genetic markers correlated with treatment response . We conclude that the gene polymorphisms under investigation are not strongly predictive of anti - P01375 response in RA patients from Greece .",
"Enhanced abdominal aortic aneurysm formation in thrombin - activatable procarboxypeptidase B - deficient mice . OBJECTIVE : To determine whether procarboxypeptidase B ( Q96IY4 ) (-/-) mice are susceptible to accelerated abdominal aortic aneurysm ( AAA ) development secondary to unregulated P10451 - mediated mural inflammation in the absence of P15086 inhibition . METHODS AND RESULTS : Thrombin / thrombomodulin cleaves thrombin - activatable Q96IY4 or thrombin - activatable fibrinolysis inhibitor , activating P15086 , which inhibits the generation of plasmin and inactivates proinflammatory mediators ( complement C5a and thrombin - cleaved osteopontin [ P10451 ] ) . P02649 (-/-) P10451 (-/-) mice are protected from experimental AAA formation . Murine AAAs were created via intra - aortic porcine pancreatic elastase ( PPE ) infusion . Increased mortality secondary to AAA rupture was observed in Q96IY4 (-/-) mice at the standard PPE dose . At reduced doses of PPE , Q96IY4 (-/-) mice developed larger AAAs than wild - type controls ( 1 . 01 +/- 0 . 27 versus 0 . 68 +/- 0 . 05 mm ; P = 0 . 02 [ mean +/- SD ] ) . P01031 (-/-) and P10451 (-/-) mice were not protected against AAA development . Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in Q96IY4 (-/-) mice . CONCLUSIONS : This study establishes the role of P15086 in experimental AAA disease , indicating that P15086 has a broad anti - inflammatory role in vivo . Enhanced AAA formation in the PPE model is the result of increased plasmin generation , not unregulated C5a - or P10451 - mediated mural inflammation .",
"Anti - complement therapy for glomerular diseases . A major shift in our understanding of glomerular diseases is the focus on which components of the complement pathway are involved in mediating kidney injury . For example , the membranoproliferative glomerulonephritis lesion is no longer classified solely by ultrastructural findings on biopsy and is now divided into immune - complex - mediated lesions vs complement - mediated lesions . In turn , this emphasis on complement leads to interest in therapies that target complement as potential disease - modifying agents . DB01257 , the first available anti - complement therapy , blocks at the level of P01031 and has revolutionized the treatment of atypical hemolytic uremic syndrome . Whether this agent will work equally well for the far more heterogeneous entities of P01024 glomerulonephritis and dense deposit disease remains unclear . Instead , newer agents that target P01024 may turn out to be the most effective and specific therapy for these P01024 glomerulopathies .",
"___MASK89___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK89___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK89___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK89___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"A new rabbit model for the study on cervical compressive myelopathy . Development process and pathology of myelopathy due to chronic spinal cord compression have not been fully elucidated . This study was conducted in order to establish an experimental model which can efficiently produce myelopathy and be useful in the studies on myelopathy due to chronic spinal cord compression . Under electrophysiological monitoring of the spinal cord , anterior compression was produced on P01031 using a plastic screw . Two weeks later , a plastic plate was inserted under the P01031 arch . For the subsequent 10 months on average , walking pattern and MR images were periodically monitored . Before the sacrifice , electrophysiological test was performed and then histopathological examination was done . Palsy appeared at 5 months on average after the addition of posterior compression . Mean compression ratio of the spinal cord calculated on MR images was 34 % . All animals with compression showed a high intramedullary signal intensity , and the mean contrast - to - noise ratio ( P21554 ) in the compressed area was 49 % . Electrophysiological test showed a significant decrease in the amplitude of spinal cord evoked potentials ( SCEPs ) at the given compression level . Histology showed flattening of the anterior horn , disappearance and necrosis of anterior horn cells in the gray matter ; and demyelination and axonal degeneration in the white matter . The antero - posterior compression produces the condition of spinal canal stenosis . Repeated antero - posterior compression to the spinal cord is important in establishing myelopathy . The present animal model was evaluated to be useful in the studies on myelopathy ."
] |
[
"___MASK28___",
"___MASK43___",
"___MASK45___",
"___MASK47___",
"___MASK62___",
"___MASK72___",
"___MASK73___",
"___MASK83___",
"___MASK89___"
] |
___MASK83___
|
MH_train_312
|
interacts_with DB00315?
|
[
"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .",
"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .",
"The transcriptional regulator gene E2 of the Human Papillomavirus ( HPV ) 16 influences the radiosensitivity of cervical keratinocytes . BACKGROUND : Clinical studies have demonstrated that HPV induced tumors constitute a specific subclass of cancer with a better response to radiation treatment . The purpose of this study was to investigate meaning of viral E2 - gene for radiosensitivity . METHODS : W12 cells contain episomal HPV 16 genomes , whereas P28222 cells , which derive from the W12 line , contain HPV DNA as integrated copies . Clonogenic survival was analyzed using 96 - well in vitro test . Using flow cytometry cell cycle analyses were performed . Expression of P06400 and p53 were analyzed using intracellular staining . RESULTS : W12 cells ( intact E2 gene ) showed a lower survival fraction than P28222 cells . W12 cells developed a G2 / M block 24 h after irradiation with 2 Gy whereas P28222 showed no G2 / M bloc . After irradiation P28222 cells developed polyploidy and P06400 - positive cells decreased . W12 cells showed no change of P06400 - positive cells . CONCLUSIONS : Depending on E2 gene status differences in cell cycle regulation might cause radioresistance . The E2 / E7 / P06400 pathway seems to influence HPV - induced radiosensitivity . Our experiments demonstrated an effect of HPV on radiosensitivity of cervical keratinocytes via viral transcription regulator E2 pathway .",
"Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment - resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5 - Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine - blocking and anti - inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis - based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro - imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines .",
"A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome - wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc . ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0 . 01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40 . 9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico - pathological indicators of poor prognosis : a high Gleason score , elevated Ki - 67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki - 67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer - specific mortality ( log - rank test , P = 0 . 007 ) and biochemical recurrence - free survival ( log - rank test , P = 0 . 0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors .",
"Intrauterine factors as determinants of depressive disorder . Although the etiology of major depressive disorder ( MDD ) is unknown , it is precipitated in susceptible individuals by adverse events . This review examines the role of intrauterine factors resulting from exposure to stress hormones in the increased vulnerability of the organism to MDD . Severe maternal stress or alcohol intake during the second and third trimesters causes excess release of corticotropin releasing hormone ( P06850 ) and cortisol . These hormones reduce birth weight ; impair the feedback regulation of the hypothalamic pituitary adrenal axis ( Q9Y251 ) axis and P08908 and 5 - Q13049 signaling in key brain areas . Similar changes are seen in patients with MDD and in experimental animals after chronic inescapable stress , prenatal stress or alcohol , which also induce depressive - like behavior in rats , alterations in sleep and circadian rhythms reminiscent of those in humans with MDD . Clinical improvement of MDD by antidepressants is accompanied by normalization of the regulation of the Q9Y251 axis and of serotoninergic transmission .",
"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .",
"Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .",
"Mapping of the serotonin P28221 beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants . Abnormal brain serotonin function may be characteristic of several neuropsychiatric disorders . Thus , it is important to identify polymorphic genes and screen for functional variants at loci coding for genes that control normal serotonin functions . P28221 beta is a terminal serotonin autoreceptor which may play a role in regulating serotonin synthesis and release . Using an SSCP technique we screened for P28221 beta coding sequence variants in psychiatrically interviewed populations , which included controls , alcoholics , and alcoholic arsonists and alcoholic violent offenders with low P04141 concentrations of the main serotonin metabolite 5 - HIAA . A common polymorphism was identified in the P28221 beta gene with allele frequencies of 0 . 72 and 0 . 28 . The SSCP variant was caused by a silent G to C substitution at nucleotide 861 of the coding region . This polymorphism could also be detected as a HincII RFLP of amplified DNA . DNAs from informative CEPH families were typed for the HincII RFLP and analyzed with respect to 20 linked markers on chromosome 6 . Multipoint analysis placed the P28221 beta receptor gene between markers D6S286 and D6S275 . A maximum two - point lod score of 10 . 90 was obtained to D6S26 , which had been previously localized on 6q14 - 15 . Chromosomal aberrations involving this region have been previously shown to cause retinal anomalies , developmental delay , and abnormal brain development . This region also contains the gene for North Carolina - type macular dystrophy .",
"Computer - aided design and synthesis of 5 - substituted tryptamines and their pharmacology at the P28221 receptor : discovery of compounds with potential anti - migraine properties . The design and synthesis of a series of novel 5 - substituted tryptamines with pharmacological activity at P28221 and other monoamine receptors is described . Structural modifications of N - and C - linked ( principally hydantoin ) analogues at the 5 - position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the P28221 and 5 - Q13049 receptor subtypes . Conformations of the active molecules were computed which , when overlaid , suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at P28221 and 5 - Q13049 receptors . This pharmacophore is composed of a protonated amine site , an aromatic site , a hydrophobic pocket , and two hydrogen - bonding sites . A \" selectivity site \" was also identified which , if occupied , induced sensitivity for P28221 over 5 - Q13049 in this series of molecules . The development and use of the pharmacophore models in compound design is described . In addition , the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed . Utilizing the pharmacophore model in conjunction with the physicochemical constraints of molecular size and log DpH7 . 4 led to the discovery of DB00315 ( 6 ) , a new selective P28221 agonist with good oral absorption and potential use in the treatment of migraine .",
"5 - HT2 receptor involvement in conditioned olfactory learning in the neonate rat pup . These experiments addressed the role of 5 - HT2 receptors in conditioned olfactory learning . Ritanserin , a 5 - Q13049 / 2C antagonist , was injected subcutaneously into postnatal day ( P01160 ) 7 pups before or after conditioned olfactory training to a peppermint odor . When the pups were tested for olfactory preference on P01160 8 , those injected with ritanserin before training failed to acquire an odor preference whereas those injected after training learned . This suggested that the 5 - HT2 receptor is required only in the acquisition of conditioned olfactory learning . Injection of ritanserin directly into the olfactory bulb before training also blocked preference for the peppermint odor . In pups that had depletion of the 5 - HT input to the bulb , subcutaneous injection of a 5 - Q13049 / 2C agonist was sufficient to maintain conditioned olfactory learning , confirming the importance of 5 - HT in learning .",
"5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .",
"Receptor selectivity of the cloned opossum G protein - coupled receptor kinase 2 ( P25098 ) in intact opossum kidney cells : role in desensitization of endogenous alpha2C - adrenergic but not serotonin 1B receptors . To characterize the specificity of endogenously expressed G protein - coupled receptor kinases ( GRKs ) for endogenous Gi - coupled alpha2C - adrenergic and serotonin 1B ( P28222 ) receptors in the opossum kidney ( OK ) cell line , we have isolated a 3 . 073 - kb OK - P25098 clone encoding a 689 - amino acid protein that shares 94 . 2 % amino acid identity with rat P25098 . Northern blot analysis revealed the presence of P25098 mRNA transcripts of 5 . 0 and 3 . 0 kb in OK cells . In intact OK cells , preincubation ( 45 min ) with agonist ( 5 - HT or UK 14304 , 1 microM ) reduced the maximal inhibition of forskolin - induced DB02527 accumulation mediated by endogenous P28222 and alpha2C - adrenergic receptors by 12 +/- 2 % or 17 +/- 4 % , respectively . In transfected OK cells overexpressing OK - P25098 , agonist - induced desensitization of the alpha2C - adrenergic receptor , but not the P28222 receptor , was enhanced by 2 - to 4 - fold . Conversely , in cells overexpressing the kinase - inactive mutant OK - P25098 - K220R , alpha2C - adrenergic receptor desensitization was selectively abolished , whereas desensitization of the P28222 receptor was slightly enhanced . Similarly , depletion of GRK - 2 protein by stable transfection of full - length antisense OK - P25098 cDNA blocked the desensitization of alpha2C - adrenergic receptors but not of P28222 receptors . These results represent the first evidence of the coexistence of P25098 - dependent ( for alpha2C receptors ) and P25098 - independent ( for P28222 receptors ) mechanisms of desensitization in intact cells and demonstrate the selectivity of P25098 for distinct Gi - coupled receptors .",
"Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .",
"Inhibition of the trigemino - vascular system with P28221 agonist drugs : selectively targeting additional sites of action . Inappropriate activation of the trigemino - vascular system is thought to be important in the pathogenesis of a migraine attack . The P28221 agonist sumatriptan , which is highly effective in the acute treatment of migraine , inhibits trigemino - vascular activation in animals , although its actions are normally limited to peripheral components of the trigemino - vascular system . DB00315 , a novel P28221 agonist drug , which is also highly effective in the acute treatment of migraine , acts not only at these sites , but , additionally within the brainstem , inhibiting trigemino - vascular activation centrally as well as peripherally . This article describes the pre - clinical development of DB00315 and considers , specifically , the approaches taken in the design of a molecule with attributes which facilitate access to brainstem components of the trigeminal pathway and combine this with good oral bioavailability .",
"The tolerability and pharmacokinetics of the novel antimigraine compound DB00315 in healthy male volunteers . 1 . DB00315 is a novel and selective agonist at P28221 receptors , with central and peripheral actions , currently in development for the acute oral treatment of migraine . 2 . The pharmacokinetic and tolerability profiles of single oral doses from 1 - 50 mg DB00315 were investigated in 12 healthy male volunteers in a double - blind , placebo - controlled , dose - escalating study . 3 . DB00315 was well tolerated with most adverse experiences of mild and transient nature . 4 . Absorption was rapid with dose - independent kinetics . Median tmax was 2 - 4 h although 50 - 85 % of eventual Cmax was attained within 1 h . The t1 / 2 was 2 . 5 - 3 h with a high apparent plasma clearance ( CL / F > 2000 ml min - 1 ) and apparent volume of distribution ( Vz / F ) of 400 - 500 l . 5 . Three metabolites were detected in plasma and urine , one of which , the N - desmethyl metabolite , has P28221 agonist activity . 6 . DB00315 showed no clinically significant effects on blood pressure , heart rate , ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment .",
"Clinical safety of DB00315 : aggregated data from patients and volunteers to date . The tolerability of DB00315 , a novel , selective and highly effective P28221 receptor agonist in development for the acute treatment of migraine , has been evaluated in a number of clinical pharmacology and patient studies across the dose range 1 - 50 mg . DB00315 has been well tolerated across the entire dose range and no clinically relevant changes in routine laboratory parameters , blood pressure or ECG recordings have been observed . Adverse experiences reported are generally dose related , mild to moderate and resolve spontaneously . Chest - related symptoms occur infrequently and the cardiovascular safety profile of DB00315 is considered particularly favourable . DB00315 , therefore , possesses a desirable safety profile which is well suited to broad - based outpatient administration .",
"Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and / or physiological stress . When people feel stress , the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin - releasing hormone ( P06850 ) , adrenocorticotropic hormone ( DB01285 ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of DB01285 and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20 - 240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma DB01285 - like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma DB01285 - IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress - related disease .",
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK17___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK17___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK17___ .",
"Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"[ Clinical efficacy of zolmitriptan in migraine ] . Zolmitriptan ( previously known as DB00315 ) is a serotoninergic P28222 / D agonist with high oral bioavailability with a double , central and peripheral , action mechanism . Evaluation of its clinical efficacy was developed in a program of clinical studies ( search and confirmation of dosis , comparative and long term studies ) and through analysis of efficacy in different clinical situations . Zolmitriptan shows a high effectiveness in the treatment of migraine crisis , significantly reduces the headaches by 2 hours of its administration , reduce the symptoms associated with migraine ( nausea , photophobia and phonophobia ) and improves the quality of life of the migraine patient . The efficacy is independent of the type of migraine characteristics of the patient as well as of the administration of other concomitant medications . The dosis of 2 . 5 mg of zolmitriptan has been found to be the optimum considering both efficacy and tolerability .",
"Cocaine potentiates multiple 5 - Q13049 receptor signaling pathways and is associated with decreased phosphorylation of 5 - Q13049 receptors in vivo . Cocaine addiction is a chronic relapsing disorder in which the underlying mechanisms are not well understood . Here , we used Sprague - Dawley rats injected with either saline ( 1 ml / kg ) or cocaine ( 15 mg / kg ) for 7 days ( b . i . d , i . p ) to study the effect of cocaine on several components of 5 - Q13049 receptor signaling in prefrontal cortex ( PFCx ) . We detected enhanced activation of 5 - Q13049 receptor - mediated phospholipase C beta ( PLCβ ) and extracellular regulated kinase 1 / 2 activity in PFCx of cocaine - treated rats . Although we were unable to detect changes in the protein levels of several proteins associated with 5 - Q13049 receptor signaling such as caveolin - 1 , postsynaptic density protein 95 , β - arrestin 2 , etc . , we found a significant reduction in the phosphorylation status of cortical 5 - Q13049 receptors . This phenomenon was associated with reduced levels of G - protein receptor kinase 5 ( P34947 ) , but not P25098 or P51812 , proteins . Our results suggest that decreased phosphorylation of 5 - Q13049 receptors could mediate , at least in part , the cocaine - induced potentiation of multiple 5 - Q13049 receptor signaling pathways in rat PFCx . As discussed in this manuscript , we hypothesize that preventing these neuroadaptations in 5 - Q13049 receptor signaling may alleviate some of the aversive withdrawal - associated symptoms that contribute to relapse to cocaine abuse .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK41___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , ___MASK89___ - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK61___ did not displace ___MASK89___ from AR while significant displacing activity was elicited by ___MASK89___ , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK53___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .",
"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK72___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK72___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"Cortical spreading depression - associated hyperemia in rats : involvement of serotonin . We investigated whether the vasoactive neurotransmitter serotonin ( 5 - HT ) is involved in cortical spreading depression ( Q9Y600 ) - associated hyperemia in the rat . We focused on the 5 - HT2 receptor , which is engaged in 5 - HT induced small arteriolar relaxation in cats , as well as on the P28221 / 1B receptor , the binding site of the potent antimigraine drug sumatriptan . In male barbiturate anaesthetized Wistar rats ( n = 25 ) CSDs were elicited by brain topical application of 1 M DB00761 , and the DC - potential and regional cerebral blood flow ( rCBF , by Laser Doppler flowmetry ) were measured over the same hemisphere through dura and thinned bone , respectively . Intravenous application of 8 mg / kg of the 5 - Q13049 / 2C receptor antagonist ritanserin ( group I ; n = 8 ) significantly reduced the hyperperfusion amplitude during Q9Y600 by approximately 44 % ( p < 0 . 05 , from 342 +/- 124 to 194 +/- 97 % , baseline before Q9Y600 = 100 % ) , and prolonged its duration by approx . 30 % . Vehicle alone ( group II ; n = 4 ) did not affect Q9Y600 hyperperfusion . The highly selective P28221 / 1B receptor agonist DB00315 was given in two doses : 100 micrograms / kg i . v . ( n = 5 ) had no effect on Q9Y600 hyperperfusion , while 800 micrograms / kg ( n = 5 ) increased hyperperfusion significantly ( p < 0 . 05 , from 224 +/- 86 to 310 +/- 148 % ) . We conclude that serotonin is , probably via 5 - HT2 receptors , involved in the modulation of the regional cerebral blood flow increase during Q9Y600 . Novel highly selective receptor antagonists may help to discriminate the differential contribution of various 5 - HT receptor subspecies .",
"Binding of 5H - dibenzo [ b , e ][ 1 , 4 ] diazepine and chiral 5H - dibenzo [ a , d ] cycloheptene analogues of clozapine to dopamine and serotonin receptors . 5H - Dibenzo [ b , e ][ 1 , 4 ] diazepine , dibenz [ b , f ] oxepin , and 5H - dibenzo [ a , d ] cycloheptene analogues of clozapine [ 8 - chloro - 11 -( 4 - methylpiperazino )- 5H - dibenzo [ b , e ][ 1 , 4 ] diazepine ] were evaluated for their binding affinity to dopamine D - 1 , D - 2 , and D - 4 and serotonin S - 2A ( 5 - Q13049 ) , S - 2C ( P28335 ) and S - 3 ( 5 - Q9H205 ) receptors . The diazepine analogues display selective binding to the dopamine D - 4 and serotonin S - 2A receptors similar to that of clozapine , but none has a dopamine D - 4 selectivity ( Ki for the dopamine D - 2A receptor / Ki for the dopamine D - 4 receptor ) greater than that of clozapine . All of the oxepin analogues also show substantial binding to the dopamine D - 4 and serotonin S - 2A receptors with 10 -( 4 - methylpiperazino ) dibenz [ b , f ] oxepin having a dopamine D - 4 selectivity greater than that of clozapine . Some of the 5H - dibenzo -[ a , d ] cycloheptene analogues also show strong binding to both the dopamine D - 4 and serotonin S - 2A receptors , 5 - methyl - 10 -( 4 - methylpiperazino )- 5H - dibenzo [ a , d ] cycloheptene having a dopamine D - 4 selectivity of 7 . 8 as compared to 10 for clozapine but a serotonin S - 2A selectivity ( Ki for the dopamine D - 2 receptor / Ki for the serotonin S - 2A receptor ) of 2 . 0 as compared to 28 for clozapine . The serotonin S - 2A selectivity of 2 - chloro - 10 -( 4 - methylpiperazino )- 5H - dibenzo [ a , d ]- cycloheptene ++ + is 200 . As an extension of these studies , chiral 5 - substitute 10 -( 1 , 2 , 3 , 6 - tetrahydro - 1 - methyl - 4 - pyridinyl )- 5H - dibenzo [ a , d ] cyclohept ene analogues show a substantial enantiospecificity toward dopamine and serotonin receptor subtypes , ( R ) -(-)- 5 - methyl compound having a 2 - fold higher dopamine D - 4 selectivity than its ( S ) -(+) enantiomer as the result of enhanced binding to the dopamine D - 4 receptor rather than diminished binding to the dopamine D - 2 receptor . ( pRa , pSb ) -(+)- 5 -( 2 - Propylidene )- 10 - ( 1 , 2 , 3 , 6 - tetrahydro - 1 - met hyl - 4 - pyridinyl ) - 5H - dibenzo [ a , d ] cycloheptene is 17 times more active in binding to the dopamine D - 4 receptor than is its pSa , P06400 enantiomer while being only 1 . 5 times more active in binding to the dopamine D - 2 receptor .",
"P05362 - independent lymphocyte transmigration across high endothelium : differential up - regulation by interferon gamma , tumor necrosis factor - alpha and interleukin 1 beta . The adhesion of lymphocytes to cytokine - treated high endothelium was studied using cultured high endothelial cells ( O14777 ) . Pretreatment of the O14777 layer with a variety of cytokines caused up - regulation of lymphocyte adhesion with the effects ordered interferon gamma ( P01579 ) greater than tumor necrosis factor - alpha ( P01375 ) greater than or equal to interleukin 1 beta ( IL 1 beta ) . Increased lymphocyte adhesion was found to be independent of P05362 as expression by O14777 was not increased by cytokines and antibodies against P05362 did not block adhesion . The peptide CS1 and anti - beta 1 integrin subunit antibodies , however , caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on O14777 and alpha 4 beta 1 on lymphocytes . Study of the kinetics of lymphocyte adhesion showed that the effects of P01579 and P01375 were persistent and remained detectable 2 . 5 h after removal of the cytokines whereas the effects of IL 1 beta were transient and were not sustained beyond 1 h . All of the cytokines used caused transient increases in the number of surface - bound lymphocytes with P01579 greater than P01375 greater than or equal to IL 1 beta , however , the most dramatic effect was on the transmigration of lymphocytes across the O14777 . Both P01579 and P01375 caused sustained increased transmigration with P01579 having the greater effect . IL 1 beta had little effect on transmigration . This model demonstrates that the binding and transmigration of lymphocytes across O14777 can be differentially regulated by the actions of individual cytokines . These results support the concept that locally produced cytokines regulate O14777 function within the lymph node .",
"Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK89___ ) in castrated male and female mice subjected to ___MASK89___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK89___ in mice CPs .",
"Serotonergic stimulation of corticotropin - releasing hormone and pro - opiomelanocortin gene expression . The neurotransmitter serotonin ( 5 - HT ) stimulates adrenocorticotropic hormone ( DB01285 ) secretion from the anterior pituitary gland via activation of central 5 - HT1 and 5 - HT2 receptors . The effect of 5 - HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin - releasing hormone ( P06850 ) . We therefore investigated the possible involvement of P06850 in the serotonergic stimulation of DB01285 secretion in male rats . Increased neuronal 5 - HT content induced by systemic administration of the precursor 5 - hydroxytryptophan ( 5 - HTP ) in combination with the 5 - HT reuptake inhibitor fluoxetine raised P06850 mRNA expression in the paraventricular nucleus ( PVN ) by 64 % , increased pro - opiomelanocortin ( P01189 ) mRNA in the anterior pituitary lobe by 17 % and stimulated DB01285 secretion five - fold . Central administration of 5 - HT agonists specific to P08908 , P28222 , 5 - Q13049 or P28335 receptors increased P06850 mRNA in the PVN by 15 - 50 % , P01189 mRNA in the anterior pituitary by 15 - 27 % and DB01285 secretion three - to five - fold , whereas a specific 5 - Q9H205 agonist had no effect . Systemic administration of a specific anti - P06850 antiserum inhibited the DB01285 response to 5 - HTP and fluoxetine and prevented the 5 - HTP and fluoxetine - induced P01189 mRNA response in the anterior pituitary lobe . Central or systemic infusion of 5 - HT increased DB01285 secretion seven - and eight - fold , respectively . Systemic pretreatment with the anti - P06850 antiserum reduced the DB01285 responses to 5 - HT by 80 % and 64 % , respectively . It is concluded that 5 - HT via activation of P08908 , 5 - Q13049 , P28335 and possibly also P28222 receptors increases the synthesis of P06850 in the PVN and P01189 in the anterior pituitary lobe , which results in increased DB01285 secretion . Furthermore , the results indicate that P06850 is an important mediator of the DB01285 response to 5 - HT .",
"DB00315 , a new central and peripherally acting P28221 receptor agonist in the acute oral treatment of migraine : a double - blind , placebo - controlled , dose - range finding study . DB00315 is a novel , centrally and peripherally , acting 5 - hydroxytryptamine1D receptor agonist . We investigated the efficacy and safety of 1 , 5 , and 25 mg of oral DB00315 in the acute treatment of migraine in a randomized , double - blind , placebo - controlled , parallel - group clinical trial involving 84 patients . The proportion of patients in whom the headache improved within 2 hours from moderate or severe to mild or no pain ( primary efficacy measure ) was 15 % for placebo - treated patients and 27 % ( 1 mg ) , 62 % ( 5 mg ) , and 81 % ( 25 mg ) for patients treated with DB00315 . Treatment differences compared with placebo were 12 % ( 95 % CI - 12 , 37 ; p = 0 . 460 ) for 1 mg DB00315 , 47 % ( CI 21 , 73 ; p < 0 . 005 ) for 5 mg DB00315 , and 66 % ( CI 43 , 89 ; p < 0 . 001 ) for 25 mg DB00315 . Photophobia and nausea also showed improvement after DB00315 . Adverse events were generally mild and transient in all treatment groups . There were no clinically significant changes in ECG recordings , blood pressure , or laboratory tests . Oral DB00315 ( 5 and 25 mg ) is highly effective and well tolerated in the acute treatment of migraine . The response rates and treatment differences compared with placebo in this study suggest possible superiority over existing antimigraine therapies . This needs to be confirmed in formal comparative trials .",
"The clinical effectiveness of DB00315 in the acute treatment of migraine . Efficacy with currently marketed antimigraine compounds is less than optimal . DB00315 is a novel and selective P28221 receptor agonist in development for the acute treatment of migraine . It shows evidence of both central and peripheral activity within the trigemino - vascular system and it is rapidly absorbed following oral administration . In clinical studies in migraine patients , a headache response at 2 hours has been observed in 65 - 81 % of patients at doses above 1 mg . Favourable response rates are reported as early as 1 hour post - dose and efficacy rates continue to improve up to 4 hours . Headache recurrence is reported by 25 - 35 % of patients and DB00315 is also effective in relieving the non - headache symptoms of migraine .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK15___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .",
"Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .",
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Acute migraine therapy : the newer drugs . In 1996 , our knowledge of acute antimigraine therapy expanded in three major areas . First , large surveys have confirmed the remarkable efficacy profile of sumatriptan in clinical practice . No satisfying clinical , pharmacokinetic or genetic explanations were found for its major shortcomings : nonresponders , headache recurrence and noncardiac chest symptoms . Second , the novel P28222 / D agonists zolmitriptan ( DB00315 ) , rizatriptan ( MK - 462 ) , eletriptan ( UK - 116 , 044 ) , avitriptan ( BMS - 180048 ) and alniditan ( R091274 ) were all proved superior to placebo for attack treatment , but their advantages over sumatriptan are yet to be analysed in more detail . A higher lipophilicity explains ( except for alniditan ) their greater oral bioavailability and better central nervous system penetration . A central action now proved experimentally in animals and in humans for P28222 / D agonists such as zolmitriptan may be advantageous for the antimigraine efficacy , but it could also increase sedation . Third , an endothelin ( Ro470203 , DB00559 ) and a neurokinin 1 ( RPR100893 ) receptor antagonist were found to be ineffective in migraine . Both compounds are potent inhibitors of neurogenic plasma extravasation in rat dura mater , which might suggest that this pharmacological property does not necessarily predict efficacy in aborting migraine attacks .",
"Evaluation of the long - term safety and efficacy of DB00315 in the treatment of migraine . DB00315 is an orally active P28221 agonist with both central and peripheral actions that is currently being developed as an acute antimigraine treatment . Several studies have demonstrated the safety and efficacy of DB00315 in the treatment of a single migraine headache . The objectives of this open study are to assess the safety and efficacy of DB00315 when used for a period of up to one year . Patients can treat as many migraine headaches as desired with an oral treatment regimen of DB00315 . An initial 5 mg dose for treatment of the migraine headache may be followed with a second 5 mg dose to treat recurrence should it develop . Safety assessments include electrocardiograms , the frequency , intensity and duration of adverse experiences , and routine haematology , urinalysis and clinical chemistry measures . Data presented here are an interim view of the database as of August 1995 and should be considered as preliminary observations . No clinically significant serious adverse experiences have been reported . The adverse experience and efficacy profile appears to be consistent with previous DB00315 studies and this dosing regimen of DB00315 was well tolerated during multiple exposures . Notably , response rates are as good after both initial and repeated exposure ( up to 5 migraines ) .",
"___MASK17___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK17___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK17___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK17___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK94___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"___MASK38___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response ."
] |
[
"___MASK15___",
"___MASK17___",
"___MASK38___",
"___MASK41___",
"___MASK53___",
"___MASK61___",
"___MASK72___",
"___MASK89___",
"___MASK94___"
] |
___MASK15___
|
MH_train_313
|
interacts_with DB05294?
|
[
"[ DB05294 for advanced non - small cell lung cancer : a meta - analysis ] . BACKGROUND AND OBJECTIVE : DB05294 is a small molecule inhibitor against vascular endothelial growth factor receptor ( VEGFR ) and epidermal growth factor receptor ( P00533 ) . The aim of this study is to evaluate the efficacy and safety of vandetanib as a second - line treatment for advanced non - small cell lung cancer ( NSCLC ) . METHODS : We selected randomized controlled trials ( RCTs ) on vandetanib for NSCLC from PubMed , Medline , Embase , P01282 and CNKI . Meta - analysis was completed using software Review Manager 5 . 0 . RESULTS : Compared with the control group ( single other targeted therapy or chemotherapy group ) , there were statistical differences in progression free survival ( PFS ) ( OR = 1 . 23 , 95 % CI : 1 . 05 - 1 . 45 ) , partial response ( PR ) ( OR = 2 . 15 , 95 % CI : 1 . 59 - 2 . 93 ) , disease control ( DC ) ( OR = 1 . 22 , 95 % CI : 1 . 06 - 1 . 40 ) , diarrhea ( OR = 1 . 59 , 95 % CI : 1 . 38 - 1 . 83 ) , nausea ( OR = 0 . 69 , 95 % CI : 0 . 57 - 0 . 83 ) , rash ( OR = 2 . 07 , 95 % CI : 1 . 71 - 2 . 49 ) , constipation ( OR = 0 . 81 , 95 % CI : 0 . 67 - 0 . 97 ) , and vomiting ( OR = 0 . 72 , 95 % CI : 0 . 60 - 0 . 87 ) in the vandetanib group , but there were no differences in overall survival ( OS ) , stable disease ( SD ) , fatigue , cough , anorexia and dyspnea . CONCLUSIONS : DB05294 might have more superior efficacy as a second - line treatment for NSCLC , but its advantages in terms of safety were not demonstrated .",
"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"VEGFR and P00533 inhibition increases epithelial cellular characteristics and chemotherapy sensitivity in mesenchymal bladder cancer cells . The present study investigated the effect of VEGFR and P00533 inhibition via vandetanib ( DB05294 ) on epithelial - mesenchymal transition ( EMT ) in bladder cancer . Markers of EMT ( P00533 , VEGR , P12830 and vimentin ) were interogated by Western blotting at baseline and after treatment with P01133 , P15692 , vandetanib , cisplatin , or their combination using representative epithelial - and mesenchymal - type human bladder cancer cells . Morphological changes induced by these treatments were examined by microscopy over various time courses . The effect of these changes on cisplatin chemotherapy sensitivity was assessed by MTT assay . RT4 and HTB3 cells had epithelial features while CRL1749 and J82 cells had mesenchymal features . After treatment with P01133 , the epithelial - type cells demonstrated increased intercellular separation and pseudopodia , with these changes blocked by vandetanib . In contrast , the mesenchymal cells did not exhibit any morphological changes with the P01133 treatment but adopted a clustered / epithelial appearance after the administration of vandetanib . Western blotting shows that treatment of epithelial cells with vandetanib increased the expression of P12830 . In comparison , mesenchymal cells demonstrated decreased vimentin expression with the treatment of vandetanib in the presence of P01133 and P15692 . Improved growth inhibition was seen in the epithelial cells but not in mesenchymal cells with the concurrent treatment of vandetanib and cisplatin . Sequential treatment of mesenchymal cells with vandetanib followed by cisplatin demonstrated synergy with improved cisplatin activity . The findings offer a novel role of vandetanib on the EMT in bladder cancer , providing insight into EMT in bladder cancer .",
"Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade . The outcome for patients with lung cancer has not changed significantly for more than two decades . Several studies show that the overexpression of vascular endothelial growth factor ( P15692 ) / vascular permeability factor and epidermal growth factor ( P01133 ) and their receptors correlates with the clinical outcome for lung cancer patients . However , clinical trials of agents that target either of these pathways alone have been disappointing . We hypothesize that targeting both the tumor and its vasculature by simultaneously blocking the VEGFR and P00533 pathways will improve the treatment of locoregional lung cancer . Human lung cancer specimens were first examined for the activation of P15692 receptor 2 ( P35968 ) and P01133 receptor ( P00533 ) for tumor and tumor - associated endothelial cells , and both were found to be activated . The effects of DB05294 ( ZACTIMA ) , a small - molecule inhibitor of P35968 and P00533 tyrosine kinases , were then studied in vitro using human lung cancer and microvascular endothelial cells . In vitro , DB05294 inhibited P00533 , P35968 , mitogen - activated protein kinase and Akt phosphorylation , P01133 - and P15692 - induced proliferation , and endothelial cell tube formation and also induced apoptosis . DB05294 was further studied in vivo using an orthotopic mouse model of non - small cell lung cancer using NCI - H441 human lung adenocarcinoma cells . The inhibition of both P35968 and P00533 signaling pathways by DB05294 resulted in profound antiangiogenic , antivascular , and antitumor effects . These results provide a basis for the development of clinical strategies for the combination of selective protein tyrosine kinase inhibitors that block both P00533 and VEGFR signaling as part of the management of locally advanced lung cancer .",
"Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by DB05294 , an inhibitor of VEGFR tyrosine kinase with additional activity against P00533 tyrosine kinase . DB05294 is a vascular endothelial growth factor receptor ( VEGFR ) and epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor . The present study was undertaken to investigate the direct antiproliferative effect of DB05294 on human nasopharyngeal carcinoma ( NPC ) in vitro and the antitumor activity on NPC xenografts in vivo . Results indicated that DB05294 treatment inhibited P00533 phosphorylation and led to a dose - and time - dependent decrease in NPC cell ( CNE - 1 , CNE - 2 and C666 - 1 ) proliferation . Further investigation demonstrated G0 / P55008 cell cycle arrest in all 3 cell lines , which was associated with an upregulation of P38936 and / or p27 , and downregulation of P11802 , Q00534 and P24941 . DB05294 treatment also induced apoptosis in CNE - 1 and CNE - 2 cells . The apoptosis mechanisms involved reduction of Bcl - 2 and / or Bcl - XL , induction of Bak and / or Bax , and activation of caspases - 3 , - 9 and / or - 8 . The in vivo antitumor activity was evaluated in CNE - 2 and C666 - 1 xenografted nude mice . Administration of DB05294 ( 25 - 100 mg / kg / day , once - daily , p . o . ) produced a dose - dependent inhibition of tumor growth and prolonged survival in both models . This study suggests that DB05294 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0 / P55008 arrest and apoptosis , and potent antitumor effects on NPC xenografts in vivo . It indicates that DB05294 may offer a new and effective treatment for human NPC .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK72___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK72___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK8___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .",
"Antitumor effect of vandetanib through P00533 inhibition in head and neck squamous cell carcinoma . BACKGROUND : The epidermal growth factor receptor ( P00533 ) and vascular endothelial growth factor receptor ( VEGFR ) have been implicated as therapeutic targets for head and neck squamous cell carcinoma ( HNSCC ) . DB05294 is a small - molecule tyrosine kinase inhibitor ( TKI ) with dual specificity for P00533 and VEGFR . Here we characterize the phenotypic and biochemical effects of vandetanib on various HNSCC cell lines . METHODS : In vitro models were used for studying tumor cell viability , invasion , and signaling as well as in vivo xenograft models . RESULTS : Treatment with vandetanib reduced viability , invasion , and tumor growth of HNSCC cell lines . Phosphorylation levels of mitogen - activated protein kinase ( MAPK ) and signal transducer and activator of transcription 3 ( P40763 ) were reduced in vandetanib - treated HNSCC cells . Additionally , vandetanib abrogates P01133 - induced P40763 activity and P40763 target gene expression . CONCLUSIONS : We demonstrated that vandetanib inhibits the growth of head and neck cancer cell lines . The antitumor effects of vandetanib appear to be exerted via the P00533 inhibitory effect of the compound .",
"Recent developments of targeted therapies in the treatment of non - small cell lung cancer . Non small cell lung cancer ( NSCLC ) is a lethal disease with poor prognosis . The main percentage of NSCLC patients are diagnosed to have an advanced disease . Standard treatment , such as chemotherapy and radiotherapy , has apparently reached a plateau of effectiveness in improving survival of advanced NSCLC patients . Hence , considerable efforts have started to be made in order to identify novel targets for new biological agents which may safely and effectively be administered to advanced NSCLC patients . P00533 ( P00533 ) and vascular endothelial growth factor ( P15692 ) and its receptors play an essential role in tumour proliferation . Approaches targeting P00533 and P15692 include monoclonal antibodies ( mAbs ) and small molecules inhibiting the corresponding receptor - tyrosine kinase activity . Erlotinib is a small molecule inhibitor of P00533 tyrosine - kinase which has brought significant improvements in median survival , quality of life and related symptoms , in an unselected population of advanced NSCLC patients in the second - or third - line setting . DB00112 , an anti - P15692 recombinant humanized mAb , is the first targeted agent which , when combined with chemotherapy , reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC . DB05294 , a small molecule targeting P15692 tyrosine - kinase activity , showing early evidence of antitumour activity and the excellent toxicity profile , seems to be a promising agent for the treatment of advanced NSCLC . This review shows the latest and the future developments of erlotinib , bevacizumab and DB05294 in the treatment of advanced NSCLC patients .",
"Endothelial progenitor cells in relation to endothelin - 1 and endothelin receptor blockade : a randomized , controlled trial . AIMS : Endothelial progenitor cells ( EPC ) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis . Patients with both diabetes and vascular disease have low numbers of circulating EPC . The endothelium - derived peptide , endothelin - 1 ( ET - 1 ) , is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction . Therefore , we investigated the relation between EPC and plasma ET - 1 and the effect of dual ET - 1 receptor antagonist treatment . METHODS : In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual P25101 / ETB receptor antagonist ___MASK68___ treatment ( 125mg bid ; n = 17 ) or placebo ( n = 19 ) for four weeks . Different EPC subpopulations were enumerated by flow cytometry using triple staining ( P28906 , CD133 , P35968 ) at baseline at the end of treatment . Viability was assessed by 7AAD and Annexin - V - staining . RESULTS : Baseline ET - 1 levels correlated significantly with P02741 levels . Patients with ET - 1 levels above the median value had higher levels of P28906 (+) CD133 (+) and P28906 (+) P35968 (+) EPC . There was no difference in P28906 (+) and P28906 (+) CD133 (+) P35968 (+) cells , markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET - 1 levels below or above the median . Four week treatment with ___MASK68___ did not change EPC levels . CONCLUSION : Among patients with type 2 diabetes and vascular disease , high plasma levels of ET - 1 are associated with higher number of EPC . The recruitment of EPC does not seem to be regulated via ET - 1 receptor activation since treatment with a dual ET - 1 receptor blocker did not affect circulating EPC numbers .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK8___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"___MASK12___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK12___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .",
"DB05294 enhances paclitaxel antiproliferative and apoptotic effects in breast carcinoma cells . Chemotherapy employing paclitaxel and docetaxel is widely used for treating early - stage breast cancer and metastasis , which is frequently associated with overexpression of epidermal growth factor receptor ( P00533 ) and resistance to apoptosis . DB05294 , a dual tyrosine kinase inhibitor of P00533 and VEGFR , inhibits cell proliferation of solid tumors , including breast . Phase III clinical trials using DB05294 in non - small cell lung carcinoma when combined with standard chemotherapy appear promising . In order to improve the antineoplastic activity of paclitaxel , we presently investigated the effects of DB05294 in combination with paclitaxel in P00533 and VEGFR expressing human breast cancer cell lines MCF - 7 and MDA - MB - 231 . DB05294 synergistically decreased cell viability when used in combination with paclitaxel . DB05294 inhibited cyclin D1 and cyclin E expression and induced p53 expression when combined with paclitaxel . The combination of DB05294 with paclitaxel versus either agent alone also more potently down - regulated the antiapoptotic bcl - 2 protein , up - regulated pro - apoptotic signaling events involving expression of bax , activation of caspase - 3 and caspase - 7 proteins , and induced poly ( ADP - ribose ) polymerase resulting in apoptosis . DB05294 combined with paclitaxel inhibited anchorage - independent colony formation and invasion of breast cancer cells in vitro as compared to either single agent , indicating a potential involvement of altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells . Collectively , our studies indicate that incorporating an anti - P00533 plus VEGFR strategy ( DB05294 ) with chemotherapy ( paclitaxel ) , where clinical studies of dose - intensive paclitaxel therapy are currently in progress , may be more effective in treating patients with locally advanced or metastatic breast cancer than either approach alone .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK13___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK8___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"iSubgraph : integrative genomics for subgroup discovery in hepatocellular carcinoma using graph mining and mixture models . The high tumor heterogeneity makes it very challenging to identify key tumorigenic pathways as therapeutic targets . The integration of multiple omics data is a promising approach to identify driving regulatory networks in patient subgroups . Here , we propose a novel conceptual framework to discover patterns of miRNA - gene networks , observed frequently up - or down - regulated in a group of patients and to use such networks for patient stratification in hepatocellular carcinoma ( HCC ) . We developed an integrative subgraph mining approach , called iSubgraph , and identified altered regulatory networks frequently observed in HCC patients . The miRNA and gene expression profiles were jointly analyzed in a graph structure . We defined a method to transform microarray data into graph representation that encodes miRNA and gene expression levels and the interactions between them as well . The iSubgraph algorithm was capable to detect cooperative regulation of miRNAs and genes even if it occurred only in some patients . Next , the miRNA - mRNA modules were used in an unsupervised class prediction model to discover HCC subgroups via patient clustering by mixture models . The robustness analysis of the mixture model showed that the class predictions are highly stable . Moreover , the Kaplan - Meier survival analysis revealed that the HCC subgroups identified by the algorithm have different survival characteristics . The pathway analyses of the miRNA - mRNA co - modules identified by the algorithm demonstrate key roles of Myc , Q01094 , let - 7 , P01137 , P01375 and P00533 in HCC subgroups . Thus , our method can integrate various omics data derived from different platforms and with different dynamic scales to better define molecular tumor subtypes . iSubgraph is available as MATLAB code at http :// www . cs . umd . edu /~ ozdemir / isubgraph / .",
"DB05294 restores head and neck squamous cell carcinoma cells ' sensitivity to cisplatin and radiation in vivo and in vitro . PURPOSE : We investigated whether vandetanib , an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor - 2 ( P35968 ) , epidermal growth factor receptor ( P00533 ) , and rearranged during transfection ( P07949 ) , could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma ( HNSCC ) . EXPERIMENTAL DESIGN : P48449 - 19 and P0CJ72 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib , cisplatin , and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model . Treatment effects were assessed using clonogenic survival assay , tumor volume , bioluminescence imaging , tumor growth delay , survival , microvessel density , tumor and endothelial cell apoptosis , and P00533 and Akt phosphorylation data . RESULTS : DB05294 plus cisplatin radiosensitized HNSCC cells in vitro and in vivo . The combination treatment with vandetanib , cisplatin , and radiation was superior to the rest of treatments ( including the double combinations ) in antitumoral effects , prolonging survival , decreasing cervical lymph node metastases in vivo . It also increased both tumor and tumor - associated endothelial cell apoptosis and decreased microvessel density in vivo . An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo . All vandetanib - containing treatments inhibited P00533 and Akt phosphorylation in vitro and in vivo . CONCLUSION : The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC . Further study of this regimen in clinical trials may be warranted .",
"Role of vandetanib in the management of medullary thyroid cancer . Traditionally available treatments , like cytotoxic chemotherapy and external - beam radiation therapy , are limited and essentially ineffective for metastatic medullary thyroid carcinoma ( P04629 ) . In the last decade , small - molecule tyrosine kinase inhibitors ( TKI ) have been introduced in the field of thyroid cancer , after having been shown effective in a wide variety of other tumors . This review focuses on vandetanib ( DB05294 , Zactima ™ ; AstraZeneca ) and its role in the treatment of P04629 . DB05294 is an oral TKI that targets P15692 receptors 2 and 3 , P07949 , and at higher concentrations , the epidermal growth factor ( P01133 ) receptor . This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg / day dosage of vandetanib have antitumor activity on advanced P04629 . A phase III trial ( ZETA trial ) evaluating vandetanib in 331 patients with locally advanced or metastatic P04629 showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo . Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea , rash , fatigue and nausea being the most commonly experienced by patients . DB05294 is currently approved in the United States for unresectable locally advanced or metastatic P04629 and has become a new standard of care in this rare and indolent pathology .",
"Growth inhibition by tyrosine kinase inhibitors in mesothelioma cell lines . Clinical outcome following chemotherapy for malignant pleural mesothelioma is poor and improvements are needed . This preclinical study investigates the effect of five tyrosine kinase inhibitors ( PTK787 , DB05294 , ZD1839 , SU6668 and SU11248 ) on the growth of three mesothelioma cell lines ( NCI H226 , NCI H28 and MSTO 211H ) , the presence of growth factor receptors and inhibition of their downstream signalling pathways . GI50 values were determined : DB05294 and SU11248 , mainly P35968 inhibitors , gave the lowest GI50 across all cell lines ( 3 . 5 - 6 . 9 microM ) whereas ZD1839 gave a GI50 in this range only in H28 cells . All cell lines were positive for P00533 , but only H226 cells were positive for P35968 by Western blotting . DB05294 and ZD1839 inhibited P01133 - induced phosphorylation of P00533 , AKT and P29323 , whereas P15692 - induced phosphorylation of P35968 was completely inhibited with 0 . 1 microM SU11248 . P35968 was detected in tumour samples by immunohistochemistry . P35968 tyrosine kinase inhibitors warrant further investigation in mesothelioma .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK38___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .",
"[ ___MASK93___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK93___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Role of nitrative and oxidative DNA damage in inflammation - related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8 - dihydro - 2 '- deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 and γ - P16104 with 8 - oxodG and 8 - nitroguanine in inflammation - related cancer tissues suggest that DNA base damage leads to double - stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 - modulated P35228 expression via P40763 and P00533 in Epstein - Barr - virus - associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 - mediated JAK / P40763 pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation - related cancers .",
"DB05294 , an inhibitor of vascular endothelial growth factor receptor tyrosine kinase , inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non - small cell lung cancer model . DB05294 is a novel , orally active inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 ) tyrosine kinase , with some additional activity against epidermal growth factor receptor ( P00533 ) tyrosine kinase . The purpose of this study was to determine the potential of DB05294 in the control of established experimental lung metastasis and pleural effusions produced by human non - small cell lung cancer ( NSCLC ) cells . PC14PE6 ( adenocarcinoma ) and H226 ( squamous cell carcinoma ) cells express high levels of P00533 and only PC14PE6 cells overexpress P15692 . Neither DB05294 nor the P00533 tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro . Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5 - 7 weeks . In addition , PC14PE6 cells produced bloody pleural effusions . Daily oral treatment with DB05294 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells , but did reduce the lung weight and the size of lung nodules . DB05294 also inhibited the production of pleural effusions by PC14PE6 cells . Histological analyses of lung lesions revealed that DB05294 treatment inhibited activation of P35968 and reduced tumor vascularization and tumor cell proliferation . Therapeutic effects of DB05294 were considered likely to be due to inhibition of P35968 tyrosine kinase because gefitinib was inactive in this model . These results indicate that DB05294 , an inhibitor of P35968 , may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC .",
"P05305 activates P25101 receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL . OBJECTIVE : Lipid retention in the vessel wall by glycosaminoglycan ( GAG ) chains on chondroitin / dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells ( VSMC ) have recently been established as an early event in human coronary artery atherosclerosis . GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein ( LDL ) . The aim of this study was to determine if proteoglycans produced by endothelin - 1 treated VSMCs had increased binding to human LDL , to examine the effect of endothelin - 1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway . METHODS AND RESULTS : P05305 stimulated an increase in [( 35 ) S ] sulfate and [( 3 ) H ] glucosamine incorporation into proteoglycans produced by human VSMC . The increase was due to an increase in GAG chain size assessed by SDS - PAGE and size exclusion chromatography . Increased radiolabel incorporation was inhibited by an ET ( A ) but not an ET ( B ) receptor antagonist . P05305 stimulated an increase in the 6 : 4 position sulfation ratio on the disaccharides of the GAG chains , an effect that was blocked by ___MASK68___ . The P01133 receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin - 1 . Inhibition of protein kinase C ( PKC ) with GF109203X or down regulation by PMA pre - treatment attenuated the effect of endothelin - 1 on GAG synthesis . CONCLUSION : These data demonstrate that endothelin - 1 stimulates changes in GAG chain structure that increase binding to LDL . This action of endothelin - 1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction .",
"17 ___MASK41___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"DB05294 for the treatment of non - small - cell lung cancer . INTRODUCTION : The use of targeted therapies in the treatment of advanced non - small - cell lung cancer ( NSCLC ) is increasing , especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity . Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor ( VEGFR ) and epidermal growth factor receptor ( P00533 ) . DB05294 is an orally available inhibitor of VEGFR and P00533 signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways . AREAS COVERED : This review encompasses the clinical efficacy , safety and tolerability of vandetanib in advanced NSCLC . Of particular interest are the randomized Phase III clinical trials , which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens . EXPERT OPINION : DB05294 has anti - tumour activity in NSCLC , with improved objective responses and disease control . However , significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC .",
"Current status of vandetanib ( DB05294 ) in the treatment of non - small cell lung cancer . DB05294 ( DB05294 ) is an oral small molecule inhibitor of multiple intracellular receptor kinases , including the vascular endothelial growth factor receptor ( VEGFR ) - 2 and epidermal growth factor receptor ( P00533 ) . Both VEGFR and P00533 pathways have emerged as instrumental in the growth and metastasis of multiple malignancies , including non - small cell lung cancer ( NSCLC ) . Indeed , inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC . As there is considerable cross talk between these pathways , dual inhibition with such agents has become an attractive strategy , with encouraging Phase II clinical trial data to date . The convenience of one oral agent targeting both pathways is clear , and clinical trials have established the maximum tolerated daily dose of vandetanib , with data from randomized Phase III trials emerging . This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib , and speculate on the future of this agent in NSCLC .",
"Use of novel second - line targeted therapies in non - small cell lung cancer . Non - small cell lung cancer ( NSCLC ) is the leading cause of cancer death in the United States and throughout the world . This is largely because more than half of lung cancer cases present as metastatic disease , making local therapy for cure impossible . The last decade has seen significant improvement in first - line treatment of NSCLC , including the use of new chemotherapeutic agents with more effective therapeutic profiles . However , standard cytotoxic regimens are still limited and it remains critical to better understand and develop new treatment options for refractory disease . This has included some new second - line therapeutic approaches and has led to a focus on molecular targeted therapy , including agents that block the epidermal growth factor receptor ( P00533 ) or angiogenesis . P00533 - targeted agents such as gefitinib , erlotinib , and cetuximab have been successfully used for NSCLC treatment , with studies reporting overall response rates of 18 . 4 % , 8 . 9 % , and 3 . 3 % , respectively . Angiogenesis inhibitors such as bevacizumab and DB05294 have also improved treatment outcome . DB00112 had an overall response rate of 27 % when used in combination with paclitaxel and carboplatin , and DB05294 had an overall response rate of 26 % when used in combination with docetaxel . Using these compounds alone or in combination may improve the survival and quality of life of patients with lung cancer in the refractory setting .",
"The retinoid signalling molecule , O95361 , is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro . Retinoid therapy is used for chemo - prevention in immuno - suppressed patients at high risk of developing skin cancer . The retinoid signalling molecule , tripartite motif protein 16 ( O95361 ) , is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid - sensitive neuroblastoma . We sought to determine the role of O95361 in skin squamous cell carcinoma ( SCC ) pathogenesis . We have shown that O95361 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC . SCC cell lines exhibited lower cytoplasmic and nuclear O95361 expression compared with primary human keratinocyte ( PHK ) cells due to reduced O95361 protein stability . Overexpressed O95361 translocated to the nucleus , inducing growth arrest and cell differentiation . In SCC cells , O95361 bound to and down regulated nuclear Q01094 , this is required for cell replication . Retinoid treatment increased nuclear O95361 expression in retinoid - sensitive PHK cells , but not in retinoid - resistant SCC cells . Overexpression of O95361 reduced SCC cell migration , which required the C - terminal P07949 finger protein ( RFP ) - like domain of O95361 . The mesenchymal intermediate filament protein , vimentin , was directly bound and down - regulated by O95361 and was required for O95361 - reduced cell migration . Taken together , our data suggest that loss of O95361 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity .",
"Antipruritic activity of the kappa - opioid receptor agonist , P04629 - 820 . The effects of the kappa - opioid receptor agonist , P04629 - 820 , (-)- 17 -( cyclopropylmethyl )- 3 , 14beta - dihydroxy - 4 , 5alpha - epoxy - 6beta - [ N - methyl - trans - 3 -( 3 - furyl ) acrylamido ] morphinan hydrochloride , on the itch sensation were compared with those of histamine H1 receptor antagonists , using the mouse pruritogen - induced scratching model . Peroral administration of P04629 - 820 reduced the numbers of DB05875 - or histamine - induced scratches dose dependently . No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments , indicating that the inhibition of scratches was not due to the effect on general behavior . Furthermore , the scratching inhibitory activity of P04629 - 820 was dose dependently antagonized by the specific kappa - opioid receptor antagonist , nor - binaltorphimine , suggesting that the inhibitory activity was mediated via kappa - opioid receptors . P35367 antagonists , chlorpheniramine and ketotifen , did not inhibit DB05875 - induced scratches , or did so only partially . Both antihistamines inhibited the histamine - induced scratches completely . These results suggest that P04629 - 820 has antipruritic activity which is mediated by kappa - opioid receptors , and is effective in both antihistamine - sensitive and - resistant pruritus .",
"DB05294 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model . Angiogenesis inhibitors have been used to treat some cancers , but the therapeutic potential of these agents for gastric cancer has remained unclear . To investigate their therapeutic potential , we examined the effect of DB05294 , an agent that selectively targets vascular endothelial growth factor receptor - 2 ( P35968 ; P35968 ) tyrosine kinase and epidermal growth factor receptor ( P00533 ) tyrosine kinase , in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line , 58As1 . DB05294 ( 100 mg / kg / day , p . o . , 2 weeks ) significantly inhibited tumor growth ( p < 0 . 05 vs . control ) and reduced tumor dissemination into the peritoneal cavity ( p < 0 . 05 vs . control ) . In addition , to identify putative tumor biomarkers that would reflect the effects of DB05294 treatment in clinical settings , we examined the gene expression profiles of implanted gastric tumors treated with DB05294 in vivo . Twenty - eight candidate genes were identified , including P17936 , P35318 , Q9BY76 , O00469 , Q99576 , Q92597 , P09104 , Q9Y5L2 and O60238 , which are known to be hypoxia - inducible genes . These genes and gene products may be useful biomarkers for monitoring the effects of DB05294 treatment . DB05294 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line , 44As3 . In conclusion , our results suggest that DB05294 may have clinical activity against gastric cancer , particularly undifferentiated gastric cancer with peritoneal dissemination . We also identified putative biomarkers for monitoring the pharmacodynamic effects of DB05294 by gene expression profiling .",
"New insights in drug development for the non - small cell lung cancer therapy . Non - small cell lung cancer ( NSCLC ) remains a major problem worldwide . Since most patients with NSCLC have advanced disease at diagnosis , to date , chemotherapy , with third - generation platinum - based doublets , represents the standard of care . However , a plateau has been reached with the use of cytotoxic chemotherapy in advanced NSCLC . Advances in the knowledge of tumour biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment . To date , erlotinib and gefitinib , epidermal growth factor receptor tyrosine kinase ( P00533 - TK ) inhibitors have been licensed , erlotinib worldwide and gefitinib in Asian countries , for refractory NSCLC . Currently , bevacizumab , an anti - vascular endothelial growth factor ( P15692 ) monoclonal antibody , is the only clinically available antiangiogenic agent licensed , in combination with carboplatin plus paclitaxel , for first - line therapy of advanced NSCLC patients in the United States . Several new biologic agents are being evaluated in clinical research and some of them , such as DB05294 , sorafenib and sunitinib , due to the reported preliminary results and the oral administration seem to be promising targeted agents for the treatment of NSCLC . Aim of this review is to discuss about the new insights in targeted agents development for the treatment of NSCLC patients .",
"Identification of candidate small - molecule therapeutics to cancer by gene - signature perturbation in connectivity mapping . Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene - expression similarities . The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and / or toxicological properties . Challenges remain , however , as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following - up investigation can be maximised . We introduce a new concept , gene - signature perturbation , which aims to test whether an identified connection is stable enough against systematic minor changes ( perturbation ) to the gene - signature . We applied the perturbation method to three independent datasets obtained from the GEO database : acute myeloid leukemia ( AML ) , cervical cancer , and breast cancer treated with letrozole . We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs . In the case of AML , we found that the prevalent compounds were retinoic acids and Q07869 activators . For cervical cancer , our results suggested that potential drugs are likely to involve the P00533 pathway ; and with the breast cancer dataset , we identified candidates that are involved in prostaglandin inhibition . Thus the gene - signature perturbation approach added real values to the whole connectivity mapping process , allowing for increased specificity in the identification of possible therapeutic candidates .",
"Systemic therapy of advanced urothelial cancer . Advanced bladder / urothelial cancer remains an incurable terminal disease , and accounts for 3 % of the cancer related mortality in the United States . Systemic chemotherapy achieves palliation , survival benefit , and occasional long - term remissions . The two regimens that have been widely adopted consist of either cisplatin and gemcitabine , or the MVAC ( methotrexate , vinblastine , doxorubicin and cisplatin ) regimen . Novel therapies are being evaluated in metastatic bladder cancer to improve survival outcomes . A randomized trial of larotaxel ( a novel taxane ) and cisplatin vs cisplatin and gemcitabine in frontline therapy of metastatic urothelial cancer is ongoing . The studies evaluating therapies targeted frontline involve cisplatin and gemcitabine with or without cetuximab ( ongoing ) , and with or without bevacizumab ( CALGB proposed trial ) . With the advent of adjuvant / neoadjuvant cisplatin - based therapy , and improvement in supportive care , more patients are being considered for second - line therapies in urothelial cancer thus making this a field of emerging importance . The only phase III trial in pretreated urothelial cancer compared vinflunine with best supportive care , and revealed no significant survival improvement . Clinical trials are ongoing with pazopanib , a P15692 inhibitor , and DB05294 , a P15692 and P00533 inhibitor . The biggest hurdle to progress in advanced bladder cancer has been the slow accrual to studies in the United States . Making clinical trial participation a priority in bladder cancer is the dire need of the moment . At the same time , it is essential to take into account the changing needs of the population afflicted with bladder cancer , and tailor the therapeutic trials to fit a contemporary patient .",
"In vitro effects and ex vivo binding of an P00533 - specific immunotoxin on rhabdomyosarcoma cells . PURPOSE : Rhabdomyosarcoma ( RMS ) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy . New therapeutic strategies based on targeted immunotherapy are therefore much in demand . The epidermal growth factor receptor ( P00533 ) has all the characteristics of an ideal target . It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors . We therefore tested the activity of the P00533 - specific recombinant immunotoxin ( IT ) 425 ( scFv )- P25101 ' against P00533 (+) RMS cells in vitro and ex vivo . METHODS : We tested the specific binding and internalization behavior of 425 ( scFv )- P25101 ' in RMS cell lines in vitro by flow cytometry , compared to the corresponding imaging probe 425 ( scFv )- P60880 monitored by live cell imaging . The cytotoxic activity of 425 ( scFv )- P25101 ' was tested using cell viability and apoptosis assays . Specific binding of the IT was confirmed on formalin - fixed paraffin - embedded tissue samples from two RMS patients . RESULTS : We confirmed the specific binding of 425 ( scFv )- P25101 ' to RMS cells in vitro and ex vivo . Both the IT and the corresponding imaging probe were rapidly internalized . The IT killed P00533 (+) RMS cells in a dose - dependent manner , while showing no effect against control cells . It showed specific apoptotic activity against one selected RMS cell line . CONCLUSIONS : This is the first study showing the promising therapeutic potential of a recombinant , P00533 - targeting , P25101 '- based IT on RMS cells . We confirmed the selective killing with IC50 values of up to 50 pM , and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material .",
"Receptor tyrosine kinases : the main targets for new anticancer therapy . Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity . The major prerequisite to develop such drugs is to understand the targets that these agents should attack . In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules . The clinically most effective compounds function as tyrosine kinase inhibitors . In the past , various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth . Having shown their expression characteristics in different tumor entities , specific inhibitors of the DB00171 binding sites of these receptors or antibodies were developed and entered clinical trials . The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug , whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein . The future will define indications for such drugs by tumor kinase profiles instead of tumor entities . Gleevec , inhibiting the P11274 - P00519 tyrosine kinase ; DB00317 , inhibiting the P01133 - receptor tyrosine kinase ; Herceptin , inhibiting the Her2 / neu tyrosine kinase and PTK787 / ZK222584 , inhibiting the P15692 - receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas DB05294 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors .",
"An update on molecularly targeted therapies in second - and third - line treatment in non - small cell lung cancer : focus on P00533 inhibitors and anti - angiogenic agents . DB01248 , pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors ( gefitinib and erlotinib ) are recommended second - line therapy for advanced non - small cell lung cancer ( NSCLC ) patients with disease progression . Although erlotinib is the only recommended third - line therapy , several drugs are being used in the clinic . Recent studies have focused on combining targeted agents with approved therapies , including broad - spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti - angiogenic agents targeting the vascular endothelial growth factor receptor , platelet - derived growth factor receptor and fibroblast growth factor receptor pathways . Here , we review targeted therapies that are being evaluated in second - and third - line settings in NSCLC , including the ErbB Family Blocker afatinib ( DB08916 ) , multityrosine kinase inhibitors ( pelitinib [ Q9Y259 - 56 ] ) , neratinib [ HKI - 272 ] , canertinib [ DB05424 ] , lapatinib [ GW - 572016 ] , dacomitinib [ PF - 299804 ] ) and multitargeted anti - angiogenic agents ( vandetanib [ DB05294 ] , sunitinib [ SU11248 ] , sorafenib [ BAY43 - 9006 ] , nintedanib [ BIBF1120 ] , axitinib [ AG - 013736 ] , cediranib [ DB04849 ] , motesanib [ Q99217 706 ] , linifanib [ ABT869 ] and pazopanib [ DB06589 ] ) .",
"Vascular endothelial growth factor receptor - 1 contributes to resistance to anti - epidermal growth factor receptor drugs in human cancer cells . PURPOSE : The resistance to selective P00533 inhibitors involves the activation of alternative signaling pathways , and Akt activation and P15692 induction have been described in P00533 inhibitor - resistant tumors . Combined inhibition of P00533 and other signaling proteins has become a successful therapeutic approach , stimulating the search for further determinants of resistance as basis for novel therapeutic strategies . EXPERIMENTAL DESIGN : We established human cancer cell lines with various degrees of P00533 expression and sensitivity to P00533 inhibitors and analyzed signal transducers under the control of P00533 - dependent and P00533 - independent pathways . RESULTS : Multitargeted inhibitor vandetanib ( DB05294 ) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild - type and P00533 inhibitor - resistant human colon , prostate , and breast cancer cells . We found that the resistant cell lines exhibit , as common feature , P17948 / Flt - 1 overexpression , increased secretion of P15692 and placental growth factor , and augmented migration capabilities and that vandetanib is able to antagonize them . Accordingly , a new kinase assay revealed that in addition to P15692 receptor ( VEGFR ) - 2 , P07949 , and P00533 , vandetanib efficiently inhibits also P17948 . The contribution of P17948 to the resistant phenotype was further supported by the demonstration that P17948 silencing in resistant cells restored sensitivity to anti - P00533 drugs and impaired migration capabilities , whereas exogenous P17948 overexpression in wild - type cells conferred resistance to these agents . CONCLUSIONS : This study shows that P17948 contributes to anti - P00533 drug resistance in different human cancer cells . Moreover , vandetanib inhibits P17948 activation , cell proliferation , and migration , suggesting its potential utility in patients resistant to P00533 inhibitors .",
"DB05294 , designed to inhibit P35968 and P00533 signaling , had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of P35968 . PURPOSE : To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer . EXPERIMENTAL DESIGN : A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging . Core 18 - gauge needle biopsies and dynamic contrast - enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy . Biopsy samples were subjected to reverse - phase protein lysate array endpoint analysis . Cytokine concentrations were measured by enzyme - linked immunosorbent assay in serially collected plasma samples . RESULTS : Twelve patients entered the study , and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months . Adverse events included rash , diarrhea , and prolonged QT interval corrected for heart rate , but not hypertension . Exploratory analyses showed that epidermal growth factor receptor ( P00533 ) phosphorylation was reduced in the eight paired biopsy sets obtained ; vascular endothelial growth factor ( P15692 ) receptor - 2 phosphorylation was not consistently affected nor were dynamic contrast - enhanced Q9BWK5 permeability and flow parameters . Serial plasma P15692 concentrations were variable and did not significantly change in the 11 patients assessed . CONCLUSIONS : DB05294 300 mg daily monotherapy had no significant clinical benefit in this disease setting . Proteomic analysis of paired biopsies detected both phosphorylated - P00533 and phosphorylated - P15692 receptor - 2 in ovarian tumor tissue , but only phosphorylated - P00533 was measurably inhibited by vandetanib .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"Combined inhibition of vascular endothelial growth factor and epidermal growth factor signaling in non - small - cell lung cancer therapy . Elucidation of molecular pathways that promote malignancies has led to the identification of the epidermal growth factor receptor ( P00533 ) and vascular endothelial growth factor ( P15692 ) as key components involved in regulation of tumor proliferation and angiogenesis , respectively . Biologic agents that target these individual pathways have proven effective in treating patients with advanced non - small - cell lung cancer ( NSCLC ) , adding to previously available therapies and often with fewer side effects . However , inhibition of a single molecular pathway does not account for alternate pathways or biologic adaptations that eventually lead to resistance . Therefore , combining P00533 and P15692 inhibition is currently under investigation as a means to overcome resistance and promote synergy . Erlotinib , an anti - P00533 agent , and bevacizumab , an anti - P15692 agent , are both approved in NSCLC , demonstrating single - agent activity . The phase II trials evaluating the combination of erlotinib and bevacizumab have shown efficacy as first - line therapy or in patients with previously treated NSCLC either alone or with chemotherapy . Dual inhibition of P00533 and P15692 pathways has also been accomplished by the novel agents vandetanib and DB05007 , which are able to target both pathways . DB05294 has also demonstrated activity in patients with advanced NSCLC either alone or with chemotherapy in phase I / II studies . Another novel agent , DB05007 , has demonstrated promising single - agent activity in patients who have been resistant to previous anti - P00533 therapy . Further evaluation of combined P00533 and P15692 inhibition is under investigation .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK68___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK68___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"Endothelial progenitor cells induce transplant arteriosclerosis via P17948 / 2 activity . BACKGROUND : Acute rejection ( AR ) after organ transplantation results in transplant arteriosclerosis ( TA ) . Endothelial progenitor cells ( EPCs ) are involved in tissue repair and blood vessel formation but are suspected to be a cause of TA . METHODS : In this study , we introduced a syngeneic and allogeneic abdominal aortic transplant model with C57BL / 6 and BALB / c mice . Syngeneic and allogeneic grafts were histopathologically analyzed after transplantation . Bone marrow - derived EPCs were injected into transplant model animals to observe their distribution and temporal concentration changes . Changes of vascular endothelial growth factor receptor 1 ( P17948 ) , phosphorylated P17948 ( pVEGFR - 1 ) , P35968 , pVEGFR - 2 , protein kinase B ( Akt ) , pAkt , extracellular signal - regulated kinase 1 ( Erk1 ) , pErk1 levels in EPCs upon VEGF165 and the VEGFR inhibitor DB05294 exposure were analyzed in vitro with western blotting . RESULTS : In the allogeneic transplant group , two weeks after transplantation , formations of new intima layers could be observed , and its proliferation gradually increased to four and six weeks post - transplantation ( p < 0 . 05 ) , accompanied by significant arterial stenoses . Exogenous EPCs mainly localized to the damaged sites of the transplant arteries . In vivo , DB05294 caused a significant dose dependent decrease of transplant hyperplasia ( p < 0 . 05 ) and inhibited P15692 related proliferation , migration and adhesion of EPCs . CONCLUSION : DB05294 treatment can reduce arteriosclerosis induced by abdominal aorta transplantation by blocking VEGFRs in EPCs .",
"Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .",
"DB05294 -- a novel inhibitor of VEGFR and P00533 tyrosine kinase activity . Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth . Inhibitors of tumour blood vessel formation are therefore being sought , in particular , inhibitors of vascular endothelial growth factor - A ( P15692 ) - signalling , which has a pivotal role in stimulating neovascular growth and survival . DB05294 is an orally bioavailable inhibitor of P15692 receptor - 2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both P15692 - induced signalling in endothelial cells and tumour - induced angiogenesis . Consistent with inhibition of angiogenesis , once - daily oral dosing of DB05294 produced significant broad - spectrum antitumour activity in a panel of histologically diverse human tumour xenografts . In addition to its antiangiogenic properties , DB05294 also has activity against the epidermal growth factor receptor ( P00533 ) tyrosine kinase , which could impart a direct inhibitory effect on tumour cell growth and survival . This may be particularly relevant in tumours with a dependency upon P00533 signalling , for example in certain tumours harbouring activating mutations in P00533 . P07949 kinase has also been identified as a third target for DB05294 . This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment .",
"3 - hydroxy - 3 - methylglutaryl - coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis . BACKGROUND & AIMS : Inhibition of 3 - hydroxy - 3 - methylglutaryl - coenzyme A ( HMG - DB01992 ) reductase blocks the mevalonate metabolic pathway , which is necessary for the isoprenylation of a number of small guanosine triphosphatases . We examined the effects of P04035 inhibitors , fluvastatin and lovastatin , on human pancreatic cancer cell invasion in vitro and experimental liver metastasis in vivo . METHODS : Cell invasion was studied in a modified Boyden chamber assay . The translocation of RhoA was assessed by immunoblotting . Experimental liver metastases were induced in nude mice by intrasplenic inoculation of ASPC - 1 human pancreatic cancer cells . RESULTS : ___MASK12___ and lovastatin inhibited the in vitro cancer cell invasion induced by epidermal growth factor ( P01133 ) in a manner sensitive to P01024 transferase , a specific inhibitor of Rho . Treatment of ASPC - 1 cells with fluvastatin markedly attenuated the P01133 - induced translocation of RhoA from the cytosol to the membrane fraction and caused cell rounding . The effects of fluvastatin could be reversed by the addition of all - trans - geranylgeraniol . Administration of fluvastatin to nude mice reduced both metastatic tumor formation in the liver and the growth of established liver metastases at doses recommended for the treatment of hypercholesterolemia in humans . CONCLUSIONS : P04035 inhibitors can be antimetastatic agents with the potential for useful clinical applications .",
"Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .",
"Pan - Q07869 Agonist , ___MASK13___ , Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats . Introduction . The aim of this study was to investigate the effect of bezafibrate as a pan - Q07869 agonist on angiogenesis and serum nitrite , the main metabolite of nitric oxide ( NO ) , vascular endothelial growth factor ( P15692 ) and P15692 receptor - 2 ( P35968 ) concentrations in hindlimb ischemia model of normal and type I diabetic rats . Methods . 28 male Wistar rats were divided into control and diabetic groups . Then , all rats underwent unilateral hindlimb ischemia . After recovery , they were randomly assigned to one of the following experimental groups : ( 1 ) control ; ( 2 ) control + bezafibrate ( 400 mg / kg / day ) ; ( 3 ) diabetic ; ( 4 ) diabetic + beztafibrate . After three weeks , blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb . Results . ___MASK13___ increased capillary density and capillary / fiber ratio in ischemic leg of diabetic and control rats ( P < 0 . 05 ) . Serum P15692 and P35968 concentrations did not alter after bezafibrate administration , however , serum nitrite concentration was significantly higher in bezafibrate - treated groups than non - treated groups ( P < 0 . 05 ) . Discussion . It seems that bezafibrate , as a pan Q07869 agonist , restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and / or treatment of peripheral artery disease in diabetic subjects .",
"Targeted therapy in head and neck cancer . Head and neck squamous cell carcinoma ( HNSCC ) of multi - factorial etiopathogenesis is rising worldwide . Treatment - associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies . Molecular targeted therapy , with the potential for increased selectivity and fewer adverse effects , hold promise in the treatment of HNSCC . In an attempt to improve outcomes in HNSCC , targeted therapeutic strategies have been developed . These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis . Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches . Targeted agents for HNSCC expected to improve the effectiveness of current therapy include P00533 inhibitors ( Cetuximab , DB01269 , Zalutumumab ) , P00533 tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( DB00112 , DB05294 ) , and various inhibitors of , e . g . , Src - family kinase , PARP , proteasome , P42345 , P36551 , and heat shock protein . Moreover , targeted molecular therapy can also act as a complement to other existing cancer therapies . Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control , without exacerbating the treatment related toxicities . Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use , whereas remainder exhibits mixed result and necessitates further studies . Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment .",
"Targeting the P00533 pathway for cancer therapy . Clinical studies have shown that HER - 2 / Neu is over - expressed in up to one - third of patients with a variety of cancers , including B - cell acute lymphoblastic leukemia ( B - ALL ) , breast cancer and lung cancer , and that these patients are frequently resistant to conventional chemo - therapies . Additionally , in most patients with multiple myeloma , the malignant cells over - express a number of epidermal growth factor receptors ( P00533 ) s and their ligands , HB - P01133 and amphiregulin , thus this growth - factor family may be an important aspect in the patho - biology of this disease . These and other , related findings have provided the rationale for the targeting of the components of the P00533 signaling pathways for cancer therapy . Below we discuss various aspects of P00533 - targeted therapies mainly in hematologic malignancies , lung cancer and breast cancer . Beside novel therapeutic approaches , we also discuss specific side effects associated with the therapeutic inhibition of components of the P00533 - pathways . Alongside small inhibitors , such as DB01259 ( DB01259 , GW572016 ) , Gefitinib ( DB00317 , ZD1839 ) , and Erlotinib ( Tarceva , DB00530 ) , a significant part of the review is also dedicated to therapeutic antibodies ( e . g . : DB00072 / Herceptin , DB06366 / DB06366 / rhuMab - 2C4 , Cetuximab / Erbitux / IMC - C225 , DB01269 / Abenix / DB01269 , and also DB05294 ) . In addition , we summarize , both current therapy development driven by antibody - based targeting of the P00533 - dependent signaling pathways , and furthermore , we provide a background on the history and the development of therapeutic antibodies .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK34___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"DB05294 therapy in medullary thyroid cancer . The U . S . Food and Drug Administration ( FDA ) approved vandetanib in April 2011 for the treatment of unresectable , locally advanced or metastatic medullary thyroid cancer ( P04629 ) . In Europe it was approved in March 2012 , but only for the treatment of aggressive and symptomatic P04629 . This small molecule is a tyrosine kinase inhibitor of several growth factors involved in cellular proliferation and angiogenesis , including the epidermal growth factor receptor ( P00533 ) and the vascular endothelial growth factor receptors 2 and 3 ( P35968 , P35916 ) . In addition , vandetanib is an inhibitor of the P07949 ( rearranged during transfection ) gene , a proto - oncogene often mutated in familial P04629 . Since P04629 is a rare disease , for which no previous medical therapies are approved , vandetanib is the first drug shown to be effective in a large phase III trial treating patients with metastatic or locally advanced P04629 . Common adverse events are diarrhea , nausea , hypertension , headache and QT prolongation that are manageable and are commonly outweighed by the benefits of vandetanib in terms of delaying disease progression and inducing tumor response .",
"Vascular endothelial growth factor trap in non small cell lung cancer . Several drugs currently in development target the vascular endothelial growth factor ( P15692 ) pathway , a validated target in the treatment of non - small cell lung cancer ( NSCLC ) . Most clinical trial data generated to date have been with either bevacizumab , a monoclonal antibody to P15692 , or small - molecule inhibitors of P15692 receptor ( VEGFR ) tyrosine kinase activity ( sunitinib , sorafenib , and DB05294 ) . DB08885 , an engineered soluble receptor made from extracellular domains of P17948 and P35968 , binds to all isoforms of P15692 and to placental growth factor . DB08885 binds to P15692 and P49765 with markedly higher affinity than bevacizumab . The toxicities seen in phase I trials of s . c . and i . v . administration of DB08885 , hypertension and proteinuria , are similar to those seen with other molecules that target the P15692 pathway . In the s . c . DB08885 phase I trial , significant radiographic improvement was observed in a patient with heavily pretreated NSCLC . Ongoing phase I trials are evaluating combinations of DB08885 with platinum - based doublets and single - agent docetaxel . The activity of single - agent DB08885 in NSCLC is being assessed in a multicenter phase II trial ."
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___MASK68___
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MH_train_314
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interacts_with DB00790?
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[
"In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling . The mechanism by which thrombotic vessel occlusion occurs independently of plaque development or endothelial cell ( EC ) disruption remains unclear , largely because of an inability to visualize the formation of thrombus , especially at the single - platelet level in real time . Here we demonstrate that rapidly developing thrombi composed of discoid platelets can be induced in the mesenteric capillaries , arterioles , and large - sized arteries of living mice , enabling characterization of the kinetics of thrombosis initiation and the multicellular interrelationships during thrombus development . Platelet aggregation without EC disruption was triggered by reactive oxygen species ( ROS ) photochemically induced by moderate power laser irradiation . The inflammatory cytokines P01375 - α and IL - 1 could be key components of the EC response , acting through regulation of P04275 mobilization to the cell surface . Thrombus formation was then initiated by the binding of platelet GPIbα to endothelial P04275 in our model , and this effect was inhibited by the ROS scavenger DB06151 . Actin linker talin - dependent activation of alphaIIb - beta3 integrin or Rac1 in platelets was required for late - phase thrombus stability . Our novel imaging technology illustrates the molecular mechanism underlying inflammation - based thrombus formation by discoid platelets on undisrupted ECs and suggests control of ROS could be a useful therapeutic target for the prevention of thrombotic diseases .",
"[ An effect of perindopril on the level of tumor necrosis factor - alpha and matrix metalloproteinase - 9 in peripheral blood in the acute period of atherothrombotic ischemic stroke and myocardial infarction ] . Twenty - nine patients with acute atherothrombotic ischemic stroke and 36 patients with acute Q - wave myocardial infarction have been studied . Each group has been stratified into 2 subgroups : patients of subgroups A received an P12821 inhibitor perindopril in the complex therapy from the 1st day of disease . Patients of subgroups B were not assigned to this drug . Along with routine tests , the level of tumor necrosis factor - alpha and matrix metalloproteinase - 9 ( P14780 ) measured with ELISA using test - systems ( Q02223 Diagnostics , USA ) and reagents ( R & D , England ) have been determined . The administration of perindopril did not cause side - effects , including arterial hypotonia after the first dosage , in patients in the acute period of atherothrombotic ischemic stroke and myocardial infarction . DB00790 may decrease the activity of P14780 in these patients and produces an anticytokine effect . Some similar mechanisms of ischemic lesions of the heart and the brain and a commonness of biochemical \" response \" to the same medical intervention ( the administration of an P12821 inhibitor perindopril ) in patients of both groups were found . The results support the pathogenetic validity of perindopril therapy in the secondary prevention of ischemic stroke and myocardial infarction .",
"DB00790 decreases P wave dispersion in patients with stage 1 hypertension . INTRODUCTION : P12821 inhibitors prevent atrial fibrillation episodes by effective control of blood pressure and improving electrical and structural remodelling in the atria . Increased P wave dispersion ( P35670 ) is a non - invasive electrocardiographic marker for paroxysmal atrial fibrillation . The aim of the study was to evaluate the effect of perindopril treatment on P35670 in hypertensive patients . METHODS : Forty - eight hypertensive patients ( mean age 57 . 4 +/- 11 . 8 years , 18 men ) were included . Blood pressure values were determined and 12 - lead electrocardiograms were recorded at the beginning and at the first week , first month , third month and sixth month of the perindopril treatment . The difference between maximum and minimum P wave durations was calculated as P35670 . RESULTS : PWDs were significantly shortened at the first , third and sixth months ( 41 . 7 +/- 8 . 8 ms , Q04695 +/- 6 . 9 ms and 38 . 3 +/- 7 . 1 ms , respectively ) compared with baseline and first - week measurements ( 54 . 3 +/- 9 . 2 ms and 49 . 0 +/- 9 . 1 ms , respectively , p < 0 . 001 ) . Baseline P35670 was correlated with body mass index ( r = 0 . 32 , p = 0 . 026 ) , while P35670 at the sixth month of treatment was significantly correlated with left atrial volume index ( r = 0 . 30 , p = 0 . 042 ) . Multiple linear regression analysis revealed that P35670 at the sixth month was related to baseline P35670 ( p = 0 . 001 ) . CONCLUSION : DB00790 treatment significantly reduced P35670 in hypertensive patients .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice : role of cholinergic neurotransmission , cerebral blood flow and brain energy metabolism . Evidences indicate that inhibition of central P00797 angiotensin system ( DB01367 ) ameliorates memory impairment in animals and humans . Earlier we have reported involvement of central angiotensin converting enzyme ( P12821 ) in streptozotocin induced neurodegeneration and memory impairment . The present study investigated the role of central P12821 in cholinergic neurotransmission , brain energy metabolism and cerebral blood flow ( Q03701 ) in model of memory impairment induced by injection of scopolamine in mice . DB00790 ( 0 . 05 and 0 . 1 mg / kg , PO ) was given orally for one week before administration of scopolamine ( 3mg / kg , IP ) . Then , memory function was evaluated by Morris water maze and passive avoidance tests . Q03701 was measured by laser Doppler flowmetry . Biochemical and molecular parameters were estimated after the completion of behavioral studies . DB00747 caused impairment in memory which was associated with reduced Q03701 , acetylcholine ( ACh ) level and elevated acetylcholinesterase ( P22303 ) activity and malondialdehyde ( MDA ) level . DB00790 ameliorated scopolamine induced amnesia in both the behavioral paradigms . Further , perindopril prevented elevation of P22303 and MDA level in mice brain . There was a significant increase in Q03701 and ACh level in perindopril treated mice . However , scopolamine had no significant effect on DB00171 level and mRNA expression of angiotensin receptors and P12821 in cortex and hippocampus . But , perindopril significantly decreased P12821 activity in brain without affecting its mRNA expression . The study clearly showed the interaction between P12821 and cholinergic neurotransmission and beneficial effect of perindopril can be attributed to improvement in central cholinergic neurotransmission and Q03701 .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK71___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"P01308 - like growth factor - 1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2 - overexpressing breast cancer cells via Src - focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 ) - targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 - positive metastatic breast cancer . Increased expression or signaling from the insulin - like growth factor - 1 receptor ( IGF - 1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF - 1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF - 1R was invasion , which was mediated by both Src - focal adhesion kinase ( Q05397 ) signaling and Q08050 ( FoxM1 ) . Cotargeting IGF - 1R and P04626 using either IGF - 1R antibodies or IGF - 1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF - 1R and P04626 in trastuzumab - resistant cells . Constitutively active Src blocked the anti - invasive effect of IGF - 1R / P04626 cotargeted therapy . Furthermore , knockdown of FoxM1 blocked DB01277 - mediated invasion , and dual targeting of IGF - 1R and P04626 reduced expression of FoxM1 . Re - expression of FoxM1 restored the invasive potential of IGF - 1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF - 1R and P04626 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1 .",
"Neurophysiological investigations of two hundred men with erectile dysfunction . Interest of bulbocavernosus reflex and pudendal evoked responses . Two - Hundred consecutive patients complaining of impotence have had complete urological and neurophysiological investigations to determine a possible organic cause of their sexual dysfunction . All patients had urological and neurological history and examination : nocturnal penile plethysmography , papaverine intracavernosus injection , penile arterial doppler and / or arteriography , cavernography - cavernometry , serum hormonal levels , and bulbocavernosus reflex ( P11274 ) . Peripheral conduction velocities and pudendal - evoked responses ( O15534 ) were also performed if neurological history or examination and / or P11274 were abnormal . Only 30 patients ( 15 % ) had an abnormal P11274 . In 17 patients , a neurological associated disorder was found . Four patients had normal erections during plethysmography , despite their complaints . Nine patients with an isolated prolonged P11274 also presented a vascular abnormality that could explain impotence . Abnormal O15534 was observed only in 6 patients , 4 of them with a prolonged P11274 as well . These results suggest that O15534 is not an interesting neurophysiological routine test for the diagnosis of neurogenic impotence and that the relationship between an abnormal P11274 and neurogenic impotence is doubtful .",
"A role for plasma transforming growth factor - beta and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome ? BACKGROUND : We have previously shown that the angiotensin - converting enzyme ( P12821 ) inhibitor perindopril reduced aortic diameter by 3 - 7mm in Marfan syndrome ( MFS ) patients . Excessive signalling by the transforming growth factor - beta ( TGF - beta ) has been implicated in the development of aortic dilatation . We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF - beta and matrix metalloproteinase ( MMP ) levels . METHODS : 17 MFS patients ( aged 33 +/- 5 ( mean +/- SD ) ) on standard beta - blocker therapy were randomised to also receive perindopril ( n = 10 ) or placebo ( n = 7 ) for 24 weeks in a double blind study . Aortic root diameters were assessed at four sites via transthoracic echocardiography . Venous blood samples were analysed for latent and active TGF - beta , P08253 and P08254 levels . RESULTS : DB00790 significantly reduced aortic root diameters relative to placebo in both end - systole and end - diastole ( by 1 . 2 - 3mm / m ( 2 ) , p < 0 . 001 ) . In addition , compared to placebo perindopril significantly reduced latent TGF - beta levels by 14 . 0 +/- 4 . 5ng / ml ( p = 0 . 01 ) , active TGF - beta levels by 4 +/- 1ng / ml ( p = 0 . 02 ) , P08253 levels by 22 +/- 6ng / ml ( p < 0 . 001 ) , and P08254 levels by 5 +/- 1ng / ml ( p < 0 . 001 ) . There were moderately strong correlations between the pre / post intervention change in aortic diameters and the change in both latent ( r = 0 . 49 - 0 . 76 , p = 0 . 001 - 0 . 04 ) and active TGF - beta ( r = 0 . 59 - 0 . 73 , p = 0 . 002 - 0 . 02 ) , P08253 ( r = 0 . 63 - 0 . 75 , p = 0 . 001 - 0 . 007 ) , and P08254 plasma levels ( r = 0 . 81 - 0 . 83 , p < 0 . 0001 ) . CONCLUSIONS : Plasma TGF - beta , P08253 and P08254 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS .",
"Vascular endothelial growth factor expression and glomerular endothelial cell loss in the remnant kidney model . BACKGROUND : Vascular endothelial growth factor ( P15692 ) is constitutively expressed in the glomerulus where it may have a role in the maintenance of capillary endothelial cell integrity . The present study sought to examine changes in P15692 expression in a model of progressive renal disease and to assess the effects of angiotensin converting enzyme ( P12821 ) inhibition . METHODS : Subtotal nephrectomized ( STNx ) rats were randomly assigned to receive vehicle ( n = 10 ) or the P12821 inhibitor perindopril ( 8 mg / l drinking water ) for 12 weeks duration ( n = 10 ) . Sham - operated rats were used as controls ( n = 10 ) . Glomerular capillary endothelial cell density was evaluated by immunostaining for the pan - endothelial cell marker Q06609 - 1 and P15692 expression was assessed by quantitative in situ hybridization . RESULTS : In STNx rats glomerular capillary endothelial cell density was reduced to 19 % that of sham rats ( P < 0 . 01 ) with a concomitant reduction in glomerular P15692 expression , also to 19 % of sham rats ( P < 0 . 01 ) . DB00790 treatment was associated with normalization of both capillary endothelial cell density and glomerular P15692 mRNA . CONCLUSIONS : Reduction in glomerular P15692 expression is a feature of the renal pathology that follows subtotal nephrectomy . In the context of the known functions of this growth factor , these findings suggest that diminution in P15692 may contribute to the demonstrated loss of glomerular endothelium that develops in this model of progressive renal disease .",
"Differential radiosensitisation by ZD1839 ( ___MASK90___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK90___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer . Gefitinib ( ___MASK90___ (®) , ZD1839 ) is a small molecule inhibitor of the epidermal growth factor receptor ( P00533 ) tyrosine kinase . We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive ( BT474 and SKBR3 ) or insensitive ( MCF7 - GFPLC3 and JIMT - 1 ) to gefitinib . Our data show that elevation of autophagy in gefitinib - treated breast cancer cells correlated with downregulation of AKT and P27361 / 2 signaling early in the course of treatment . Inhibition of autophagosome formation by BECLIN - 1 or O95352 siRNA in combination with gefitinib reduced the abundance of autophagic organelles and sensitized SKBR3 but not MCF7 - GFPLC3 cells to cell death . However , inhibition of the late stage of gefitinib - induced autophagy with hydroxychloroquine ( HCQ ) or bafilomycin A1 significantly increased ( p < 0 . 05 ) cell death in gefitinib - sensitive SKBR3 and BT474 cells , as well as in gefitinib - insensitive JIMT - 1 and MCF7 - GFPLC3 cells , relative to the effects observed with the respective single agents . Treatment with the combination of gefitinib and HCQ was more effective ( p < 0 . 05 ) in delaying tumor growth than either monotherapy ( p > 0 . 05 ) , when compared to vehicle - treated controls . Our results also show that elevated autophagosome content following short - term treatment with gefitinib is a reversible response that ceases upon removal of the drug . In aggregate , these data demonstrate that elevated autophagic flux is an early response to gefitinib and that targeting P00533 and autophagy should be considered when developing new therapeutic strategies for P00533 expressing breast cancers .",
"The frequency of clinical pregnancy and implantation rate after cultivation of embryos in a medium with granulocyte macrophage colony - stimulating factor ( GM - P04141 ) in patients with preceding failed attempts of O00253 . The application in IVF practice of modern techniques can improve positive outcome of each cycle in the assisted reproductive technology ( O00253 ) programs and the effectiveness of treatment as a whole . There are embryos in the female reproductive tract in physiological medium which contain various cytokines and growth factors . It plays an important role in the regulation of normal embryonic development , improve implantation and subsequently optimizing the development of the fetus and the placenta . Granulocyte macrophage colony - stimulating factor ( GM - P04141 is one of the cytokines playing an important role in reproductive function . Addition of recombinant GM - P04141 to the culture medium can makes closer human embryos culture to in vivo conditions and improve the efficacy O00253 cycles . The analysis of culture embryos in EmbryoGen medium has shown that fertilization rate embryo culture and transfer to patients with previous unsuccessful attempts increases clinical pregnancy rate compared to the control group Q04695 versus 27 . 8 % , respectively . It is noted that the implantation rate ( on 7 weeks ' gestation ) and progressive clinical pregnancy rate ( on 12 weeks ' gestation ) were significantly higher in group embryos culture in EmbryoGen medium compared to standard combination of medium ( B1AKI9 + VA ) , and were 20 . 4 and 17 . 4 % versus 11 . 6 and 9 . 1 % , respectively .",
"Mast cell degranulation mediates bronchoconstriction via serotonin and not via renin release . To verify the recently proposed concept that mast cell - derived renin facilitates angiotensin II - induced bronchoconstriction bronchial rings from male Sprague - Dawley rats were mounted in Mulvany myographs , and exposed to the mast cell degranulator compound 48 / 80 ( 300 microg / ml ) , angiotensin I , angiotensin II , bradykinin or serotonin ( 5 - hydroxytryptamine , 5 - HT ) , in the absence or presence of the renin inhibitor aliskiren ( 10 micromol / l ) , the P12821 inhibitor captopril ( 10 micromol / l ) , the angiotensin II type 1 ( AT1 ) receptor blocker irbesartan ( 1 micromol / l ) , the mast cell stabilizer cromolyn ( 0 . 3 mmol / l ) , the 5 - Q13049 / 2C receptor antagonist ketanserin ( 0 . 1 micromol / l ) or the alpha1 - adrenoceptor antagonist phentolamine ( 1 micromol / l ) . Bath fluid was collected to verify angiotensin generation . Bronchial tissue was homogenized to determine renin , angiotensinogen and serotonin content . Compound 48 / 80 contracted bronchi to 24 +/- 4 % of the DB00761 - induced contraction . Ketanserin fully abolished this effect , while cromolyn reduced the contraction to 16 +/- 5 % . DB09026 , captopril , irbesartan and phentolamine did not affect this response , and the angiotensin I and II levels in the bath fluid after 48 / 80 exposure were below the detection limit . Angiotensin I and II equipotently contracted bronchi . DB01197 shifted the angiotensin I curve approximately 10 - fold to the right , whereas irbesartan fully blocked the effect of angiotensin II . Bradykinin - induced constriction was shifted approximately 100 - fold to the left with captopril . Serotonin contracted bronchi , and ketanserin fully blocked this effect . Finally , bronchial tissue contained serotonin at micromolar levels , whereas renin and angiotensinogen were undetectable in this preparation . In conclusion , mast cell degranulation results in serotonin - induced bronchoconstriction , and is unlikely to involve renin - induced angiotensin generation .",
"Endometrial regenerative cells : a novel stem cell population . Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle . Thus , we hypothesized that a stem cell - like population exist and can be isolated from menstrual blood . Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for > 68 doublings and retained expression of the markers P21926 , CD29 , CD41a , P16070 , P13987 , CD73 , CD90 and CD105 , without karyotypic abnormalities . Proliferative rate of the cells was significantly higher than control umbilical cord derived DB05914 , with doubling occurring every 19 . 4 hours . These cells , which we termed \" Endometrial Regenerative Cells \" ( ERC ) were capable of differentiating into 9 lineages : cardiomyocytic , respiratory epithelial , neurocytic , myocytic , endothelial , pancreatic , hepatic , adipocytic , and osteogenic . Additionally , ERC produced P08254 , P09238 , GM - P04141 , angiopoietin - 2 and DB00102 at 10 - 100 , 000 fold higher levels than two control cord blood derived mesenchymal stem cell lines . Given the ease of extraction and pluripotency of this cell population , we propose ERC as a novel alternative to current stem cells sources .",
"Bayesian meta - analysis of tissue angiotensin - converting enzyme inhibitors for reduction of adverse cardiovascular events in patients with diabetes mellitus and preserved left ventricular function . The role of angiotensin - converting enzyme ( P12821 ) inhibitors in diabetic patients with preserved ventricular function is uncertain . Tissue P12821 inhibitors have been defined by increased lipophilicity and structural characteristics that result in greater tissue - specific P12821 binding when compared with plasma P12821 inhibitors . A Bayesian meta - analysis of randomized trials was conducted to evaluate tissue P12821 inhibitors in prevention of cardiovascular disease among patients with diabetes mellitus and preserved left ventricular function . Four trials were selected that evaluated 2 different P12821 inhibitors and included 10 , 328 patients ( 43 , 517 patient - years ) . The DB00790 Substudy in Coronary Artery Disease and Diabetes ( PERSUADE ) and the DB00790 Protection Against Recurrent Stroke Study ( PROGRESS ) compared the effects of perindopril vs a placebo , and the Heart Outcomes Prevention Evaluation ( HOPE ) and the Non - P01308 - Dependent Diabetes , Hypertension , Microalbuminuria , Proteinuria , Cardiovascular Events , and Ramipril ( DIABHYCAR ) study investigated the impact of ramipril vs a placebo . Bayesian meta - analysis of sequential trials and sensitivity analysis of therapeutic response were subsequently computed . Bayesian meta - analysis determined reduced risk of cardiovascular mortality ( PB =. 991 ) , myocardial infarction ( PB =. 999 ) , and the need for invasive coronary revascularization ( PB =. 995 ) when compared with placebo . Total mortality was also decreased ( PB =. 967 ) , while the risk of stroke ( PB =. 907 ) and hospitalization for heart failure ( PB =. 923 ) were impacted . Bayesian meta - analysis of randomized trials suggests that tissue P12821 inhibitors decrease the probability that diabetic patients with preserved left ventricular function will experience myocardial infarctions and cardiovascular death and reduce overall mortality .",
"A comparison of the pharmacokinetics and tolerability of the novel antimigraine compound zolmitriptan in adolescents and adults . This open - label , parallel - group study assessed pharmacokinetics and tolerability of zolmitriptan , a P28222 / 1D agonist for the acute treatment of migraine , and its active metabolite , 183C91 , in adolescents compared with adults . Twenty - one healthy adolescent and 18 healthy adult volunteers ( with and without history of migraine ) received a single 5 - mg dose of zolmitriptan . Mean ages were 14 . 5 years ( range 12 - 17 ) for adolescents ( 13 girls , 8 boys ) and Q04695 years ( range 18 - 65 ) for adults ( 12 women , 6 men ) . The area under the curve ( AUC ) and highest observed plasma concentration ( Cmax ) of zolmitriptan were similar in both age groups ; the half - life was 3 . 01 hours in adolescents versus 3 . 75 hours in adults . The AUC and Cmax of 183C91 , however , were 36 % and 39 % higher in adolescents , respectively ; the half - life was similar in both age groups . Adverse events were similar in both groups in terms of nature , intensity , and frequency . Exposure to zolmitriptan was not significantly different in adolescents compared with adults , but a shorter half - life in adolescents suggests faster elimination in this age group . Exposure to 183C91 was higher in adolescents , suggesting that formation of the metabolite is at least one of the elimination routes of zolmitriptan that occurs at a faster rate in adolescents .",
"Acute effects of sarpogrelate , a 5 - Q13049 receptor antagonist on cytokine production in endotoxin shock model of rats . Serotonin ( 5 - HT ) ( 2A ) receptors are involved in cytokine production in infection or sepsis . Therefore , 5 - HT ( 2A ) receptor antagonist might be useful to treat sepsis . The present study investigates the effects of a 5 - HT ( 2A ) receptor antagonist , sarpogrelate on endotoxin shock . Catheters were inserted into the femoral artery and vein of Sprague - Dawley rats . First , sarpogrelate 0 ( control ) , 3 , or 10 mg / kg dissolved in 0 . 5 ml of distilled water has been given , followed by endotoxin 10 mg / kg in saline 0 . 5 ml 5 min later . Blood pressure , pulse rate and survival rate were monitored in 20 rats per dose . Blood gas and plasma cytokine concentrations were measured in 8 rats per dose . In four rats each of sarpogrelate 0 , 3 , or 10 mg / kg , and sham operation , the lung histology was examined . Zero , 15 , and 12 rats survived for 8 h in the control , 3 mg / kg , and 10 mg / kg groups , respectively . The control group had the lowest blood pressure , pulse rate , pH and arterial oxygen tension , and the highest arterial carbon dioxide tension and plasma IL - 1beta concentration . The increase of P01375 was significantly lower in 3 mg / kg group than in the control group . Pathological changes of the lung were inhibited in 3 and 10 mg / kg groups . In conclusion , sarpogrelate might be effective to decrease production of pro - inflammatory cytokines , to keep hemodynamics , to inhibit lung damage , and to decrease mortality in endotoxin shock .",
"___MASK83___ interferes with the inflammatory phase of healing in experimental colonic anastomoses . BACKGROUND : Delayed wound healing is a serious side effect of P42345 inhibitor - based immunosuppression after solid organ transplantation . The aim of this study was to test the hypothesis that the P42345 inhibitor everolimus interferes with the inflammatory phase of healing in experimental colonic anastomoses . MATERIALS AND METHODS : Thirty male Sprague - Dawley rats received a colonic anastomosis . Then , animals were randomized to three groups of daily treatment with either vehicle or everolimus in two different dosages ( 1 . 0mg / kg or 3 . 0mg / kg ) . After 7 d , rats were sacrificed , and mechanical , histologic , and biochemical parameters of intestinal healing were assessed . RESULTS : Anastomotic bursting pressure was significantly decreased by everolimus in both dosages , whereas hydroxyproline content was reduced only by the high everolimus dosage . ___MASK83___ diminished cellular proliferation and new vessel growth . Furthermore , both quantity as well as quality of newly synthesized collagen fibers in the anastomotic granulation tissue was reduced . On the other hand , myeloperoxidase - positive ( P05164 ) cells and interleukin - 6 ( P05231 ) concentrations were increased , as was the activity of matrix - metalloproteinases P08253 and P14780 . CONCLUSION : ___MASK83___ interferes with the inflammatory phase of healing . However , it remains unclear whether this phenomenon is involved in everolimus impairment of experimental anastomotic repair .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK83___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"PC12 cell activation by epidermal growth factor receptor : role of autophosphorylation sites . PC12 cells have been used as a model system for neuronal differentiation due to their ability to alter their phenotype to a sympathetic neuron - like cell in response to nerve growth factor or fibroblast growth factor . Under some conditions , epidermal growth factor ( P01133 ) can also induce PC12 cells to differentiate . To study signaling from the P01133 receptor without the confounding effects of endogenous P01133 receptors we generated a chimeric receptor comprised of the ectodomain of platelet - derived growth factor ( PDGF ) receptor in - frame with the transmembrane and cytoplasmic domains of P01133 receptor , termed O15534 . Expression of O15534 in PC12 cells confers the ability of PDGF to induce differentiation whereas PDGF has no effect on untransfected PC12 cells . This response is kinase activity - dependent since a kinase - deficient mutant ( K721M ) fails to induce differentiation in response to PDGF . Mutation of five tyrosine residues that are autophosphorylated in response to P01133 either individually or in combination had minimal effects on the ability of these receptors to induce morphological PC12 cell differentiation . The O15534 mutant with all five autophosphorylation sites mutated to phenylalanine ( 5YF ) was equivalently capable of interacting with several important signaling molecules , including Shc , Grb2 , Gab1 , phospholipase Cgamma , and Cbl . Furthermore , both the phosphatidylinositol 3 - kinase ( PI3K ) / Akt and Ras / Erk pathways were activated in a sustained manner when O15534 or 5YF - expressing cells were stimulated with PDGF . Our results show that the five autophosphorylation sites in the extra - kinase C - terminal domain of P00533 are not required for the ability of P00533 to induce morphological differentiation of PC12 cells .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK42___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Dual effect of angiotensin - converting enzyme inhibition on angiogenesis in type 1 diabetic mice . OBJECTIVE : We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor ( ACEI ) on both retinal and hind limb neovascularization in diabetic mice . METHODS AND RESULTS : Diabetic mice ( streptozotocin , 40 mg / kg ) were treated with or without ACEI ( DB00790 , 3 mg / kg per day ) or AT1 receptor blocker ( DB00796 , 20 mg / kg ) for 4 months . Hind limb ischemia was then induced by right femoral artery ligature for 1 additional month . In the ischemic leg , angiographic score , capillary density , and foot perfusion were increased by 2 . 7 , 2 . 0 - fold , and 1 . 6 - fold , respectively , in ACEI - treated diabetic mice compared with untreated diabetic animals ( P < 0 . 01 ) . ACEI also raised vascular endothelial growth factor ( P15692 ) protein level by 1 . 4 - fold in ischemic diabetic leg . This ACEI pro - angiogenic effect was totally blunted in diabetic bradykinin B2 receptor - deficient animals , suggesting that it was mediated by the bradykinin pathway . In the diabetic retina , angiotensinogen and P12821 mRNA levels were increased by 2 . 8 - fold and 4 . 1 - fold , respectively ( P < 0 . 01 versus nondiabetic mice ) , highlighting a local activation of renin - angiotensin system . Diabetes also raised P15692 protein level by 1 . 5 - fold ( P < 0 . 05 versus nondiabetic mice ) . Treatments with ACEI and AT1 receptor blocker hampered diabetes - induced P15692 upregulation and retinal neovascularization . CONCLUSIONS : P12821 inhibition improved neovascularization in the diabetic ischemic leg through activation of bradykinin signaling , whereas it reduced vessel growth in the diabetic retina through inhibition of overacting Ang II pathway .",
"P62158 interacts with angiotensin - converting enzyme - 2 ( Q9BYF1 ) and inhibits shedding of its ectodomain . P12821 - 2 ( Q9BYF1 ) is a regulatory protein of the renin - angiotensin system ( DB01367 ) and a receptor for the causative agent of severe - acute respiratory syndrome ( P49591 ) , the P49591 - coronavirus . We have previously shown that Q9BYF1 can be shed from the cell surface in response to phorbol esters by a process involving P01375 converting enzyme ( P78536 ; P78536 ) . In this study , we demonstrate that inhibitors of calmodulin also stimulate shedding of the Q9BYF1 ectodomain , a process at least partially mediated by a metalloproteinase . We also show that calmodulin associates with Q9BYF1 and that this interaction is decreased by calmodulin inhibitors .",
"P00797 - angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension . Endothelium - dependent / nitric oxide ( NO ) - mediated vasodilation is impaired in hypertensive individuals . DB01686 ( DB01686 ) , an endogenous inhibitor of NO synthase , is synthesized by many types of cells including vascular endothelial cells . The serum level of DB01686 is elevated in patients with essential hypertension , but the mechanism for this increase is unknown . Therefore , the present study examined whether the renin - angiotensin system ( DB01367 ) is involved . Patients with essential hypertension [ systolic blood pressure ( BP ) > 160 mmHg and / or diastolic BP > 95 mmHg ] were randomized to an angiotensin - converting enzyme ( P12821 ) inhibitor treatment group ( perindopril , 4mg / day for 4 weeks , n = 7 ) , an angiotensin II type 1 ( AT1 ) receptor antagonist treatment group ( losartan , 50 mg / day for 4 weeks , n = 7 ) or a beta - blocker treatment group ( bisoprolol , 5 mg / day for 4 weeks , n = 7 ) . Before and after the treatment , BP , serum concentration of DB01686 and plasma concentration of P04275 ( P04275 , a biological marker of endothelial injury ) were measured . DB00790 , losartan and bisoprolol decreased BP to a similar extent , and either perindopril or losartan , but not bisoprolol , significantly decreased serum DB01686 and plasma P04275 . These findings suggest that the DB01367 may contribute to the mechanism of increased serum DB01686 as well as to the endothelial injury observed in hypertensive patients . The vasculoprotective actions of P12821 inhibitors or AT1 receptor antagonists may be explained at least in part by amelioration of the endothelial injury through a decrease in the serum DB01686 concentration .",
"Inhibition of the renin - angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia . Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers . Cachexia reduces mobility and quality of life and accounts for 20 - 30 % of all cancer - related deaths . Activation of the renin - angiotensin system causes skeletal muscle wasting and weakness . We tested the hypothesis that treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , perindopril , would enhance whole body and skeletal muscle function in cachectic mice bearing Colon - 26 ( C - 26 ) tumors . CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C - 26 tumor cells inducing either a mild or severe cachexia . The following day , one cohort of C - 26 mice began receiving perindopril in their drinking water ( 4 mg kg (- 1 ) day (- 1 ) ) for 21 days . In mild and severe cachexia , perindopril increased measures of whole body function ( grip strength and rotarod ) and reduced fatigue in isolated contracting diaphragm muscle strips ( p < 0 . 05 ) . In severely cachectic mice , perindopril reduced tumor growth , improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ ( p < 0 . 05 ) , which was associated with increased oxidative enzyme capacity ( succinate deyhydrogenase , p < 0 . 05 ) . DB00790 attenuated the increase in Q969Q1 and P05231 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased . These findings support the therapeutic potential of P12821 inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials . Since P12821 inhibition alone did not enhance body or muscle mass , co - treatment with an anabolic agent may be required to address these aspects of cancer cachexia .",
"A 3 - D model for P08908 - receptor agonists based on stereoselective methyl - substituted and conformationally restricted analogues of 8 - hydroxy - 2 -( dipropylamino ) tetralin . The enantiomers of cis - and trans - 1 , 2 , 3 , 4 , 4a , 5 , 10 , 10a - octahydro - 9 - hydroxy - 1 - propylbenzo [ g ] quinolines ( 10 and 11 , respectively ) and the enantiomers of trans - 1 , 2 , 3 , 4 , 4a , 5 , 6 , 10b - octahydro - 10 - hydroxy - 4 - propylbenzo [ f ] quinoline ( 12 ) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X - ray crystallography and molecular mechanics ( P08253 ) calculations . The compounds , which are conformationally restricted analogues of the potent 5 - hydroxytryptamine ( 5 - HT ) receptor agonist 8 - hydroxy - 2 - ( dipropylamino ) tetralin ( 8 - OH - DPAT ; 1 ) have been evaluated for central 5 - HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats . In addition , we have evaluated the ability of these compounds and a number of previously reported analogues to displace [ 3H ] - 8 - OH - DPAT from P08908 - binding sites . The enantiomers of 12 behave as potent P08908 - receptor agonists , whereas the octahydrobenzo [ g ] quinoline derivatives are much less potent or inactive . In general , the affinities of the compounds correlate well with their agonist potencies . The set of compounds under study is accommodated by a novel computer - graphics - derived model for P08908 - receptor agonism . The model consists of a flexible pharmacophore and a partial receptor - excluded volume .",
"P00797 - angiotensin system modulation : the weight of evidence . Modulation of the renin - angiotensin system is considered to be the most complete way to manage high - risk patients including those with hypertension . P12821 ( P12821 ) inhibitors are effective at reducing the morbidity and mortality of patients with overt clinical heart failure , asymptomatic left ventricular dysfunction , and uncomplicated myocardial infarction . Furthermore , recent trials like the Heart Outcomes Prevention Evaluations ( HOPE ) study and the EUropean trial on Reduction Of cardiac events with DB00790 in stable coronary Artery disease ( EUROPA ) support extending the use of P12821 inhibitors to the routine / first - line treatment of patients with an increased global cardiovascular risk . Although some investigators have seen the development of angiotensin II receptor blockers ( ARBs ) as a more effective and tolerable way of reproducing the benefits of P12821 inhibition , there remain important concerns regarding the distinct pharmacologic profiles and modes of action of these two classes of drugs . Careful evaluation of data from recent large - scale studies revealed that , unlike P12821 inhibitors , ARBs are either neutral or may actually increase rates of myocardial infarction despite similar levels of blood pressure reduction . The fact that this effect is most apparent when ARBs are compared with placebo in the absence of concomitant P12821 inhibitors suggests that differential effects on the angiotensin II type 2 ( AT ( 2 ) ) receptors may be important . Other important pharmacologic differences are also known to be present and may be of direct relevance . The weight of available evidence therefore supports the use of appropriate P12821 inhibitor regimens , although not ARBs , in the treatment of global cardiovascular risk .",
"Serum concentrations of growth factors in women with and without endometriosis : the action of anti - endometriosis medicines . Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis . Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis . Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease . In the present study , we investigate the soluble levels of vascular endothelial growth factor ( P15692 ) , epidermal growth factor - receptor ( P01133 - R ) , granulocyte / macrophage - colony stimulating factor ( GM - P04141 ) , P01308 - like growth factor - 1 ( DB01277 ) and interferon - gamma ( P01579 ) in the serum of 28 women with and 20 without endometriosis . We also compared these levels before , during and after treatment with danazol and leuprorelin acetate depot , the two therapeutic regiments of choice concerning this disease . We found that only sVEGF levels were higher in women with endometriosis in comparison to controls ( P < 0 . 001 ) while sEGF - R is not present . GM - P04141 , DB01277 and P01579 soluble levels are not affected in either healthy or endometriotic subjects . The 6 - month treatment with danazol decreased sVEGF levels ( P < 0 . 02 ) and increased sEGF - R levels ( P < 0 . 001 ) . These observations support the view that P15692 may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold . However , future studies will be focused on the anti - angiogenic control of the action of P15692 in patients with endometriosis .",
"___MASK83___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK83___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .",
"Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .",
"Q92731 mediates increased activation of PI3K / Akt signaling and improved myocardial function in female hearts following acute ischemia . Females have a lower incidence of heart failure and improved survival after myocardial ischemia - reperfusion ( I / R ) compared with males . Although estrogen - suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3 - kinase ( PI3K ) / protein kinase B ( Akt ) pathway , it is unclear whether this action is mediated via estrogen receptor beta ( ERbeta ) . Therefore , we hypothesized that ERbeta mediates estrogen - induced cardioprotection through PI3K / Akt and antiapoptotic signaling in females but not in males . Isolated male and female hearts from ERbeta knockout ( ERbetaKO ) and wild - type ( WT ) mice ( n = 5 mice / group ) were subjected to 20 - min ischemia followed by 60 - min reperfusion ( Langendorff ) . Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female , but not male , hearts . Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts , which was associated with increased expression of caspase - 3 and - 8 , as well as decreased Bcl - 2 levels compared with WT . However , myocardial P40763 , O14543 ( suppressor of cytokine signaling 3 ) , P15692 , and P01375 receptors 1 and 2 levels did not change in ERbetaKO of either sex following I / R . Furthermore , deficiency of ERbeta increased myocardial JNK activation in females but increased P27361 / 2 activity in males during acute I / R . We conclude that ERbeta mediates myocardial protection via upregulation of PI3K / Akt activation , decreased caspase - 3 and - 8 , and increased Bcl - 2 in female hearts following I / R . These findings provide evidence of ERbeta - mediated PI3K / Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction .",
"DB00790 : possible use in cancer therapy . Since angiogenesis is essential for the growth of any solid tumor , emerging efforts are being made to develop antiangiogenic therapy . To date , however , no antiangiogenic agent has become widely available for the clinical setting . Angiotensin I - converting enzyme ( P12821 ) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer . Studies have found that an P12821 inhibitor , perindopril , is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose . The potent angiogenic factor , vascular endothelial growth factor ( P15692 ) , is significantly suppressed by perindopril and also inhibits P15692 - induced tumor growth . In vitro studies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells . Since perindopril is already in widespread clinical use without serious side effects , it may represent a potential new strategy for anticancer therapy .",
"The use of microcalorimetry and HPLC for the determination of degradation kinetics and thermodynamic parameters of DB00790 Erbumine in aqueous solutions . DB00790 Erbumine ( O15534 ) is one of the newly used angiotensin - converting enzyme inhibitors ( P12821 inhibitors ) and is used for the treatment of patients with hypertension and symptomatic heart failure . It has two main degradation pathways , i . e . the degradation by hydrolysis and the degradation by cyclization . An isothermal heat conduction microcalorimetry ( MC ) and high pressure liquid chromatography ( HPLC ) were used for the characterization of aqueous solutions of O15534 and its stability properties . The rates of heat evolved during degradation of perindopril were measured by MC as a function of temperature and pH and from these data rate constant and change in enthalpy of the reactions were determined . With the HPLC method the concentration of perindopril and its degradation products were measured as a function of time in aqueous solutions of different pH that were stored at different temperatures . We demonstrated that reactions of degradation of perindopril at observed conditions follow the first order kinetics . The Arrhenius equation for each pH was determined . At pH 6 . 8 only one degradation pathway is present , i . e . the degradation by hydrolysis . Degradation constants for this pathway calculated from MC data are in good agreement with those obtained from HPLC . MC as a non - specific technique was shown to be useful in studies of O15534 when one reaction was present in the sample and also when more chemical and physical processes were simultaneously running .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Establishment of a double Philadelphia chromosome - positive acute lymphoblastic leukemia - derived cell line , TMD5 : effects of cytokines and differentiation inducers on growth of the cells . A double Philadelphia chromosome ( Ph ) - positive leukemia cell line with common - B cell phenotype , designated TMD5 , was established from the blast cells of a patient with double Ph - positive acute lymphoblastic leukemia . TMD5 cells expressed 190 kDa P11274 / P00519 chimeric protein and 145 kDa P00519 protein . The cells proliferated without added growth factors . Autocrine growth mechanism was not recognized . The addition of growth factors such as DB00099 , GM - P04141 , P08700 , P05231 , or Stem Cell Factor did not affect the growth . Herbimycin A suppressed the growth of TMD5 cells at the low concentration that did not affect Ph - negative cells . It suppressed tyrosine phosphorylation of intracellular proteins in TMD5 cells . Dexamethasone and dibutyryl cyclic AMP also suppressed the growth . They , however , did not affect the phosphorylation significantly . Neither all - trans retinoic acid nor interferon - alpha affected the growth . TMD5 cells , characterized minutely here and rare in that they have double Ph chromosomes , will be a useful tool for the study of Ph - positive leukemia .",
"Role of angiotensin II in the remodeling induced by a chronic increase in flow in rat mesenteric resistance arteries . Angiotensin II is a potent growth factor involved in arterial wall homeostasis . In resistance arteries , chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy . Nevertheless , the role of angiotensin II in this remodeling is unknown . We investigated the effect of blocking angiotensin II production or receptor activation on flow - induced remodeling of mesenteric resistance arteries . Arteries were ligated in vivo to generate high - flow arteries compared with normal flow ( control ) vessels located at a distance . Arteries were isolated after 1 week for in vitro analysis . Arterial diameter , media surface , endothelial NO synthase expression , superoxide production , and extracellular signal - regulated kinase 1 / 2 phosphorylation were higher in high - flow than in control arteries . P12821 inhibition ( perindopril ) and angiotensin II type 1 receptor blockade ( candesartan ) prevented arterial wall hypertrophy without affecting diameter enlargement . The nonselective vasodilator hydralazine had no effect on remodeling . Although perindopril and candesartan increased endothelial NO synthase expression in high - flow arteries , hypertrophy remained in rats treated with N ( G )- nitro - l - arginine methyl ester and mice lacking endothelial NO synthase . DB00790 and candesartan reduced oxidative stress in high - flow arteries , but superoxide scavenging did not prevent hypertrophy . Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high - flow vessels . P27361 / 2 activation in high - flow arteries was prevented by perindopril and candesartan and not by hydralazine . P27361 / 2 inhibition in vivo ( U0126 ) prevented hypertrophy in high - flow arteries . Thus , a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide , whereas hypertrophy was associated with extracellular signal - regulated kinase 1 / 2 activation by angiotensin II .",
"P00533 activation and inhibition in 3D in vitro models of normal skin and human cutaneous squamous cell carcinoma . The transmembrane tyrosine kinase epidermal growth factor receptor ( P00533 ) is considered a key player in the development of cutaneous squamous cell carcinoma ( SCC ) , which is the second most common malignancy in white populations . Inhibition of P00533 with the small molecule tyrosine kinase inhibitor erlotinib is currently under clinical investigation in cutaneous SCC patients . In this study , we investigated the effects of P00533 activation and inhibition on normal and malignant in vitro human skin equivalents ( HSEs ) . In healthy HSEs , increasing P01133 concentrations ranging from 5 to 50 ng / mL resulted in a dramatic decrease in epidermal proliferation as immunohistochemically assessed by Ki67 and increased epidermal stress as assessed by Q04695 after 2 weeks of air - exposed culture . Also , higher concentrations of P01133 induced remarkable epidermal disorganization with loss of proper stratification . Similar effects were observed in HSEs generated with cutaneous SCC cell lines SCC - 12B2 and SCC - 13 . Treatment of both healthy and SCC - HSEs with 10 μM erlotinib resulted in efficient reduction of epidermal thickness from 10 to 3 viable cell layers and counteracted P01133 - induced epidermal stress . Remarkably , erlotinib treatment caused severe desquamation in healthy HSEs , reminiscent of xerosis as a known side - effect in patients treated with erlotinib . The presented three - dimensional organotypic SCC models appear suitable for further investigations on the morphological and functional impacts of modifying P00533 signaling in cutaneous SCC , without burdening patients or mice . The effective inhibition of epidermal growth by erlotinib in our HSEs confirms the therapeutic potential of this tyrosine kinase inhibitor for cutaneous SCC patients .",
"Ds - echinoside A , a new triterpene glycoside derived from sea cucumber , exhibits antimetastatic activity via the inhibition of NF - κB - dependent P14780 and P15692 expressions . Ds - echinoside A ( DSEA ) , a non - sulfated triterpene glycoside , was isolated from the sea cucumber Pearsonothuria graeffei . In vitro and in vivo investigations were conducted on the effects of DSEA on tumor cell adhesion , migration , invasion , and angiogenesis . In this study , we found that DSEA inhibited the proliferation of human hepatocellular liver carcinoma cells Hep G2 , with a half - maximal inhibitory concentration ( IC₅₀ ) of 2 . 65 μmol / L , and suppressed Hep G2 cell adhesion , migration , and invasion in a dose - dependent manner . DSEA also reduced tube formation of human endothelial cells ECV - 304 on matrigel in vitro and attenuated neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay in vivo . Immunocytochemical analysis revealed that DSEA significantly decreased the expression of matrix metalloproteinase - 9 ( P14780 ) , which plays an important role in the degradation of basement membrane in tumor metastasis and angiogenesis . DSEA also increased the protein expression level of tissue inhibitor of metalloproteinase - 1 ( P01033 ) , an important regulator of P14780 activation . From the results of Western blotting , the expressions of nuclear factor - kappa B ( NF - κB ) and vascular endothelial growth factor ( P15692 ) were found to be remarkably reduced by DSEA . These findings suggest that DSEA exhibits a significant anti - metastatic activity through the specific inhibition of NF - κB - dependent P14780 and P15692 expressions .",
"Synthesis and biological evaluation of novel pyrrolidine - 2 , 5 - dione derivatives as potential antidepressant agents . Part 1 . A series of 3 -( 1H - indol - 3 - yl ) pyrrolidine - 2 , 5 - dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 - HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5 - Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists .",
"Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .",
"Src and P61073 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib . ___MASK42___ is a dual P00533 and ErbB - 2 tyrosine kinase inhibitor that has significantly improved the clinical outcome of ErbB - 2 - overexpressing breast cancer patients . However , patients inexorably develop mechanisms of resistance that limit the efficacy of the drug . In order to identify potential targets for therapeutic intervention in lapatinib - resistant patients , we isolated , from ErbB - 2 - overexpressing SK - Br - 3 breast cancer cells , the SK - Br - 3 Lap - R - resistant subclone , which is able to routinely grow in 1 µM lapatinib . Resistant cells have a more aggressive phenotype compared with parental cells , as they show a higher ability to invade through a matrigel - coated membrane . ___MASK42___ - resistant cells have an increased Src kinase activity and persistent levels of activation of P27361 / 2 and AKT compared with parental cells . Treatment with the Src inhibitor saracatinib in combination with lapatinib reduces AKT and P27361 / 2 phosphorylation and restores the sensitivity of resistant cells to lapatinib . SK - Br - 3 Lap - R cells also show levels of expression of P61073 that are higher compared with parental cells and are not affected by Src inhibition . Treatment with saracatinib or a specific P61073 antibody reduces the invasive ability of SK - Br - 3 Lap - R cells , with the two drugs showing cooperative effects . Finally , blockade of Src signaling significantly increases P50591 - induced cell death in SK - Br - 3 Lap - R cells . Taken together , our results demonstrate that breast cancer cells with acquired resistance to lapatinib have a more aggressive phenotype compared with their parental counterpart , and that Src signaling and P61073 play an important role in this phenomenon , thus representing potential targets for therapeutic intervention in lapatinib - resistant breast cancer patients .",
"Effect of dipterinyl calcium pentahydrate on hepatitis B virus replication in transgenic mice . BACKGROUND : Dipterinyl calcium pentahydrate ( P12821 ) has previously been shown to inhibit MDA - MB - 231 human breast cancer xenographs in nude mice in a manner correlated with increases in plasma IL - 12 and P05112 concentrations , and decreases in plasma P05231 levels . P12821 also inhibits indoleamine 2 , 3 - dioxygenase ( P14902 ) , an immuno - inhibitory enzyme , in human PBMCs ( Peripheral Blood Mononuclear Cells ) . METHODS : In the present study , P12821 was administered per os , once daily for 14 days to hepatitis B virus ( HBV ) transgenic mice at 23 , 7 . 3 , and 2 . 3 mg / ( kg d ) . Multivariate stepwise regression and MANOVA analyses , by gender and treatment , of liver HBV DNA and RNA measures , liver core and serum HBe antigen assays , serum cytokine / chemokine profiles , and P14902 metabolite measurements were performed . RESULTS : P12821 caused a significant dose - response reduction of log liver HBV DNA as measured by PCR in the female HBV mice . The gender dependence of the anti - HBV DNA activity was explained by the P12821 Effects Model ( P12821 - EM ) ( p = . 001 ) which includes three serum biomarker changes caused by P12821 : 1 ) decreased P13500 ; 2 ) decreased Kyn / DB00150 ( an estimation of P14902 activity ) ; and 3 ) increased GM - P04141 . CONCLUSIONS : Immunomodulation via P14902 or P48775 ( tryptophan 2 , 3 - dioxygenase ) pathways , along with serum P13500 and GM - P04141 are proposed to play roles in the anti - HBV mechanism of P12821 based upon their coordinated modulation in the reduction of viral DNA replication in HBV mice .",
"P12821 activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus . The renin - angiotensin system plays an important role in the elevation of asymmetric dimethylarginine ( DB01686 ) , an endogenous inhibitor of nitric oxide synthase , in hypertensive patients , so the present study was designed to examine whether angiotensin - converting enzyme ( P12821 ) activity is also involved in the mechanism of DB01686 elevation in type 2 diabetes mellitus ( NIDDM ) . A crossover study was performed to determine if P12821 inhibition with perindopril ( 4 mg / day ) for 4 weeks decreases serum DB01686 concentration and plasma P04275 ( P04275 ) level ( a marker of endothelial injury ) in 11 patients with NIDDM . None of the patients was treated with insulin or oral hypoglycemic drugs , and none had major diabetic complications . Before the protocol began , serum DB01686 and plasma P04275 were significantly higher in the 11 NIDDM patients , when compared with 8 control subjects without diabetes . DB00790 did not affect blood pressure or glucose metabolism , but did significantly decrease serum DB01686 and plasma P04275 . These results suggest that endothelial injury associated with DB01686 elevation may be present even in patients with non - complicated NIDDM , and that increased activity of P12821 may be involved in such endothelial dysfunction .",
"___MASK28___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK28___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Tyrosine phosphorylation enhances P43351 - mediated annealing by modulating its DNA binding . P43351 protein has an important role in homology - directed DNA repair by mediating Q06609 nucleoprotein filament formation on single - stranded DNA ( ssDNA ) protected by replication protein - A ( RPA ) and annealing of RPA - coated ssDNA . In human , cellular response to DNA damage includes phosphorylation of P43351 by c - P00519 kinase at tyrosine 104 . To address how this phosphorylation modulates P43351 function , we used an amber suppressor technology to substitute tyrosine 104 with chemically stable phosphotyrosine analogue ( p - Carboxymethyl - L - phenylalanine , pCMF ) . The P43351 ( Y104pCMF ) retained ssDNA - binding activity characteristic of unmodified P43351 but showed lower affinity for double - stranded DNA ( dsDNA ) binding . Single - molecule analyses revealed that P43351 ( Y104pCMF ) specifically targets and wraps ssDNA . While P43351 ( Y104pCMF ) is confined to ssDNA region , unmodified P43351 readily diffuses into dsDNA region . The Y104pCMF substitution also increased the ssDNA annealing rate and allowed overcoming the inhibitory effect of dsDNA . We propose that phosphorylation at Y104 enhances ssDNA annealing activity of P43351 by attenuating dsDNA binding . Implications of phosphorylation - mediated activation of P43351 annealing activity are discussed .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK42___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK11___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK11___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti - tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( ___MASK90___ , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI - 571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) .",
"GPIbalpha - selective activation of platelets induces platelet signaling events comparable to Q9HCN6 activation events . Platelet glycoprotein ( GP ) Ib - IX - V , which binds P04275 ( P04275 ) , and Q9HCN6 , which binds collagen , form an adhesion - signaling complex on platelets and mediate platelet adhesion in flowing blood . Platelet activation following engagement of GPIb - IX - V / Q9HCN6 by P04275 / collagen is critical for initiation and development of a protective thrombus across a site of damaged or exposed endothelium . We examined platelet aggregation and signaling following selective engagement of platelet GPIbalpha ( the major ligand - binding subunit of GPIb - IX - V ) by a multivalent surface - expressed GPIbalpha - binding P04275 - A1 domain on COS - 7 cells . COS - 7 cells expressing the P04275 - A1 domain containing an R543W mutation ( a gain - of - function mutation found in Type 2B von Willebrand ' s Disease ) were used as a selective agonist for GPIb - IX - V . When incubated in a cell - to - platelet ratio of up to 1 : 1200 , P04275 - A1 / R543W cells caused rapid , spontaneous aggregation of washed platelets that was GPIbalpha - and alpha ( IIb ) beta ( 3 )- dependent ( blocked by inhibitory anti - P04275 - A1 , anti - GPIbalpha and anti - alpha ( IIb ) beta ( 3 ) antibodies ) . Platelet aggregation was also sensitive to inhibitors of Src , phosphoinositide 3 - kinase ( P19957 - kinase ) or Syk , confirming a role for these proteins in GPIbalpha - mediated signal transduction . Platelet tyrosine phosphorylation patterns and specific tyrosine phosphorylation of Syk after GPIbalpha engagement by P04275 - A1 / R543W was comparable to that induced by engagement of Q9HCN6 by collagen or collagen - related peptide ( CRP ) . These data indicate signaling events triggered by specific ligation of GPIbalpha can lead to robust platelet activation and help define GPIb - IX - V as both an adhesion and signaling receptor on platelets .",
"[ Expression of P11274 / P00519 fusion gene in circulating endothelial cells from chronic myelogenous leukemia patients and its clinical significance ] . Several studies have shown that the tumor endothelial cells are different from the normal tissue endothelial cells . These tumor endothelial cells may contribute to tumor neo - vasculogenesis . This study was purposed to analyze the biologic features and determine the expression level of CD133 and P11274 / P00519 fusion gene in circulating endothelial cells ( CEC ) isolated from peripheral blood of CML patients , as well as to investigate the role of CEC in disease progression . Mononuclear cells were isolated from peripheral blood by density gradient centrifugation ; CEC were sorted by P29966 and harvested in the endothelial growth medium . The morphologic features of CEC were observed by microscopy , the cell growth rate was calculated by cell counting , and the cells were identified by immunofluorescence staining for the expression of CD31 , P28906 , P04275 and CD133 . The expression of P11274 / P00519 fusion gene was examined by Q5TCZ1 in 12 CML patients . The results indicated that the isolated CEC displayed the typical cobble - stone morphology . These cells could be identified by the positive immunofluorescence staining for CD31 , P28906 and P04275 , and showed more increased proliferative potential as compared to that of healthy donors . It was found that the positive rate of CD133 was 31 . 29 % in CML patients , which was significantly different from that of healthy donors ( P < 0 . 05 ) . In 12 CML patients , CEC carried the same chromosome aberration as the leukemia cells ( 10 . 77 % ) . Higher expression level of CD133 and P11274 / P00519 fusion gene positively correlated with progression of disease . It is concluded that the CEC may participate in invasion and angiogenesis in patients with CML and possibly correlate to the spreading and progression of the disease .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK30___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Mammalian stress granules and processing bodies . The packaging of cytoplasmic mRNA into discrete RNA granules regulates gene expression by delaying the translation of specific transcripts . Specialized RNA granules found in germ cells direct the timing of maternal mRNA translation to promote germ cell development in the early embryo and establish the germ line for the next generation . Similarly , select neuronal mRNA transcripts are packaged into translationally inert RNA granules , transported to sites where their protein products are required , and only then activated and translated . Following translation , however , newly inactivated mRNAs released from polysomes can also be packaged into dynamic , transient structures known as stress granules ( SGs ) and processing bodies ( PBs ) . Stress granules are composed largely of stalled preinitiation complexes , and contain mRNA , small ribosomal subunits , eIF3 , P06730 , eIF4G , and PABP , as their core components . PBs are associated with mRNA decay and contain the decapping enzymes P12821 / 2 , the 5 ' to 3 ' exonuclease Xrn1 , the Lsm proteins ( 1 - 7 ) , and the scaffolding proteins hedls / GE - 1 and GW182 . Both SGs and PBs contain mRNA , P06730 , microRNAs and argonaute proteins , and various regulators of mRNA stability and translation ( TTP , RCK / p54 , and Q9BZB8 ) . Thus , SGs and PBs share some protein and mRNA components , but also contain a number of unique markers specific to each structure . We describe markers and staining procedures used to identify these distinct types of RNA granules , describe conditions that promote their assembly and disassembly , and establish P67809 as a useful marker of SGs and PBs .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK67___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"___MASK76___ binding to human and rat dopamine and 5 - HT receptors . ___MASK76___ ( ___MASK76___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK76___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK76___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK76___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Different effects of perindopril and enalapril on monocyte cytokine release in coronary artery disease patients with normal blood pressure . BACKGROUND : Favorable effects of angiotensin - converting enzyme ( P12821 ) inhibitor treatment on the incidence of cardiovascular and cerebrovascular mortality and morbidity are not limited to patients with elevated blood pressure . As suggested by our previous results , the physicochemical and pharmacokinetic differences between drugs may markedly contribute to the strength of pleiotropic effects of P12821 inhibitors . METHODS : The present study was aimed at comparing the effects of serum - and tissue - type P12821 inhibitors on monocyte release of proinflammatory cytokines in normotensive patients with stable coronary artery disease . The participants were randomized to 90 - day treatment with enalapril ( 20 mg daily , n = 29 ) , perindopril ( 4 mg daily , n = 27 ) or placebo ( n = 28 ) . Plasma levels of lipids , glucose , insulin and high sensitivity P02741 ( hsCRP ) , as well as monocyte release of proinflammatory cytokines were determined before and after 30 days of therapy , and at the end of the treatment . RESULTS : Lipopolysaccharide - stimulated monocytes from normotensive patients with stable coronary artery disease released significantly more P01375 - α , interleukin - 1β and monocyte chemoattractant protein - 1 in comparison with monocytes from 23 matched control subjects . Their baseline hsCRP levels were also higher . DB00790 reversed the disease - induced changes in cytokine release and reduced plasma hsCRP , while the effect of enalapril was much more limited . The effect on both drugs on cytokine release was stronger in insulin - resistant than insulin - sensitive subjects . CONCLUSIONS : Our results indicate that perindopril is superior to enalapril in producing monocyte - suppressing and systemic anti - inflammatory effects in normotensive patients with coronary artery disease . This action may contribute to the clinical effectiveness of tissue P12821 inhibitors in the therapy of atherosclerosis - related disorders , particularly in insulin - resistant subjects ."
] |
[
"___MASK11___",
"___MASK28___",
"___MASK30___",
"___MASK42___",
"___MASK67___",
"___MASK71___",
"___MASK76___",
"___MASK83___",
"___MASK90___"
] |
___MASK83___
|
MH_train_315
|
interacts_with DB00197?
|
[
"Anti - inflammatory effects of troglitazone in nondiabetic obese subjects independent of changes in insulin sensitivity . BACKGROUND : Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers . We investigated whether , in the absence of changes in glucose , thiazolidinediones ( TZDs ) have anti - inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers . METHODS : We performed a randomised double - blind placebo - controlled crossover study with troglitazone ( 400 mg daily for eight weeks ) in 15 normoglycaemic obese subjects . We measured plasma high - sensitivity P02741 ( hsCRP ) , interleukin - 6 ( P05231 ) , leptin , tissue - type plasminogen activator ( tPA ) , plasminogen activator inhibitor - 1 ( P05121 ) and tumour necrosis factor - alpha ( P01375 ) after each of the two treatment periods and in 13 age - and sex - matched lean individuals . RESULTS : Obese subjects were insulin resistant ( decreased glucose infusion rate ( GIR ) during euglycaemic hyperinsulinaemic clamp ) and had higher plasma levels of hsCRP , P05231 , leptin , tPA , and P05121 compared with lean subjects . P01375 also tended to be higher . DB00197 improved insulin sensitivity ( mean increase in whole body glucose uptake 23 . 1 +/- 10 . 5 % ( p = 0 . 047 ) ) and normalised plasma concentrations of hsCRP , tPA and P01375 , whereas it did not significantly change P05231 , leptin and P05121 . Changes in GIR did not correlate with changes in inflammatory markers . CONCLUSION : DB00197 induces suppression of some of the inflammatory markers that are elevated in normoglycaemic obese subjects . The suppression of inflammatory markers , however , does not correlate with improvement in insulin sensitivity , suggesting involvement of partially differential mechanisms in these effects of TZDs .",
"[ Dyslipidemia in insulin resistance and its improvement by troglitazone ] . Dyslipideia in insulin resistant state are characterized by 3 major components ; increased triglyceride levels , decreased high - density lipoprotein ( HDL ) cholesterol , and change in the composition of low - density lipoprotein ( LDL ) cholesterol particle which results in small - dense LDL . P01308 resistance is thought to lead to overproduction of very low - density lipoprotein ( VLDL ) cholesterol through the decreased peripheral lipoprotein lipase ( P06858 ) activity , increased production of apolipoprotein B - 100 and decreased clearance of remnant particles . DB00197 , an insulin action enhancer , decreases the triglyceride level , increases HDL cholesterol level and decreases th proportion of small - dense LDL through the direct effect on lipoprotein metabolism . However , activation of P37231 is considered to possese potential atherogeneity and more closer examination is needed .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK40___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK40___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"DB00197 inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo . P37231 ( PPARgamma ) has been implicated in the differentiation and growth inhibition of cancer cells . We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma ( HCC ) cell growth , proliferation , and apoptosis in vitro and in vivo . We also studied relationships between PPARgamma activation and cyclooxygenase - 2 ( P35354 ) expression . Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone . Cell growth was determined via WST - 1 assay , proliferation by cell cycle analysis and proliferating cell nuclear antigen ( P12004 ) Western blotting , and apoptosis by flow cytometry and TUNEL . Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored , and the effects of treatment with troglitazone were determined . In resected HCCs , PPARgamma expression was less compared with the histologically normal surrounding liver . In cultures of Hep3B and Huh7 cells , basal expression of PPARgamma was relatively low , but troglitazone caused dose - dependent induction of PPARgamma expression . Cell cycle analysis revealed a decreased proportion of cells in S phase , with arrest at G0 / P55008 . Concomitant downregulation of P12004 and an increase in TUNEL staining , cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone . DB00197 - mediated PPARgamma activation also suppressed P35354 expression and induced p27 in HCC cells . Administration of troglitazone to Huh7 tumor - bearing mice significantly reduced tumor growth and caused tumor regression . In conclusion , collectively , these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC . PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth .",
"DB00197 , a P37231 activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by P01375 . BACKGROUND : Cytokine mediated induction of the mucosal addressin cell adhesion molecule - 1 ( Q13477 ) expression is associated with the onset and progression of inflammatory bowel disease ( Q9UKU7 ) . RESULTS : Using western blotting and cell - based ELISA , we show in this study that troglitazone , an activator of the peroxisome proliferator - activated receptor - gamma ( P37231 ) , widely used in the treatment of diabetes , has as well recently been highlighted as protective in models of inflammation and cancer . We found that troglitazone ( 10 - 40 microM ) , significantly reduced the P01375 ( 1 ng / ml ) mediated induction of endothelial Q13477 in a dose - dependent manner , achieving a 34 . 7 % to 98 . 4 % reduction in induced Q13477 . Trogliazone ( 20 microM ) reduced P01375 induced P19320 , P05362 and P16581 expression . Moreover , troglitazone significantly reduced alpha4beta7 - integrin dependent lymphocyte adhesion to P01375 cultured endothelial cells . CONCLUSIONS : These results suggest that P37231 agonists like troglitazone may be useful in the clinical treatment of Q9UKU7 .",
"The ratio of plasminogen activator inhibitor type - 1 activity to the concentration of plasminogen activator inhibitor type - 1 protein in diabetes : adding insult to injury . BACKGROUND : This study was performed to delineate the relationship between plasminogen activator inhibitor type - 1 ( P05121 ) activity and P05121 protein to characterize the functional importance of elevated P05121 in diabetes . METHODS : P05121 activity ( chromogenic substrate kinetic assay ) and protein ( enzyme - linked immunosorbent assay ) were assayed in baseline central venous catheter - acquired samples from 170 patients with type 2 diabetes studied in the DB00197 Atherosclerosis Regression Trial ( TART ) . RESULTS : The data demonstrated that the ratio of P05121 activity to the concentration of P05121 protein is increased as a function of increasing concentrations of P05121 protein in blood . CONCLUSIONS : The results demonstrate that the ratio of P05121 activity to the concentration of P05121 protein is higher when the concentration of P05121 is elevated . The nonlinearity appears to depend on the fact that the rate of disappearance of P05121 activity in blood is a function of the concentration of P05121 protein .",
"Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia . Gastric cancer is the second leading cause of cancer death worldwide . Predisposing factors include achlorhydria , Helicobacter pylori infection , oxyntic atrophy and Q03403 - expressing metaplasia . In parietal cells , apical potassium channels comprising the P51787 alpha subunit and the Q9Y6J6 beta subunit provide a K (+) efflux current to facilitate gastric acid secretion by the apical H (+) K (+) ATPase . Accordingly , genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion . Other evidence has suggested a role for Q9Y6J6 in human gastric cancer cell proliferation , independent of its role in gastric acidification . Here , we demonstrate that 1 - year - old Kcne2 (-/-) mice in a pathogen - free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda , 6 - fold increased stomach mass , increased Ki67 and nuclear P12004 D1 expression , and Q03403 - and cytokeratin 7 - expressing metaplasia . Some Kcne2 (-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum , and neoplastic invasion of thin walled vessels in the sub - mucosa . Finally , analysis of human gastric cancer tissue indicated reduced parietal cell Q9Y6J6 expression . Together with previous findings , the results suggest Q9Y6J6 disruption as a possible risk factor for gastric neoplasia .",
"Direct attenuation of plasminogen activator inhibitor type - 1 expression in human adipose tissue by thiazolidinediones . Adipose tissue produces substantial amounts of plasminogen activator inhibitor type - 1 ( P05121 ) , an established cardiovascular risk factor . This study evaluated P05121 expression in human adipose tissue in response to thiazolidinediones , insulin sensitising drugs activating peroxisome proliferator - activated receptor - gamma ( P37231 ) . DB00197 , rosiglitazone , and ciglitazone significantly reduced P05121 protein expression in human preadipocytes under basal conditions and after stimulation of the cells with TGF - beta . Pioglitazone had no effect . In human adipocytes all four thiazolidinediones significantly attenuated P05121 expression . Signalling appeared to be mediated via P37231 and effects reflected , at least in part , changes in transcription . Accordingly , patients with insulin resistance may benefit from treatment with thiazolidinediones with respect to diminution of P05121 expression in adipose tissue and consequent potential reduction of cardiovascular risk .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK64___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"Clinical and functional characterization of the Pro1198Leu Q09428 gene mutation associated with permanent neonatal diabetes mellitus . AIMS / INTRODUCTION : The adenosine triphosphate ( DB00171 ) - sensitive potassium ( KATP ) channel is a key component of insulin secretion in pancreatic β - cells . Activating mutations in Q09428 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus ( NDM ) . The aim was to investigate clinical and functional characterization of the Pro1198Leu Q09428 gene mutation associated with permanent NDM ( PNDM ) . MATERIALS AND METHODS : The coding regions and conserved splice sites of Q14654 , Q09428 and P01308 were screened for mutations in a 12 - year - old girl diagnosed with PNDM . The functional property of the mutant channel identified was examined with patch - clamp experiments in COS - 1 cells . We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient . RESULTS : We identified a heterozygous missense mutation ( c . 3593 C > T , Pro1198Leu ) in Q09428 . The mutated residue ( P1198 ) is located within a putative binding site of sulfonylureas , such as tolbutamide or gliclazide . In patch - clamp experiments , the mutant channel was less DB00171 sensitive than the wild type . Furthermore , the sensitivity to tolbutamide was also reduced in the mutant channel . In addition to the tolbutamide / gliclazide binding site , glibenclamide is thought to also bind to another site . ___MASK36___ was more effective than other sulfonylureas in vitro and in the patient . The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide . CONCLUSIONS : We identified the Pro1198Leu Q09428 mutation in a PNDM patient , and clarified the functional and clinical characterization . The present findings provide new information for understanding PNDM .",
"Bone marrow stroma confers resistance to Apo2 ligand / P50591 in multiple myeloma in part by regulating O15519 . Apo2 ligand ( Apo2L ) / P50591 induces apoptosis of cancer cells that express the specific receptors while sparing normal cells . Because the tumor microenvironment protects myeloma from chemotherapy , we investigated whether hemopoietic stroma induces resistance to Apo2L / P50591 apoptosis in this disease . Apo2L / P50591 - induced death was diminished in myeloma cell lines ( RPMI 8226 , U266 , and MM1s ) directly adhered to a human immortalized HS5 stroma cell line but not adhered to fibronectin . In a Transwell assay , with myeloma in the upper well and HS5 cells in the lower well , Apo2L / P50591 apoptosis was reduced when compared with cells exposed to medium in the lower well . Using HS5 and myeloma patients ' stroma - conditioned medium , we determined that soluble factor ( s ) produced by stroma - myeloma interactions are responsible for a reversible Apo2 / P50591 apoptosis resistance . Soluble factor ( s ) attenuated procaspase - 8 , procaspase - 3 , and poly ( ADP - ribose ) polymerase cleavage and diminished mitochondrial membrane potential changes without affecting Bcl - 2 family proteins and / or Apo2L / P50591 receptors . Soluble factor ( s ) increased the baseline levels of the anti - apoptotic protein O15519 in all cell lines tested . Inhibition of O15519 by means of RNA interference increased Apo2 / P50591 sensitivity in RPMI 8226 cells . Unlike direct adhesion to fibronectin , soluble factor ( s ) have no impact on O15519 redistribution within cellular compartments . Cyclohexamide restored Apo2L / P50591 sensitivity in association with down - regulation of O15519 , suggesting that O15519 synthesis , not intracellular traffic , is essential for soluble factor ( s ) to regulate O15519 . Additionally , P05231 conferred resistance to Apo2L / P50591 - mediated apoptosis in association with increased O15519 levels . In conclusion , the immune cytotoxic effect of Apo2L / P50591 can be restored at least in part by O15519 pathway inhibitors .",
"Effect of atorvastatin on endothelial function and inflammation in long - duration type 1 diabetic patients without coronary heart disease and arterial hypertension . AIM : We evaluated the ability of atorvastatin , an P04035 inhibitor , to affect endothelial function and inflammation in long - duration ( > 10 years ) type 1 diabetes mellitus ( T1DM ) patients without coronary heart disease ( Q8NE62 ) and arterial hypertension ( AH ) . METHODS AND RESULTS : We randomized 204 Caucasians with long - duration T1DM into either the atorvastatin 40 mg / day plus hypolipaemic diet group ( n = 154 ) or the placebo plus hypolipaemic diet group ( n = 50 ) for 6 months . Endothelium - dependent flow - mediated ( FMD ) and endothelium - independent flow - mediated vasodilatation , serum levels of plasminogen activator inhibitor - 1 ( P05121 ) , P04275 ( P04275 ) and high sensitivity P02741 ( hs - CRP ) were estimated before and after treatment . After 6 months of therapy , FMD was increased by 44 % in the atorvastatin plus diet group compared with the placebo plus diet group . Treatment with atorvastatin led to a significant reduction in levels of P05121 and hs - CRP ; however , the elevation of P04275 level was observed . In the placebo plus diet group , we observed a significant reduction in levels of hs - CRP but not of P04275 and P05121 . CONCLUSIONS : ___MASK100___ improves endothelial function and reduces some proinflammatory and prothrombotic markers of atherosclerosis in T1DM patients without Q8NE62 and AH . The surprising effect of atorvastatin on serum P04275 levels in T1DM requires further study .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Differential activation of peroxisome proliferator - activated receptor - gamma by troglitazone and rosiglitazone . The antidiabetic thiazolidinediones , which include troglitazone and rosiglitazone , are ligands for the nuclear receptor peroxisome proliferator - activated receptor ( Q07869 ) - gamma and exert their antihyperglycemic effects by regulation of P37231 - responsive genes . We report here that P37231 activation by troglitazone depends on the experimental setting . DB00197 acts as a partial agonist for P37231 in transfected muscle ( C2C12 ) and kidney ( P29320 293T ) cells , producing a submaximal transcriptional response ( 1 . 8 - to 2 . 5 - fold activation ) compared with rosiglitazone ( 7 . 4 - to 13 - fold activation ) . Additionally , troglitazone antagonizes rosiglitazone - stimulated P37231 transcriptional activity . Limited protease digestion of P37231 suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone . Consistent with this finding , an in vitro coactivator association assay demonstrated that troglitazone - bound P37231 recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone - bound receptor . In contrast to these observations , troglitazone behaves as a full agonist of P37231 in 3T3L1 adipocytes . Two - dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types . Thus , troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others . These differences could be caused by variations in the amount of specific cofactors , differences in Q07869 response elements , or the presence of different isoforms of P37231 .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK94___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"P37231 and aging : one link through klotho ? P37231 , a transcription factor involved in adipogenesis , glucose homeostasis , bone turnover , and inflammation , has now been shown to increase klotho expression . Q9UEF7 is predominantly expressed by the kidney and functions at the tubule and in the circulation as an anti - aging factor and a hormone participating in mineral metabolism . The finding that klotho is upregulated by P37231 may prompt further exploration of the role and mechanism of action of P37231 in aging and bone diseases .",
"DB00197 stimulates beta - arrestin - dependent cardiomyocyte contractility via the angiotensin II type 1A receptor . P37231 ( Q07869 gamma ) agonists are commonly used to treat cardiovascular diseases , and are reported to have several effects on cardiovascular function that may be due to Q07869 gamma - independent signaling events . Select angiotensin receptor blockers ( ARBs ) interact with and modulate Q07869 gamma activity , thus we hypothesized that a Q07869 gamma agonist may exert physiologic effects via the angiotensin II type 1 ( A ) receptor ( AT1 ( A ) R ) . In AT1 ( A ) R - overexpressing P29320 293 cells , both angiotensin II ( Ang II ) and the Q07869 gamma agonist troglitazone ( Trog ) enhanced AT1 ( A ) R internalization and recruitment of endogenous beta - arrestin 1 / 2 ( beta arr1 / 2 ) to the AT1 ( A ) R . A fluorescence assay to measure diacylglycerol ( DAG ) accumulation showed that although Ang II induced AT1 ( A ) R - G ( q ) protein - mediated DAG accumulation , Trog had no impact on DAG generation . Trog - mediated recruitment of beta arr1 / 2 was selective to AT1 ( A ) R as the response was prevented by an ARB - and Trog - mediated beta arr1 / 2 recruitment to beta1 - adrenergic receptor ( beta 1AR ) was not observed . In isolated mouse cardiomyocytes , Trog increased both % and rate of cell shortening to a similar extent as Ang II , effects which were blocked with an ARB . Additionally , these effects were found to be beta arr2 - dependent , as cardiomyocytes isolated from beta arr2 - KO mice showed blunted contractile responses to Trog . These findings show for the first time that the Q07869 gamma agonist Trog acts at the AT1 ( A ) R to simultaneously block G ( q ) protein activation and induce the recruitment of beta arr1 / 2 , which leads to an increase in cardiomyocyte contractility .",
"Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .",
"Stimulation of the peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy . Monocytes and macrophages play a key role in the progression of atheromatous changes . The peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) can limit macroangiopathy through the control of cytokine transcription . The objectives of this study were to examine the influence of Q07869 gamma and its agonist ( rosiglitazone ) on the TNFalpha , P05231 , P10145 and P22301 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion . TNFalpha , P05231 , P10145 , P22301 and Q07869 gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy ( real - time PCR [ Applied Biosystems ] ) . As indicators of endothelial lesion , concentration of thrombomodulin ( immunoassay [ Diagnostica Stago ] ) and amount of circulating blood endothelial cells ( immunofluorescence method with MoAb Q8N0X4 - HEC19 ) were determined . Following rosiglitazone therapy , a statistically significant downward tendency of TNFalpha ( p = 0 . 026 ) and P10145 ( p = 0 . 008 ) gene expression was noted . Before and following rosiglitazone treatment , Q07869 gamma , P05231 and P22301 gene expression was undetectable in studied monocytes in vivo . In conclusion , TNFalpha and P10145 play an important role in monocyte atherogenic activity . Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines ( Q07869 gamma - independent pathway ) .",
"Natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor - A ( P16066 ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild - type mice ; untreated UUO in P16066 KO mice ; and P01160 treated ( 0 . 05 microg / kg / min ) UUO in wild - type mice . We measured histological and immunohistochemical findings ( alpha - SMA and F4 / 80 ) , tissue cGMP levels , various mRNA expression levels by real - time PCR analysis , and transcription factor levels ( AP - 1 and NF - kappaB ) in renal tissue . RESULTS : Compared with wild - type UUO mice , NPRA - KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha - SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF - beta , collagen I , collagen III , P05121 , renin and angiotensinogen , whereas there were no differences in F4 / 80 positive cells or the mRNA expression levels of P05362 , osteopontin , or P13500 between the two groups . In contrast , P01160 pre - treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF - beta , collagen I , collagen III , P05121 , P05362 , osteopontin , P13500 , renin , and angiotensinogen . NPRA - KO UUO mice had higher AP - 1 levels than wild - type UUO mice and P01160 pre - treatment reduced AP - 1 and NF - kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF - beta / collagen pathway and exogenous P01160 pre - treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF - beta / collagen and NF - kappaB / inflammatory pathways .",
"Targeting other abnormal signaling pathways in sarcoma : P00533 in synovial sarcomas , P37231 in liposarcomas .",
"Development of stable cell lines expressing different subtypes of GABAA receptors . The experiments reported here were motivated by our interest to express in stably - transfected cells large amounts of recombinant rat GABAA receptors . For this , we developed an original two step selection strategy , in which the first step consisted of transfecting P29320 293 cells with rat GABAA receptor alpha and beta subunits . G 418 resistant colonies isolated at this step were screened for [ 3H ] muscimol binding to select for those that coexpressed alpha - and beta - subunits . The best alpha and beta subunit expressing colony was then supertransfected with a plasmid coding for the gamma rat GABAA receptor subunit and a mutant P00374 gene . After a second round of selection , this time in presence of methotrexate , those colonies that coexpressed ternary alpha beta gamma GABAA receptor combinations were distinguished using [ 3H ] flumazenil as a probe . This strategy was applied to the isolation of 3 GABAA receptor clones , alpha 1 beta 2 gamma 2s , alpha 3 beta 2 gamma 2s and alpha 5 beta 3 gamma 2s , that expressed relatively high levels of these proteins . These 3 cell lines exhibited pharmacological and functional properties similar to cells transiently - transfected with equivalent subunit combinations . These cell lines therefore provide attractive models with which to evaluate the intrinsic activity and potency of compounds at recombinant GABAA receptor subtypes .",
"Identification of candidate small - molecule therapeutics to cancer by gene - signature perturbation in connectivity mapping . Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene - expression similarities . The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and / or toxicological properties . Challenges remain , however , as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following - up investigation can be maximised . We introduce a new concept , gene - signature perturbation , which aims to test whether an identified connection is stable enough against systematic minor changes ( perturbation ) to the gene - signature . We applied the perturbation method to three independent datasets obtained from the GEO database : acute myeloid leukemia ( AML ) , cervical cancer , and breast cancer treated with letrozole . We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs . In the case of AML , we found that the prevalent compounds were retinoic acids and Q07869 activators . For cervical cancer , our results suggested that potential drugs are likely to involve the P00533 pathway ; and with the breast cancer dataset , we identified candidates that are involved in prostaglandin inhibition . Thus the gene - signature perturbation approach added real values to the whole connectivity mapping process , allowing for increased specificity in the identification of possible therapeutic candidates .",
"Simultaneous inhibition of epidermal growth factor receptor ( P00533 ) signaling and enhanced activation of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) receptor - mediated apoptosis induction by an scFv : sTRAIL fusion protein with specificity for human P00533 . P00533 ( P00533 ) signaling inhibition by monoclonal antibodies and P00533 - specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction . P01375 - related apoptosis - inducing ligand ( P50591 ) is a promising anti - cancer agent with tumor - selective apoptotic activity . Here we present a novel approach that combines P00533 - signaling inhibition with target cell - restricted apoptosis induction using a P50591 fusion protein with engineered specificity for P00533 . This fusion protein , scFv425 : sTRAIL , comprises the P00533 - blocking antibody fragment scFv425 genetically fused to soluble P50591 ( sTRAIL ) . Treatment with scFv425 : sTRAIL resulted in the specific accretion to the cell surface of P00533 - positive cells only . P00533 - specific binding rapidly induced a dephosphorylation of P00533 and down - stream mitogenic signaling , which was accompanied by cFLIP ( L ) down - regulation and Bad dephosphorylation . P00533 - specific binding converted soluble scFv425 : sTRAIL into a membrane - bound form of P50591 that cross - linked agonistic P50591 receptors in a paracrine manner , resulting in potent apoptosis induction in a series of P00533 - positive tumor cell lines . Co - treatment of P00533 - positive tumor cells with the P00533 - tyrosine kinase inhibitor ___MASK85___ resulted in a potent synergistic pro - apoptotic effect , caused by the specific down - regulation of O15519 . Furthermore , in mixed culture experiments binding ( L ) of scFv425 : sTRAIL to P00533 - positive target cells conveyed a potent apoptotic effect toward P00533 - negative bystander tumor cells . The favorable characteristics of scFv425 : sTRAIL , alone and in combination with ___MASK85___ , as well as its potent anti - tumor bystander activity indicate its potential value for treatment of P00533 - expressing cancers .",
"DB00197 antagonizes tumor necrosis factor - alpha - induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF - kappaB . DB00197 ( Q96PF1 ) , a member of the thiazolidinedione class of anti - diabetic compounds and a peroxisome proliferator activator receptor - gamma ( P37231 ) agonist , restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo . The mechanisms underlying its in vivo function are not understood . Here we investigated the potential functional interaction between P37231 and NF - kappaB in adipocytes . We show that Q96PF1 selectively blocked tumor necrosis factor - alpha - induced and NF - kappaB - dependent repression of multiple adipocyte - specific genes and induction of growth phase and other genes . This occurs without interfering with NF - kappaB expression , activation , nuclear translocation , or DNA binding and without suppressing NF - kappaB - dependent survival signals . Notably , the expressions of some tumor necrosis factor - alpha - induced genes in adipocytes were unaffected by P37231 activation . In reporter gene assays in HeLa cells , ectopic expression of P37231 abolished induction of a NF - kappaB - responsive reporter gene by the p65 subunit ( RelA ) of NF - kappaB , and the inhibition was further enhanced in the presence of Q96PF1 . Conversely , overexpression of p65 inhibited induction of a P37231 - responsive reporter gene by activated P37231 in a dose - dependent manner . The inhibitory effect was independent of the presence of NF - kappaB - binding sites in the promoter region . Other NF - kappaB family members , p50 and c - Rel as well as the S276A mutant of p65 , blocked P37231 - mediated gene transcription less effectively . Thus , p65 antagonizes the transcriptional regulatory activity of P37231 in adipocytes , and P37231 activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes . Our data suggest that inhibition of NF - kappaB activity is a mechanism by which P37231 agonists improve insulin sensitivity in vivo and that adipocyte NF - kappaB is a potential therapeutic target for obesity - linked type 2 diabetes .",
"The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease . Superantigens have been implicated in a number of diseases including Kawasaki disease ( KD ) , a multi - system vasculitis resulting in coronary artery aneurysms . We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract ( LCWE ) . Using this animal model of KD , we have identified three pathogenic steps leading to coronary artery aneurysm formation . These steps include T cell activation and proliferation , production of the proinflammatory cytokine tumour necrosis factor ( P01375 ) - α and up - regulation of matrix metalloproteinase 9 ( P14780 ) , an elastolytic protease . In addition to their cholesterol - lowering effects , 3 - hydroxy - 3 - methylglutaryl ( HMG ) coenzyme A ( DB01992 ) reductase inhibitors ( statins ) have pleotropic immunomodulatory properties . Thus , we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model . ___MASK100___ inhibited lymphocyte proliferation in response to superantigen stimulation in a dose - dependent manner . This inhibition was also observed for production of soluble mediators of inflammation including interleukin ( IL ) - 2 and P01375 - α . The inhibitory effect on proliferation was rescued completely by mevalonic acid , confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of P04035 . Similarly , P01375 - α - induced P14780 production was reduced in a dose - dependent manner in response to atorvastatin . Inhibition of extracellular - regulated kinase ( P29323 ) phosphorylation appears to be the mechanism responsible for inhibition of P14780 production . In conclusion , atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms , suggesting that statins may have therapeutic benefit in patients with KD .",
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK100___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"Differential radiosensitisation by ZD1839 ( ___MASK85___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK85___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"Pharmacogenomics of methadone maintenance treatment . ___MASK93___ is the major opioid substitution therapy for opioid dependence . Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines . Nevertheless many genetic factors have been investigated including those affecting its metabolism ( P20813 - consistent results ) , efflux transport ( P - gp - inconsistent results ) , target μ - opioid receptor ( μ - opioid receptor - inconsistent results ) and a host of other receptors ( P14416 ) and signaling elements ( P48051 and P32121 ; not replicated ) . None by themselves have been able to substantially explain dosage variation ( the major but not sole end point ) . When multiple genes have been combined such as P08183 , P20813 , P35372 and P14416 a greater contribution to dosage variation was found but not as yet replicated . As stabilization of dosage needs to be made rapidly , it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed , which may or may not tailor to different ethnic groups and each country ' s policy towards an outcome that benefits all .",
"DB00197 inhibits isolated cell proliferation , and induces apoptosis in isolated rat mesangial cells . BACKGROUND / AIMS : DB00197 is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator - activated receptor - gamma ( P37231 ) . The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria . There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function . We determined the effect of troglitazone on isolated rat mesangial cell proliferation . METHODS : We determined P37231 mRNA expression in isolated rat mesangial cells . Chronic effects of 10 (- 6 ) to 10 (- 4 ) mol / l troglitazone on mesangial cell proliferation and mitogen - activated protein ( Q96HU1 ) kinase activity were also determined . The effects of troglitazone on apoptosis were investigated in rat mesangial cells . RESULTS : Rat P37231 mRNA was detected in isolated rat mesangial cells . Living cell number , assessed by colorimetric [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ] ( MTT ) assay , was significantly decreased with 10 (- 4 ) mol / l troglitazone . The addition of 10 (- 6 ) to 10 (- 4 ) mol / l troglitazone dose - dependently inhibited 5 - bromo - 2 '- deoxyuridine ( BrdU ) uptake into isolated rat mesangial cells . The addition of 10 (- 4 ) and 10 (- 5 ) mol / l troglitazone significantly reduced Q96HU1 kinase activity . DB00197 at the concentrations of 10 (- 6 ) to 10 (- 4 ) mol / l dose - dependently increased DNA fragmentation rates , indicating that troglitazone may cause apoptosis in rat mesangial cells . Bax and Bcl - xL proteins were not changed , although Bcl - 2 proteins increased with troglitazone . CONCLUSIONS : The present data demonstrated that troglitazone inhibits cell proliferation , and induces apoptosis in rat mesangial cells , raising a possibility that it directly affects renal function .",
"[ Inhibitive effect of troglitazone on TGF - beta ( 1 ) and fibronectin expression in human peritoneal mesothelial cells ] . OBJECTIVE : To investigate the effect of the peroxisome proliferator activated receptor - gamma ( P37231 ) agonist troglitazone on TGF - beta ( 1 ) and fibronectin ( Fn ) expression in human peritoneal mesothelial cells ( HPMCs ) . METHODS : HPMCs were cultured from human omentum by an enzyme digestion method , growing in medium containing 30 mmol / L D - glucose . TGF - beta ( 1 ) and Fn expression were measured in HPMCs in the presence and absence of 15 micromol / L troglitazone . The mRNA expressions of P37231 , TGF - beta ( 1 ) and Fn were determined by semi - quantification reverse transcriptive PCR ( RT - PCR ) . The protein of TGF - beta ( 1 ) was determined by enzyme - linked immunosorbent assay ( ELISA ) and proteins of P37231 and Fn were determined by Western blot . RESULTS : The mRNA and protein expression of TGF - beta ( 1 ) and Fn were significantly increased in HPMCs stimulated with 30 mmol / L D - glucose compared with the control group with P00748 media ( P < 0 . 01 ) . Obvious decrease of TGF - beta ( 1 ) was found in troglitazone ( 15 micromol / L ) treated group compared with group stimulated with 30 mmol / L D - glucose ( P < 0 . 05 ) . Exposure of HPMCs to troglitazone reduced the Fn secretion ( P < 0 . 05 ) . CONCLUSION : DB00197 reduced the expression of TGF - beta ( 1 ) in HPMCs stimulated by 30mmol / L D - glucose , and reduced Fn production . P37231 agonists may have a specific role in ameliorating the course of progressive peritoneal fibrosis under long - term peritoneal dialysis states .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"DB00197 suppresses transforming growth factor - beta1 - induced collagen type I expression in keloid fibroblasts . BACKGROUND : Peroxisome proliferator - activated receptor ( Q07869 ) - gamma agonists are increasingly used in patients with diabetes and some studies have suggested a beneficial effect on organ fibrosis . However their effects on dermal fibrosis in keloids are unknown . OBJECTIVE : To investigate the effect of the P37231 agonist troglitazone on transforming growth factor ( TGF ) - beta1 - induced collagen type I expression in keloid fibroblasts . METHODS : Keloid fibroblasts were cultured and exposed to different concentrations of troglitazone in the presence of TGF - beta1 . The mRNA expression of P37231 was determined by semiquantitative reverse transcriptase - polymerase chain reaction . The protein of P37231 , Q15796 , P84022 , phoshpo - Q15796 / 3 and collagen type I was determined by Western blotting and collagen synthesis was evaluated by measuring ( 3 ) H - proline incorporation . The effect of troglitazone on cell viability was evaluated by the colorimetric conversion of 3 -[ 4 , 5 - dimethylthiazol - 2 - yl ]- 2 , 5 - diphenyltetrazolium bromide . RESULTS : P37231 was expressed at a moderate level in keloid fibroblasts . DB00197 depressed TGF - beta1 - stimulated collagen type I expression and collagen synthesis in keloid fibroblasts in a concentration - dependent manner . Moreover , troglitazone inhibited expression and phosphorylation of TGF - beta1 - induced Q15796 / 3 . Cell viability was unaffected . These inhibitory effects of troglitazone were reversed by the P37231 - specific antagonist GW9662 . CONCLUSIONS : Our data suggest that P37231 is present in keloid fibroblasts and P37231 activation inhibits TGF - beta1 - induced collagen type I expression at least in part by decreasing collagen synthesis . P37231 may be a promising therapeutic target for keloids .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK96___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Population pharmacokinetic study of memantine : effects of clinical and genetic factors . BACKGROUND AND OBJECTIVE : Memantine , a frequently prescribed anti - dementia drug , is mainly eliminated unchanged by the kidneys , partly via tubular secretion . Considerable inter - individual variability in plasma concentrations has been reported . We aimed to investigate clinical and genetic factors influencing memantine disposition . METHODS : A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting . Patients were genotyped for common polymorphisms in renal cation transporters ( O15245 / 2 / 5 , Q96FL8 , P08183 ) and nuclear receptors ( O75469 , Q14994 , RXR , Q07869 ) involved in transporter expression . RESULTS : The average clearance was 5 . 2 L / h with a 27 % inter - individual variability ( percentage coefficient of variation ) . Glomerular filtration rate ( p = 0 . 007 ) and sex ( p = 0 . 001 ) markedly influenced memantine clearance . O75469 rs1523130 was identified as the unique significant genetic covariate for memantine clearance ( p = 0 . 006 ) , with carriers of the O75469 rs1523130 CT / TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype . CONCLUSION : The better understanding of inter - individual variability of memantine disposition might be beneficial in the context of individual dose optimization .",
"[ Genetic polymorphisms and cancer risk ] . While hereditary disease genes have a high lifelong cumulative incidence rate ( penetrance ) , the penetrance for polymorphism genotypes is not high . Polymorphisms relating to cancer incidence are classified into 1 . carcinogen metabolizing enzymes ( CYPs , GSTs , P15559 , etc . ) , 2 . DNA repair enzymes ( O15527 , P18887 , P18074 , etc . ) , 3 . DNA synthesis and methylation ( P42898 , MS , etc . ) , 4 . cytokines and inflammation - related enzymes ( IL - 1B , P01375 - A , P05164 , etc . ) , and 5 . sex hormone metabolizing enzymes and the receptors ( P11511 , P31213 , ER , etc . ) . Since genotypes can not be manipulated , they are not the factors subject to prevention . However , the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes ( gene - environment interaction ) , opens the door to genotype applications for disease prevention practice .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK93___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"P37231 ligand prevents the development of chronic pancreatitis through modulating NF - kappaB - dependent proinflammatory cytokine production and pancreatic stellate cell activation . PURPOSE : Thiazolidinedione derivatives ( TZDs ) are known to be ligands of peroxisome proliferator - activated receptor gamma ( PPARgamma ) . In this study , we investigated the effect of a TZD , troglitazone , on inflammation and fibrogenesis in the pancreas of an experimental model of chronic pancreatitis . MATERIAL AND METHODS : Male WBN / Kob rats with spontaneous chronic pancreatitis were fed rat chow containing 0 . 2 % troglitazone from 1 to 4 months of age . Immunohistochemical studies of rat pancreas were carried out with monoclonal mouse antibody against human alpha - smooth muscle actin ( alpha - SMA ) or rabbit polyclonal antibody against collagen type I , collagen type III , or fibronectin . Cytokine production was measured by enzyme - linked immunosorbent assay . The inhibitory action of troglitazone on nuclear factor - kappaB ( NF - kappaB ) binding activity in activated macrophages was also investigated . RESULTS : Long - term administration of troglitazone reduced inflammatory cell infiltration and fibrosis in the pancreas of WBN / Kob rats , and expression of alpha - SMA , procollagen I , III , and fibronectin was significantly reduced by troglitazone . The increase in P01375 production by activated macrophages was significantly decreased by troglitazone . Peritoneal macrophages isolated from WBN / Kob rats produced a large amount of P01375 , whereas those from troglitazone - treated WBN / Kob rats produced only a marginal amount of P01375 . Lipopolysaccharide - induced NF - kappaB binding activity in peritoneal macrophages was also significantly reduced by troglitazone . CONCLUSIONS : DB00197 prevented the progression of chronic pancreatitis via inhibition of Q13201 synthesis and proinflammatory cytokine production mediated by the inhibition of NF - kappaB activity .",
"Effect of troglitazone on P04798 induction . Several peroxisome proliferators enhance P04798 activity , but the mechanisms involved in this enhancement remain unknown . In this study , we examined the effect of troglitazone , a peroxisome proliferator - activated receptor - gamma ( P37231 ) agonist , on P04798 gene expression and explored the mechanisms involved in these effects . DB00197 increased gene expression of P04798 mRNA and also increased P04798 - specific 7 - ethoxyresorufin - O - deethylase ( EROD ) activity in a dose - dependent manner . Moreover , concomitant treatment with troglitazone and GW9662 , a Q07869 antagonist , markedly reduced the troglitazone - inducible EROD activity . Luciferase reporter assays using Hepa - 1c1c7 cells showed a significant transactivation by troglitazone with a reporter plasmid containing a region from - 1395 to + 7 of the P04798 gene . We found that a putative peroxisome proliferator - response element ( PPRE ) between - 521 and - 500 is located in the P04798 gene promoter . Their inactivation by deletion mutagenesis suppressed the inductive effect of troglitazone on P04798 promoter activation . Electrophoretic mobility shift assay revealed that troglitazone induced the activation of the P37231 to a form capable of binding specifically to the PPRE sequence of the P04798 gene promoter . Furthermore , troglitazone increased the formation of the benzo [ a ] pyrene ( BaP ) - DNA adduct . Overall , our results suggest that troglitazone induces P04798 enzyme activity and gene expression through P37231 activation , and may be involved in carcinogenesis .",
"Selective modulation of promoter recruitment and transcriptional activity of PPARgamma . P37231 ( PPARgamma ) is a nuclear receptor regulated by the insulin - sensitizing thiazolidinediones ( TZDs ) . We studied selective modulation of endogenous genes by PPARgamma ligands using microarray , RNA expression kinetics , and chromatin immunoprecipitation ( ChIP ) in 3T3 - Q9NUQ9 adipocytes . We found over 300 genes that were significantly regulated the TZDs pioglitazone , rosiglitazone , and troglitazone . TZD - mediated expression profiles were unique but overlapping . Ninety - one genes were commonly regulated by all three ligands . TZD time course and dose - response studies revealed gene - and TZD - specific expression kinetics . PEPCK expression was induced rapidly but Q16654 expression was induced gradually . DB00197 EC50 values for PEPCK , Q16654 , and P41220 regulation were greater than those for pioglitazone and rosiglitazone . TZDs differentially induced histone acetylation of and PPARgamma recruitment to target gene promoters . Selective modulation of PPARgamma by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes .",
"Ligands of peroxisome proliferator - activated receptor - gamma induce apoptosis in AR42J cells . INTRODUCTION : Peroxisome proliferator - activated receptor - gamma ( P37231 ) is a ligand - activated transcription factor that controls growth , differentiation , and inflammation in different tissues . Roles of P37231 activation in pancreatic acinar cells are poorly characterized . AIMS : To examine the effects of P37231 activation on the induction of apoptosis in rat pancreatic AR42J cells . METHODOLOGY : AR42J cells were treated with ligands of P37231 , and induction of apoptosis was evaluated by cell viability , DNA - fragmentation , and flow cytometry . RESULTS : Treatment of the cells with ligands of P37231 ( 15 - deoxy - open triangle12 , 14 - prostaglandin J2 or troglitazone ) induced apoptosis in a dose - dependent manner . DB00197 - induced apoptosis was not blocked by inhibitors of caspases ( acetyl - DEVD - aldehyde and benzoyloxycarbonyl - VAD - fluoromethylketone ) . DB00197 induced the expression of pancreatitis - associated protein - 1 and clusterin mRNAs . DB00197 activated c - Jun NH2 - terminal kinase / stress - activated protein kinase , but inhibited the activation of extracellular signal - regulated kinases 1 / 2 . DB00197 did not activate NF - kappaB , suggesting a role of NF - kappaB - independent pathways . In AR42J cells and isolated pancreatic acini , P37231 gene and protein were detected . In addition , troglitazone increased the Q07869 - dependent transcriptional activity , suggesting that P37231 is functional in AR42J cells . CONCLUSION : These results indicate that activation of P37231 induces apoptosis in AR42J cells and imply that P37231 may be a potential therapeutic target of pancreatic inflammation , because of its anti - inflammatory effects in addition to its proapoptotic effects .",
"Coadministration of acetaminophen and troglitazone : pharmacokinetics and safety . DB00197 , a P37231 agonist , enhances the actions of insulin on muscle and liver . It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite . Acetaminophen also undergoes metabolism by conjugation . This three - way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa . No statistically or clinically relevant differences in area under the concentration - time curve extrapolated to infinity ( AUCinfinity ) were observed for troglitazone , its quinone metabolite , or acetaminophen . A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant . No statistically or clinically relevant differences were observed in maximum concentration ( Cmax ) , time to Cmax ( tmax ) , or elimination half - life of troglitazone , its two main metabolites , and acetaminophen or in acetaminophen urinary sulfate excretion , although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone . Adverse events were minor and similar between treatments . These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences .",
"[ Clinical effect and side effect of troglitazone ] . DB00197 , a P37231 agonist , is a new drug for type 2 diabetes . The drug decreases blood glucose via enhancing insulin action . Recently Sankyo pharmaceutical company is warning severe hepatotoxicity by troglitazone . It recommends to examine liver function every month in diabetic patients treated with the drug in order early to find drug - induced hepatitis . In Japan 153 diabetic patients treated with the drug developed severe hepatitis and 8 of them died of drug - side effects . Quinone metabolite of troglitazone predominantly in the liver to a sulfate conjugate and activation of Q07869 gamma and O75469 ( pregnane X receptor ) by troglitazone are supposed to be factors of hepatotoxic mechanism .",
"Delineating biological pathways unique to embryonic stem cell - derived insulin - producing cell lines from their noninsulin - producing progenitor cell lines . To identify unique biochemical pathways in embryonic stem cell - derived insulin - producing cells as potential therapeutic targets to prevent or delay beta - cell dysfunction or death in diabetic patients , comparative genome - wide gene expression studies of recently derived mouse insulin - producing cell lines and their progenitor cell lines were performed using microarray technology . Differentially expressed genes were functionally clustered to identify important biochemical pathways in these insulin - producing cell lines . Biochemical or cellular assays were then performed to assess the relevance of these pathways to the biology of these cells . A total of 185 genes were highly expressed in the insulin - producing cell lines , and computational analysis predicted the pentose phosphate pathway ( PPP ) , clathrin - mediated endocytosis , and the peroxisome proliferator - activated receptor ( Q07869 ) signaling pathway as important pathways in these cell lines . P01308 - producing ERoSHK cells were more resistant to hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - induced oxidative stress . Inhibition of PPP by dehydroepiandrosterone and 6 - aminonicotinamide abrogated this H ( 2 ) O ( 2 ) resistance with a concomitant decrease in PPP activity as measured by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ( MTT ) assay . Clathrin - mediated endocytosis , which is essential in maintaining membrane homeostasis in secreting cells , was up - regulated by glucose in ERoSHK but not in their progenitor ERoSH cells . Its inhibition by chlorpromazine at high glucose concentration was toxic to the cells . DB00197 , a P37231 agonist , up - regulated expression of Ins1 and Ins2 but not Glut2 . Gene expression analysis has identified the PPP , clathrin - mediated endocytosis , and the Q07869 signaling pathway as the major delineating pathways in these insulin - producing cell lines , and their biological relevance was confirmed by biochemical and cellular assays .",
"___MASK36___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"P37231 ligands modulate effects of LPS in stimulated rat synovial fibroblasts . This work demonstrated the constitutive expression of peroxisome proliferator - activated receptor ( Q07869 ) - gamma and Q07869 in rat synovial fibroblasts at both mRNA and protein levels . A decrease in P37231 expression induced by 10 microg / ml lipopolysaccharide ( LPS ) was observed , whereas Q07869 mRNA expression was not modified . 15 - Deoxy - Delta ( 12 , 14 )- prostaglandin J ( 2 ) ( 15d - PGJ ( 2 ) ) dose - dependently decreased LPS - induced cyclooxygenase ( P36551 ) - 2 ( - 80 % ) and inducible nitric oxide synthase ( P35228 ) mRNA expression ( - 80 % ) , whereas troglitazone ( 10 microM ) only inhibited P35228 mRNA expression ( - 50 % ) . 15d - PGJ ( 2 ) decreased LPS - induced interleukin ( IL ) - 1 beta ( - 25 % ) and tumor necrosis factor ( P01375 ) - alpha ( - 40 % ) expression . Interestingly , troglitazone strongly decreased P01375 expression ( - 50 % ) but had no significant effect on P01584 expression . 15d - PGJ ( 2 ) was able to inhibit DNA - binding activity of both nuclear factor ( NF ) - kappa B and AP - 1 . DB00197 had no effect on NF - kappa B activation and was shown to increase LPS - induced AP - 1 activation . 15d - PGJ ( 2 ) and troglitazone modulated the expression of LPS - induced P35228 , P35354 , and proinflammatory cytokines differently . Indeed , troglitazone seems to specifically target P01375 and P35228 pathways . These results offer new insights in regard to the anti - inflammatory potential of the P37231 ligands and underline different mechanisms of action of 15d - PGJ ( 2 ) and troglitazone in synovial fibroblasts .",
"DB00197 sensitizes tumor cells to P50591 - induced apoptosis via down - regulation of FLIP and Survivin . Induction of apoptosis by the death ligand P50591 might be a promising therapeutic approach in cancer therapy . However , since not all tumor cells are sensitive to P50591 , there is a need for the development of strategies to overcome P50591 - resistance . The results of the present study show that the anti - diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to P50591 - induced apoptosis . This process is accompanied by a substantial increase of active caspase 8 and active caspase 3 , but it is independent of troglitazone ' s effects on the nuclear receptor P37231 . DB00197 induces a pronounced reduction in protein expression levels of the anti - apoptotic Q14790 - inhibitory protein ( FLIP ) without affecting FLIP mRNA levels . Further , protein and mRNA expression levels of the anti - apoptotic protein Survivin significantly decrease upon treatment with troglitazone . Moreover , sensitization to P50591 is partly accompanied by an up - regulation of the P50591 receptor , O14763 . A combined treatment with troglitazone and P50591 might be a promising experimental therapy because troglitazone sensitizes tumor cells to P50591 - induced apoptosis via various mechanisms , thereby minimizing the risk of acquired tumor cell resistance .",
"Regulation of angiotensin II receptors beyond the classical pathway . The DB01367 ( renin - angiotensin system ) plays a role not only in the cardiovascular system , including blood pressure regulation , but also in the central nervous system . AngII ( angiotensin II ) binds two major receptors : the AT ( 1 ) receptor ( AngII type 1 receptor ) and AT ( 2 ) receptor ( AngII type 2 receptor ) . It has been recognized that AT ( 2 ) receptor activation not only opposes AT ( 1 ) receptor actions , but also has unique effects beyond inhibitory cross - talk with AT ( 1 ) receptor signalling . Novel pathways beyond the classical actions of DB01367 , the P12821 ( angiotensin - converting enzyme ) / AngII / AT ( 1 ) receptor axis , have been highlighted : the Q9BYF1 / Ang -( 1 - 7 ) [ angiotensin -( 1 - 7 ) ] / Mas receptor axis as a new opposing axis against the P12821 / AngII / AT ( 1 ) receptor axis , novel AngII - receptor - interacting proteins and various AngII - receptor - activation mechanisms including dimer formation . Q6RW13 ( AT ( 1 )- receptor - associated protein ) and Q9ULD2 ( AT ( 2 )- receptor - interacting protein ) are well - characterized AngII - receptor - associated proteins . These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states . Moreover , the possible cross - talk between Q07869 ( peroxisome - proliferator - activated receptor ) - γ and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of DB01367 in the metabolic syndrome , and interestingly some ARBs ( AT ( 1 )- receptor blockers ) have been reported to have an AT ( 1 )- receptor - blocking action with a partial Q07869 - γ agonistic effect . These emerging concepts concerning the regulation of AngII receptors are discussed in the present review .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"P37231 promotes epithelial to mesenchymal transformation by Rho GTPase - dependent activation of P27361 / 2 . P37231 ( PPARgamma ) causes epithelial to mesenchymal transformation ( EMT ) in intestinal epithelial cells , as evidenced by reorganization of the actin cytoskeleton , acquisition of a polarized , mesenchymal cellular morphology , increased cellular motility , and colony scattering . This response is due to activation of Cdc42 , resulting in P38936 - activated kinase - dependent phosphorylation and activation of Q02750 DB00133 ( 298 ) and activation of P27361 / 2 . Dominant negative Q02750 , P36507 , and P28482 block PPARgamma - induced EMT , whereas constitutively active Q02750 and P36507 induce a mesenchymal phenotype similar to that evoked by PPARgamma . PPARgamma also stimulates P27361 / 2 phosphorylation in the intestinal epithelium in vivo . PPARgamma induces the P42336 subunit of phosphoinositide 3 - kinase ( PI3K ) , and inhibition of PI3K blocks PPARgamma - dependent phosphorylation of Q02750 DB00133 ( 298 ) , activation of P27361 / 2 , and EMT . We conclude that PPARgamma regulates the motility of intestinal epithelial cells through a mitogen - activated protein kinase cascade that involves PI3K , Cdc42 , P38936 - activated kinase , Q02750 , and P27361 / 2 . Regulation of cellular motility through Rho family GTPases has not been previously reported for nuclear receptors , and elucidation of the mechanism that accounts for the role of PPARgamma in regulating motility of intestinal epithelial cells provides fundamental new insight into the function of this receptor during renewal of the intestinal epithelium .",
"Disruption of ERalpha signalling pathway by PPARgamma agonists : evidences of PPARgamma - independent events in two hormone - dependent breast cancer cell lines . P37231 ( PPARgamma ) is a nuclear receptor that can be activated by natural ligands such as 15 - deoxy - delta ( 12 , 14 )- prostaglandin J2 ( 15d - PGJ ( 2 ) ) as well as synthetic drugs such as thiazolidinediones . The treatment of human breast cancer cell lines with PPARgamma agonists is known to have antiproliferative effects but the role of PPARgamma activation in the process remains unclear . In the present study , we investigated the effects of four PPARgamma agonists , Rosiglitazone ( RGZ ) , DB09201 ( CGZ ) , DB00197 ( Q96PF1 ) and the natural agonist 15d - PGJ ( 2 ) , on estrogen receptor alpha ( ERalpha ) signalling pathway in two hormone - dependent breast cancer cell lines , MCF - 7 and ZR - 75 - 1 . In both of them , Q96PF1 , CGZ and 15d - PGJ ( 2 ) induced an inhibition of ERalpha signalling associated with the proteasomal degradation of ERalpha . ZR - 75 - 1 cells were more sensitive than MCF - 7 cells to these compounds . Treatments that induced ERalpha degradation inhibited cell proliferation after 24 h . In contrast , 24 h exposure to RGZ , the most potent activator of PPARgamma disrupted neither ERalpha signalling nor cell proliferation . 9 - cis retinoic acid never potentiated the proteasomal degradation of ERalpha . PPARgamma antagonists ( T0070907 , BADGE and GW 9662 ) did not block the proteolysis of ERalpha in MCF - 7 and ZR - 75 - 1 cells treated with Q96PF1 . ERalpha proteolysis still occurred in case of PPARgamma silencing as well as in case of treatment with the PPARgamma - inactive compound Delta2 - Q96PF1 , demonstrating a PPARgamma - independent mechanism . The use of thiazolidinedione derivatives able to trigger ERalpha degradation by a PPARgamma - independent pathway could be an interesting tool for breast cancer therapy .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK48___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .",
"Synthetic peroxisome proliferator - activated receptor - gamma agonists restore impaired vasorelaxation via DB00171 - sensitive K + channels by high glucose . The present study was designed to examine whether in the human artery , synthetic peroxisome proliferator - activated receptor ( Q07869 ) - gamma agonists restore vasorelaxation as well as hyperpolarization via DB00171 - sensitive K + channels impaired by the high concentration of D - glucose and whether the restoration may be mediated by the antioxidant capacity of these agents . The isometric force and membrane potential of human omental arteries without endothelium were recorded . The production rate of superoxide was evaluated using a superoxide - generating system with xanthine - xanthine oxidase in the absence of smooth muscle cells . ___MASK36___ abolished vasorelaxation and hyperpolarization in response to levcromakalim . Addition of D - glucose ( 20 mM ) but not L - glucose ( 20 mM ) reduced this vasorelaxation and hyperpolarization . Synthetic P37231 agonists ( troglitazone and rosiglitazone ) and / or an inhibitor of superoxide generation ( 4 , 5 - dihydroxy - 1 , 3 - benzene - disulfonic acid , Tiron ) , but not a Q07869 agonist ( fenofibrate ) , restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D - glucose . DB00197 and rosiglitazone , but not fenofibrate , decreased the production rate of superoxide without affecting uric acid generation . These findings suggest that synthetic P37231 agonists recover the function of DB00171 - sensitive K + channels reduced by the high concentration of glucose in human vascular smooth muscle cells and that the effect of these agonists may be mediated in part by their antioxidant capacity .",
"Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .",
"[ P00797 - angiotensin - aldosterone system and fibrinolysis ] . Experimental , genetic and clinical evidence suggests that the renin - angiotensin - aldosterone system ( RAAS ) may participate in the pathogenesis of thromboembolic cardiovascular disorders such as coronary heart disease . This interrelationship may involve mechanisms other than changes in arterial blood pressure . In addition to various possible interactions , accumulating evidence suggests that the RAAS is involved in the regulation of the fibrinolytic system . Several recent studies have shown that stimulation of the RAAS may be associated with an activation of plasminogen activator inhibitor 1 ( P05121 ) . Since profibrinolytic factors ( especially tissue plasminogen activator [ t - PA ] ) remain unchanged , increased activity of the RAAS may thus alter the fibrinolytic balance towards a decreased fibrinolytic activity . These findings may be of special importance for a variety of clinical problems such as the long - term effect of a low NaCl - intake on cardiovascular morbidity and mortality and the possible value of drugs indirectly or directly interfering with the RAAS such as diuretics , P12821 - inhibitors and angiotensin II Type 1 ( AT1 ) receptor antagonists .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Gamma tocopherol upregulates the expression of 15 - S - HETE and induces growth arrest through a Q07869 gamma - dependent mechanism in PC - 3 human prostate cancer cells . Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer . Our previous studies in the colon have demonstrated that gamma - tocopherol treatment could upregulate the expression of peroxisome proliferator - activated preceptors ( Q07869 ) gamma , a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation . In this study , we explored the possibility that gamma - tocopherol could induce growth arrest in PC - 3 prostate cancer cells through the regulation of fatty acid metabolism . Growth arrest ( 40 % ) and Q07869 gamma mRNA and protein upregulation was achieved with gamma - tocopherol within 6 h . gamma - Tocopherol - mediated growth arrest was demonstrated to be Q07869 gamma dependent using the agonist GW9662 and a Q07869 gamma dominant negative vector . gamma - tocopherol was shown not to be a direct Q07869 gamma ligand , but rather 15 - S - HETE ( an endogenous Q07869 gamma ligand ) was upregulated by gamma - tocopherol treatment . 15 - Lipoxygenase - 2 , a tumor suppressor and the enzyme that converts arachidonic acid to 15 - S - HETE , was upregulated at 3 h following gamma - tocopherol treatment . Expression of proteins downstream of the Q07869 gamma pathway were examined . P12004 D1 , cyclin D3 , bcl - 2 , and NFkappa B proteins were found to be downregulated following gamma - tocopherol treatment . These data demonstrate that the growth arrest mediated by gamma - tocopherol follows a P37231 - dependent mechanism ."
] |
[
"___MASK100___",
"___MASK36___",
"___MASK40___",
"___MASK48___",
"___MASK64___",
"___MASK85___",
"___MASK93___",
"___MASK94___",
"___MASK96___"
] |
___MASK36___
|
MH_train_316
|
interacts_with DB00688?
|
[
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK64___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK57___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"Cloning and expression of the chromosomal immune interferon gene of the rat . The chromosomal immune interferon gene of the rat ( P01579 ) was identified by screening a recombinant rat lambda phage library with a human P01579 cDNA probe . In contrast to the genes of other rat IFNs , this rat P01579 chromosomal gene contains introns and its structural organization closely resembles that of the human and murine P01579 genes . The rat P01579 gene encodes a signal sequence of 19 amino acids followed by the mature P01579 protein of 137 amino acids . The gene was expressed under control of the simian virus 40 ( SV40 ) early promoter in Chinese hamster ovary ( CHO ) cells deficient in dihydrofolate reductase ( P00374 ) after co - transformation with a plasmid containing the mouse P00374 gene . Initial transformants with a P00374 + phenotype produced P01579 titres ranging from 20 to 1600 units / ml . After stepwise increases in the concentration of methotrexate ( MTX ) in the growth medium of transformed CHO cells , MTX - resistant clones producing 80 000 - 100 000 units per ml were isolated . Protein analysis of supernatants of these MTX - resistant cells by polyacrylamide gel electrophoresis revealed a product with an apparent mol . wt . of 18 000 daltons which was not detectable in the growth medium of P00374 + transformants that did not produce IFN . The product was identified as rat P01579 and constituted approximately 5 % of the proteins excreted from these cells .",
"Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy . Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped . Here , we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic / immunosuppressive drugs methotrexate ( MTX ) and mycophenolate mofetil ( DB00688 ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co - expression of human dihydrofolate reductase ( P00374 ( FS ) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 ( IY ) ; T333I , S351Y ) conferred T cell resistance to the cytocidal and anti - proliferative effects of these drugs at concentrations that can be achieved clinically ( up to 0 . 1 µM MTX and 1 . 0 µM DB00603 ) . Furthermore , using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells , in vivo selection studies demonstrate that huEGFRt (+) P00374 ( FS +) P12268 ( IY +) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4 . 4 - fold ) , DB00688 alone ( 2 . 9 - fold ) , or combined MTX and DB00688 ( 4 . 9 - fold ) . These findings demonstrate the utility of both P00374 ( FS )/ MTX and P12268 ( IY )/ DB00688 for in vivo selection of lentivirally transduced human T cells . Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK6___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"A fluorine - labeled methotrexate as a probe for monitoring tumor antifolate pharmacokinetics : synthesis , in vitro cytotoxicity , and pilot in vivo 19F magnetic resonance spectra . The synthesis and characterization of 3 '- fluoromethotrexate ( FMTX ) , a novel fluorine - labeled analogue of methotrexate , are presented . Molecular modeling studies indicate that the fluorine atom causes only minimal changes in the structure / binding in the complex of the antifolate with thymidine synthetase and dihydrofolate reductase ( P00374 ) . The in vitro cytotoxicity of this compound is shown to be equivalent to that of the parent antifolate compound . While the focus of this report is the synthetic technique of FMTX , it is also demonstrated that tumor accumulation of the labeled compound in vivo can be observed via 19F magnetic resonance spectroscopy ( P59665 ) in a human tumor xenograft model .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK46___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK24___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"___MASK80___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK80___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK80___ is a promising pharmacological tool in the treatment of renal edema .",
"___MASK93___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .",
"Cyclooxygenase inhibitors modulate NK activities that control metastatic disease . Cyclooxygenase ( P36551 ) inhibitors have demonstrated efficacy in models of human cancer but the relevant mechanisms have not all been elucidated . Both Cox - dependent as well as Cox - independent mechanisms have been implicated . Using a syngeneic model of metastatic breast cancer , we have investigated the effect of Cox inhibitors on NK functions that are critical to the control of metastatic disease . NK recognition of target cells is governed by a balance of activating and inhibiting receptors that bind ligands including MHC class I . We now show that treatment of tumor cells with the nonselective P23219 / P35354 inhibitor indomethacin or the selective P35354 inhibitor celecoxib leads to decreased expression of the MHC class I molecules Ld and Kd . Downregulated class I expression is associated with concomitant increased sensitivity to NK cell - mediated lysis . Both P36551 inhibitors limit tumor metastasis and this therapeutic effect is dependent on NK but not T cell function . Antimetastatic activity is also lost in the absence of interferon - gamma ( P01579 ) . Both P36551 inhibitors also suppress local tumor growth of subcutaneously implanted mammary tumor cells in immune competent Balb / cByJ mice . This therapeutic activity is lost in the absence of either P01730 + or CD8 + T cells , but is not compromised by the loss of NK activity . Thus , the mechanism of tumor inhibition differs in the context of local versus metastatic disease . Taken together , these findings are consistent with a mechanism not previously described , whereby P36551 inhibitors may relieve MHC - mediated inhibition of NK cytotoxicity leading to recognition and lysis of metastatic tumor cells .",
"In vivo protection of activated Tyr22 - dihydrofolate reductase gene - modified canine T lymphocytes from methotrexate . BACKGROUND : Nonmyeloablative allogeneic hematopoietic stem cell ( P19526 ) transplantation can cure malignant and nonmalignant diseases affecting the hematopoietic system , such as severe combined immunodeficiencies , aplastic anemia and hemoglobinopathies . Although nonmyeloablative is favored over myeloablative transplantation for many patients , graft rejection remains problematic . One strategy for decreasing rejection is to protect donor activated T cells in the graft from methotrexate ( MTX ) by genetically modifying the cells to express MTX - resistant dihydrofolate reductase ( Tyr22 - P00374 ) , leaving the immunosuppressive effects of MTX to act solely on activated host T lymphocytes , shifting the balance to favor allogeneic engraftment . METHODS : To evaluate MTX resistance of Tyr22 - P00374 (+) T lymphocytes in vivo , we transplanted dogs with autologous P28906 (+) cells modified with yellow fluorescent protein ( YFP ) and P00374 - green fluorescent protein ( GFP ) lentivirus vectors . Dogs were then treated with a standard MTX regimen days 1 , 3 , 6 and 11 ) following immune activation with a foreign antigen as a surrogate assay to mimic early transplantation . RESULTS : P00374 - GFP (+) gene marking was maintained in CD3 (+) CD25 (+) and P01730 (+) T lymphocytes after MTX treatment , whereas the level of T lymphocytes that expressed only a fluorescent reporter ( YFP (+) ) decreased . These data show that Tyr22 - P00374 expression protects T lymphocytes from MTX toxicity in dogs , highlighting a clinically relevant application for preserving donor T lymphocytes during post - transplantation immunosuppression . CONCLUSIONS : The findings of the present study have implications for the clinical translation of MTX - resistant T cells to facilitate engraftment of allogeneic cells following nonmyeloablative conditioning and to minimize the risk of rejection . In summary , Tyr22 - P00374 expression in T lymphocytes provides chemoprotection from MTX - mediated elimination in the context of immune activation in vivo .",
"Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .",
"Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13 . Autosomal dominant hypophosphatemic rickets ( P30518 ) is an inherited disorder of isolated renal phosphate wasting , the pathogenesis of which is unknown . We performed a genome - wide linkage study in a large kindred to determine the chromosome location of the P30518 gene . Two - point LOD scores indicate that the gene is linked to the markers D12S314 [ Z ( theta ) = 3 . 15 at theta = 0 . 0 ] , vWf [ Z ( theta ) = 5 . 32 at theta = 0 . 0 ] , and P01730 [ Z ( theta ) = 3 . 53 at theta = 0 . 0 ] . Moreover , multilocus analysis indicates that the P30518 gene locus is located on chromosome 12p13 in the 18 - cM interval between the flanking markers D12S100 and D12S397 . These data are the first to establish a chromosomal location for the P30518 locus and to provide a framework map to further localize the gene . Such studies will permit ultimate identification of the P30518 gene and provide further insight into phosphate homeostasis .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK92___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK36___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK36___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .",
"Monocytic AML cells inactivate antileukemic lymphocytes : role of NADPH oxidase / gp91 ( phox ) expression and the P09874 / PAR pathway of apoptosis . Dysfunction of T cells and natural killer ( NK ) cells has been proposed to determine the course of disease in acute myeloid leukemia ( AML ) , but only limited information is available on the mechanisms of lymphocyte inhibition . We aimed to evaluate to what extent human malignant AML cells use NADPH oxidase - derived reactive oxygen species ( ROS ) as an immune evasion strategy . We report that a subset of malignant myelomonocytic and monocytic AML cells ( French - American - British [ FAB ] classes M4 and M5 , respectively ) , recovered from blood or BM of untreated AML patients at diagnosis , expressed the NADPH oxidase component gp91 ( phox ) . Highly purified FAB M4 / M5 AML cells produced large amounts of ROS on activation and triggered poly -[ ADP - ribose ] polymerase - 1 - dependent apoptosis in adjacent NK cells , P01730 (+) T cells , and CD8 (+) T cells . In contrast , immature ( FAB class M1 ) and myeloblastic ( FAB class M2 ) AML cells rarely expressed gp91 ( phox ) , did not produce ROS , and did not trigger NK or T - cell apoptosis . Microarray data from 207 AML patients confirmed a greater expression of gp91 ( phox ) mRNA by FAB - M4 / M5 AML cells than FAB - M1 cells ( P < 10 (- 11 ) ) or FAB - M2 cells ( P < 10 (- 9 ) ) . Our data are suggestive of a novel mechanism by which monocytic AML cells evade cell - mediated immunity .",
"Expression of P20839 is regulated in response to mycophenolate concentration . DB04335 5 '- monophosphate dehydrogenase ( IMPDH ) catalyzes de novo guanine nucleotide synthesis . ___MASK64___ ( DB00603 ) exerts immunosuppressive effects by inhibiting IMPDH . The aim of this study was to investigate gene expressions of two IMPDH isoforms , during in vivo exposure to DB00603 . Healthy volunteers ( n = 5 ) were given single doses of 100 , 250 , 500 and 1000 mg mycophenolate mofetil ( DB00688 ) . Blood was sampled pre - dose and at 1 , 2 , 4 , 6 , 8 , 12 , and 24 h post - dose . The expressions of P20839 and 2 were quantified in P01730 + cells and whole blood by real - time reverse transcription - PCR . Following DB00688 doses of 500 mg , the expression of P20839 and 2 in P01730 + cells was reduced 39 % ( P = 0 . 043 ) and 10 % ( P = 0 . 043 ) , respectively . Smaller reductions ( ns ) were observed after 1000 mg DB00688 . Similar trends were demonstrated for whole blood . The largest reductions of P20839 occurred at DB00603 AUC ( 0 - 12 h ) of 20 mg h / L . Below this , increasing DB00603 exposure correlated with larger reductions of P20839 expression ( P01730 + cells : r =- 0 . 82 , P < 0 . 001 , and whole blood : r =- 0 . 50 , P = 0 . 04 , n = 17 ) , while higher DB00603 exposure seemed to be associated with smaller reductions of expression ( P01730 + cells : r = 0 . 42 , ns , and whole blood : r = 0 . 77 , P = 0 . 039 , n = 8 ) . The concentration - dependent modulation of P20839 and 2 expressions by DB00603 might impact IMPDH activity . Knowledge of the regulation of the two IMPDH isoenzymes in vivo by DB00603 is of importance considering pharmacodynamic monitoring and optimization of DB00603 treatment ."
] |
[
"___MASK24___",
"___MASK36___",
"___MASK46___",
"___MASK57___",
"___MASK64___",
"___MASK6___",
"___MASK80___",
"___MASK92___",
"___MASK93___"
] |
___MASK93___
|
MH_train_317
|
interacts_with DB09029?
|
[
"Inhibition of Q16552 as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 , ( 3 ) an Q16552 vaccine , ( 4 ) methods to block the Q16552 receptor and ( 5 ) small - molecule inhibitors of Q16552 . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 antibodies , an Q16552 receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 ( an Q16552 antibody ) , Brodalumab ( an Q16552 receptor antibody ) and two small - molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 drugs , as related to drug pharmacodynamics , Q16552 receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor - related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small - molecule inhibitors of NF - κB and P40763 , like synthetic triterpenoids .",
"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK84___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Luteinizing Hormone - Releasing Hormone ( P01148 ) - I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo . The objective of this study was to determine the effects of an luteinizing hormone - releasing hormone ( P01148 ) - I antagonist , DB00050 , on human multiple myeloma ( MM ) cells and to elucidate the mechanisms of action . We showed that P01148 - I and P22888 - I genes were expressed in MM cell lines and primary MM cells . Treatment with DB00050 inhibited growth and colony - forming ability of myeloma cells , including cell lines resistant to arsenic trioxide , bortezomib , or lenalidomide . DB00050 induced apoptosis in myeloma cells including primary myeloma cells . In addition , DB00050 inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects . DB00050 downregulated the nuclear factor - kappa B ( NF - κB ) pathway activity and the expression of cytokines , including interleukin 6 , insulin - like growth factor 1 , P15692 , and stromal - derived factor 1 , important for myeloma cell growth and survival in myeloma cells and / or marrow stromal cells from myeloma patients . DB00050 decreased the phosphorylation of extracellular signal regulated kinase 1 / 2 and P40763 in myeloma cells , two crucial pathways for myeloma cells growth and survival . Moreover , the expression of P38936 and p53 was increased , whereas that of antiapoptotic proteins Bcl - 2 and Bcl - x ( L ) was reduced by DB00050 . Our findings indicate that DB00050 induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating DB00050 for the treatment of MM .",
"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .",
"Bone marrow stromal cells derived P13500 reverses the inhibitory effects of multiple myeloma cells on osteoclastogenesis by upregulating the Q9Y6Q6 expression . Multiple myeloma ( MM ) cells are responsible for aberrant osteoclast ( OC ) activation . However , when cocultured monocytes , but not OC precursors , with MM cells , we made a novel observation that MM cells inhibited receptor activator of nuclear factor κB ligand ( O14788 ) - induced increase of OC differentiation , OC gene expression , signaling pathways and bone resorption activity . Our results showed that MM cells produced multiple inhibitory cytokines of osteoclastogenesis , such as P22301 , which activated P40763 signaling and induce OC inhibition . However , cocultures of bone marrow stromal cells ( BMSCs ) reversed MM - induced OC inhibition . We found that MM cells increased production of P13500 from BMSCs and BMSC - derived P13500 enhanced OC formation . Mechanistic studies showed that P22301 downregulated Q9Y6Q6 expression in monocytes and thus , inhibited O14788 - induced OC formation . In contrast , P13500 upregulated Q9Y6Q6 expression and thus , enhanced OC formation . Overall , our studies for the first time demonstrated that MM cell have inhibitory effects on osteoclastogenesis by producing inhibitory cytokines . Our results further indicate that activation of osteoclastogenesis in bone marrow requests the crosstalk of MM cells , BMSCs and their produced cytokines . Thus , our studies provide evidences that targeting bone marrow microenvironmental cells and / or cytokines may be a new approach to treating MM bone destruction .",
"Functional P40763 deficiency compromises the generation of human T follicular helper cells . T follicular helper ( Tfh ) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab - secreting cells . Accordingly , it is important to identify the molecular requirements for Tfh cell development and function . We previously found that IL - 12 mediates the differentiation of human P01730 (+) T cells to the Tfh lineage , because IL - 12 induces naive human P01730 (+) T cells to acquire expression of Q9HBE4 , P41182 , Q9Y6W8 , and P32302 , which typify Tfh cells . We have now examined P01730 (+) T cells from patients deficient in IL - 12Rβ1 , P29597 , P42224 , and P40763 to further explore the pathways involved in human Tfh cell differentiation . Although P42224 was dispensable , mutations in P42701 , P29597 , or P40763 compromised IL - 12 - induced expression of Q9HBE4 by human P01730 (+) T cells . Defective expression of Q9HBE4 by P40763 - deficient P01730 (+) T cells resulted in diminished B - cell helper activity in vitro . Importantly , mutations in P40763 , but not P42701 or P29597 , also reduced Tfh cell generation in vivo , evidenced by decreased circulating P01730 (+) P32302 (+) T cells . These results highlight the nonredundant role of P40763 in human Tfh cell differentiation and suggest that defective Tfh cell development and / or function contributes to the humoral defects observed in P40763 - deficient patients .",
"___MASK59___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK59___ , in the USA in 2003 .",
"___MASK77___ for joints and bones . ___MASK77___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK77___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK77___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK49___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK49___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK49___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK49___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK49___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK49___ increased the protein expression of hepatic P05181 and ___MASK49___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK49___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK49___ and RFP - induced hepatotoxicity .",
"___MASK77___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK77___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK77___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .",
"Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Synthetic triterpenoid induces P15428 expression and suppresses inflammation - driven colon carcinogenesis . Colitis - associated colon cancer ( CAC ) develops as a result of inflammation - induced epithelial transformation , which occurs in response to inflammatory cytokine - dependent downregulation of 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 expression and suppress cyclooxygenase - 2 ( P35354 ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 ( 11 )- dien - C28 - methyl ester ( CDDO - Me ) suppresses CAC in mice . In a spontaneous , inflammation - driven intestinal neoplasia model , deletion of Q13485 specifically in T cells led to progressive production of inflammatory cytokines , including P01375 - α , IFN - γ , P35228 , P05231 , IL - 1β ; as well as activation of P42224 and P40763 ; along with suppression of P15428 expression . Oral administration of CDDO - Me to mice with Q13485 - deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 . Induction of P15428 by CDDO - Me was dose dependent in epithelial cells and was abrogated following treatment with TGF - β signaling inhibitors in vitro . Furthermore , CDDO - Me - dependent P15428 induction was not observed in P84022 -/- mice . Similarly , CDDO - Me suppressed azoxymethane plus dextran sodium sulfate - induced carcinogenesis in wild - type animals , highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans .",
"Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway . OBJECTIVE : Inducible costimulator ( Q9Y6W8 ) is a member of the P10747 family . Although inflammation is an essential pathological feature of myocarditis , the role of Q9Y6W8 in myocarditis remains unclear . METHODS AND RESULTS : Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis ( EAM ) . Flow cytometry was used to examine expression of Q9Y6W8 on myocardial infiltrating cells . Anti - Q9Y6W8 antibody or Q9Y6W8 - immunoglobulin ( ICOSIg ) was administered intravenously , and rats were killed on day 14 or 21 to study effects of Q9Y6W8 / Q9Y6W8 - ligand ( O75144 ) pathway blockade during the antigen priming phase ( days 0 - 14 ) or immune response phase ( days 14 - 21 ) , respectively . The heart weight to body weight ratio was determined , and histological examination and echocardiogram were performed to evaluate the severity of the disease . Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed . Flow cytometry revealed that the majority of infiltrating cells , especially P01730 - positive cells , expressed Q9Y6W8 . Blockade of the Q9Y6W8 / O75144 pathway during the immune response phase attenuated EAM development . However , blockade of the Q9Y6W8 / O75144 pathway during the antigen priming phase did not attenuate and exacerbate EAM . Blockade of T cell activation through Q9Y6W8 suppressed expression of cytokines including P27352 - gamma , P05112 , P05231 , P22301 , P01584 , and P01375 and inhibited T cell proliferation in vitro . CONCLUSIONS : Blockade of T cell activation through Q9Y6W8 during the immune response phase regulates development of EAM , and therefore , Q9Y6W8 may be an effective target for treating myocarditis .",
"Molecular dissection of human oncostatin M - mediated signal transductions through site - directed mutagenesis . The binding of oncostatin M ( OM ) to type I and type II receptor complexes elicits various biological responses by activating MEK / P29323 and JAK / P35610 signaling pathways . Some OM effects are clinically desirable such as reducing hyperlipidemia through the activation of hepatic P01130 transcription , a downstream event of P29323 activation . The OM pro - inflammatory responses via induction of acute phase protein gene expression have been associated with P35610 activation . In this study , by conducting site - directed mutagenesis , bioassays and molecular modeling we have defined 4 OM residues that are differently involved in the activation of P29323 or P35610 signaling pathway in HepG2 cells . We show that mutation of Lys163 to alanine totally abolished OM - mediated signaling , possibly because such mutation causes the disruption of a stabilizing H - bond pattern at the OM interface with receptors . G120A mutation equally impaired activations of P29323 and P35610 signaling pathways also by impairing the OM / cognate protein interactions . Interestingly , mutations of Gln20 and Asn123 differentially affected OM signaling through the two pathways . Q20A and N123A retained strong activity in inducing P29323 phosphorylation but they showed diminished ability in activating P42224 and P40763 . We further showed that mutations at Gln20 and Asn123 reduced OM induction of inflammatory gene fibrinogen - beta to a greater extent than that of P01130 gene . The mutation of Asn123 is directly related to local structural modification at site 3 of OM . Collectively these results provide a structural basis of OM - mediated signaling and suggest a potential to improve OM therapeutic properties via structural modification .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK64___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Androgen metabolism and JAK / P35610 pathway genes and prostate cancer risk . BACKGROUND : Prostate cancer ( PC ) is the most frequently diagnosed solid tumor in U . S . men . Genome - wide association studies ( GWAS ) have identified over 40 risk - associated single nucleotide polymorphisms ( SNPs ) , including variants in androgen pathway genes ( e . g . , KLK3 and AR ) . Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC . METHODS : In this hypothesis - testing study , we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor ( AR ) . A total of 187 SNPs were genotyped in 1458 cases and 1351 age - matched controls from a population - based study . PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models . RESULTS : Single SNP analyses showed evidence ( p < 0 . 05 ) for associations with 14 SNPs in 9 genes : Q99801 , P37058 , P42330 , Q06520 , P05093 , KLK3 , O60674 , Q13772 and P40763 . The most significant result was observed for rs2253502 in P37058 ( odds ratio , OR = 0 . 57 , 95 % CI : 0 . 39 - 0 . 84 ) . In addition , five SNPs in four genes ( P05093 , P51659 , Q13772 , and Q06520 ) were associated with more aggressive disease ( p < 0 . 01 ) . CONCLUSIONS : Our results replicate previously reported associations for SNPs in P05093 , P37058 , ARK1C3 , Q99801 , Q13772 and KLK3 . In addition , novel associations were observed for SNPs in O60674 , P51659 , and Q06520 . These results will require replication in larger studies .",
"___MASK71___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK71___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK71___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK71___ inhibits activated T cells . We show that in vitro , ___MASK71___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK71___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK71___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK71___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK71___ to treat chronic inflammatory disease .",
"Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK71___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK71___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK71___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK71___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .",
"Interferon - γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin ( ET ) - 1 and transforming growth factor ( TGF ) β2 . Systemic sclerosis ( SSc ) is a complex disease characterized by vascular alterations , activation of the immune system and tissue fibrosis . Previous studies have implicated activation of the interferon pathways in the pathogenesis of SSc . The goal of this study was to determine whether interferon type I and / or type II could play a pathogenic role in SSc vasculopathy . Human dermal microvascular endothelial cells ( HDMVECs ) and fibroblasts were obtained from foreskins of healthy newborns . The RT Profiler PCR Array System was utilized to screen for EndoMT genes . Treatment with IFN - α or IFN - γ downregulated Fli1 and P33151 . In contrast , IFN - α and IFN - γ exerted opposite effects on the expression of α - SMA , P29279 , ET - 1 , and TGFβ2 , with IFN - α downregulating and IFN - γ upregulating this set of genes . Blockade of TGFβ signaling normalized IFN - γ - mediated changes in Fli1 , P33151 , P29279 , and ET - 1 levels , whereas upregulation of α - SMA and TGFβ2 was not affected . DB00559 treatment was more effective than TGFβ blockade in reversing the actions of IFN - γ , including downregulation of α - SMA and TGFβ2 , suggesting that activation of the ET - 1 pathway plays a main role in the IFN - γ responses in HDMECs . IFN - γ induced expression of selected genes related to endothelial - to - mesenchymal transition ( EndoMT ) , including Snail1 , P02751 , P05121 , Q15672 , P40763 , P41220 , and components of the WNT pathway . The effect of IFN - γ on EndoMT was mediated via TGFβ2 and ET - 1 signaling pathways . This study demonstrates distinct effects of IFN - α and IFN - γ on the biology of vascular endothelial cells . IFN - γ may contribute to abnormal vascular remodeling and fibrogenesis in SSc , partially via induction of EndoMT .",
"Binding of C / EBPbeta to the P02741 ( CRP ) promoter in Hep3B cells is associated with transcription of CRP mRNA . Expression of the acute phase protein P02741 ( CRP ) is tightly regulated in hepatocytes . Although very little CRP mRNA is transcribed normally , inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation . P05231 and IL - 1beta are believed to be the major cytokines responsible for induction of CRP and other acute phase proteins . Our previous studies , using transient transfection and EMSA experiments , implicated involvement of the transcription factors C / EBPbeta , P40763 , Rel p50 , and c - Rel in CRP induction . In the current study we used chromatin immunoprecipitation assays to determine the kinetics of transcription factor occupancy of these transcription factors on the endogenous CRP promoter . All of these transcription factors were found bound to the endogenous CRP promoter in the absence of cytokines , but cytokine treatment markedly increased binding of only C / EBPbeta . In addition , c - Rel and TATA box - binding protein ( P20226 ) appeared to occupy the promoter in parallel in the presence of cytokines . In the absence of cytokines , CRP mRNA accumulation was not measurable but began to increase by 3 h after exposure of cells to IL - 1beta plus P05231 , peaking at 12 h with secondary peaks at 18 and 24 h . The secondary peaks in mRNA expression paralleled the pattern of binding of c - Rel and P20226 to the CRP promoter . We conclude that the CRP promoter has a low level of transcription factor occupancy in the absence of cytokines and induction occurs with binding of C / EBP , and that c - Rel and P20226 are important for modulating CRP expression .",
"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK34___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .",
"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .",
"___MASK34___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .",
"Not all monoclonals are created equal - lessons from failed drug trials in Crohn ' s disease . The recent success of the anti - integrin antibody DB09033 can barely conceal the fact that the biologics armamentarium in Crohn ' s disease has barely evolved beyond P01375 blockers so far . This contrasts with other immune - related diseases considered mechanistically and genetically closely related , such as psoriasis and rheumatoid arthritis , where approved biologics target a variety of independent biological mechanisms . Several pharmacological assets that entered clinical development have proven ineffective , or less effective than originally anticipated . While blockade of Q16552 and its receptor via DB09029 and Brodalumab , respectively , worsened Crohn ' s disease , the beneficial effect of IL - 12 / 23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn ' s disease patients who have previously failed on P01375 blockers . Clinical development of the IFNγ blocker DB05111 was stopped despite demonstrating some clinical benefit , while the T cell co - stimulation blocker ___MASK71___ did not exhibit any hint towards efficacy in Crohn ' s disease . Here I review results from these individual development programmes , and also reflect on the lack of efficacy of the P01375 blocker DB00005 . I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years . Finally , I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn ' s disease .",
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK2___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism ( s ) by which chronic inflammation drives cancer initiation and promotion include increased production of pro - inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo - oxygenase - 2 ) , 5 - P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro - inflammatory transcription factors such as NF - κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP - 1 ( activator protein 1 ) and HIF - 1α ( hypoxia - inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation - associated molecules are activated by a number of environmental and lifestyle - related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer .",
"[ ___MASK76___ sodium ( Photofrin - II ) ] . ___MASK76___ sodium ( ___MASK76___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK76___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions ."
] |
[
"___MASK2___",
"___MASK34___",
"___MASK49___",
"___MASK59___",
"___MASK64___",
"___MASK71___",
"___MASK76___",
"___MASK77___",
"___MASK84___"
] |
___MASK77___
|
MH_train_318
|
interacts_with DB00188?
|
[
"Serum deprivation alters the expression and the splicing at exons 7 , 8 and 15 of the beta - amyloid precursor protein in the P13671 glioma cell line . Amyloid deposition characterizes the pathological lesions of Alzheimer ' s disease . We investigated the effect of serum deprivation on the regulation of beta - amyloid precursor protein ( P05067 ) mRNA expression in P13671 glioma cells . Serum deprivation increased P05067 mRNA levels approximately 4 - fold over controls . This increase was accompanied by changes in the pattern of alternative splicing , including the novel alternatively spliced site at exon 15 . The proportion of isoforms containing exons 7 and 8 significantly increased from 61 % to 68 % , while isoforms lacking these exons decreased from 14 % to 8 % . The proportion of leukocyte - derived P05067 , which is a novel alternatively spliced isoform lacking exon 15 , significantly increased from 19 % to 40 % . Among the six major isoforms produced by the two independent splicing sites , L - APP752 which contains exons 7 and 8 , but lacks exon 15 , increased the most ( approximately 10 - fold ) . Our findings provide evidence linking P05067 expression to alterations in alternative splicing at exon 15 . These results demonstrate that in glial cells , P05067 mRNA regulation involves the alteration in alternative splicing at exons 7 , 8 and 15 , suggesting that not only increased expression but also an imbalance in the relative abundance of the six P05067 isoforms in stressed condition might affect the amyloidogenesis in Alzheimer ' s disease .",
"Molecular weight and biochemical profile of a chemically modified heparin derivative , Suleparoide . Recently , a new chemically modified derivative of heparin ( Suleparoide , Syntex Laboratories Buenos Aires , Argentina ) was introduced for the prophylaxis of thrombosis and treatment of vascular disorders . This agent is claimed to contain a depolymerized , chemically modified , heparin derivative with similar biologic actions as heparan sulfate . To study the pharmacologic profile of this agent , we have defined its molecular weight distribution profile , utilizing a computerized gel permeation chromatographic system equipped with ultraviolet and refractive index detectors . Suleparoide exhibited a normal molecular distribution profile with no contaminants . It exhibited a weight average of 9 . 3 K DA and an apparent peak MW of 8 . 0 K DA . Approximately 50 % of the molecular components were < 5 . 0 K DA and 40 % > 5 . 0 K DA . The results from these studies on the mechanisms show that Suleparoide has anticoagulant activity primarily mediated through ___MASK34___ Cofactor - II ( P05546 ) and because of its novel mechanism of action , further investigations on the biochemical profile of Suleparoide are carried out . Global clotting tests such as Activated Partial P13726 Time ( APTT ) , Heptest and Thrombin Time ( TT ) revealed a concentration dependent effect in all assays . Plasma samples supplemented with Suleparoide exhibited no significant anti - Xa and anti - IIa activities . However , in the P05546 mediated inhibitory assay for IIa , Suleparoide exhibited significant activity . In contrast , the P01008 ( DB11598 ) mediated inhibition of IIa was much weaker .",
"Characterization of bortezomib - adapted I - 45 mesothelioma cells . BACKGROUND : DB00188 , a proteasome - specific inhibitor , has emerged as a promising cancer therapeutic agent . However , development of resistance to bortezomib may pose a challenge to effective anticancer therapy . Therefore , characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib - mediated cancer therapy . RESULTS : The present study reports the development of I - 45 - BTZ - R , a bortezomib - resistant cell line , from the bortezomib - sensitive mesothelioma cell line I - 45 . I - 45 - BTZ - R cells showed no cross - resistance to the chemotherapeutic drugs cisplatin , 5 - fluorouracil , and doxorubicin . Moreover , the bortezomib - adapted I - 45 - BTZ - R cells had decreased growth kinemics and did not over express proteasome subunit beta5 ( P28074 ) as compared to parental I - 45 cells . I - 45 - BTZ - R cells and parental I - 45 cells showed similar inhibition of proteasome activity , but I - 45 - BTZ - R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib . Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response ( UPR ) in the bortezomib - adapted cells , while higher doses induced UPR with concomitant cell death , as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum ( ER ) stress - related pro - apoptotic protein P35638 . In addition , bortezomib exposure did not induce the accumulation of the pro - apoptotic proteins p53 , Mcl - 1S , and noxa in the bortezomib - adapted cells . CONCLUSION : These results suggest that UPR evasion , together with reduced pro - apoptotic gene induction , accounts for bortezomib resistance in the bortezomib - adapted mesothelioma cell line I - 45 - BTZ - R .",
"P28222 and other related serotonergic proteins are altered in APPswe mutation . Serotonergic dysfunction is implicated in Alzheimer ' s disease ( AD ) . In addition , reductions in brain of both monoamine synthesis and release have been reported . Serotonin 1B receptors ( P28222 ) , along with serotonin transporter ( P31645 ) are among the regulators of extracellular 5 - HT levels . We investigated the effect of the familial AD P05067 ( P05067 ) K670N / M671L double mutation , P05067 Swedish mutation ( APPswe ) , on the expression of P28222 , P31645 , P21397 , p11 and 5 - HT and its metabolite 5 - HIAA in SH - SY5Y human neuroblastoma cell line stably transfected with APPswe mutation . In addition , hippocampal expressions of P28222 and P31645 were assessed in wild type and transgenic mice expressing APPswe mutation ( Tg2576 ) at different age groups . We found a reduction of P28222 as well as P31645 in both APPswe in vitro and ex vivo . P11 and 5HT were also reduced , whereas 5HT turnover and P21397 were increased . Our results indicate that APPswe induced decreased P28222 expression and 5 - HT release , as well as increased P21397 activity and 5 - HT breakdown . Further studies to explore the detailed mechanism behind reduced P28222 and P31645 in AD and their clinical implications are needed .",
"Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V P10721 mutation . The majority of patients with systemic mast cell disease express the imatinib - resistant Asp816Val ( D816V ) mutation in the P10721 receptor tyrosine kinase . Limited treatment options exist for aggressive systemic mastocytosis ( P17405 ) and mast cell leukemia ( Q8WXI8 ) . We evaluated whether PKC412 , a small - molecule inhibitor of P10721 with a different chemical structure from imatinib , may have therapeutic use in advanced SM with the D816V P10721 mutation . We treated a patient with Q8WXI8 ( with an associated myelodysplastic syndrome ( P43034 ) / myeloproliferative disorder [ P53602 ] ) based on in vitro studies demonstrating that PKC412 could inhibit D816V P10721 - transformed Ba / P13726 cell growth with a 50 % inhibitory concentration ( IC50 ) of 30 nM to 40 nM . The patient exhibited a partial response with significant resolution of liver function abnormalities . In addition , PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in P10721 phosphorylation and D816V P10721 mutation frequency . The patient died after 3 months of therapy due to progression of her P43034 / P53602 to acute myeloid leukemia ( AML ) . This case indicates that P10721 tyrosine kinase inhibition is a feasible approach in SM , but single - agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK56___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"___MASK34___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK34___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK34___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .",
"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .",
"Immunoaffinity purification of the functional 20S proteasome from human cells via transient overexpression of specific proteasome subunits . The proteasome is a multi - subunit proteolytic complex that plays a central role in protein degradation in all eukaryotic cells . It regulates many vital cellular processes therefore its dysfunction can lead to various pathologies including cancer and neurodegeneration . Isolation of enzymatically active proteasomes is a key step to the successful study of the proteasome regulation and functions . Here we describe a simple and efficient protocol for immunoaffinity purification of the functional 20S proteasomes from human P29320 293T cells after transient overexpression of specific proteasome subunits tagged with 3xFLAG . To construct 3xFLAG - fusion proteins , DNA sequences encoding the 20S proteasome subunits P28074 , P28066 , and P25788 were cloned into mammalian expression vector pIRES - hrGFP - 1a . The corresponding recombinant proteins P28074 - 3xFLAG , P28066 - 3xFLAG , or P25788 - 3xFLAG were transiently overexpressed in human P29320 293T cells and were shown to be partially incorporated into the intact proteasome complexes . 20S proteasomes were immunoprecipitated from P29320 293T cell extracts under mild conditions using antibodies against FLAG peptide . Isolation of highly purified 20S proteasomes were confirmed by SDS - PAGE and Western blotting using antibodies against different proteasome subunits . Affinity purified 20S proteasomes were shown to possess chymotrypsin - and trypsin - like peptidase activities confirming their functionality . This simple single - step affinity method of the 20S proteasome purification can be instrumental to subsequent functional studies of proteasomes in human cells .",
"RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including Q00535 . The molecular target ( s ) cooperating with proteasome inhibition in multiple myeloma ( MM ) remain unknown . We therefore measured proliferation in MM cells transfected with 13 984 small interfering RNAs in the absence or presence of increasing concentrations of bortezomib . We identified 37 genes , which when silenced , are not directly cytotoxic but do synergistically potentiate the growth inhibitory effects of bortezomib . To focus on bortezomib sensitizers , genes that also sensitized MM to melphalan were excluded . When suppressed , the strongest bortezomib sensitizers were the proteasome subunits P28066 , P49721 , P49720 , and Q99436 providing internal validation , but others included Q9UIG0 , Q00535 , Q9NRR3 , O15151 , Q9Y5B8 , Q92930 , P19532 , P21580 , Q13470 , P11387 , P63027 , and P25490 . The strongest hit Q00535 also featured prominently in pathway analysis of primary screen data . P12004 - dependent kinase 5 ( Q00535 ) is expressed at high levels in MM and neural tissues with relatively low expression in other organs . Viral shRNA knockdown of Q00535 consistently sensitized 5 genetically variable MM cell lines to proteasome inhibitors ( bortezomib and carfilzomib ) . Small - molecule Q00535 inhibitors were demonstrated to synergize with bortezomib to induce cytotoxicity of primary myeloma cells and myeloma cell lines . Q00535 regulation of proteasome subunit P28074 was identified as a probable route to sensitization .",
"___MASK68___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .",
"Cytotoxic effects of bortezomib in myelodysplastic syndrome / acute myeloid leukemia depend on autophagy - mediated lysosomal degradation of Q9Y4K3 and repression of P25786 . DB00188 ( Velcade ) is used widely for the treatment of various human cancers ; however , its mechanisms of action are not fully understood , particularly in myeloid malignancies . DB00188 is a selective and reversible inhibitor of the proteasome . Paradoxically , we find that bortezomib induces proteasome - independent degradation of the Q9Y4K3 protein , but not mRNA , in myelodysplastic syndrome ( P43034 ) and acute myeloid leukemia ( AML ) cell lines and primary cells . The reduction in Q9Y4K3 protein coincides with bortezomib - induced autophagy , and subsequently with apoptosis in P43034 / AML cells . RNAi - mediated knockdown of Q9Y4K3 sensitized bortezomib - sensitive and - resistant cell lines , underscoring the importance of Q9Y4K3 in bortezomib - induced cytotoxicity . DB00188 - resistant cells expressing an shRNA targeting Q9Y4K3 were resensitized to the cytotoxic effects of bortezomib due to down - regulation of the proteasomal subunit α - 1 ( P25786 ) . To determine the molecular consequences of loss of Q9Y4K3 in P43034 / AML cells , in the present study , we applied gene - expression profiling and identified an apoptosis gene signature . Knockdown of Q9Y4K3 in P43034 / AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem / progenitor function . In summary , we describe herein novel mechanisms by which Q9Y4K3 is regulated through bortezomib / autophagy - mediated degradation and by which it alters P43034 / AML sensitivity to bortezomib by controlling P25786 expression .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK21___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Changes in the levels of some acute - phase proteins in human immunodeficiency virus - 1 infected patients , following interleukin - 2 treatment . Intermittent interleukin ( IL ) - 2 administration to human immunodeficiency virus ( HIV ) - 1 infected patients is well documented and generally used , but there is limited information about the changes of acute - phase protein ( P05067 ) levels in response to this treatment . Fifteen patients undergoing highly active anti - retroviral therapy ( HAART ) treatment , with undetectable viral load , but low P01730 + cell count ( < 300 / microl ) , have been treated with 3 . 6 M IU Proleukine administered twice daily by subcutaneous injection over 5 days . P02741 ( CRP ) , D - dimer , P01024 , P02748 , C1 - inh and alpha - 2HS glycoprotein levels were measured immediately before P60568 administration , as well as on day 5 and 2 - 3 weeks thereafter . After P60568 administration , both mean D - dimer and CRP levels increased significantly ( P < 0 . 001 ) , but returned ( P < 0 . 001 ) to baseline within the subsequent 2 - 3 weeks . Alpha - 2HS glycoprotein decreased immediately after P60568 administration . No significant differences were detected in the levels of P01024 , P02748 and C1 - inh . A significant , positive correlation ( r = 0 . 5178 , P = 0 . 0008 ) was ascertained between the changes of CRP level , measured immediately before as well as 5 days after P60568 administration , and changes in P01730 T cell counts measured 2 - 3 weeks before and after treatment , respectively . P60568 administration induces rapid elevation of two major APPs ( CRP , D - dimer ) . The positive correlation observed between the changes of CRP levels and P01730 + cell counts after P60568 administration may indicate that the abrupt , but transitory overproduction of CRP might contribute to the P01730 + cell count - increasing effect of the drug and / or may be associated with serious side effects .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK5___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Cytokines and acute phase proteins associated with acute swine influenza infection in pigs . This study set out to investigate the cytokines and acute phase proteins ( APPs ) associated with the acute stages of experimentally - induced swine influenza virus ( SIV ) infection in 3 - week - old , colostrum - deprived , caesarean - derived piglets . The piglets were inoculated intratracheally with 10 ( 7 . 5 ) 50 % egg infective dose [ EID ( 50 ) ] Swine / Belgium / 1 / 98 ( H1N1 ) SIV and were euthanased at time - points between 0 and 120h post - inoculation ( PI ) . Broncho - alveolar lavage fluid ( BALF ) , lung homogenates and sera were examined for inflammatory mediators by bioassay or ELISA . Interferon ( IFN ) - α , interleukin ( IL ) - 6 , IL - 1 and tumour necrosis factor ( P01375 ) - α peaked in BALF 24 - 30h PI , when virus titres and the severity of clinical signs were maximal . Whereas IFN - γ and IL - 12 , but not Q14116 , increased in tandem in BALF , serum cytokine concentrations were either undetectable or were up to 100 - fold lower . The P05067 P02741 ( CRP ) and haptoglobin peaked 24h later than the cytokines and reached higher levels in serum than in BALF . In contrast , lipopolysaccharide ( LPS ) - binding protein ( P18428 ) only increased in BALF . Lung virus titres tightly correlated with BALF IFN - α , P05231 , IL - 1 , P01375 - α , IFN - γ and IL - 12 , as well as with serum P05231 , IFN - α and IFN - γ . Signs of disease correlated with the same cytokines in BALF and serum , as well as with BALF P18428 and serum CRP . The findings suggest that IFN - γ and IL - 12 play a role in the pathogenesis of SIV and that APPs are induced by cytokines . This influenza infection model may have value in assessing the therapeutic potential of cytokine antagonists .",
"Dissociation of Akt / P31749 and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer ' s disease . Previous studies demonstrated that the P19525 ( double - stranded RNA - activated protein kinase ) pathway was activated while the P42345 ( mammalian target of rapamycin ) pathway was inhibited in Alzheimer ' s disease ( AD ) . Here , we analysed upstream and downstream factors of P42345 in brain of P05067 ( SL )/ P49768 KI mice displaying a massive neuronal loss in hippocampus . While P42345 levels were not modified , we found a great activation of Akt with a robust accumulation of P - Akt ( ( T308 ) ) in non - apoptotic neurons at 6 months of age . At the opposite , a significant decrease of the P08133 / 85S6K activation was observed in brain of P49768 KI and P05067 ( SL )/ P49768 KI mice with a very weak or no nucleocytoplasmic P - P08133 / 85S6K ( ( T389 ) ) staining in apoptotic neurons of P05067 ( SL )/ P49768 KI mice . Furthermore , the activation of Erk1 / 2 , Q13541 and p70S6K ( ( T421 / S424 ) ) ( substrate of Erk1 / 2 ) , except P06730 , was not modified . These findings demonstrate a clear dissociation between Akt and ribosomal S6K signaling markers in these mice which could be involved in the AD pathological process .",
"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .",
"Production and characterization of monoclonal antibodies against urea derivatives . A panel of monoclonal antibodies was generated against the urea - based hapten N -( 2 - N - chloroacetylaminobenzyl )- N '- 4 - chlorophenylurea as a tool for building up sensitive immune assays to detect urea derivatives and to screen them for catalytic antibodies ( Abs ) . Eleven hybridomas were obtained that produced Abs reactive to the hapten . All Abs were of IgG class . Cross reactivities of the Abs to different haptens were examined , especially to a possible transition - state analog . Only four of the hybridomas ( R2 - DA10 / P08709 , R2 - GE7 / H2 , R2 - P25786 / A5 , R2 - Q9UBN7 / P08709 ) produced Abs crossreactive with the transition - state analog . From the 11 hybridomas , hybridoma B76 - BF5 was chosen for further characterization . Compared to the other Abs , B76 - BF5 showed the strongest binding and had a rather restricted specificity . These Abs could be used to build up a sensitive enzyme immunoassay for the detection of the hapten . All Abs were screened for crossreactivity with the pesticides monuron and diuron . No reactivity could be detected . In addition , the nucleotide sequences of the variable light and heavy chain genes of the similarly reactive Abs B76 - BF5 , B76 - BB3 , R2 - DA10 / P08709 , and R2 - GA6 / P46379 were determined to clarify whether structure and binding specificity of these Abs showed any correlation .",
"Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children ' s Cancer Group Study . PURPOSE : ___MASK68___ is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real - time RT - PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children ' s Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event - free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome .",
"Proteases and lipoprotein receptors in Alzheimer ' s disease . Alzheimer ' s disease ( AD ) is the leading cause of senile dementia , and is a complex disorder . The pathological hallmarks of AD were discovered by Dr . Alois Alzheimer in 1907 , and include deposits of amyloid or senile plaques and neurofibrillar tangles . Plaques are composed of a peptide , termed the Abeta peptide , that is derived by proteolytic processing of the amyloid precursor protein ( P05067 ) , while neurofibrillar tangles result from a hyperphosphorylation of the tau protein . Mechanisms associated with the formation of plaques and neurofibrillar tangles and their respective contributions to the disease process have been intensely investigated . Proteolytic processing of P05067 that results in the generation of the Abeta peptide is now well understood and is influenced by several proteins . Recent evidence suggests that the Abeta levels are carefully regulated , and several proteases play an important role in removing the Abeta peptide . Finally , it is becoming apparent that several members of the P01130 family play important roles in the brain , and may modulate the course of AD .",
"___MASK85___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK85___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .",
"Separation and purification of the tonoplast ATPase and pyrophosphatase from plants with constitutive and inducible Crassulacean acid metabolism . Tonoplast vesicles were isolated from Kalanchoe daigremontiana Hamet et Pierrer de la Bâthie and Mesembryanthemum crystallinum L . , exhibiting constitutive and inducible crassulacean acid metabolism ( P62158 ) , respectively . Membrane - bound proteins were detergent - solubilized with 2 % of Triton X - 100 . During P62158 induction in M . crystallinum , ATPase activity increases four - fold , whereas pyrophosphatase activity decreases somewhat . With all plants , ATPase and pyrophosphatase could be separated by size - exclusion chromatography ( SEC , Sephacryl S 400 ) , and the ATPase was further purified by diethylaminoethyl - ion - exchange chromatography . Sodium - dodecyl - sulfate electrophoresis of the SEC fractions from K . daigremontiana containing maximum ATPase activity separates several protein bands , indicating subunits of 72 , 56 , 48 , 42 , 28 , and 16 kDa . Purified ATPase from M . crystallinum in the P01024 and P62158 states shows a somewhat different protein pattern . With M . crystallinum , an increase in DB00171 - hydrolysis and changes in the subunit composition of the native enzyme indicate that the change from the P01024 to the P62158 state is accompanied by de - novo synthesis and by structural changes of the tonoplast ATPase .",
"Free energy force field ( FEFF ) 3D - QSAR analysis of a set of Plasmodium falciparum dihydrofolate reductase inhibitors . Free energy force field ( FEFF ) 3D - QSAR analysis was used to construct ligand - receptor binding models for a set of 18 structurally diverse antifolates including pyrimethamine , cycloguanil , methotrexate , aminopterin and trimethoprim , and 13 pyrrolo [ 2 , 3 - d ] pyrimidines . The molecular target ( ' receptor ' ) used was a 3D - homology model of a specific mutant type of Plasmodium falciparum ( Pf ) dihydrofolate reductase ( P00374 ) . The dependent variable of the 3D - QSAR models is the IC50 inhibition constant for the specific mutant type of PfDHFR . The independent variables of the 3D - QSAR models ( the descriptors ) are scaled energy terms of a modified first - generation AMBER force field combined with a hydration shell aqueous solvation model and a collection of 2D - QSAR descriptors often used in QSAR studies . Multiple temperature molecular dynamics simulation ( P43034 ) and the genetic function approximation ( GFA ) were employed using partial least square ( PLS ) and multidimensional linear regressions as the fitting functions to develop FEFF 3D - QSAR models for the binding process . The significant FEFF energy terms in the best 3D - QSAR models include energy contributions of the direct ligand - receptor interaction . Some changes in conformational energy terms of the ligand due to binding to the enzyme are also found to be important descriptors . The FEFF 3D - QSAR models indicate some structural features perhaps relevant to the mechanism of resistance of the PfDHFR to current antimalarials . The FEFF 3D - QSAR models are also compared to receptor - independent ( RI ) 4D - QSAR models developed in an earlier study and subsequently refined using recently developed generalized alignment rules .",
"___MASK92___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK92___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK97___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib - selected variants of Jurkat T cell lymphoblastic lymphoma / leukemia line . To study the mechanism of acquired resistance to bortezomib , a new antitumor drug that is the first therapeutic proteasome inhibitor , we established a series of bortezomib - resistant T lymphoblastic lymphoma / leukemia cell lines , designated the JurkatBs , from the parental Jurkat line via repeated drug selection . There were no significant differences in the growth curves or colony formation between the JurkatB cells and parental Jurkat cells . The effects of bortezomib on cytotoxicity , cell cycle arrest , and induction of apoptosis were decreased in JurkatB cells compared with parental Jurkat cells . A mutation in the proteasome beta5 subunit ( P28074 ) gene ( G322A ) , which encodes an amino acid change from Ala to DB00156 at polypeptide position 108 , was detected by sequencing full - length cDNA clones and direct polymerase chain reaction products of the P28074 gene . DB00188 caused less inhibition of chymotrypsin - like activity in resistant cells . When the G322A mutant P28074 was retrovirally introduced into parental Jurkat cells , it conferred bortezomib resistance to these cells , resulting in decreased cytotoxicity , apoptosis , and inhibition of chymotrypsin - like activity . The predicted structure of A108T - mutated P28074 shows a conformational change that suggests decreased affinity to bortezomib . In short , the G322A mutation of the P28074 gene is a novel mechanism for bortezomib resistance .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK52___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK52___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK52___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK52___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK52___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"P02649 interrupts interleukin - 1beta signaling in vascular smooth muscle cells . OBJECTIVES : P02649 ( apoE ) exerts antiatherogenic effects but precise mechanisms remain unclear . We here investigated the effect of apoE on intracellular signaling by interleukin - 1beta ( IL - 1beta ) , a proinflammatory cytokine present in atherosclerotic lesions . METHODS AND RESULTS : IL - 1beta - induced expression and activation of inducible nitric oxide synthase and cyclooxygenase - 2 were inhibited by apoE in vascular smooth muscle cells ( VSMCs ) . These inhibitory effects were linked to the suppression of both NF - kappaB and activating protein - 1 ( AP - 1 ) transactivation , suggesting that the interruption of IL - 1beta signaling occurs upstream of transcription factors . Studies in VSMCs overexpressing IL - 1beta signaling intermediates revealed that NF - kappaB transactivation was inhibited by apoE in MyD88 - and P51617 - but not in Q9Y4K3 - transfected cells . Furthermore , apoE prevented P51617 phosphorylation and P51617 - Q9Y4K3 but not MyD88 - P51617 complex formation . Inhibitory effects of apoE on IL - 1beta signaling were abolished after silencing P01130 - related protein - 1 ( Q07954 ) expression with siRNA . In addition , inhibitors of adenylyl cyclase and protein kinase A ( PKA ) restored IL - 1beta signaling in apoE - treated VSMCs , whereas apoE stimulated PKA activity . ApoE inhibited VSMC activation in response to Q14116 but not to tumor necrosis factor - alpha or polyinosinic : polycytidylic acid . CONCLUSION : ApoE targets P51617 activation and thereby interrupts IL - 1beta and Q14116 signaling in VSMCs . This antiinflammatory effect represents a novel antiatherogenic activity of apoE .",
"A ' metastasis - prone ' signature for early - stage mismatch - repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics . Metastasis is the major cause of cancer mortality . We aimed to find a metastasis - prone signature for early stage mismatch - repair proficient sporadic colorectal cancer ( CRC ) patients for better prognosis and informed use of adjuvant chemotherapy . The genome - wide expression profiles of 82 age - , ethnicity - and tissue - matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array . Metastasis - negative patients have 5 years or more of follow - up . A 10 x 10 two - level nested cross - validation design was used with several families of classification models to identify the optimal predictor for metastasis . The best classification model yielded a 54 gene - set ( 74 probe sets ) with an estimated prediction accuracy of 71 % . The specificity , sensitivity , negative and positive predictive values of the signature are 0 . 88 , 0 . 58 , 0 . 84 and 0 . 65 , respectively , indicating that the gene - set can improve prognosis for early stage sporadic CRC patients . These 54 genes , including node molecules P31946 , Q99683 , P02545 , P05067 , P50148 , P13726 , Q13469 , and P21980 , integrate multiple bio - functions in various compartments into an intricate molecular network , suggesting that cell - wide perturbations are involved in metastasis transformation . Further , querying the ; Connectivity Map ' with a subset ( 70 % ) of these genes shows that DB00145 - DB00117 - Lys and securinine could reverse the differential expressions of these genes significantly , suggesting that they have combinatorial therapeutic effect on the metastasis - prone patients . These two perturbagens promote wound - healing , extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early - stage CRC .",
"The complete primary structure of mouse 20S proteasomes . The proteasome is a large multicatalytic proteinase that plays a role in the generation of peptides for presentation by major histocompatibility complex class I molecules . The 20S proteolytic core of mammalian proteasomes is assembled from a group of 17 protein subunits that generate a distinctive pattern of spots upon two - dimensional gel electrophoresis . The genes for most of these subunits have been cloned from humans and rats . We isolated cDNA clones for the mouse orthologues of ten of the subunits [ P25786 ( P06681 ) , P25787 ( P01024 ) , P25788 ( Q99618 ) , P25789 ( P02748 ) , P28066 ( ZETA ) , P60900 ( IOTA ) , O14818 ( P13671 - I ) , P49721 ( P10643 - I ) , P49720 ( Q99622 - II ) , and P28074 ( X ) ] to complete the cloning of all of the mouse subunits . Using antisera raised against these subunits or their orthologues , we verified the identity of these proteins by two - dimensional NEPHGE - PAGE .",
"Q14116 produced by thymic epithelial cells induces development of dendritic cells with CD11b in the fetal thymus . Thymic dendritic cells ( DCs ) are suggested to be involved in T cell selection ; however , their exact origin and function remain to be established . Although DCs in the adult thymus are mostly CD8alpha (+) CD11b (-) , we found that CD8alpha (-) CD11b (+) DCs were abundantly present in the fetal thymus and they possessed antigen - presenting activity . Interestingly , these CD11b (+) DCs were significantly decreased in mice deficient for TNFR - associated factor 6 ( Q9Y4K3 ) , a key signaling molecule downstream of IL - 1 and tumor necrosis factor - alpha that have been known to induce DCs from intra - thymic precursor cells . CD11b (+) DCs were induced from P01730 (-) CD8 (-) thymocytes by fetal thymic epithelial cells ( TECs ) . Analysis of cytokine expression in TECs revealed that none of the cytokines previously shown to induce DCs were expressed . Instead , we found strong expression of Q14116 that transmits signals through Q9Y4K3 . Q14116 induced CD11b (+) DCs from P01730 (-) CD8 (-) thymocytes in vitro , which exhibited strong antigen - presenting activity and formed conjugates with P01730 (+) CD8 (+) T cells efficiently . Taken together , these results strongly suggest that CD11b (+) DCs are differentiated from P01730 (-) CD8 (-) thymocytes by Q14116 produced from TECs and that they are involved in T cell selection in the fetal thymus .",
"Crystal structure of Lysbeta ( 1 ) 82 - Lysbeta ( 2 ) 82 crosslinked hemoglobin : a possible allosteric intermediate . The crystal structure of human hemoglobin crosslinked between the Lysbeta82 residues has been determined at 2 . 30 A resolution . The crosslinking reaction was performed under oxy conditions using bis ( 3 , 5 - dibromosalicyl ) fumarate ; the modified hemoglobin has increased oxygen affinity and lacks cooperativity . Since the crystallization occurred under deoxy conditions , the resulting structure displays conformational characteristics of both the ( oxy ) R and the ( deoxy ) T - states . beta82XLHbA does not fully reach its T - state conformation due to the presence of the crosslink . The R - state - like characteristics of deoxy beta82XLHbA include the position of the distal Hisbeta63 ( E7 ) residue , indicating a possible reason for the high oxygen affinity of this derivative . Other areas of the molecule , particularly those thought to be important in the allosteric transition , such as Tyrbeta145 ( P25786 ) and the switch region involving Proalpha ( 1 ) 44 ( P06729 ) , Thralpha ( 1 ) 41 ( P13671 ) and Hisbeta ( 2 ) 97 ( FG4 ) , are in intermediate positions between the R and T - states . Thus , the structure may represent a stabilized intermediate in the allosteric transition of hemoglobin .",
"Analysis of a 26 - kb region linked to the Mhc in zebrafish : genomic organization of the proteasome component beta / transporter associated with antigen processing - 2 gene cluster and identification of five new proteasome beta subunit genes . Sequencing of zebrafish ( Danio rerio ) bacterial artificial chromosome and P1 artificial chromosome genomic clone fragments and of cDNA clones has led to the identification of five new loci coding for beta subunits of proteasomes ( PSMB ) . Together with the four genes identified previously , nine PSMB genes have now been defined in the zebrafish . Six of the nine genes reside in the zebrafish MHC ( Mhc ) class I region , four of them reside in a single cluster closely associated with TAP2 on a 26 - kb long genomic fragment , and two reside at some distance from the fragment . In addition to homologues of the human genes P28074 through P28065 , two new genes , A5LHX3 and PSMB12 , have been found for which there are no known corresponding genes in humans . The new genes reside in the PSMB cluster in the Mhc . Homology and promoter region analysis suggest that the Mhc - associated genes might be inducible by P01579 . The zebrafish class I region contains representatives of three phylogenetically distinguishable groups of PSMB genes , X , Y , and Z . It is proposed that these genes were present in the ancestral PSMB region before Mhc class I genes became associated with it .",
"___MASK92___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK68___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK97___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK97___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK97___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance .",
"G ( alpha ) 12 / 13 inhibition enhances the anticancer effect of bortezomib through P28074 downregulation . DB00188 is a proteasome inhibitor approved for anticancer therapy . However , variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits . G ( alpha )( 12 / 13 ) serves modulators or signal transducers in diverse pathways . This study investigated whether cancer cells display differential sensitivity to bortezomib with reference to G ( alpha )( 12 / 13 ) expression , and if so , whether G ( alpha )( 12 / 13 ) affects the expression of proteasome subunits and their activities . DB00188 treatment exhibited greater sensitivities in Huh7 and SNU886 cells ( epithelial type ) than SK - Hep1 and SNU449 cells ( mesenchymal type ) that exhibited higher levels of G ( alpha )( 12 / 13 ) . Overexpression of an active mutant of G ( alpha )( 12 ) ( Galpha ( 12 ) QL ) or G ( alpha )( 13 ) ( G ( alpha )( 13 ) QL ) diminished the ability of bortezomib to induce cytotoxicity in Huh7 cells . Moreover , transfection with the minigene that disturbs G protein - coupled receptor - G protein coupling ( CT12 or Q9NXZ2 ) increased it in SK - Hep1 cells . Consistently , MiaPaCa2 cells transfected with CT12 or Q9NXZ2 exhibited a greater sensitivity to bortezomib . Evidence of G ( alpha )( 12 / 13 ) ' s antagonism on the anticancer effect of bortezomib was verified in the reversal by G ( alpha )( 12 ) QL or G ( alpha )( 13 ) QL of the minigenes ' enhancement of cytotoxity . Real - time polymerase chain reaction assay enabled us to identify P28074 , multicatalytic endopeptidase complex - like - 1 , and proteasome activator subunit - 1 repression by CT12 or Q9NXZ2 . Furthermore , G ( alpha )( 12 / 13 ) inhibition enhanced the ability of bortezomib to repress P28074 , as shown by immunoblotting and proteasome activity assay . Moreover , this inhibitory effect on P28074 was attenuated by G ( alpha ) G ( alpha )( 12 ) QL or G ( alpha )( 13 ) QL . In conclusion , the inhibition of G ( alpha )( 12 / 13 ) activities may enhance the anticancer effect of bortezomib through P28074 repression , providing insight into the G ( alpha )( 12 / 13 ) pathway for the regulation of proteasomal activity .",
"___MASK56___ - induced human keratinocytes toxicity is mediated by P40763 inhibition . BACKGROUND : P42345 ( P42345 ) inhibitors are associated with dermatological adverse events . The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 ( P40763 ) protein and the dermatological adverse events associated with the P42345 inhibitor everolimus . METHODS : We evaluated the effects of P40763 activity and related signal transduction activities on everolimus - induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST - 8 assay , and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis . Apoptosis was evaluated using an imaging cytometric assay . RESULTS : The cell growth inhibitory effects of everolimus were enhanced by stattic or P50402 - 21 , which are selective inhibitors of P40763 , treatment in HaCaT cells , although such effects were not observed in Caki - 1 and HepG2 cells . Phosphorylation at tyrosine 705 of P40763 was decreased by treatment with everolimus in a dose - dependent manner in HaCaT cells ; in contrast , phosphorylation at serine 727 was not decreased by everolimus , but slightly increased . Furthermore , we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of P40763 in HaCaT cells resisted the cytostatic activity of everolimus . CONCLUSIONS : These findings suggest that P40763 activity may be a biomarker of everolimus - induced dermatological toxicity .",
"Regulation of P28074 protein and β subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 ( P40763 ) : potential role in bortezomib - mediated anticancer therapy . The ubiquitin - proteasome system facilitates the degradation of ubiquitin - tagged proteins and performs a regulatory role in cells . Elevated proteasome activity and subunit expression are found in several cancers . However , the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome . This study was initiated to elucidate the mechanisms involved in the regulation of β subunits of the mammalian proteasome . Suppression of P40763 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β subunits of the 20 S core complex in DU145 cells . Notably , P28074 , a molecular target of bortezomib , was shown to be a target of P40763 . Knockdown of P40763 decreased P28074 protein . Inhibition of phospho - P40763 substantially reduced P28074 protein levels in cells expressing constitutively active - P40763 . Accumulation of activated P40763 resulted in the induction of P28074 promoter and protein levels . In addition , a direct correlation was observed between the endogenous levels of P28074 and constitutively active P40763 . P28074 and P40763 protein levels remained unaltered following the inhibition of proteasome activity . The P01133 - induced concerted increase of β subunits was blocked by inhibition of the P01133 receptor or P40763 but not by the PI3K / AKT or MEK / P29323 pathways . Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in P40763 - inhibited cells . Combined treatments with bortezomib and inhibitor of P40763 abrogated proteasome activity and enhanced cellular apoptosis . Overall , we demonstrate that aberrant activation of P40763 regulates the expression of β subunits , in particular P28074 , and the catalytic activity of the proteasome .",
"Structural analysis and chromosomal localization of the mouse Psmb5 gene coding for the constitutively expressed beta - type proteasome subunit . The proteasome is a multi - subunit protease responsible for the production of peptides presented by major histocompatibility complex class I molecules . Accumulated evidence indicates that , upon stimulation with interferon - gamma ( P01579 ) , three beta - type subunits , designated P28065 , P28062 , and P40306 , are incorporated into the 20S proteasome by displacing the housekeeping beta - type subunits designated P28072 , P28074 , and Q99436 , respectively . These changes in the subunit composition appear to facilitate class I - mediated antigen presentation , presumably by altering the cleavage specificities of the proteasome . In the present study , we determined the organization of the mouse gene Psmb5 , coding for the P28074 subunit . Psmb5 is made up of three exons , spanning approximately 5 kilobases . Its exon - intron organization differs radically from those of the other P01579 - regulated , beta - type subunit genes including Lmp7 with which Psmb5 is believed to share an immediate common ancestor . The structure of the mouse Psmb5 gene is identical to that of its recently characterized human counterpart . Thus , the unique organization of the gene coding for the P28074 subunit appears to have been established before mammalian radiation . As well as the Psmb5 gene , the mouse genome contains a processed pseudogene designated Psmb5 - ps . Interspecific backcross mapping showed that Psmb5 maps close to the Gtrgal2 locus on chromosome 14 and that Psmb5 - ps is located in the vicinity of the Psme3 locus on chromosome 11 . These results were confirmed by fluorescent in situ hybridization analysis that localized Psmb5 to band P06681 to proximal D1 of chromosome 14 and Psmb5 - ps to band D of chromosome 11 .",
"Interleukin - 1 receptor - associated kinase 2 is critical for lipopolysaccharide - mediated post - transcriptional control . O43187 , a member of the interleukin - 1 receptor - associated kinase ( P51617 ) family , has been implicated in Toll - like receptor ( TLR ) - mediated signaling . We generated O43187 - deficient mice to examine its function in detail . These mice are resistant to lipopolysaccharide - induced septic shock , because of impaired O00206 - mediated induction of pro - inflammatory cytokines and chemokines . Although O43187 deficiency did not affect O00206 - mediated NFkappaB activation , a reduction of lipopolysaccharide ( LPS ) - mediated mRNA stabilization contributed to the reduced cytokine and chemokine production observed in bone marrow - derived macrophages from O43187 - deficient mice . Furthermore , the ratios of LPS - induced cytokine and chemokine mRNAs in translation - active ( polysomal ) versus translation - inactive ( free ribosomes ) pools were reduced in O43187 - deficient macrophages compared with wild type macrophages . Importantly , LPS - induced phosphorylation of P46734 / 6 , Q9BUB5 , and P06730 was significantly reduced in O43187 - deficient macrophages compared with wild type macrophages . Moreover , LPS stimulation induced an interaction of O43187 with Q9Y4K3 , P46734 / 6 , and P49137 , implicating a critical role for mitogen - activated protein kinase signaling in LPS - induced O43187 - mediated post - transcriptional control . These results reveal that O43187 is required for LPS - mediated post - transcriptional control of cytokine and chemokine expression , which plays an essential role in O00206 - induced septic shock .",
"Molecular genetic classification of central nervous system malformations . Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis , such as neurulation , neuroblast migration , and axonal pathfinding . This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically . A scheme based purely on genetic mutations would not be practical , in part because only in a few dysgeneses are the specific defects known , but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others . The same genes serve different functions at different stages and are involved in multiple organ systems . Some complex malformations , such as holoprosencephaly , result from several unrelated defective genes . Finally , a pure genetic classification would be too inflexible to incorporate some anatomic criteria . The basis for the proposed scheme is , therefore , disturbances in patterns of genetic expression ; polarity gradients of the axes of the neural tube ( eg , upregulation or downregulation of genetic influences ) ; segmentation ( eg , deletions of specific neuromeres , ectopic expression ) ; mutations that cause change in cell lineage ( eg , dysplastic gangliocytoma of cerebellum , myofiber differentiation within brain ) ; and specific genes or molecules that mediate neuroblast migration in its early ( eg , filamin - 1 ) , middle ( eg , P43034 , double - cortin ) , or late course ( eg , reelin , Q9NUQ9 - P62158 ) . The proposed scheme undoubtedly will undergo many future revisions , but it provides a starting point using currently available data .",
"DB00188 - resistant myeloma cell lines : a role for mutated P28074 in preventing the accumulation of unfolded proteins and fatal ER stress . DB00188 is an effective agent for treating multiple myeloma ( MM ) . To investigate the underlying mechanisms associated with acquired resistance to this agent , we established two bortezomib - resistant MM cell lines , KMS - 11 / BTZ and OPM - 2 / BTZ , the 50 % inhibitory concentration values of which were respectively 24 . 7 - and 16 . 6 - fold higher than their parental cell lines . No activation of caspase and BH3 - only proteins such as Noxa was noted in bortezomib - resistant cells after exposure to the drug . The accumulation of polyubiquitinated proteins was reduced in bortezomib - resistant cells compared with the parental cells , associated with avoidance of catastrophic ER stress as assessed by downregulation of P35638 expression . These resistant MM cells have a unique point mutation , G322A , in the gene encoding the proteasome beta5 subunit ( P28074 ) , likely resulting in conformational changes to the bortezomib - binding pocket of this subunit . KMS - 11 parental cells transfected to express mutated P28074 also showed reduced bortezomib - induced apoptosis compared with those expressing wild - type P28074 or the parental cells . Expression of mutated P28074 was associated with the prevention of the accumulation of unfolded proteins . Thus , a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the P28074 gene .",
"No evidence of mutations of the P28074 ( beta - 5 subunit of proteasome ) in a case of myeloma with clinical resistance to DB00188 .",
"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .",
"Effect of aerobic exercise on miRNA - O00206 signaling in atherosclerosis . O00206 ( O00206 ) - tumor necrosis factor receptor 6 ( Q9Y4K3 ) signaling is activated in atherosclerosis ( AS ) , inducing inflammatory mediators . Because miR - 146a , a O00206 microRNA ( miRNA ) , can regulate O00206 signaling during inflammatory responses , this study investigated the effects of aerobic exercise on O00206 - targeted miRNAs in AS . P02649 - null mice fed a high - fat diet for 12 weeks were separated into 3 groups : ( i ) no treatment ( AS ) , ( ii ) statin treatment ( AD ) , or ( iii ) aerobic exercise ( AE ) . Plaques and foam cells were observed in the untreated control and statin groups , respectively , but not in the AE group . Reduced angiotensin II ( Ang II ) and endothelin 1 ( ET1 ) levels were observed in the AE group . Both treatment groups significantly altered the expression of inflammatory cytokine expression and reduced vascular O00206 levels . Increased miR - 146a and miR - 126 and reduced miR - 155 levels were observed in both treatment groups ( all , P < 0 . 001 ) . miR - 146a interacted with the 3 ' untranslated region of the Q9Y4K3 gene , reducing its expression . Thus , aerobic exercise and statins may induce miR - 146a expression , thereby reducing vascular TRAF and O00206 signaling and vascular inflammatory injury in AS . Further analysis of this pathway may provide insight into the protective effects of aerobic exercise on vascular disease as well as new therapeutic targets .",
"Proteasomal serine hydrolases are up - regulated by and required for influenza virus infection . Interactions between viruses and their host cells are important determinants of virus replication and of immune responses to the virus . However , these interactions and resulting consequences of these interactions remain poorly defined . Numerous recent quantitative proteomic approaches have measured host proteins affected by virus infection . Here , we used activity - based protein profiling ( P05067 ) to measure functional alterations in host serine hydrolases after influenza A virus infection of Madin - Darby canine kidney and human A549 lung cells . We identified 62 serine proteases . We then combined the P05067 approach with stable isotope labeling to directly measure how serine hydrolase activities were affected by virus infection . Differentially regulated SHs mapped into a few key cellular pathway systems , most notably the proteasomal system . The specific serine protease inhibitors DB06692 and Pefablock and specific proteasomal inhibitors DB00188 and MG132 significantly inhibited influenza virus growth . Some inhibitors also down - regulated activities of several proteasomal proteins , including P25786 , P25787 , and PMSB3 . Genetic knockdown of PMSA2 also attenuated influenza virus replication . These findings further our understanding of enzymatic cellular processes affected by influenza virus and may be beneficial in the search for additional antiviral therapeutic targets .",
"Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal differential cellular gene expression in response to enterovirus 71 infection . Insights into the host antiviral strategies as well as viral disease manifestations can be achieved through the elucidation of host - and virus - mediated transcriptional responses . An oligo - based microarray was employed to analyse mRNAs from rhabdomyosarcoma cells infected with the MS / 7423 / 87 strain of enterovirus 71 ( EV71 ) at 20 h post infection . Using Acuity software and LOWESS normalization , 152 genes were found to be downregulated while 39 were upregulated by greater than twofold . Altered transcripts include those encoding components of cytoskeleton , protein translation and modification ; cellular transport proteins ; protein degradation mediators ; cell death mediators ; mitochondrial - related and metabolism proteins ; cellular receptors and signal transducers . Changes in expression profiles of 15 representative genes were authenticated by real - time reverse transcription polymerase chain reaction ( RT - PCR ) , which also compared the transcriptional responses of cells infected with EV71 strain 5865 / Sin / 000009 isolated from a fatal case during the Singapore outbreak in 2000 . Western blot analyses of P04114 , P10909 , O15075 and P11926 proteins correlated protein and transcript levels . Two - dimensional proteomic maps highlighted differences in expression of cellular proteins ( P48643 , P23528 , P06733 , P04792 , P25787 and P16949 ) following EV71 infection . Expression of several apoptosis - associated genes was modified , coinciding with apoptosis attenuation observed in poliovirus infection . Interestingly , doublecortin and P62158 kinase - like 1 ( O15075 ) involved in brain development , was highly expressed during infection . Thus , microarray , real - time RT - PCR and proteomic analyses can elucidate the global view of the numerous and complex cellular responses that contribute towards EV71 pathogenesis ."
] |
[
"___MASK21___",
"___MASK34___",
"___MASK52___",
"___MASK56___",
"___MASK5___",
"___MASK68___",
"___MASK85___",
"___MASK92___",
"___MASK97___"
] |
___MASK92___
|
MH_train_319
|
interacts_with DB00674?
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[
"Parathyroid hormone - responsive P84022 - related factor , Tmem119 , promotes osteoblast differentiation and interacts with the bone morphogenetic protein - Runx2 pathway . The mechanisms whereby the parathyroid hormone ( PTH ) exerts its anabolic action on bone are incompletely understood . We previously showed that inhibition of P27361 / 2 enhanced P84022 - induced bone anabolic action in osteoblasts . These findings suggested the hypothesis that changes in gene expression associated with the altered P84022 - induced signaling brought about by an P27361 / 2 inhibitor would identify novel bone anabolic factors in osteoblasts . We therefore performed a comparative DNA microarray analysis between empty vector - transfected mouse osteoblastic MC3T3 - E1 cells and PD98059 - treated stable P84022 - overexpressing MC3T3 - E1 cells . Among the novel factors , Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF - β . The levels of Tmem119 increased with time in cultures of MC3T3 - E1 cells and mouse mesenchymal ST - 2 cells committed to the osteoblast lineage by P12643 . PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3 - E1 cells . MC3T3 - E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2 , osteocalcin , alkaline phosphatase , and β - catenin , whereas Tmem119 augmented P12643 - induced Runx2 levels in mesenchymal cells . Tmem119 interacted with Runx2 , Q15797 , and Q99717 in C2C12 cells . In conclusion , we identified a P84022 - related factor , Tmem119 , that is induced by PTH and promotes differentiation in mouse osteoblastic cells . Tmem119 is an important molecule in the pathway downstream of PTH and P84022 signaling in osteoblasts .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK50___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK25___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Association of P35462 and Q13224 with impulse control and related behaviors in Parkinson ' s disease . We aimed to assess whether allelic variants of dopamine receptor , glutamate receptor , and serotonin transporter genes are associated with the appearance of impulse control and related behaviors ( ICRB ) in Parkinson ' s disease ( PD ) with dopamine replacement therapy ( P29323 ) . We surveyed ICRB in consecutive Korean patients with PD who were treated with stable P29323 using modified Minnesota Impulsive Disorders Interview over a period of 4 months . In the 404 patients who completed the interview and the 559 Korean healthy normal controls , genotyping was performed for variants of the P35462 p . S9G , P14416 Taq1A , Q13224 c . 366C > G , c . 2664C > T and c .- 200T > G , and the promoter region of the serotonin transporter gene ( 5 - HTTLPR ) . Behavioral abnormalities suggestive of ICRB including compulsive buying , gambling , sexual behavior and eating , and punding , were present in 14 . 4 % of the patients . Variants of P14416 and 5 - HTTLPR were not associated with the risk of developing ICRB . However , the AA genotype of P35462 p . S9G and the CC genotype of Q13224 c . 366C > G were more frequent in patients with ICRB than in nonaffected patients ( odds ratio [ OR ] = 2 . 21 , P = 0 . 0094 ; and 2 . 14 , P = 0 . 0087 , after adjusting for age and sex ) . After controlling for clinical variables in the multivariate analysis , carriage of either AA genotype of P35462 or CC genotype of Q13224 was identified as an independent risk factor for ICRB ( adjusted OR : 2 . 57 , P = 0 . 0087 ) . Variants of P35462 p . S9G and Q13224 c . 366C > G may be associated with the appearance of ICRB in PD .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Dacomitinib ( PF - 00299804 ) , an irreversible Pan - HER inhibitor , inhibits proliferation of P04626 - amplified breast cancer cell lines resistant to trastuzumab and lapatinib . The human P01133 ( HER ) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies . ___MASK63___ and lapatinib are standard treatments for P04626 - amplified breast cancer , but a significant number of patients do not respond or develop resistance to these drugs . Here we evaluate the in vitro activity of dacomitinib ( PF - 00299804 ) , an irreversible small molecule pan - HER inhibitor , in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands , and with variable sensitivity to trastuzumab and lapatinib . Forty - seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC ( 50 ) values . P04626 - amplified lines were far more likely to respond to dacomitinib than nonamplified lines ( RR , 3 . 39 ; P < 0 . 0001 ) . Furthermore , P04626 mRNA and protein expression were quantitatively associated with response . Dacomitinib reduced the phosphorylation of P04626 , P00533 , Q15303 , AKT , and P29323 in the majority of sensitive lines . Dacomitinib exerted its antiproliferative effect through a combined G ( 0 )- G ( 1 ) arrest and an induction of apoptosis . Dacomitinib inhibited growth in several P04626 - amplified lines with de novo and acquired resistance to trastuzumab . Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib . This study identifies P04626 - amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in P04626 - amplified breast cancers resistant to trastuzumab and lapatinib .",
"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK97___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK97___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Human gray matter : feasibility of single - slab 3D double inversion - recovery high - spatial - resolution MR imaging . The purpose of this study was to develop and prospectively evaluate the feasibility of a single - slab three - dimensional ( 3D ) double inversion - recovery , or P30518 , sequence for magnetic resonance imaging at 1 . 5 T . The study was approved by the local ethics committee , and informed consent was obtained from six healthy control subjects ( one woman , five men ; age range , 26 - 47 years ) and two patients with multiple sclerosis ( one woman , aged 39 ; one man , aged 56 ) . Gray matter ( GM ) - only images were obtained by selectively suppressing cerebrospinal fluid ( P04141 ) and white matter ( WM ) signals . Whole - brain high - spatial - resolution 3D images ( 1 . 2 x 1 . 2 x 1 . 3 mm ) were acquired within 10 minutes . Cortical and deep GM structures were clearly delineated from WM and P04141 , and there were regional differences in GM signal intensity . No flow artifacts from blood or P04141 were observed . These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK35___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"___MASK66___ - induced proliferation and differentiation of neural progenitor cells isolated from rat postnatal cerebellum . Previous studies have shown that the serotonin - reuptake inhibitor ( SSRI ) fluoxetine affects neural progenitors derived from postnatal cerebellum or adult hippocampus and stimulates their proliferation . In the human cerebellum , the proliferation of cerebellar granule cells ( CGC ) continues until the 11th postnatal month and could be influenced in infants by breastfeeding - delivered SSRIs . Current information about fluoxetine effects on postnatal cerebellar neural progenitors is limited . Here we report the characterization of fluoxetine actions on rat postnatal cerebellar neural progenitors . RT - PCR and immunostaining revealed the expression of serotonin transporter ( P31645 ) , 5HT ( 1A ) receptors , tryptophan hydroxylase ( P17752 ) , and serotonin ( 5HT ) . Protracted in vitro fluoxetine treatment increased cell proliferation and differentiation . The proliferative effects of fluoxetine , 5HT , and the selective agonist of 5HT ( 1A ) receptors trans - 8 - hydroxy - 2 -( N - n - propyl - N - 3 '- iodo - 2 '- propenyl ) aminotetralin ( 8 - OH - PIPAT ) were abolished by the selective antagonist of 5HT ( 1A ) receptors , N -[ 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N -( 2 - pyridinyl ) cyclohexanecarboxamide trihydrochloride ( WAY - 100635 ) . Furthermore , fluoxetine - induced activation of both the DB02527 - response element - binding ( CREB ) protein and extracellular signal - regulated protein kinases ( P27361 / 2 ) , which was abolished by the selective inhibitor of Q96HU1 kinase kinase ( MEK ) 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( 2 - aminophenylthio ) butadiene ( U0126 ) , and increased cyclin D1 expression . All these effects were prevented by WAY - 100635 . Collectively , our results demonstrate that rat postnatal cerebellum contains neural progenitors capable of proliferating and differentiating in response to fluoxetine exposure , possibly through the activation of 5HT ( 1A ) receptors . The relevance of these findings for possible SSRI effects on the developing postnatal / infant human cerebellum should be explored .",
"Elevation of P13500 and P13500 / P15692 ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients . Amyotrophic lateral sclerosis ( P35858 ) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons . In this study , we measured monocyte chemotactic protein - 1 ( P13500 ) and vascular endothelial growth factor ( P15692 ) levels in cerebrospinal fluid ( P04141 ) and serum by enzyme - linked immunosorbent assay ( ELISA ) in 42 P35858 patients , and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls . P13500 levels in P04141 were significantly higher in P35858 patients than in the control group . P15692 levels in P04141 tended to be lower in P35858 patients than in the control group , but not significantly . A positive correlation was found between P13500 levels in P04141 of P35858 patients and the total Norris scale . The elevation of P13500 / P15692 ratio in P04141 was more specific to P35858 patients compared to other neurological diseases such as Parkinson ' s disease ( PD ) and spinocerebellar ataxia ( SCA ) and to controls . Our data suggested that both P13500 levels and P13500 / P15692 ratio in P04141 may be useful markers for the clinical diagnosis of P35858 .",
"Sulfonylureas inhibit cytokine - induced eosinophil survival and activation . Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases . We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits P05113 - induced survival . This inhibition can not be overcome by increasing concentrations of P05113 and is not due to the blocking of Na + channels by lidocaine . Here we report that one class of K + channel blockers , the sulfonylureas , inhibits eosinophil survival in a manner similar to lidocaine . The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of P05113 . In contrast , increasing concentrations of P08700 or granulocyte - macrophage P04141 overcome glyburide inhibition . Glyburide also blocks cytokine - induced eosinophil superoxide production . Similar results were seen with the sulfonylureas tolbutamide and glipizide . Interestingly , the effects of glyburide are not antagonized by the DB00171 - sensitive K + channel openers cromakalim , pinacidil , or diazoxide . Although Scatchard analysis of [ 3H ] glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor ( Q09428 ) is not present on eosinophils , human eosinophils do express mRNA homologous to the sulfonylurea receptor family , in keeping with the presence of a sulfonylurea receptor . Finally , coculture of eosinophils with combinations of glyburide , lidocaine , and dexamethasone resulted in synergistic inhibition of cytokine - mediated eosinophil survival and superoxide production . These results have intriguing clinical implications for the treatment of eosinophil - associated diseases .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK28___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK65___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK65___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .",
"Repeated exposure of human fibroblasts to ionizing radiation reveals an adaptive response that is not mediated by interleukin - 6 or TGF - β . Exposing cells to a low dose can protect them against a subsequent higher exposure . This phenomenon is known as adaptive response and is frequently observed in a variety of cells . Even though similarities are suspected with other non - targeted effects , such as bystander effects , the exact mechanism behind adaptive response is not fully clarified . In this study human primary fibroblasts were tested for their response to ionizing radiation ( IR ) after administrating a low priming dose ( 0 . 1 - 0 . 5Gy ) . Both the abundance of γ P16104 as a marker for double - stranded breaks and the levels of cytokines , secreted in the medium , were monitored in time . Upon challenge , IR - primed cells showed modified γ P16104 spot size distributions and altered repair kinetics , consistent with an adaptive response . In addition , 24h after priming with IR , four cytokines were significantly upregulated in the medium - GM - P04141 ( 1 . 33 × ) ; P05231 ( 4 . 24 × ) ; P10145 ( 1 . 33 × ) ; TGF - β ( 1 . 46 × ) . In order to mimick the protective effect of IR priming , we primed the cells with either P05231 or TGF - β . This did not elicit an altered γ P16104 response as observed in IR - primed cells , indicating that the adaptive response in these primary fibroblasts is regulated in an P05231 and TGF - β independent manner .",
"Endothelial Q09428 - 8 acts in an P29323 - independent pathway during atrioventricular cushion development . Q09428 - 8 , a conserved leucine - rich repeats protein , was first identified as a positive regulator of Ras pathway in Caenorhabditis elegans . Biochemical studies indicated that Q09428 - 8 interacts with Ras and Raf , leading to the elevated P29323 activity . However , the physiological role of Q09428 - 8 during mammalian development remains unclear . Here we found that germline deletion of Q09428 - 8 in mice resulted in early embryonic lethality . Inactivated Q09428 - 8 specifically in mouse endothelial cells ( ECs ) revealed that Q09428 - 8 is essential for embryonic heart development . Q09428 - 8 deficiency in ECs resulted in late embryonic lethality , and the mutant mice displayed multiple cardiac defects . The reduced endothelial - mesenchymal transformation ( EMT ) and the reduced mesenchyme proliferation phase were observed in the atrioventricular canal ( AVC ) within the mutant hearts , leading to the formation of hypoplastic endocardial cushions . However , P29323 activation did not appear to be affected in mutant ECs , suggesting that Q09428 - 8 may act in an P29323 - independent pathway to regulate AVC development .",
"P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"The peptidyl - prolyl isomerase Pin1 regulates granulocyte - macrophage colony - stimulating factor mRNA stability in T lymphocytes . Cytokine production is associated with both the normal and pathologic inflammatory response to injury . Previous studies have shown that the immunosuppressants cyclosporin A or FK506 , which interact with the peptidyl - propyl isomerases cyclophilin A and FK506 - binding protein ( P62942 ) , respectively , block cytokine expression . A third member of the peptidyl - propyl isomerase family , Pin1 is expressed by immune and other cells . Pin1 has been implicated in cell cycle progression , is overexpressed in human tumors , and may rescue neurons from tau - associated degeneration . However , the role of Pin1 in the immune system remains largely unknown . In this study , we analyze the role of Pin1 in GM - P04141 expression by human PBMC and P01730 + lymphocytes . We show that Pin1 isomerase activity is necessary for activation - dependent , GM - P04141 mRNA stabilization , accumulation , and protein secretion , but not non - AU - rich elements containing cytokine mRNAs , including TGF - beta and P05112 . Mechanistically , Pin1 mediated the association of the AU - rich element - binding protein , Q14103 , with GM - P04141 mRNA , which determined the rate of decay by the exosome .",
"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK65___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .",
"House dust mite allergen exerts no direct proinflammatory effects on human keratinocytes . BACKGROUND : Dermatophagoides pteronyssinus is a trigger of atopic dermatitis . Many D pteronyssinus allergens are proteases that can elicit airway inflammation by stimulating the release of cytokines and chemokines by bronchial epithelial cells . OBJECTIVE : We sought to investigate whether D pteronyssinus allergens can exert a similar activity on skin keratinocytes . METHODS : Primary cultures of keratinocytes from healthy subjects or patients with atopic dermatitis and normal human bronchial epithelial cells were compared for cytokine production in response to D pteronyssinus extract . RESULTS : Keratinocytes , but not bronchial epithelial cells , displayed a modest dose - dependent release of IL - 1alpha and IL - 1 receptor antagonist but no induction of their mRNA after exposure to D pteronyssinus . However , D pteronyssinus also degraded these cytokines . On the other hand , D pteronyssinus extract induced bronchial epithelial cells , but not keratinocytes , to increased expression of P10145 / P10145 and GM - P04141 mRNA and protein . These effects were efficiently abrogated by a mixture of cysteine and serine protease inhibitors . Both P10145 and GM - P04141 were fully resistant to D pteronyssinus proteolytic attack . No induction of monocyte chemoattractant protein 1 / P13500 , RANTES / P13501 , or P01579 - induced protein of 10 kd / P02778 was detected in either cell type . Only bronchial epithelial cells expressed protease - activated receptor ( PAR ) 4 mRNA , whereas P25116 , P55085 , and PAR - 3 mRNA was found in both cell types . D pteronyssinus did not affect PAR mRNA signals . CONCLUSIONS : Although D pteronyssinus can cause proteolysis - dependent release of cytokines from keratinocytes , it appears incapable of activating de novo expression of cytokines and chemokines , arguing against a direct proinflammatory activity of house dust mite on the skin .",
"A 4 - week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys . ___MASK63___ is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 ( P04626 ) . Women with P04626 - positive tumors have an increased risk of brain metastases . The blood - brain barrier and blood - cerebrospinal fluid ( P04141 ) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and P04141 following standard intravenous administration . To evaluate the potential of effects on the central nervous system , a 4 - week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0 , 3 , or 15 mg . No trastuzumab - related effects on body weight , clinical signs , neurological function , clinical pathology , or anatomic pathology were noted . The applied doses and P04141 concentrations achieved in the current study exceeded those reported in patients after intrathecal administration . The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in P04626 - positive breast cancer .",
"P40933 affects serotonin system and exerts antidepressive effects through IL15Rα receptor . Contrary to the reduction of depressive - like behavior observed in several strains of cytokine receptor knockout mice , mice lacking the specific receptor for interleukin ( IL ) - 15 showed increased immobility in tail suspension and modified forced swimming tests . There was also a reduction in social interactions . The hippocampus of the IL15Rα knockout mice had decreased mRNA for 5 - HT ( 1A ) , increased mRNA for 5 - HT ( 2C ) , and region - specific changes of serotonin reuptake transporter ( P31645 ) immunoreactivity . ___MASK66___ ( the classic antidepressant ___MASK66___ , which inhibits 5 - HT ( 2C ) and P31645 ) reduced the immobility of the IL15Rα knockout mice in comparison with their pretreatment baseline . Together with the unchanged performance of the IL15Rα knockout mice on the rotarod , this response to fluoxetine indicates that the immobility reflects depression . Wildtype mice responded to P40933 treatment with improvement of immobility induced by forced swimming , whereas the knockout mice failed to respond . Thus , the cognate P40933 receptor is necessary for the antidepressive activity of P40933 . In ex vivo studies , P40933 decreased synaptosomal uptake of 5 - HT , and modulated the expression of 5 - HT ( 2C ) and P31645 in cultured neurons in a dose - and time - dependent manner . Thus , the effect of P40933 on serotonin transmission may underlie the depressive - like behavior of IL15Rα knockout mice . We speculate that P40933 is essential to maintain neurochemical homeostasis and thereby plays a role in preventing neuropsychiatric symptoms .",
"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK68___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .",
"Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . DB00989 was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . DB00989 provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .",
"Transcriptional profiles during the differentiation and maturation of monocyte - derived dendritic cells , analyzed using focused microarrays . Dendritic cells ( DC ) are professional antigen - presenting cells capable of initiating primary immune responses . They have been intensively studied and are used in both basic immunology research and clinical immunotherapy . However , the genetic pathways leading to DC differentiation and maturation remain poorly understood . Using focused microarrays with oligonucletotide probes for 120 genes encoding co - stimulatory molecules , chemokines , chemokine receptors , cytokines , cytokine receptors , TLRs , and several other related molecules , we analyzed the kinetics of gene expression for the overall differentiation process of monocytes into mature DC . In parallel , we compared the transcriptional profiles in DC maturation in the presence of LPS , P01375 or trimeric P29965 . We found similar transcriptional profiles for early immature DC and immature DC , respectively generated by culturing monocytes with GM - P04141 and P05112 for three or six days . We identified sets of common and stimuli - specific genes , the expression of which changed following stimulation with LPS , P01375 or P29965 . A dynamic analysis of the entire DC differentiation and maturation process showed that some important inflammatory and constitutive chemokines are transcribed in both immature and mature DC . The correlative expression kinetics of the gene pairs P14778 / P27930 , P40933 / Q13261 , Q9NNX6 / P13598 and Q9NNX6 / P32942 imply that they all play crucial roles in mediating DC functions . Thus , our analysis with focused microarrays shed light on the transcriptional kinetics of DC differentiation and maturation , and this method may also prove useful for identifying novel marker genes involved in DC functions ."
] |
[
"___MASK25___",
"___MASK28___",
"___MASK35___",
"___MASK50___",
"___MASK63___",
"___MASK65___",
"___MASK66___",
"___MASK68___",
"___MASK97___"
] |
___MASK50___
|
MH_train_320
|
interacts_with DB01277?
|
[
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Clinical significance of proliferation , apoptosis and senescence of nasopharyngeal cells by the simultaneously blocking P01133 , DB01277 receptors and Bcl - xl genes . BACKGROUND : In previous work , we constructed short hairpin RNA ( shRNA ) expression plasmids that targeted human P01133 and DB01277 receptors messenger RNA , respectively , and demonstrated that these vectors could induce apoptosis of human nasopharyngeal cell lines ( CNE2 ) and inhibit ligand - induced pAkt and pErk activation . METHOD : We have constructed multiple shRNA expression vectors of targeting P00533 , P08069 and Bcl - xl , which were transfected to the CNE2 cells . The mRNA expression was assessed by RT - PCR . The growth of the cells , cell cycle progression , apoptosis of the cells , senescent tumor cells and the proteins of P00533 , P08069 and Bcl - xl were analyzed by MTT , flow cytometry , cytochemical therapy or Western blot . RESULTS : In group of simultaneously blocking P00533 , P08069 and Bcl - xl genes , the mRNA of P00533 , P08069 and Bcl - xl expression was decreased by ( 66 . 66 ± 3 . 42 ) % , ( 73 . 97 ± 2 . 83 ) % and ( 64 . 79 ± 2 . 83 ) % , and the protein expressions was diminished to ( 67 . 69 ± 4 . 02 ) % , ( 74 . 32 ± 2 . 30 ) % , and ( 60 . 00 ± 3 . 34 ) % , respectively . Meanwhile , the cell apoptosis increased by 65 . 32 ± 0 . 18 % , 65 . 16 ± 0 . 25 % and 55 . 47 ± 0 . 45 % , and senescent cells increased by 1 . 42 ± 0 . 15 % , 2 . 26 ± 0 . 15 % and 3 . 22 ± 0 . 15 % in the second , third and fourth day cultures , respectively . CONCLUSIONS : Simultaneously blocking P00533 , P08069 and Bcl - xl genes is capable of altering the balance between proliferating versus apoptotic and senescent cells in the favor of both of apoptosis and senescence and , therefore , the tumor cells regression .",
"Effect of short - term medroxyprogesterone acetate on left ventricular mass : role of insulin - like growth factor - 1 . Previous studies using 17beta - estradiol and medroxyprogesterone acetate ( DB00603 ) have shown that hormone replacement therapy ( HRT ) increases left ventricular mass ( LVM ) . To determine if insulin - like growth factor - 1 ( DB01277 ) is associated with the increase in LVM , we measured DB01277 and IGF - binding protein - 3 ( P17936 ) levels in 19 postmenopausal women before and after 8 weeks of oral treatment with DB00603 5 mg / d . LVM was measured by two - dimensional echocardiography . Changes in DB01277 , P17936 , and LVM from baseline were analyzed by paired ttest . Regression analysis was used to determine if changes in the DB01277 axis with DB00603 treatment affect the increase in LVM . LVM increased 4 . 4 % during the study ( P = . 006 vbaseline ) . DB01277 increased 17 % with DB00603 ( P = . 008 ) , whereas P17936 did not change . The DB01277 / P17936 ratio increased 16 . 8 % ( P = . 0003 ) . Regression analysis of LVM with DB01277 , P17936 , and the DB01277 / P17936 ratio suggested that DB01277 during DB00603 therapy explains 2 . 4 % and the DB01277 / P17936 ratio explains 3 . 2 % of the variation in LVM . There was no effect of P17936 on LVM . Most of the variation in LVM with DB00603 ( 90 . 5 % ) was explained by baseline LVM . The DB01277 / P17936 ratio on DB00603 treatment was inversely related to the change in LVM : women with a lower LVM at baseline had the greatest increase in LVM with DB00603 . These findings suggest that DB00603 increases DB01277 and LVM . Because the increase in DB01277 with DB00603 treatment explains a fraction of the increase in LVM , other mechanisms must also be operative .",
"P61073 negatively regulates keratinocyte proliferation in IL - 23 - mediated psoriasiform dermatitis . P61073 is expressed by basal keratinocytes ( KCs ) , but little is known about its function in inflamed skin . We crossed P02533 - Cre and P61073 ( flox / flox ( f / f ) ) transgenic mice , resulting in mice with specific loss of the P61073 gene in P02533 - expressing cells ( P02533 - CXCR4KO ) , including basal KCs . P02533 - CXCR4KO pups had no obvious skin defects . We compared P02533 - CXCR4KO and P61073 ( f / f ) control mice in an IL - 23 - mediated psoriasiform dermatitis model and measured skin edema , and histologic and immunohistological changes . IL - 23 - treated P02533 - CXCR4KO mice showed a 1 . 3 - fold increase in mean ear swelling , a 2 - fold increase in epidermal thickness , and greater parakeratosis . IL - 23 - treated wild - type ( WT ) mice showed weak P61073 expression in areas of severe epidermal hyperplasia , but strong P61073 expression in nonhyperplastic regions , suggesting that P61073 may regulate KC proliferation . To test this hypothesis , we overexpressed P61073 in HaCaT KC cells and treated them with Q9GZX6 and / or P48061 ( chemokine ( C - X - C motif ) ligand 12 ) . P48061 blocked Q9GZX6 - mediated HaCaT cell proliferation in vitro and synergized with Q9GZX6 in upregulating O14543 ( suppressor of cytokine signaling 3 ) , a key regulator of P40763 ( signal transducer and activator of transcription 3 ) . O14543 was required for P61073 - mediated growth inhibition . In human psoriatic skin , both P61073 and O14543 were upregulated in the junctional region at the border of psoriatic plaques . Thus , P61073 has an unexpected role in inhibiting KC proliferation and mitigating the effects of proliferative T helper type 17 cytokines .",
"Reference values for serum levels of insulin - like growth factor ( DB01277 ) and P17936 ( P17936 ) and their ratio in Chinese adolescents . OBJECTIVE : To establish the reference values for serum levels of DB01277 and P17936 and their ratio in Chinese adolescents aged 12 - 19 years . DESIGN AND METHODS : 2102 Chinese adolescents were randomly selected from all secondary schools in Hong Kong with 1734 having DB01277 and P17936 levels as measured by automated chemiluminescent assays ( IMMULITE 2000 ) . LMS ( Lambda - Mu - Sigma ) method was used to generate reference percentile curves for DB01277 , P17936 and their ratio . RESULTS : After excluding participants with abnormal thyroid function , 798 boys and 894 girls were included in the analysis with a mean ( +/- SD ) age of 15 . 3 ( +/- 2 . 0 ) and 15 . 7 years ( +/- 2 . 0 ) , respectively . Both serum DB01277 and P17936 levels tended to be higher in girls than boys before the age of 16 . In boys , there was progressive decline in DB01277 after a pubertal peak at the age of 13 - 14 . In girls , there was a similar decline after the age of 12 . In both boys and girls , there was progressive age - dependent decline in P17936 after the age of 15 - 16 . The pattern of changes for DB01277 / P17936 ratio was similar to that of the DB01277 levels . CONCLUSIONS : These reference values of DB01277 and P17936 in healthy adolescents should facilitate the clinical management of adolescents with GH - IGF axis disorders .",
"Associations of proinflammatory cytokine levels with lipid profiles , growth , and body composition in HIV - infected children initiating or changing antiretroviral therapy . OBJECTIVES : To measure proinflammatory cytokines ( PIC ) in HIV - infected children beginning or changing antiretroviral therapy ( O00253 ) , evaluating associations with virologic , immunologic , serum lipid , growth , and body composition measures , markers of growth hormone action and glucose metabolism . METHODS : Forty - nine prepubertal HIV - infected children had measurements of viral load ( VL ) , P01730 lymphocyte count and percentage , serum lipids , apolipoprotein AI / B , DB01277 , P08833 , and P17936 , anthropometry , bioelectrical impedance analysis , P01375 - α , IL - 1 β , and P05231 at baseline and 48 weeks of O00253 . RESULTS : Baseline levels were detectable ( > 0 . 1 pg / mL ) for IL - 1 β in 28 of 48 , and for P01375 - α and Il - 6 in all 49 children . P01375 - α decreased with O00253 ( P < 0 . 001 ) and P05231 demonstrated a similar trend ( P = 0 . 065 ) . Children with 48 - week VL < 400 copies / mL had greater declines in P01375 - α ( mean 45 % ) than subjects with higher VL ( 5 % ; P = 0 . 009 ) . Each 10 % improvement in P01730 % was associated with 26 % lower P01375 - α ( P = 0 . 002 ) and 31 % lower P05231 ( P = 0 . 016 ) . Greater reductions in P01375 - α were associated with lower total / HDL cholesterol ratio ( P = 0 . 003 ) at week 48 . CONCLUSIONS : In HIV - infected children initiating or changing O00253 , PIC were detectable at baseline and decreased over 48 weeks . Better immunologic responses were associated with greater reductions in P01375 - α and P05231 . Reductions in P01375 - α were associated with improved total / HDL cholesterol ratio .",
"Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid - derived keratinocytes in vitro . Keloids are proliferative dermal growths representing a pathological wound - healing response . We report high proliferation rates in normal ( NF ) and keloid - derived fibroblasts ( KF ) cocultured with keloid - derived keratinocytes ( KK ) . IGF binding protein ( IGFBP ) - 3 mRNA and secreted P17936 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes ( NK ) . P18065 and P22692 mRNA levels were elevated , whereas P24593 mRNA was decreased in KF cocultured with KK or NK . Significant increases in P18065 and - 4 mRNA in KF cocultured with KK did not correlate with protein secretion . Downstream IGF signaling cascade components , phospho - Raf , phospho - Q02750 / 2 , phospho - MAPK , P19957 kinase , phospho - Akt , and phospho - Elk - 1 , were elevated in KF cocultured with KK . Addition of recombinant human P17936 or antibodies against P05019 or IGF - IR significantly inhibited proliferation of KF . The bioavailability of P05019 may be related to the levels of P17936 produced , which in turn influences KF proliferation , suggesting that modulation of P05019 , IGF - IR , and P17936 , individually or in combination , may represent novel approaches to the treatment of keloids .",
"Altered P05019 and IGFBPs in senescent male and female rats . The effects of senescence on muscle characteristics and the insulin - like growth factor I ( P05019 ) pathway were assessed in male and female BN / F344 rats . The mass and total ATPase activity of gastrocnemius and plantaris muscles were reduced with age and to a greater extent in males than in females . The mass and total ATPase activity of soleus muscle were not significantly altered with age . Circulating P05019 was also significantly reduced with age , 60 % in females and 21 % in males . Circulating P17936 ( P17936 ) was reduced with age . In liver and gastrocnemius muscle , mRNAs for DB01277 , P18065 , and P17936 were analyzed in young and aged males of two strains , BN / F344 and Sprague - Dawley . In BN / F344 rats , liver mRNAs were unchanged with age . Also in BN / F344 rats , muscle mRNAs for P18065 , and P17936 displayed nonsignificant trends toward increase with age . In aged Sprague - Dawley males , liver mRNA for P05019 was increased 15 % and muscle mRNA for P18065 was increased 110 % . Thus , different age - related changes in the growth hormone ( GH ) / IGF pathway occur in males and females between the sexes and strains . These changes may play a role in the muscle atrophy associated with senescence .",
"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .",
"Readjusting the localization of long QT syndrome gene on chromosome 11p15 . Long QT syndrome ( LQT ) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia . A first locus for LQT has been identified on chromosome 11p15 . 5 ( LQT1 ) , closely linked to P01112 . To refine the location of LQT1 , microsatellites were genotyped in 8 French families and the following order was determined : tel - P01112 - P21917 - D11S922 - D11S4046 - P01344 - P01308 - TH - D11S1318 - D11S1323 - D11S1338 - D11S90 9 - D11S1346 - cen . By haplotype analysis , 12 crossing - over events were identified in affected and unaffected subjects , delineating the LQT1 candidate region to 7 cM . This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to P01112 .",
"Growth hormone reserve in adult beta thalassemia patients . Reduced serum insulin - like growth factor - 1 ( DB01277 ) and hypogonadotrophic hypogonadism are common features of adult beta - thalassemia , and warrant evaluation of the growth hormone ( GH ) - DB01277 axis . The aim of this study was to determine GH reserve in beta - thalassemia patients ( 9 females , 7 males , 15 major , 1 intermedia ) , age 29 . 3 +/- 6 . 9 years , BMI 21 . 3 +/- 1 . 9 kg / m2 , and in 20 age , sex and BMI - matched healthy controls , using the GH - releasing hormone ( P01286 ) - arginine test . The associations between peak GH response and hormonal and biochemical indices were evaluated . Using BMI - related cut - off limits for peak GH response in the P01286 - arginine test , 4 / 16 beta - thalassemia patients had peak GH lower than 11 . 5 microg / l , the cut - off limit suggested for lean subjects , and were diagnosed as GH deficient ( GHD ) . Using 9 microg / l as the cut - off limit 2 / 16 patients were GHD . Reduced serum DB01277 and P17936 were present in 69 % and 19 % of the patients , respectively . Peak GH did not correlate with serum DB01277 , DB00024 , and fT4 levels or gonadal status . Neither peak GH nor DB01277 correlated with serum ferritin . Our findings suggest that GHD is present in up to a quarter of adult beta - thalassemia patients . The clinical benefits of GH therapy need to be determined . GHD alone does not account for the high prevalence of reduced DB01277 in adult beta - thalassemia .",
"P05121 -- insulin - like growth factor binding protein 3 cascade regulates stress - induced senescence . Cellular senescence is widely believed to play a key role in tumor suppression , but the molecular pathways that regulate senescence are only incompletely understood . By using a secretome proteomics approach , we identified insulin - like growth factor binding protein 3 ( P17936 ) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment . The senescence - inducing activity of P17936 is inhibited by tissue - type plasminogen activator - mediated proteolysis , which is counteracted by plasminogen activator inhibitor 1 ( P05121 ) , another secreted mediator of senescence . We demonstrate that P17936 is a critical downstream target of P05121 - induced senescence . These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence .",
"Video - assisted thoracic surgery lobectomy for lung cancer is associated with less immunochemokine disturbances than thoracotomy . OBJECTIVE : Major surgery is immunosuppressive and could have an impact on postoperative tumor immunosurveillance and recurrence in cancer patients . Low circulating levels of insulin growth factor binding protein ( IGFBP ) - 3 have been linked to advance prostate and the development of colonic cancers . This prospective study examined the early postoperative circulating levels of P17936 , matrix metalloproteinase ( MMP ) - 9 , and tissue inhibitor of metalloproteinase ( P01033 ) - 1 in early stage non - small cell lung cancer ( NSCLC ) patients undergoing major lung resection by VATS versus thoracotomy . METHODS : Forty - two consecutive patients with resectable primary NSCLC were assigned to VATS or thoracotomy approach over a 7 - month - period . Blood samples were collected preoperatively and postoperatively on days ( POD ) 1 and 3 for enzyme linked immunosorbent assay determination of P17936 , P14780 and P01033 levels in the serum . RESULTS : There were no demographic differences between the two groups . VATS lung resection was associated with lower levels of P14780 and P01033 on O43680 ( median 628 vs 1311ng / ml , p = 0 . 009 ; and 131 vs 211ng / ml , p = 0 . 004 , respectively ) but higher levels of P17936 on POD3 ( 1366 vs 1144ng / ml , p = 0 . 02 ) , when compared with the thoracotomy approach . There was no perioperative mortality . CONCLUSIONS : VATS major lung resection for NSCLC is associated with higher circulating levels of P17936 , and lower levels of P14780 and P01033 , compared to the thoracotomy approach . The clinical relevance of these postoperative changes on tumor biology following lung resection for cancer warrants further investigation .",
"Saw palmetto extract suppresses insulin - like growth factor - I signaling and induces stress - activated protein kinase / c - Jun N - terminal kinase phosphorylation in human prostate epithelial cells . A common alternative therapy for benign prostatic hyperplasia ( BPH ) is the extract from the fruit of saw palmetto ( SPE ) . BPH is caused by nonmalignant growth of epithelial and stromal elements of the prostate . IGF action is important for prostate growth and development , and changes in the IGF system have been documented in BPH tissues . The main signaling pathways activated by the binding of P05019 to the P08069 ( IGF - IR ) are the P29323 arm of the MAPK cascade and the phosphoinositol - 3 - kinase ( PI3K ) / protein kinase B ( P31749 / Akt ) cascade . We tested the hypothesis that SPE suppresses growth and induces apoptosis in the P69 prostate epithelial cell line by inhibiting P05019 signaling . Treatment with 150 microg / ml SPE for 24 h decreased P05019 - induced proliferation of P69 cells and induced cleavage of the enzyme poly ( ADP - ribose ) polymerase ( PARP ) , an index of apoptosis . Treatment of serum - starved P69 cells with 150 microg / ml SPE for 6 h reduced P05019 - induced phosphorylation of Akt ( assessed by Western blot ) and Akt activity ( assessed by an Akt kinase assay ) . Western blot analysis showed that SPE reduced P05019 - induced phosphorylation of the adapter protein insulin receptor substrate - 1 and decreased downstream effects of Akt activation , including increased cyclin D1 levels and phosphorylation of glycogen synthase kinase - 3 and P08133 ( s6k ) . There was no effect on P05019 - induced phosphorylation of MAPK , IGF - IR , or Shc . Treatment of starved cells with SPE alone induced phosphorylation the proapoptotic protein JNK . SPE treatment may relieve symptoms of BPH , in part , by inhibiting specific components of the P05019 signaling pathway and inducing JNK activation , thus mediating antiproliferative and proapoptotic effects on prostate epithelia .",
"Phase II trial of exemestane in combination with fulvestrant in postmenopausal women with advanced , hormone - responsive breast cancer . INTRODUCTION : Exemestane , the irreversible steroidal aromatase inhibitor , and fulvestrant , the pure estrogen antagonist , are active as single drugs in postmenopausal women with advanced hormone - responsive breast cancer . We designed a phase II study with the purpose of determining whether combining these 2 drugs with different and potentially complementary mechanisms of action will improve the clinical benefit . PATIENTS AND METHODS : Forty postmenopausal women with hormone - responsive advanced breast cancer received intramuscular injection of fulvestrant 250 mg every 28 days in combination with daily exemestane 25 mg until disease progression . We examined the influence of fulvestrant on exemestane pharmacokinetics and the effect of exemestane and fulvestrant on serum DB01277 ( insulin - like growth factor 1 ) and P17936 ( P17936 ) levels . RESULTS : The observed proportion of patients free of progressive disease at 6 months after the initiation of treatment with exemestane and fulvestrant was 50 % , a rate similar to that achieved with single - agent exemestane or fulvestrant in the first - or second - line setting . Pharmacokinetics parameters showed that coadministration of fulvestrant did not result in clinically relevant changes in exemestane plasma concentrations . A comparison of DB01277 and P17936 levels demonstrated the increase of 35 % and 12 % , respectively , in mean levels from baseline to day 120 . CONCLUSIONS : The combination of exemestane and fulvestrant did not improve clinical benefit . The observed lack of improved efficacy was not related to altered drug exposure .",
"MAGeCK enables robust identification of essential genes from genome - scale CRISPR / Cas9 knockout screens . We propose the Model - based Analysis of Genome - wide CRISPR / Cas9 Knockout ( MAGeCK ) method for prioritizing single - guide RNAs , genes and pathways in genome - scale CRISPR / Cas9 knockout screens . MAGeCK demonstrates better performance compared with existing methods , identifies both positively and negatively selected genes simultaneously , and reports robust results across different experimental conditions . Using public datasets , MAGeCK identified novel essential genes and pathways , including P00533 in vemurafenib - treated A375 cells harboring a P15056 mutation . MAGeCK also detected cell type - specific essential genes , including P11274 and P00519 , in KBM7 cells bearing a P11274 - P00519 fusion , and P08069 in HL - 60 cells , which depends on the insulin signaling pathway for proliferation .",
"Thyroid hormone - mediated growth and differentiation of growth plate chondrocytes involves DB01277 modulation of beta - catenin signaling . Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt / beta - catenin signaling pathway . DB01277 ( DB01277 ) has been described as a stabilizer of beta - catenin , and thyroid hormone is a known stimulator of DB01277 receptor expression . The purpose of this study was to test the hypothesis that DB01277 signaling is involved in the interaction between the thyroid hormone and the Wnt / beta - catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation . The results show that DB01277 and the IGF - receptor ( P08069 ) stimulate Wnt - 4 expression and beta - catenin activation in growth plate chondrocytes . The positive effects of DB01277 / P08069 on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1 . T ( 3 ) activates DB01277 / P08069 signaling and DB01277 - dependent PI3K / Akt / GSK - 3beta signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy . T ( 3 )- mediated Wnt - 4 expression , beta - catenin activation , cell proliferation , and terminal differentiation of growth plate chondrocytes are partially prevented by the P08069 inhibitor picropodophyllin as well as by the PI3K / Akt signaling inhibitors LY294002 and Akti1 / 2 . These data indicate that the interactions between thyroid hormone and beta - catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by DB01277 / P08069 signaling through both the Wnt and PI3K / Akt signaling pathways . While chondrocyte proliferation may be triggered by the DB01277 / P08069 - mediated PI3K / Akt / GSK3beta pathway , cell hypertrophy is likely due to activation of Wnt / beta - catenin signaling , which is at least in part initiated by DB01277 signaling or the DB01277 - activated PI3K / Akt signaling pathway .",
"DB00435 inhibits chondrocyte response to P05019 : inhibition of IGF - IRbeta tyrosine phosphorylation . Chondrocytes in arthritic cartilage respond poorly to insulin - like growth factor I ( P05019 ) . Studies with inducible nitric oxide synthase ( P35228 ) knockout mice suggest that NO is responsible for part of the cartilage insensitivity to P05019 . These studies characterize the relationship between NO and chondrocyte responses to P05019 in vitro , and define a mechanism by which NO decreases P05019 stimulation of chondrocyte proteoglycan synthesis . Lapine cartilage slices , chondrocytes , and cartilage from osteoarthritic ( OA ) human knees were exposed to NO from the donors S - nitroso - N - acetylpenicillamine ( P60880 ) or ( Z ) - 1 -[ 2 -( 2 - aminoethyl )- N -( 2 - ammonioethyl ) amino ] diazen - 1 - ium - 1 , 2 - diolate ] ( DETA NONOate ) , by transduction with adenoviral transfer of P35228 ( Ad - P35228 ) , or by activation with interleukin - 1 ( IL - 1 ) . NO synthesis was estimated from medium nitrite , and proteoglycan synthesis was measured as incorporation of ( 35 ) SO ( 4 ) . P08069 phosphorylation was evaluated with Western analysis . P60880 , DETA NONOate , endogenously synthesized NO in Ad - P35228 - transduced cells , or IL - 1 activation decreased P05019 - stimulated proteoglycan synthesis in cartilage and monolayer cultures of chondrocytes . OA cartilage responded poorly to P05019 ; however , the response to P05019 was restored by culture with N ( G )- monomethyl - L - arginine ( L - Q13145 ) . P08069 phosphotyrosine was diminished in chondrocytes exposed to NO . These studies show that NO is responsible for part of arthritic cartilage / chondrocyte insensitivity to anabolic actions of P05019 ; inhibition of receptor autophosphorylation is potentially responsible for this effect .",
"Human insulin - like growth factor I receptor internalization . Role of the juxtamembrane domain . Cytoplasmic submembrane domains of the insulin - like growth factor I ( DB01277 ) receptor ranging from glycine 940 to proline 959 were investigated for their role in endocytosis of the DB01277 ligand in rat pituitary GC cells stably expressing mutant human DB01277 receptors . Replacement of each of three tyrosine residues within the juxtamembrane domain reduced the internalization rate ( Ke ) by 33 % ( 943Y --> A ) , 47 % ( 950Y --> A ) , and 41 % ( 957Y --> A ) , respectively . Other substitutions within the submembrane region variably retarded receptor - mediated DB01277 ligand endocytosis . Thus , each amino acid appears to independently contribute to the overall ligand - stimulated DB01277 receptor internalization rate . The effect of receptor occupancy on DB01277 receptor endocytosis was also tested . The rate of 125I - labeled DB01277 internalization by transfectants overexpressing the wild type DB01277 receptor was rapid but decreased markedly in the presence of increasing unlabeled DB01277 ( ED50 = 44 , 000 receptors / cell ) . Substitution by alanine for any of the three submembrane tyrosines increased the ED50 to > 56 , 000 receptors / cell , decreased the slope ( Kic ) , and had a variable effect on Vmax in the presence of increasing unlabeled DB01277 . In contrast , 125I - labeled DB01277 endocytosis by the mutant kinase - deficient 952STOP cells was slow and not further retarded by unlabeled DB01277 . These results suggest that ligand - mediated internalization of the human P05019 is consistent with saturable interactions between the P08069 juxtamembrane region ( glycine 940 - tyrosine 957 ) and components of the endocytic apparatus .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Effects of bench step exercise on arterial stiffness in post - menopausal women : contribution of DB01277 bioactivity and nitric oxide production . OBJECTIVE : To examine the effect of bench step exercise on arterial pulse wave velocity ( PWV ) and the associated contribution of insulin - like growth factor ( IGF ) - 1 bioactivity and nitric oxide ( NO ) . DESIGN : Twenty - six elderly ( post - menopausal ) women were randomly allocated to a bench step exercise group or a control group . The participants in the bench step exercise group practiced a 12 - week home - based bench step exercise for 10 - 20min , 3 times daily ( i . e . , for a total of 140min / week at the intensity level of lactate threshold ( LT ) ) . In addition to conventional risk factors of atherosclerosis , PWV , DB01277 / IGF binding protein ( IGFBP ) - 3 molar ratio ( an index for DB01277 bioactivity ) , and urinary nitrite / nitrate ( NO ( x ) ) excretion were measured before and after the intervention . RESULTS : BMI , systolic blood pressure , fasting plasma glucose , low - density lipoprotein cholesterol , LT , and PWV were significantly improved in the bench step exercise group . A significant positive correlation between changes in PWV and DB01277 / P17936 molar ratio , and a significant negative correlation between changes in DB01277 / P17936 molar ratio and urinary NO ( x ) excretion were found in the bench step exercise group . CONCLUSION : The bench step exercise leads to improvements in not only the classical risk factors of atherosclerosis but also the arterial stiffness in elderly women , partly through NO production via DB01277 bioactivity .",
"Native and Complexed DB01277 : Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis . Infantile neuronal ceroid lipofuscinosis ( INCL ) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons . DB01277 ( DB01277 ) is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems . In circulation DB01277 is mainly bound to its carrier protein P17936 . As a therapeutic agent DB01277 has shown to be more active as free than complexed form . However , this may cause side effects during the prolonged treatment . In addition to P17936 the bioavailability of DB01277 can be modulated by using mesoporous silicon nanoparticles ( NPs ) which are optimal carriers for sustained release of unstable peptide hormones like DB01277 . In this study we compared biodistribution , pharmacokinetics , and bioavailability of radiolabeled free DB01277 , DB01277 / P17936 , and DB01277 / NP complexes in a Cln1 -/- knockout mouse model . DB01277 / NP was mainly accumulated in liver and spleen in all studied time points , whereas minor and more constant amounts were measured in other organs compared to free DB01277 or DB01277 / P17936 . Also concentration of DB01277 / NP in blood was relatively high and stable during studied time points suggesting continuous release of DB01277 from the particles .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK71___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Near - normal linear growth in the setting of markedly reduced growth hormone and DB01277 . A case report . A 14 . 2 - year - old prepubertal boy diagnosed with complete - type growth hormone deficiency and tertiary hypothyroidism , keeps growing in the height range between - 1 and - 2 SD . He has been treated with levothyroxine only . To understand the growth mechanism of this boy , we analyzed the serum growth hormone ( GH ) with a radioimmunoassay ( RIA ) , serum GH bioactivity with Nb2 and erythroid progenitor cell bioassays , and growth hormone - binding protein ( P30043 ) with a ligand - mediated immunofunctional assay ( LIFA ) . In addition , DB01277 and free DB01277 were analyzed by immunoradiometric assay ( IRMA ) and insulin - like growth factor - binding protein - 3 ( P17936 ) by Western immunoblot . Peak GH - RIA responses to insulin , arginine and GH - releasing factor , and nocturnal GH secretion , were low ( 0 . 5 - 2 . 3 ng / ml ) ; bioactive GH was low ( 0 . 313 ng / ml ) , and P30043 was elevated ( 84 ng / ml ) . The serum levels of DB01277 and free DB01277 were continuously low , 17 . 1 - 39 . 3 and 0 . 17 - 0 . 26 ng / ml , respectively . Moreover , serum P17936 levels were low ( 1 . 68 - 1 . 39 mg / l ) and P17936 protease activity was negative . P01236 and insulin were in the normal range . The result of the assay for growth - promoting activity showed that the patient ' s serum stimulated normal erythroid progenitor cells twice as potently as did healthy thin adult control serum . These results suggest that GH and DB01277 are not indispensable for maintaining physical growth in this boy . Thus , it appears that circulating GH and DB01277 are not mandatory requirements for maintaining normal physical growth , and other , as yet uncharacterized , pathways or growth factors might be sufficiently compensatory under certain conditions .",
"Physical activity , insulin - like growth factor 1 , insulin - like growth factor binding protein 3 , and survival from colorectal cancer . BACKGROUND : Recent reports have shown that physical activity improves the outcome of patients with colorectal cancer as well as breast and prostate cancer . However , the mechanisms whereby physical activity reduces cancer mortality are not well established . METHODS : Incident cases of colorectal cancer were identified among participants of the Melbourne Collaborative Cohort Study , a prospective cohort study of 41 , 528 Australians recruited from 1990 to 1994 . Information on tumour site and stage , treatments given , recurrences , and deaths were obtained from systematic review of the medical records . Baseline assessments of physical activity and body size were made , and cases with available plasma had pre - diagnosis insulin - like growth factor 1 ( DB01277 ) and insulin - like growth factor binding protein 3 ( P17936 ) levels measured . We assessed associations between these hormones and colorectal cancer specific deaths with respect to physical activity . RESULTS : A total of 526 cases of colorectal cancer were identified , of which 443 had DB01277 / P17936 levels measured . Median follow up among survivors was 5 . 6 years . For the physically active , increasing P17936 by 26 . 2 nmol / l was associated with a 48 % reduction in colorectal cancer specific deaths ( adjusted hazard ratio ( HR ) 0 . 52 ( 0 . 33 - 0 . 83 ) ; p = 0 . 006 ) . No association was seen for DB01277 ( adjusted HR 0 . 90 ( 0 . 55 - 1 . 45 ) ; p = 0 . 65 ) . For the physically inactive , neither DB01277 nor P17936 was associated with disease specific survival . CONCLUSIONS : This study supports the hypothesis that the beneficial effects of physical activity in reducing colorectal cancer mortality may occur through interactions with the insulin - like growth factor axis and in particular P17936 .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK40___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK40___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK40___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .",
"Male germ cell - specific RNA binding protein RBMY : a new oncogene explaining male predominance in liver cancer . Male gender is a risk factor for the development of hepatocellular carcinoma ( HCC ) but the mechanisms are not fully understood . The RNA binding motif gene on the Y chromosome ( RBMY ) , encoding a male germ cell - specific RNA splicing regulator during spermatogenesis , is aberrantly activated in human male liver cancers . This study investigated the in vitro oncogenic effect and the possible mechanism of RBMY in human hepatoma cell line HepG2 and its in vivo effect with regards to the livers of human and transgenic mice . RBMY expression in HepG2 cells was knocked down by RNA interference and the cancer cell phenotype was characterized by soft - agar colony formation and sensitivity to hydrogen - peroxide - induced apoptosis . The results revealed that RBMY knockdown reduced the transformation and anti - apoptotic efficiency of HepG2 cells . The expression of RBMY , androgen receptor ( AR ) and its inhibitory variant AR45 , AR - targeted genes insulin - like growth factor 1 ( DB01277 ) and insulin - like growth factor binding protein 3 ( P17936 ) was analyzed by quantitative RT - PCR . Up - regulation of AR45 variant and reduction of DB01277 and P17936 expression was only detected in RBMY knockdown cells . Moreover , RBMY positive human male HCC expressed lower level of AR45 as compared to RBMY negative HCC tissues . The oncogenic properties of RBMY were further assessed in a transgenic mouse model . Liver - specific RBMY transgenic mice developed hepatic pre - cancerous lesions , adenoma , and HCC . RBMY also accelerated chemical carcinogen - induced hepatocarcinogenesis in transgenic mice . Collectively , these findings suggest that Y chromosome - specific RBMY is likely involved in the regulation of androgen receptor activity and contributes to male predominance of HCC .",
"DB09341 intolerance in aging male P17936 transgenic mice : differential effects of human P17936 and its mutant P17936 devoid of IGF binding ability . We have reported a reduction of insulin secretion and glucose intolerance in young mice overexpressing human P17936 ( phosphoglycerate kinase [ PGK ] BP3 ) or its mutant Gly56 / Gly80 / Gly81 - P17936 ( PGKmutBP3 ) under the PGK promoter . Here , we investigated changes in glucose and lipid homeostasis with age in PGKBP3 and PGKmutBP3 mice compared with wild - type mice . Body weight , glucose tolerance , insulin tolerance , visceral fat , interscapular brown adipose tissue ( Q14032 ) , serum lipids , and pancreas histology were examined at age 3 , 6 , and 12 months . Murine P17936 was similar in all mouse genotypes and decreased with age in parallel with total DB01277 . Visceral fat and Q14032 masses increased in PGKmutBP3 mice , but not in PGKBP3 mice . DB09341 tolerance was impaired in both PGKBP3 and PGKmutBP3 mice . However , PGKBP3 mice had increased expression of uncoupling protein - 1 in Q14032 and reduced adiposity , and continued to have smaller pancreatic β - cell mass and reduced insulin secretion through age 12 months . In contrast , PGKmutBP3 mice developed insulin resistance with age in association with pancreatic β - cell hyperplasia , impaired expression of uncoupling protein - 1 in Q14032 , and increased adiposity . In addition , both PGKBP3 and PGKmutBP3 mice had elevated glycerol in the circulation , but only PGKBP3 mice had elevated free fatty acids and only PGKmutBP3 mice had elevated triglycerides . Estimated free DB01277 did not increase with age in transgenic mice , as it did in wild - type mice . Thus , overexpression of human P17936 or its mutant devoid of IGF binding ability leads to glucose intolerance with , however , different effects on insulin secretion , insulin sensitivity , and lipid homeostasis in aging mice .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK24___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Circulating levels of insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 in patients with severe head injury . There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury . We have measured the circulating level of insulin - like growth factor - 1 ( DB01277 ) and IGF binding protein - 3 ( P17936 ) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures . The serum level of DB01277 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers ( p < 0 . 01 and p < 0 . 02 , respectively ) . The level of P17936 was also significantly lower in patients with both head injury and fracture ( p < 0 . 01 ) . Our findings showed , however , that the level of DB01277 and P17936 varied from week to week in both the patients and healthy control subjects . These results indicate that the levels of circulating DB01277 and P17936 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury .",
"The food colorant erythrosine is a promiscuous protein - protein interaction inhibitor . Following our observation that erythrosine B ( FD & C Red No . 3 ) is a relatively potent inhibitor of the P01375 - R - TNFα and P25942 - CD154 protein - protein interactions , we investigated whether this inhibitory activity extends to any other protein - protein interactions ( PPI ) as well as whether any other approved food colors possess such inhibitory activity . We found erythrosine , a poly - iodinated xanthene dye , to be a non - specific promiscuous inhibitor of a number of PPIs within the tumor necrosis factor superfamily ( P01375 - R - TNFα , P25942 - CD154 , Q96RJ3 - Q9Y275 , Q9Y6Q6 - O14788 , OX40 - P23510 , 4 - 1BB - P41273 ) as well as outside of it ( P01133 - R - P01133 ) with a remarkably consistent median inhibitory concentration ( IC ( 50 ) ) in the 2 - 20 μM ( approximately 2 - 20mg / L ) range . In agreement with this , erythrosine also showed cellular effects including clear cytotoxic effects around this concentration range ( IC₅₀ ≈ 50 μM ) . Among the seven FDA - approved food colorants , only erythrosine showed consistent PPI inhibitory activity in the sub - 100 μM range , which might also explain ( at least partially ) why it also has the lowest approved acceptable daily intake ( ADI ) ( 0 . 1 mg / kg body weight / day ) . Among a number of xanthene structural analogs of erythrosine tested for activity , rose Bengal , a food colorant approved in Japan , showed similar , maybe even more pronounced , promiscuous inhibitory activity , whereas fluorescein was inactive and gallein , phloxine , and eosin were somewhat active in some of the assays .",
"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .",
"Colostrum supplementation restores insulin - like growth factor - 1 levels and alters muscle morphology following massive small bowel resection . BACKGROUND : Colostrum protein concentrate ( CPC ) contains a high level of insulin - like growth factor - 1 ( DB01277 ) . DB01277 and IGF binding protein ( IGFBPs ) may play an important role during the postresection adaptation response . As smooth muscle is an important site for DB01277 action in the intestine , this study aims to ( 1 ) investigate the effect of CPC supplementation on circulating levels and tissue expression of DB01277 , DB01277 receptor , and IGFBPs following massive small bowel resection ( MSBR ) , and ( 2 ) characterize the effect of CPC on the muscular adaptation response following MSBR . METHODS : Four - week - old piglets underwent either a 75 % MSBR or sham operation . Piglets received either a polymeric infant formula ( PIF ) diet or PIF supplemented with CPC for 8 weeks . Serum was analyzed by enzyme - linked immunosorbent assay , and ileal tissue assessed by molecular and histological analysis . RESULTS : There was no difference in DB01277 or IGFBPs mRNA among groups . CPC treatment resulted in significant increases in circulating levels of DB01277 and IGFBPs and a concurrent increase in muscle width and the number of muscle cells , but did not alter muscle cell size . CONCLUSIONS : Strategies aimed at increasing muscular adaptation may decrease Gl transit and allow greater mucosal contact time for absorption . We have shown that CPC supplementation following resection results in increased levels of circulating DB01277 , P18065 , and P17936 and muscular hypertrophy . Our results suggest that DB01277 and its mediators may play a role in the muscular adaptation response and warrant further exploration as a treatment option for short bowel syndrome .",
"Factors regulating trophoblast migration and invasiveness : possible derangements contributing to pre - eclampsia and fetal injury . Impaired trophoblast invasiveness and spiral arterial remodelling , which results in poor placental perfusion during early pregnancy , is believed to cause fetal injury and growth retardation , and also endothelial cell activation / dysfunction in a susceptible mother , leading to clinical manifestations of pre - eclampsia . This article briefly reviews the regulatory roles of certain locally active factors in trophoblast migration and invasiveness . This background is then used to discuss and debate whether derangements or dysfunction of some of these factors can manifest as early serum markers predictive of the disease , as opposed to the intermediate and late stage markers which may reflect manifestations and consequences of the disease . Of particular significance are the observed derangements in uPA / Q03405 / P05121 system , P08833 , P14210 , HB - P01133 and TGFbeta , factors which are known to regulate trophoblast migration and invasiveness in situ . An emphasis is placed on the need for longitudinal studies in order to identify predictive serum markers which may help strategies for prevention or amelioration of fetal injury and pre - eclampsia .",
"Ablation of Dicer leads to widespread perturbation of signaling pathways . Dicer is an essential ribonuclease involved in the biogenesis of miRNAs . Previous studies have reported downregulation of Dicer in multiple cancers including hepatocellular carcinoma . To identify signaling pathways that are altered upon Dicer depletion , we carried out quantitative phosphotyrosine profiling of liver tissue from Dicer knockout mice . We employed antibody - based enrichment of phosphotyrosine containing peptides coupled with SILAC spike - in approach for quantitation . High resolution mass spectrometry - based analysis identified 349 phosphotyrosine peptides corresponding to 306 unique phosphosites of which 75 were hyperphosphorylated and 78 were hypophosphorylated . Several receptor tyrosine kinases including MET , PDGF receptor alpha , DB01277 and P06213 as well as non - receptor tyrosine kinases such as Src family kinases were found to be hyperphosphorylated upon depletion of Dicer . In addition , signaling molecules such as Q9Y4H2 and P40763 were hyperphosphorylated . Activation of these signaling pathways has been implicated previously in various types of cancers . Interestingly , we observed hypophosphorylation of molecules including focal adhesion kinase and paxillin . Our study profiles the perturbed signaling pathways in response to dysregulated miRNAs resulting from depletion of Dicer . Our findings warrant further studies to investigate oncogenic effects of downregulation of Dicer in cancers .",
"Evaluation of cutaneous modifications in seventy - seven growth hormone - deficient children . Cutaneous parameters such as dermal thickness , stiffness , elasticity , skin surface lipid and hydration were evaluated using noninvasive methods in 77 growth hormone - deficient ( GHD ) children before replacement therapy and in 70 non - GHD children . We showed that in GHD children , dermis was thinner ( 0 . 70 +/- 0 . 10 vs . 0 . 80 +/- 0 . 10 mm , p < 0 . 0001 for prepubertal children and 0 . 81 +/- 0 . 10 vs . 0 . 94 +/- 0 . 11 mm , p < 0 . 0001 for pubertal children ) , stiffer ( 178 . 5 +/- 57 . 3 vs . 113 . 09 +/- 37 kPa , p < 0 . 0001 for prepubertal children and 172 . 5 +/- 61 . 7 vs . 117 . 3 +/- 42 . 5 kPa for pubertal children , p < 0 . 001 ) and less elastic ( 0 . 44 +/- 0 . 09 vs . 0 . 39 +/- 0 . 06 ( nonelasticity index ) , p < 0 . 01 for prepubertal children and 0 . 39 +/- 0 . 05 vs . 0 . 33 +/- 0 . 04 , p < 0 . 001 for pubertal children ) compared to controls . Fourteen GHD children were re - evaluated after 1 year of GH treatment : dermal thickness and skin stiffness were significantly improved ( p < 0 . 001 and p < 0 . 05 respectively ) while elasticity was not modified . During the same period , 11 controls did not show any significant cutaneous modification . DB01277 values , but not P17936 values , correlated positively with dermal thickness in GHD children , before and after 1 year of GH treatment . To conclude , GHD children exhibited specific cutaneous modifications . In a subset of GHD children , we showed that these modifications were influenced by GH treatment . More extensive studies are needed to see if these changes correlated with other GH effects .",
"Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK71___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .",
"Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .",
"Synergism between bosutinib ( ___MASK10___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Effect of dietary n - 3 polyunsaturated fatty acid supplementation on bovine uterine endometrial and hepatic gene expression of the insulin - like growth factor system . Supplementation of cattle diets with n - 3 polyunsaturated fatty acids ( n - 3 PUFA ) has been suggested to have positive effects on fertility . In addition , the actions of the insulin - like growth factor ( IGF ) system both systemically and locally have been shown to influence reproductive processes . The objective of this study was to evaluate the effect of dietary n - 3 PUFA supplementation on hepatic and endometrial expression of IGF signalling genes in cattle . Beef heifers were supplemented with a rumen protected source of either a saturated fatty acid ( palmitic acid ; CON ) or high n - 3 PUFA diet ( n - 3 PUFA ) for 45 days before slaughter and tissue recovery . Transcription level of candidate IGF signalling genes was measured by reverse transcription quantitative real - time PCR ( RT - qPCR ) in total RNA isolated from uterine endometrial and liver tissue from seven CON and seven n - 3 PUFA supplemented animals . Compared to controls , mRNA abundance in n - 3 PUFA liver tissues was higher for IGF - 2R , P08833 and P24593 ( P < 0 . 05 ) ; lower for P10912 - 1A ( P < 0 . 05 ) ; and unchanged for DB01277 , IGF - 2 , IGF - 1R , P18065 , P17936 , P22692 , P24592 , P35858 and P10912 ( total ) ( P > 0 . 05 ) . Compared to controls , mRNA abundance in n - 3 PUFA endometrial tissues was higher for IGF - 2 , IGF - 1R , IGF - 2R and P18065 ( P < 0 . 05 ) ; lower for DB01277 , P17936 and P24592 ( P < 0 . 05 ) ; and unchanged for P08833 , P22692 , P24593 and P10912 ( total ) ( P > 0 . 05 ) . Thus , dietary supplementation of cattle with n - 3 PUFA affects transcription of genes involved in IGF signalling , in a tissue dependent fashion .",
"Estradiol , progesterone , and transforming growth factor alpha regulate insulin - like growth factor binding protein - 3 ( P17936 ) expression in mouse endometrial cells . DB01277 ( IGF1 ) is involved in the proliferation of mouse and rat endometrial cells in a paracrine or autocrine manner . P01308 - like growth factor binding protein - 3 ( P17936 ) modulates actions of IGFs directly or indirectly . The present study aimed to determine whether P17936 is involved in the regulation of proliferation of mouse endometrial cells . Mouse endometrial epithelial cells and stromal cells were isolated , and cultured in a serum free medium . IGF1 stimulated DNA synthesis by endometrial epithelial and stromal cells , and P17936 inhibited IGF1 - induced DNA synthesis . DB00783 ( E2 ) decreased the Igfbp3 mRNA level in endometrial stromal cells , whereas it increased the Igf1 mRNA level . Transforming growth factor alpha ( TGFalpha ) significantly decreased P17936 expression at both the mRNA and secreted protein levels in endometrial stromal cells . Progesterone ( P4 ) did not affect the E2 - induced down - regulation of Igfbp3 mRNA expression in endometrial stromal cells , although P4 alone increased Igfbp3 mRNA levels . The present findings suggest that in mouse endometrial stromal cells E2 enhances IGF1 action through enhancement of IGF1 synthesis and reduction of P17936 synthesis , and that TGFalpha affects IGF1 actions through modulation of P17936 levels .",
"Bovine somatotropin attenuates phorbol ester - induced prostaglandin F2alpha production in bovine endometrial cells . The recent observation that bovine somatotropin ( bST ) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone ( GH ) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle . The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester - induced prostaglandin F2alpha ( PGF2alpha ) production in cultured bovine endometrial ( BEND ) cells . Serum - deprived BEND cells were incubated with or without recombinant bovine GH ( rbGH ) , insulin - like growth factor ( IGF ) - I , recombinant bovine interferon ( rbIFN ) - tau or a combination of rbGH + rbIFN - tau for 3 h and then treated with phorbol 12 , 13 - dibutyrate ( PDBu ) for an additional 6 h . Exogenous PDBu increased PGF2alpha secretion and steady - state levels of P35354 mRNA within 3 h . Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu , whereas cotreatment with P05019 amplified PDBu induction of PGF2alpha . Preincubation of cell monolayers with rbIFN - tau suppressed PGF2alpha and P35354 mRNA responses to PDBu . Inhibitory effects of rbGH and rbIFN - tau on PDBu - induced PGF2alpha production were additive . Results provide the first direct evidence that supplemental bST may interact with conceptus - secreted IFN - tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK60___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK60___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK60___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK60___ among adults with ADHD .",
"The cholinergic system is involved in regulation of the development of the hematopoietic system . Gene expression profiling demonstrated that components of the cholinergic system , including choline acetyltransferase , acetylcholinesterase and nicotinic acetylcholine receptors ( nAChRs ) , are expressed in embryonic stem cells and differentiating embryoid bodies ( EBs ) . Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast . In vivo , non - neural nAChRs are detected early during development in fetal sites of hematopoiesis . Similarly , in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver . However postpartum , the number of hematopoietic stem / progenitor cells ( O14818 ) was decreased , suggesting an impaired colonization of the fetal bone marrow with HSPCs . This correlated with increased number of circulating O14818 and decreased expression of P61073 that mediates migration of circulating cells into the bone marrow regulatory niche . In addition , protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche . While the levels of IL1alpha , IL1beta , P60568 , P15248 and P22301 were not changed , the production of hematopoiesis - supportive cytokines including DB00099 , GM - P04141 , P08700 , P05231 and P17936 was decreased . This correlated with the decreased repopulating ability of O14818 in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine . Interestingly , nicotine stimulated the production of P05112 and P05113 , implying a possible role of the cholinergic system in pathogenesis of allergic diseases . Our data provide evidence that the nicotine - induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers .",
"___MASK63___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK63___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK63___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"Molecular DB01277 and DB01277 receptor defects : from genetics to clinical management . Molecular defects of the insulin - like growth factor 1 gene ( IGF1 ) are rare in the human . Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described , resulting in a variable degree of intrauterine and postnatal growth retardation , microcephaly , developmental delay and deafness . Detailed genetic analysis and functional experiments have shown that DB01277 plays a key role in pre - and postnatal growth and development in human . Eleven patients with heterozygous and 2 patients with compound heterozygous mutations in the type 1 IGF1 receptor gene ( P08069 ) have been reported . Intrauterine and postnatal growth retardation , microcephaly and DB01277 levels above the mean of age references are consistent findings in these patients , although DB01277 levels can be low initially because of feeding problems . The first reported patients showed the most severe phenotype , but with the identification of additional patients the phenotype appears to be more variable . The functional effect of the defects has been studied by in vitro experiments . From these studies , receptor haploinsufficiency , decreased P08069 biosynthesis , interference with ligand binding and transmembrane signaling , and disruption of the intrinsic tyrosine kinase activity have been suggested as possible mechanisms with a variable pathogenetic spectrum . Data on GH treatment in these children are limited , showing a poor to modest growth response .",
"Profiling of radicular cyst and odontogenic keratocyst cytokine production suggests common growth mechanisms . The aim of this study was to compare the cytokine expression profiles of cyst fluids ( CFs ) and tissue culture supernatants ( SUPs ) from 7 radicular cysts ( RCs ) and 7 odontogenic keratocysts ( OKCs ) by using Human Cytokine Antibody Array to identify the specific cytokines involved in formation and expansion of RCs and OKCs , respectively . There were significant differences in relative expression levels of P01584 , MCP1 , MIP1 beta , P31371 , P39905 , P14210 , P17936 , Ang , P02778 , MIF , O00300 , and TGF - beta2 between RC - CF and OKC - CF ( P < . 05 ) . On the other hand , the cytokine expression patterns of RC - P60880 ( P14210 , P10145 , Q99733 , P05231 , P01033 and 2 , P09341 , P02778 , and Ang ) were similar to those of OKC - P60880 . Only the relative expression level of P09341 differed between RC - P60880 and OKC - P60880 ( P < . 05 ) . The similarities of cytokine production by tissue cultures derived from RC and OKC indicate that the expansion mechanisms of RC and OKC might involve similar biologic mechanisms other than infection .",
"Growth hormone secretion is impaired but not related to insulin sensitivity in non - obese patients with polycystic ovary syndrome . BACKGROUND : The aim of the study was to elucidate the relationship between growth hormone ( GH ) secretion and insulin resistance in polycystic ovary syndrome ( PCOS ) patients . In order to exclude the influence of obesity on these parameters , only non - obese PCOS patients were studied . METHODS : Eleven PCOS patients and 11 controls with a body mass index ( BMI ) </= 25 kg / m2 were studied . PCOS patients were studied on cycle day 14 - 15 , controls on cycle day 5 - 9 . GH secretion was determined by frequent sampling , from 20 . 00 h to 08 . 00 h . P01308 sensitivity was determined by a euglycaemic hyperinsulinaemic clamp and was expressed as the M - value . P01308 - like growth factor - 1 ( DB01277 ) and IGF - binding protein - 3 ( P17936 ) levels were determined once . RESULTS : Pooled GH levels were significantly lower in PCOS patients than controls , as was GH pulse amplitude . The number of GH pulses was not different between PCOS patients and controls . The M - value was significantly lower in PCOS patients , although a wide overlap between patients and controls was present . DB01277 and P17936 levels were not different between the groups . There was no correlation between the M - value and pooled GH or DB01277 and P17936 levels . CONCLUSION : Non - obese patients with PCOS have impaired GH secretion and some but not all have impaired insulin sensitivity . These findings indicate that these patients may also be at risk for cardiovascular diseases and / or diabetes mellitus .",
"P01308 - like growth factor binding protein - 3 , in association with DB01277 receptor , can predict prognosis in squamous cell carcinoma of the head and neck . The aim of this study was to investigate the prognostic role of insulin - like growth factor - 1 receptor ( IGF - 1R ) and IGF binding protein - 3 ( P17936 ) in patients with squamous cell carcinoma of the head and neck ( SCCHN ) . The clinical data of 131 SCCHN patients who had undergone surgical resection were retrospectively reviewed , and their intratumoral expression of IGF - 1R and P17936 was evaluated by immunohistochemistry . Thirty - six cases ( 27 . 5 % ) experienced tumor recurrence during the median follow - up period of 53 . 7months ( 95 % CI , 19 . 0 - 90 . 7months ) . IGF - 1R - positivity and P17936 - positivity were observed in 96 ( 73 . 3 % ) and 70 cases ( 53 . 4 % ) , respectively . P17936 - positivity was associated with shorter time to progression ( TTP ) by univariate ( P = 0 . 03 ) and multivariate analyses ( 95 % CI , 0 . 23 - 0 . 91 ) , whereas IGF - 1R itself failed to show its prognostic relevance . However , it was revealed that the prognostic role of P17936 expression was dependent on IGF - 1R expression in the analysis of four subgroups classified according to IGF - 1R and P17936 expression : the IGF - 1R - positive / P17936 - positive subgroup was the best prognostic group , while the IGF - 1R - negative / P17936 - positive subgroup was the worst in terms of TTP ( P = 0 . 017 ) . In conclusion , it is suggested that P17936 expression , in a state of co - expression with IGF - 1R , can predict poor prognosis in SCCHN patients .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK30___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"P17936 , hypoxia and P01375 inhibit adiponectin transcription . The thiazolidinedione rosiglitazone , an agonist ligand for the nuclear receptor P37231 , improves insulin sensitivity in part by stimulating transcription of the insulin - sensitizing adipokine adiponectin . It activates P37231 - RXR - alpha heterodimers bound to P37231 response elements in the adiponectin promoter . Rosiglitazone - stimulated adiponectin protein synthesis in 3T3 - Q9NUQ9 mouse adipocytes has been shown to be inhibited by P17936 , which can be induced by hypoxia and the proinflammatory cytokine , P01375 , two inhibitors of adiponectin transcription . The present study demonstrates that P17936 , the hypoxia - mimetic agent cobalt chloride , and P01375 inhibit rosiglitazone - induced adiponectin transcription in mouse embryo fibroblasts that stably express Q07869 - gamma2 . Native P17936 can bind RXR - alpha and inhibited rosiglitazone stimulated promoter activity , whereas an P17936 mutant that does not bind RXR - alpha did not . These results suggest that P17936 may mediate the inhibition of adiponectin transcription by hypoxia and P01375 , and that P17936 binding to RXR - alpha may be required for the observed inhibition .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK37___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"Role of growth hormone in polycystic ovarian syndrome . Given recent in - vitro and in - vivo evidence that insulin and growth hormone may have gonadotropin - augmenting effects , the putative endocrine role of serum growth hormone levels in women with polycystic ovarian syndrome ( PCOS ) has been investigated in several studies since 1990 . Obesity is a disease entity in its own right and , therefore , a confounding influence on investigations of PCOS . PCOS in the absence of obesity may be viewed as the \" authentic syndrome \" . The use of DB01277 as a marker of growth hormone secretion is not fully adequate as there is little to no correlation between this peptide and growth hormone in women with PCOS . The development of hyposomatotropinism in obese PCOS women appears to be an obesity - dependent event . The confirmed observation in both obese and lean women with and without PCOS of serum DB01277 and P17936 levels requires further delineation . Preliminary evidence suggest that GH may play a role in the lean woman with PCOS and that the presence of obesity dampens its effect . Future investigations of the role of growth hormone in PCOS are dependent on first elucidating the role of GH in adult women and in the disease state of obesity .",
"P04150 interacting protein - 1 restores glucocorticoid responsiveness in steroid - resistant airway structural cells . Glucocorticoid ( GC ) insensitivity represents a profound challenge in managing patients with asthma . The mutual inhibition of transcriptional activity between GC receptor ( GR ) and other regulators is one of the mechanisms contributing to GC resistance in asthma . We recently reported that interferon regulatory factor ( Q969Q1 ) - 1 is a novel transcription factor that promotes GC insensitivity in human airway smooth muscle ( P17405 ) cells by interfering with GR signaling ( Tliba et al . , Am J Respir Cell Mol Biol 2008 ; 38 : 463 - 472 ) . Here , we sought to determine whether the inhibition of GR function by P10914 involves its interaction with the transcriptional co - regulator GR - interacting protein 1 ( Q9Y3R0 ) , a known GR transcriptional co - activator . We here found that siRNA - mediated Q9Y3R0 depletion attenuated P10914 - dependent transcription of the luciferase reporter construct and the mRNA expression of an P10914 - dependent gene , P28907 . In parallel experiments , Q9Y3R0 silencing significantly reduced GR - mediated transactivation activities . Co - immunoprecipitation and Q86UG4 pull - down assays showed that Q9Y3R0 , through its repression domain , physically interacts with P10914 identifying Q9Y3R0 as a bona fide transcriptional co - activator for P10914 . Interestingly , the previously reported inhibition of GR - mediated transactivation activities by either P01375 and P01579 treatment or P10914 overexpression was fully reversed by increasing cellular levels of Q9Y3R0 . Together , these data suggest that the cellular accumulation of P10914 may represent a potential molecular mechanism mediating altered cellular response to GC through the depletion of Q9Y3R0 from the GR transcriptional regulatory complexes .",
"___MASK91___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"Maternal insulin - like growth factors 1 and 2 ( DB01277 , IGF - 2 ) and IGF BP - 3 and the hypertensive disorders of pregnancy . OBJECTIVE : To investigate the relationship between levels of insulin - like growth factors 1 and 2 ( DB01277 , IGF - 2 ) and insulin - like growth factor binding protein 3 ( P17936 ) in antenatal maternal serum and gestational hypertension and pre - eclampsia ( PET ) . METHODS : Prospective cohort study of 1650 low - risk Caucasian women in a University teaching hospital in London . Statistical analysis was performed using commercial software ( SPSS for Windows , version 6 . 1 , SPSS , Chicago , IL ) , with P < 0 . 05 as significant . Maternal IGF 1 , IGF 2 and IGF BP - 3 were assessed on maternal blood at booking . Blood pressure was checked at each visit in conjunction with urine analysis . The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET . RESULTS : There was no significant correlation between maternal DB01277 or P17936 levels and gestational hypertension or PET . However , a significant positive correlation does exist between maternal IGF - 2 levels and PET . CONCLUSIONS : Maternal IGF - 2 has a significant positive correlation with PET .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK63___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials ."
] |
[
"___MASK10___",
"___MASK24___",
"___MASK30___",
"___MASK37___",
"___MASK40___",
"___MASK60___",
"___MASK63___",
"___MASK71___",
"___MASK91___"
] |
___MASK40___
|
MH_train_321
|
interacts_with DB01229?
|
[
"[ ___MASK54___ : A new drug of B - cell malignancies ] . ___MASK54___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK54___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK54___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .",
"Tau hyperphosphorylation and increased P56817 and RAGE levels in the cortex of PPARβ / δ - null mice . The role of peroxisome proliferator activator receptor ( Q07869 ) β / δ in the pathogenesis of Alzheimer ' s disease has only recently been explored through the use of PPARβ / δ agonists . Here we evaluated the effects of PPARβ / δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation . PPARβ / δ - null mice showed cognitive impairment in the object recognition task , accompanied by enhanced DNA - binding activity of NF - κB in the cortex and increased expression of P05231 . In addition , two NF - κB - target genes involved in β - amyloid ( Aβ ) synthesis and deposition , the β site P05067 cleaving enzyme 1 ( Bace1 ) and the receptor for advanced glycation endproducts ( Rage ) , respectively , increased in PPARβ / δ - null mice compared to wild type animals . The protein levels of glial fibrillary acidic protein ( P14136 ) increased in the cortex of PPARβ / δ - null mice , which would suggest the presence of astrogliosis . Finally , tau hyperphosphorylation at Ser199 and enhanced levels of P10636 were associated with increased levels of the tau kinases Q00535 and phospho - P27361 / 2 in the cortex of PPARβ / δ (-/-) mice . Collectively , our findings indicate that PPARβ / δ deficiency results in cognitive impairment associated with enhanced inflammation , astrogliosis and tau hyperphosphorylation in the cortex .",
"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .",
"Antitumor effects in hepatocarcinoma of isoform - selective inhibition of Q92769 . Q92769 ( Q92769 ) is a chromatin modifier involved in epigenetic regulation of cell cycle , apoptosis , and differentiation that is upregulated commonly in human hepatocellular carcinoma ( HCC ) . In this study , we show that specific targeting of this HDAC isoform is sufficient to inhibit HCC progression . siRNA - mediated silencing of HDAC inhibited HCC cell growth by blocking cell - cycle progression and inducing apoptosis . These effects were associated with deregulation of HDAC - regulated genes that control cell cycle , apoptosis , and lipid metabolism , specifically , by upregulation of p27 and acetylated p53 and by downregulation of Q00534 and P10415 . We found that Q92769 silencing in HCC cells also strongly inhibited PPARγ signaling and other regulators of glycolysis ( ChREBPα and P14672 ) and lipogenesis ( SREBP1C and FAS ) , eliciting a marked decrease in fat accumulation . Notably , systemic delivery of Q92769 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human HCC in a murine xenograft model . Our findings offer preclinical proof - of - concept for Q92769 blockade as a systemic therapy for liver cancer .",
"Expression analysis of pediatric solid tumor cell lines using oligonucleotide microarrays . We identified patterns of differentially - expressed genes in cell lines derived from several pediatric solid tumors . Affymetrix Human Cancer G110 Arrays , carrying 1 , 700 cancer - associated genes , were applied to a panel of 11 cell lines originating from Ewing tumors ( ETs ) , neuroblastomas , and malignant melanoma of soft parts . Hierarchical clustering clearly differentiated these 3 entities and revealed groups of 75 , 102 , and 36 gene probe - sets exhibiting tumor - type specific up - regulation in these cell lines , respectively . Whereas ET lines demonstrated increased expression of microtubule - associated protein tau ( P10636 ) , protein phosphatase 1 regulatory subunit 1A ( Q13522 ) , NIMA ( never in mitosis gene a ) - related kinase 2 ( P51955 ) , and cyclin D1 ( P24385 ) , neuroblastoma samples exhibited high expression of wingless - type mouse mammary tumor virus integration site family member 11 ( O96014 ) , Drosophila frizzled homolog 2 ( Q14332 ) , and adenomatous polyposis coli ( P25054 ) which are involved in regulating free beta - catenin levels . These genes likely maintain tumor - specific characteristics and participate in key downstream regulatory mechanisms . We also correlated the expression levels of up - regulated genes in ETs with their chromosomal localization and compared these data to the comparative genomic hybridization profiles of the cell lines . We demonstrate that gains of genetic material contribute essentially to differential gene expression .",
"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .",
"___MASK30___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK30___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer : the Scottish Randomised Trial in Ovarian Cancer . PURPOSE : Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane , which has a 5 - year survival rate of approximately 45 % . The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect . PATIENTS AND METHODS : We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes ( P08183 , P33527 , Q92887 , Q9UNQ0 , P38936 , Q16678 , P10632 , P08684 , P20815 , P10636 , and P04637 ) and platinum ( Q92887 , Q9UNQ0 , P07992 , P18074 , P09211 , P05164 , and P18887 ) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery . RESULTS : No reproducible significant associations between genotype and outcome or toxicity were found for any of the genes analyzed . Previously reported genotype associations could not be replicated in this large study of a well - defined patient population within one specific clinical trial . CONCLUSION : There are no clear candidates for taxane / platinum pharmacogenetic markers . This study highlights the need for validation of putative genetic markers in large , well - defined clinical sample sets .",
"A survey of gene - specific methylation in human prostate cancer among black and white men . Gene methylation is an important molecular event in prostate carcinogenesis that may have diagnostic and prognostic significance . We evaluated the methylation status of eight genes implicated in prostate carcinogenesis . DNA was extracted from archived paraffin - embedded tumor blocks from 90 prostate cancer patients . Gene methylation status of eight genes ( P09211 , RASSF1A , RARbeta2 , P16070 , P24530 , P12830 , P07355 , and Q03135 ) was determined using real - time methylation - sensitive PCR techniques . Differences in gene methylation among race , tumor grade and disease stage were evaluated by chi - square test . Of the eight genes , P09211 , RASSF1A , and RARbeta2 methylation was highly prevalent across tumors ( > 60 % for all three genes ) whereas P16070 , P12830 and P24530 methylation was less prevalent ( 33 , 24 and 29 % , respectively ) . P07355 and Q03135 were not methylated in any of the tumors examined . Methylation of RARbeta2 , P16070 and P12830 was correlated with tumor grade but not stage . Interestingly , methylation of P24530 , a gene involved in angiogenesis , was correlated with stage of disease but not tumor grade . With the possible exception of P16070 , we did not observe differences in gene methylation between racial categories for the genes under study . In summary , our data suggest that evaluation of the methylation of a panel of genes may have diagnostic and prognostic utility in prostate cancer .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK95___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK95___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK95___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK95___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK95___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Q9UBC3 interacts with O60264 chromatin remodeling enzyme , HDACs 1 and 2 , and components of the histone methylation system . The non - random pattern of genome - wide DNA methylation in mammalian cells is established and maintained by DNA methyltransferases P26358 , 3A , and 3B . De novo DNA methyltransferase Q9UBC3 is critical for embryonic development and is mutated in ICF syndrome . Despite its importance in normal cellular functioning , little is known about how Q9UBC3 operates in the context of chromatin . Here we demonstrate that Q9UBC3 associates with four chromatin - associated enzymatic activities common to transcriptionally repressed , heterochromatic regions of the genome : DNA methyltransferase , histone deacetylase , ATPase , and histone methylase activities . By immunoprecipitation and Q86UG4 pull - down , we show that Q9UBC3 interacts with Q13547 , Q92769 , P59665 proteins , Suv39h1 , and the DB00171 - dependent chromatin remodeling enzyme O60264 . Endogenous O60264 is also associated with DNA methyltransferase activity . These proteins co - localize extensively with Q9UBC3 in heterochromatic regions . Our results therefore link Q9UBC3 to three other components of the epigenetic machinery and provide important insights into how DNA methylation patterns may be established within the chromatin environment .",
"Molecular response of HL - 60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis - related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl - 2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis - arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis - related genes ( P10415 , Q07812 , Q9HB09 , CASPASE - 3 , FAS ) after leukemia cell ( HL - 60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT - PCR , using gene - specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis - related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis - related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug - specific and time - dependent manner .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK73___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"A brief cognitive - behavioural social skills training for stabilised outpatients with schizophrenia : a preliminary study . Achieving social functioning and achieving social competence are two main objectives of psychosocial interventions for people suffering from schizophrenia . The present preliminary study presents a novel approach of social skills training ( P61278 ) based on the proposals of Kopelowicz et al . ( Kopelowicz , A . , Liberman , R . P . , and Zarate , R . , 2006 . Schizophr . Bull . 32 ( 1 ) : P28222 - 23 ) that link the treatment to seven specific target behaviours : social perception , social information processing , responding and sending skills , affiliative skills , interactional skills , and behaviour governed by social norms . Thirty - one stabilised outpatients were randomly assigned to one of two groups , P61278 ( n = 13 ) or treatment - as - usual ( n = 18 ) ( P10636 ; case management , medication adherence , psychotherapy , leisure engagement , and family support ) and were assessed at baseline in cognitive performance , clinical symptomatology , social cognition , and psychosocial functioning . These outcomes were evaluated across post - treatment and at the 6 - month follow - up appointment . P61278 subjects showed improvements in psychopathology , social discomfort , social cognition ( self - regulation statements during interactions ) , social withdrawal , interpersonal communication , and quality of life compared with the P10636 group . At the 6 - month follow - up , results were maintained for negative symptoms , social discomfort , and some functioning outcomes . Neuropsychological variables were also examined , as mediators of benefit from skills training . Results support the efficacy of the brief P61278 for outpatients with schizophrenia and show the need to implement empirically supported interventions in mental health services to enhance patients ' social functioning and quality of life .",
"An association analysis of circadian genes in anxiety disorders . BACKGROUND : The mammalian circadian system is responsible for controlling daily oscillations in physiology and behavior . Circadian genes contribute to the sleep - wake cycle and mood , and because patients with anxiety disorder often suffer from sleep disturbances , we hypothesized that variants in circadian - clock - related genes might predispose to human anxiety disorders as well . We tested this hypothesis with a genetic association analysis . METHODS : We analyzed 131 single nucleotide polymorphisms from 13 circadian - clock - related genes . The study sample consisted of 321 individuals diagnosed with an anxiety disorder and 653 matched healthy controls from a Finnish population - based cohort . RESULTS : Single nucleotide polymorphisms in two genes showed some evidence for association to social phobia : in Q8WYA1 rs2306073 ( p = . 0099 ) and in P14416 rs7131056 ( p = . 0084 ) . P10415 rs12454712 ( p = . 0029 ) and P14416 rs4245146 ( p = . 0010 ) showed evidence for association to generalized anxiety disorder , whereas rs2463107 ( p = . 0064 ) in Q96IZ0 and rs4245146 ( p = . 0029 ) in P14416 showed evidence for association to the pooled group of all anxiety disorders . Findings in P14416 became stronger when only anxiety disorder cases with comorbid alcohol use disorder were considered . CONCLUSIONS : Genes contributing to circadian rhythms might also play a role in the genetic predisposition to anxiety disorders . In addition , our study provides further support for the association of P14416 to comorbid anxiety and alcohol use disorder .",
"Q03135 tyrosine phosphorylation enhances paclitaxel - mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane - associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti - tumor agents that repress the dynamic instability of microtubules and arrest cells in the G ( 2 )/ M phase . Src phosphorylation of DB00135 - 14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 - 14 regulates paclitaxel - mediated apoptosis in MCF - 7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non - phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53 - dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti - microtubule drug resistance .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK4___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Prognostic relevance of methylation markers in patients with non - muscle invasive bladder carcinoma . There is increasing evidence for the role of epigenetic gene silencing in superficial bladder cancer . The aim of the current study was to investigate the prognostic value of epigenetic alterations in patients with non - muscle invasive bladder carcinoma . We checked the methylation status of 20 cancer associated genes ( Q8N726 , p16 CDKN2A , P35610 - 1 , O15524 , DR - 3 , DR - 6 , PIG - 7 , BCL - 2 , H - O14746 , Q07812 , P24530 , P53355 , RASSF - 1A , Q13158 , TMS - 1 , E - Cadherin , P05362 , P35625 , MLH - 1 , P35354 ) for DNA methylation . We analysed microdissected tumour samples from 105 consecutive patients with primary non - muscle invasive bladder carcinoma . Quantitative methylation analysis of CpG sites in the promoter region of the genes was performed with methylation sensitive quantitative real time PCR ( ' Methylight ' ) . Univariate analysis for association with tumour recurrence was carried out with the Kaplan - Meier analysis and the log - rank test . Follow - up data were available in 95 / 105 patients ( 91 . 4 % ) . A tumour recurrence was observed in 26 patients ( 27 . 3 % ) . We could identify six genes ( O15524 , P35610 - 1 , BCL - 2 , P53355 , P35625 , E - Cadherin ) , where methylation was associated with tumour recurrence . In Kaplan - Meier analysis , P35625 showed a significant association with recurrence free survival . Methylation of P35625 predicted prolonged disease free interval . In this study , we report a comprehensive analysis on prognostic relevance of gene methylation in non - muscle invasive bladder cancer . We identified one gene ( P35625 ) where methylation was associated with a more favourable outcome . Our data strongly support the usefulness of gene methylation as a prognostic marker in patients with non - muscle invasive bladder cancer .",
"Quantitative and qualitative pleiotropic differences between Simvastatin single and Vytorin combination therapy in hypercholesterolemic subjects . AIMS : This cross - sectional study tested the hypothesis that treatment with the combination of DB00973 / Simvastatin ( Vytorin ) leads to broader changes in the expression levels of immunomodulatory genes as compared to Simvastatin monotherapy . METHODS : Illumina ' s GenomeStudio gene expression module was used to compare gene profiles of Vytorin and Simvastatin in the peripheral blood mononuclear cells of 20 hypercholesterolemic subjects . RESULTS : The characteristics of the immunomodulatory genes , which were altered by Vytorin , differed from those genes which were altered by Simvastatin . Vytorin mostly altered the expression levels of genes related to inflammation / oxidative stress ; it downregulated the NF - KappaB and upregulated the expression of anti - inflammatory cytokine , P22301 , and anti - oxidant enzymes , P07203 and P04179 , but also upregulated the expression levels of genes involved in cellular activation , adhesion , and coagulation cascade , including P04275 , P08709 , P02776 , P10720 SELP , P05106 , P18084 . Simvastatin mostly altered the expression levels of genes related to cellular apoptosis / proliferation . It upregulated the expression levels of apoptosis - related genes O14727 , Q07812 , P46695 , and P07333 , and downregulated the expression levels of genes related to cellular proliferation , including P21246 and Q07108 . Treatment with Vytorin combination therapy modulated lipid profile and serum levels of the P02741 more effectively , than treatment with Simvastatin monotherapy . CONCLUSION : The nature of the pleiotropic effects may play a role in Vytorin ' s and Simvastatin ' s clinical efficacies .",
"P10275 - mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters . The androgen receptor ( AR ) has a critical role in promoting androgen - dependent and - independent apoptosis in testicular cells . However , the molecular mechanisms that underlie the ligand - independent apoptosis , including the activity of AR in testicular stem cells , are not completely understood . In the present study , we generated induced pluripotent stem cells ( iPSCs ) from bovine testicular cells by electroporation of octamer - binding transcription factor 4 ( Q01860 ) . The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4 , which maintained and stabilized the expression of stemness genes and pluripotency . The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters , including di ( 2 - ethyhexyl ) phthalates , di ( n - butyl ) phthalate , and butyl benzyl phthalate . Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of Q07812 / BCL - 2 , thereby favoring apoptosis . Phthalate esters also increased the expression of cyclin - dependent kinase inhibitor 1 ( P38936 ( Cip1 ) ) in a p53 - dependent manner and enhanced the transcriptional activity of p53 . The forced expression of AR and knockdown of P38936 ( Cip1 ) led to the rescue of the phthalate - mediated apoptosis . Overall , this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency , as well as for identifying the iPSC signaling pathway ( s ) that are deregulated by these chemicals .",
"Neural differentiation arrest in embryonal carcinoma cells with forced expression of Q01844 - Q01543 . Ewing ' s sarcoma / primitive neuroectodermal tumor ( Q01844 / PNET ) has a characteristic chimeric oncogene Q01844 - Q01543 , which results from chromosomal translocation t ( 11 ; 22 ) , that is believed to initiate tumorigenesis of Q01844 / PNET . However , the specific details of Q01844 / PNET oncogenesis and exact role of Q01844 - Q01543 remain largely unknown . In this study we explored the role of Q01844 - Q01543 in tumor differentiation using an embryonal carcinoma cell line P19 as a model , with forced expression of Q01844 - Q01543 in these cells . Q01844 - Q01543 has been reported to promote neural differentiation in fibroblasts , DB05914 and rhabdomyosarcoma cells . We show forced expression of Q01844 - Q01543 causes absence of retinoic acid - induced neural morphology , and decreases expression of neural - specific proteins P10636 and P13591 . Critical transcriptional factors for neural differentiation and stem cells are also altered in the presence of Q01844 - Q01543 , including decreases in levels of Q01860 and Pax - 6 , and an increase in the level of Id2 , which is a target of Q01844 - Q01543 . Increased proliferation and decreased apoptotic rates are also observed in P19 cells with forced expression of Q01844 - Q01543 . Our results raise the possibility that arrest of neural differentiation by forced expression of Q01844 - Q01543 as observed in this study may result from dysregulation of the cell cycle and cell proliferation . Taken together , our results demonstrate that the modulation of neural differentiation in P19 cells which have a stem cell - like pluripotency in vitro can provide a novel model system to study the neural differentiation effects of Q01844 - Q01543 tumorigenesis of Q01844 / PNET .",
"___MASK99___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK99___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK99___ is a promising pharmacological tool in the treatment of renal edema .",
"A critical importance of polyamine site in DB01221 receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation . We have investigated the role of N - methyl - d - aspartate receptors ( NMDARs ) and gamma - aminobutyric acid receptors type A ( GABA ( A ) Rs ) at an early stage of P19 neuronal differentiation . The subunit expression was profiled in 24 - hour intervals with RT - PCR and functionality of the receptors was verified via fluo - 3 imaging of Ca ( 2 +) dynamics in the immature P19 neurons showing that both DB01221 and GABA excite neuronal bodies , but only polyamine - site sensitive NMDAR stimulation leads to enhanced Ca ( 2 +) signaling in the growth cones . Inhibition of Q9UHB4 / Q13224 NMDARs by 1 muM ifenprodil severely impaired P19 neurite extension and fasciculation , and this negative effect was fully reversible by polyamine addition . In contrast , GABA ( A ) R antagonism by a high dose of 200 microM bicuculline had no observable effect on P19 neuronal differentiation and fasciculation . Except for the differential NMDAR and GABA ( A ) R profiles of Ca ( 2 +) signaling within the immature P19 neurons , we have also shown that inhibition of Q9UHB4 / Q13224 NMDARs strongly decreased mRNA level of P13591 - 180 , which has been previously implicated as a regulator of neuronal growth cone protrusion and neurite extension . Our data thus suggest a critical role of Q9UHB4 / Q13224 NMDARs during the process of neuritogenesis and fasciculation of P19 neurons via differential control of local growth cone Ca ( 2 +) surges and P13591 - 180 signaling .",
"On some novel extended topochemical atom ( P25101 ) parameters for effective encoding of chemical information and modelling of fundamental physicochemical properties . Extended topochemical atom ( P25101 ) indices developed by our group have been extensively applied in our previous reports for toxicity and ecotoxicity modelling in the field of quantitative structure - activity relationships ( QSARs ) . In the present study these indices have been further explored by defining additional novel parameters to model n - octanol - water partition coefficient ( two data sets ; n = 168 and 139 ) , water solubility ( n = 193 ) , molar refractivity ( n = 166 ) , and aromatic substituent constants π , MR , σ ( m ) , and σ ( p ) ( n = 99 ) . All the models developed in the present study have undergone rigorous internal and external validation tests and the models have high statistical significance and prediction potential . In terms of Q² and r² values the models developed for the datasets of whole molecules are better than those previously reported , with topochemically arrived unique ( P10636 ) indices on the same datasets of chemicals . An attempt has also been made to develop models using non - P25101 topological and information indices . Interestingly , P25101 and non - P25101 models have been found to have similar predictive capacity .",
"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .",
"Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .",
"Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( ___MASK95___ ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of ___MASK95___ ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , ___MASK95___ inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas ___MASK95___ prevented the attenuation . ___MASK95___ also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that ___MASK95___ could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .",
"DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK54___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .",
"Molecular targeting of the oncoprotein P53350 in pediatric acute myeloid leukemia : RO3280 , a novel P53350 inhibitor , induces apoptosis in leukemia cells . P53350 ( P53350 ) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer - specific small molecule drugs . RO3280 was recently identified as a novel P53350 inhibitor ; however its therapeutic effects in leukemia treatment are still unknown . We found that the P53350 protein was highly expressed in leukemia cell lines as well as 73 . 3 % ( 11 / 15 ) of pediatric acute myeloid leukemia ( AML ) samples . P53350 mRNA expression was significantly higher in AML samples compared with control samples ( 82 . 95 ± 110 . 28 vs . 6 . 36 ± 6 . 35 ; p < 0 . 001 ) . Kaplan - Meier survival analysis revealed that shorter survival time correlated with high tumor P53350 expression ( p = 0 . 002 ) . The 50 % inhibitory concentration ( IC50 ) of RO3280 for acute leukemia cells was between 74 and 797 nM . The IC50 of RO3280 in primary acute lymphocytic leukemia ( ALL ) and AML cells was between 35 . 49 and 110 . 76 nM and 52 . 80 and 147 . 50 nM , respectively . RO3280 induced apoptosis and cell cycle disorder in leukemia cells . RO3280 treatment regulated several apoptosis - associated genes . The regulation of P43146 , P38936 , Q06187 , and O14508 was verified by western blot . These results provide insights into the potential use of RO3280 for AML therapy ; however , the underlying mechanisms remain to be determined .",
"It is all in the factors : effects of cognitive remediation on symptom dimensions . BACKGROUND : Cognitive remediation ( CR ) aims primarily to improve cognition and functional outcomes . However , a limited number of studies reported a positive effect on symptoms . This limited effect may be because the symptom clusters considered are too broad and heterogeneous . This study explores , for the first time , the effect of CR on five empirically defined symptom dimensions of schizophrenia . METHOD : Participants were patients with schizophrenia taking part in a randomised controlled trial comparing CR plus treatment as usual ( CR , N = 43 ) to treatment as usual ( P10636 , N = 42 ) . All participants were assessed at baseline and 14 - weeks ( i . e . at the conclusion of treatment for the CR group ) with the Positive and Negative Symptoms Scale ( PANSS ) . Five symptom dimensions were derived from the PANSS scores : Positive ( POS ) , Negative ( NEG ) , Disorganised ( Q8IX12 ) , Excited ( EXC ) and Emotional Distressed ( P50402 ) . RESULTS : After CR , the therapy group had a significant reduction in Q8IX12 and NEG symptom dimensions compared to the P10636 group . The traditional PANSS factors showed no effect of CR on symptoms . CONCLUSION : CR can have not only a positive effect on disorganisation but also on negative symptoms . Using detailed symptom dimensions can characterise more accurately the effect of CR on symptom of schizophrenia .",
"Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .",
"Role of adiponectin in delayed embryonic development of the short - nosed fruit bat , Cynopterus sphinx . The aim of this study was to evaluate the role of adiponectin in the delayed embryonic development of Cynopterus sphinx . Q15848 receptor ( Q96A54 ) abundance was first observed to be lower during the delayed versus non - delayed periods of utero - embryonic unit development . The effects of adiponectin treatment on embryonic development were then evaluated during the period of delayed development . Exogenous treatment increased the in vivo rate of embryonic development , as indicated by an increase in weight , Q96A54 levels in the utero - embryonic unit , and histological changes in embryonic development . Treatment with adiponectin during embryonic diapause showed a significant increase in circulating progesterone and estradiol concentrations , and in production of their receptors in the utero - embryonic unit . The adiponectin - induced increase in estradiol synthesis was correlated with increased cell survival ( P10415 protein levels ) and cell proliferation ( P12004 protein levels ) in the utero - embryonic unit , suggesting an indirect effect of adiponectin via estradiol synthesis by the ovary . An in vitro study further confirmed the in vivo findings that adiponectin treatment increases P12004 levels together with increased uptake of glucose by increasing the abundance of glucose transporter 8 ( GLUT8 ) in the utero - embryonic unit . The in vitro study also revealed that adiponectin , together with estradiol but not alone , significantly increased Q96A54 protein levels . Thus , adiponectin works in concert with estradiol to increase glucose transport to the utero - embryonic unit and promote cell proliferation , which together accelerate embryonic development .",
"P10275 as a therapeutic target . Androgens function as sex hormone primarily via activation of a single androgen receptor ( AR , or P10275 ) . AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer . AR ligands of different chemical structures and / or pharmacological properties are widely used for these therapeutic applications , and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand - binding pocket ( P18428 ) of the receptor . In the past ten years , our understanding of AR structure and molecular mechanism of action has progressed extensively , which has encouraged the rapid development of newer generation of AR ligands , particularly tissue - selective AR ligands . With improved tissue selectivity , future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs . This review will provide an overview of the common therapeutic applications of currently available AR ligands , and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development .",
"The P08908 - receptor agonist flibanserin reduces drug - induced dyskinesia in O75916 - deficient mice . Drug - induced dyskinesia is a major complication of dopamine replacement therapy in advanced Parkinson ' s disease consisting of dystonia , chorea and athetosis . Agonists at P08908 - receptors attenuate levodopa - induced motor complications in non - human primates . Mice with increased dopamine D2 receptor ( P14416 ) signalling due to the lack of expression of the regulator of G - protein signalling 9 ( O75916 ) also develop dyskinesia following levodopa treatment . We investigated whether the P08908 - receptor agonist flibanserin compared with buspirone reduces motor abnormalities induced by levodopa or quinelorane , a selective dopamine D2 - receptor agonist . Following dopamine depletion via reserpine , 40 mice ( 20 wild - type and 20 O75916 knock - out ) were treated with flibanserin or buspirone in combination with levodopa or quinelorane . Motor behaviour was analysed using open field analysis . O75916 knock - out mice displayed significantly more drug - induced dystonia ( p < 0 . 04 ; t test ) than wild type . In quinelorane - treated wild - type mice flibanserin as well as buspirone significantly reduced dystonia ( p < 0 . 05 ) . In O75916 knock - out animals again both reduced quinelorane - induced dystonia . However , flibanserin was significantly more effective ( p = 0 . 003 ) . Following reserpine pretreatment and administration of levodopa wild - type and Q99697 9 knock - out mice showed mild to moderate dystonia . Surprisingly , 10 mg / kg buspirone increased dystonia in both animal groups , whereas it was decreased by 10 mg / kg flibanserin . However , compared with levodopa alone only the increase of dystonia by buspirone was significant ( p < 0 . 04 ) . ___MASK80___ showed promising antidyskinetic effects in a model of drug - induced dyskinesia . Our data underline the possible benefit of P08908 agonists in drug - induced dyskinesia .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK69___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK69___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK69___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Intracellular signaling of the aging suppressor protein Q9UEF7 . The Q9UEF7 protein deficiency is known to participate in premature aging . As an aging suppressor , Q9UEF7 is an important molecule in aging processes and its overexpression results in longevity . Due to many reasons , the insulin / insulin - like growth factor - 1 ( DB01277 ) has been considered as a key pathway in aging research . The Q9UEF7 gene is closely related to this pathway . The Q9UEF7 gene encodes a transmembrane protein that after cleavage is also found as a secreted protein . Importantly , its overexpression suppresses insulin / DB01277 signaling and thus extends the lifespan . In addition , Q9UEF7 participates in the regulation of several other intracellular signaling pathways , including regulation of Q9GZV9 signaling , DB02527 , PKC , transforming growth factor - β ( TGF - β ) , p53 / P38936 , and Wnt signaling . The aim of this review is to summarize current literature that shows the involvement of Q9UEF7 in the regulation of several intracellular pathways . The results of our review clearly indicate that Q9UEF7 participates in several intracellular signaling pathways , and by regulating them , Q9UEF7 is involved in aging and longevity .",
"Combination of ibrutinib with ABT - 199 : synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of Q06187 , AKT and P10415 pathways .",
"Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53 - deficient HT29 human colon cancer cell line . Mutations in the tumor - suppressor gene p53 have been associated with advanced colorectal cancer ( CRC ) . ___MASK69___ ( CPT - 11 ) , a P11387 inhibitor , has been recently incorporated to the adjuvant therapy . Since the DNA - damage checkpoint depends on p53 activation , the status of p53 might critically influence the response to CPT - 11 . We analysed the sensitivity to CPT - 11 in the human colon cancer cell line HT29 ( mut p53 ) and its wild - type ( wt )- p53 stably transfected subclone HT29 - A4 . Cell - cycle analysis in synchronised cells demonstrated the activation of transfected wt - p53 and a P38936 ( P38936 / CIP1 )- dependent cell - cycle blockage in the S phase . Activated wt - p53 increased apoptosis and enhanced sensitivity to CPT - 11 . In p53 - deficient cells , cDNA - macroarray analysis and western blotting showed an accumulation of the cyclin - dependent kinase ( cdk ) 1 / cyclin B complex . Subsequent p53 - independent activation of the cdk - inhibitor ( cdk - I ) P38936 ( P38936 / CIP1 ) prevented cell - cycle progression . Cdk1 induction was exploited in vivo to improve the sensitivity to CPT - 11 by additional treatment with the cdk - I P99999 - 202 . We demonstrate a gain of sensitivity to CPT - 11 in a p53 - mutated colon cancer model either by restoring wild - type p53 function or by sequential treatment with cdk - Is . Considering that mutations in p53 are among the most common genetic alterations in CRC , a therapeutic approach specifically targeting p53 - deficient tumors could greatly improve the treatment outcomes .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK53___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK53___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Neuroprotective effects of low - dose lithium in individuals at ultra - high risk for psychosis . A longitudinal Q9BWK5 / P59665 study . OBJECTIVES : To investigate if low - dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra - high risk ( UHR ) for psychosis . METHODS : Hippocampal P24752 relaxation time ( HT2RT ) and proton magnetic resonance spectroscopy ( ( 1 ) H - P59665 ) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low - dose lithium and 10 UHR patients receiving treatment as usual ( P10636 ) . HT2RT and ( 1 ) H - P59665 percentage change scores between scans were compared using repeated measures Q9UNW9 and correlated with behavioural change scores . RESULTS : Low - dose lithium significantly reduced HT2RT compared to P10636 ( p = 0 . 018 ) . No significant group by time effects was seen for any brain metabolites as measured with ( 1 ) H - P59665 , although myo - inositol , creatine , choline - containing compounds and NAA increased in the group receiving low - dose lithium and decreased or remained unchanged in subjects receiving P10636 . CONCLUSIONS : This pilot study suggests that low - dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT . Larger scale replication studies in UHR states using P24752 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low - dose lithium as potential treatments to delay or even prevent the progression to full - blown disorder .",
"Production of paired helical filament , tau - like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron - like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) - like antigen when they are subjected to heat shock ( Wallace et al . : Mol Brain Res 19 : 149 - 155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N - and C - terminal halves and the microtubule - binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full - length and C - terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF - like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer ' s disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and / or degeneration of P10636 in Alzheimer ' s disease .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK80___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK80___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .",
"High - density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy . Two extended haplotypes exist across the tau gene - H1 and H2 - with H1 consistently associated with increased risk of progressive supranuclear palsy ( PSP ) . Using 15 haplotype tagging SNPs ( htSNPs ) , capturing > 95 % of P10636 haplotype diversity , we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals . We found that PSP risk is associated with one of two major ancestral H1 haplotypes , H1B , increasing from 14 % in control individuals to 22 % in PSP patients ( P < 0 . 001 ) . In young PSP patients , the H1B risk could be localized to a 22 kb regulatory region in intron 0 ( P < 0 . 001 ) and could be fully explained by one SNP , htSNP167 , creating a P18428 - 1c / Q12800 / CP2 site , shown to regulate the expression of genes in other neurodegenerative disorders . Luciferase reporter data indicated that the 182 bp conserved regulatory region , in which htSNP167 is located , is transcriptionally active with both alleles differentially influencing expression . Further , we replicated the htSNP167 association in a second , independently ascertained US PSP patient - control sample . However , the htSNP association showed that H1 risk alone could not explain the overall differences in H1 and H2 frequencies in PSP patients and control individuals . Thus , risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP ."
] |
[
"___MASK30___",
"___MASK4___",
"___MASK53___",
"___MASK54___",
"___MASK69___",
"___MASK73___",
"___MASK80___",
"___MASK95___",
"___MASK99___"
] |
___MASK53___
|
MH_train_322
|
interacts_with DB06626?
|
[
"P04150 and histone deacetylase - 2 mediate dexamethasone - induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up - regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose - dependent and time - dependent manner , and that the DB00514 - induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre - exposure of cells to ___MASK30___ , a GR antagonist , and mutations in either the GRE3 or GRE5 cis - sites abolished the DB00514 - induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis - elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase - 2 ( Q92769 ) in P98088 - expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis - elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 - specific short interfering RNA prevented the DB00514 - induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis - sites in the P98088 promoter and mediate the DB00514 - induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases .",
"Effects of MLN518 , a dual P36888 and P10721 inhibitor , on normal and malignant hematopoiesis . Internal tandem duplications ( ITDs ) of the P07333 - like tyrosine kinase 3 ( P36888 ) receptor tyrosine kinase are found in approximately 30 % of patients with acute myelogenous leukemia ( AML ) and are associated with a poor prognosis . P36888 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant , implicating P36888 as a plausible therapeutic target . MLN518 ( formerly CT53518 ) is a small molecule inhibitor of the P36888 , P10721 , and platelet - derived growth - factor receptor ( P09619 ) tyrosine kinases with significant activity in murine models of P36888 ITD - positive leukemia . Given the importance of P36888 and P10721 for normal hematopoietic progenitor cells , we analyzed the effect of MLN518 on murine hematopoiesis under steady - state conditions , after chemotherapy - induced myelosuppression , and during bone marrow transplantation . In these assays , we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating P36888 ITD - positive leukemia in mice . We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from P36888 ITD - positive compared with ITD - negative patients with AML , at concentrations that do not significantly affect colony formation by normal human progenitor cells . In analogy to imatinib mesylate in P11274 - P00519 - positive acute leukemia , MLN518 - induced remissions may not be durable . Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols .",
"Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .",
"Combination effects of paclitaxel with signaling inhibitors in endometrial cancer cells . This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor ( P00533 ) or / and mammalian target of rapamycin ( P42345 ) inhibitors with two endometrial cancer lines O14777 - 1A and Ishikawa . Treatment was with the P00533 inhibitor RG14620 , the P42345 inhibitor rapamycin , and the conventional cytotoxic drug paclitaxel , alone or in combination . The 50 % inhibitory concentration ( IC50 ) and cell viability were determined by the MTT assay . Multiple drug effect / combination indexes ( CI ) analysis was applied to assess interactions between paclitaxel and the two inhibitors . Apoptosis and cell cycling were evaluated by flow cytometry analysis . Western blotting was performed to evaluate the related protein alteration in PI3K / AKT signaling pathway . RG14620 , rapamycin and paclitaxel showed obvious dose - dependent growth inhibition with time . The IC50 of paclitaxel at 24 hours decreased significantly when pretreated with low doses of RG14620 and ___MASK82___ alone or in combination . Moreover , combination index ( CI ) of paclitaxel with each inhibitor was larger than 1 , indicating a synergistic effect between pairs of drugs in these two cell lines . FACS analysis showed the cell apoptosis rate increased with a synergistic effect . On Western blotting , activation of PI3K / AKT pathway was detected in both two cell lines in the control case . When paclitaxel was used as a single - agent or in combinations , the protein expression of PI3K / AKT pathway totally abated , especially in O14777 - 1A cells , suggesting a role in chemoresistance . The combination of three drugs induced the greatest over - expression of caspase - 3 . Combining targeted inhibitors with cytotoxic chemotherapy appears to be a promising strategy for the effective treatment of endometrial cancer which merits further clinical investigation .",
"Donor pre - treatment with everolimus or cyclosporine does not reduce ischaemia - reperfusion injury in a rat kidney transplant model . BACKGROUND : Immunosuppressive agents have been investigated in renal ischaemia - reperfusion injury ( IRI ) and have frequently demonstrated a beneficial effect . Most studies focused on treatment of the recipient at the time of transplantation . Pre - treatment of these organs before injury ( pharmacological pre - conditioning ) may particularly protect these organs . This study aimed to investigate the possible protective effects of donor pre - treatment with cyclosporine ( DB00091 ) or the P42345 inhibitor everolimus or their combination against IRI during renal transplantation in a rat model . METHODS : Donors received vehicle , DB00091 ( 5 mg / kg ) , everolimus ( 0 . 5 mg / kg ) or CsA + everolimus . Two oral doses were administered to the donors at 24 h and again at 6 h prior to donor kidney removal . Syngeneic rat kidneys were preserved in UW solution for 24 h prior to transplantation . After 24 h of reperfusion , blood and tissue samples were collected from recipients for further analysis . RESULTS : Renal functions as determined by creatinine and necrosis scores were not different between the experimental groups . Cleaved caspase - 3 , heat shock protein 70 ( HSP70 ) , tumor - necrosis factor - alpha ( P01375 - α ) and nitrotyrosine protein levels were not statistically different between the four treatment groups at 24 h post - transplantation . Blood NMR analysis on metabolic markers for IRI reveals no beneficial effects of donor pre - treatment on the 24 - h outcome in transplantation . CONCLUSIONS : When given alone or as a combination to donors before organ recovery , cyclosporine or everolimus does not appear to ameliorate IRI .",
"P00747 activator inhibitor - 1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor - 2 - αVβ3 integrin cross talk . OBJECTIVE : P00747 activator inhibitor - 1 ( P05121 ) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion . However , no previous study has implicated P05121 in controlling vascular endothelial growth factor ( P15692 ) signaling . We tested the hypothesis that P05121 downregulates P15692 receptor - 2 ( P35968 ) activation by inhibiting a vitronectin - dependent cooperative binding interaction between P35968 and αVβ3 . APPROACH AND RESULTS : We studied effects of P05121 on P15692 signaling in human umbilical vein endothelial cells . P05121 inhibited P15692 - induced phosphorylation of P35968 in human umbilical vein endothelial cells grown on vitronectin , but not on fibronectin or collagen . P05121 inhibited the binding of P35968 to β3 integrin , P35968 endocytosis , and intracellular signaling pathways downstream of P35968 . The anti - P15692 effect of P05121 was mediated by 2 distinct pathways , one requiring binding to vitronectin and another requiring binding to very low - density lipoprotein receptor . P05121 inhibited P15692 - induced angiogenesis in vitro and in vivo , and pharmacological inhibition of P05121 promoted collateral arteriole development and recovery of hindlimb perfusion after femoral artery interruption . CONCLUSIONS : P05121 inhibits activation of P35968 by P15692 by disrupting a vitronectin - dependent proangiogenic binding interaction involving αVβ3 and P35968 . These results broaden our understanding of the roles of P05121 , vitronectin , and endocytic receptors in regulating P35968 activation and suggest novel therapeutic strategies for regulating P15692 signaling .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK100___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK93___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Transient activation of P42345 following forced treadmill exercise in rats . The beneficial effect of exercise on hippocampal plasticity is possibly mediated by increased angiogenesis and neurogenesis . In angiogenesis , insulin - like growth factor - 1 ( DB01277 ) , vascular endothelial growth factor ( P15692 ) , and hypoxia - inducible factor 1 , alpha subunit ( HIF1α ) are important factors , while the induction of neurogenesis requires signaling through the P15692 receptor , Flk - 1 ( P35968 ) . P15692 expression is believed to be regulated by two distinct P42345 ( mammalian target of ___MASK82___ ) - containing multiprotein complexes mTORC1 and mTORC2 , respectively . This study was initiated to investigate the effect of exercise on the expression of P15692 , cognate receptors , HIF1α , mTORC1 , and mTORC2 in hippocampus and frontal cortex . To this end , we measured messenger RNA ( mRNA ) levels in rat brain using quantitative real - time polymerase chain reaction ( real - time qPCR ) after forced treadmill exercise for 1 day , 2 weeks , and 8 weeks . Rats were euthanized either immediately ( 0 h ) or 24 h after last exercise session . Here , we show that exercise affected mRNA levels of P15692 , P35968 , and the coreceptor neuropilin 2 ( NRP2 ) when the rats were euthanized immediately , whereas at 24 h only the expression of P42345 was regulated after a single bout of exercise . In conclusion , the effect of treadmill exercise on the P15692 system is acute rather than chronic and there is a transient activation of P42345 . More studies are needed to understand whether this could be beneficial in the treatment of neuropsychiatric disorders .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK68___ and Tissue P00747 Activator in Occluded Arteries .",
"DB06626 modulates hypoxia - induced blood - retina barrier permeability and expression of growth factors . This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor ( P15692 ) receptors 1 / 2 ( P17948 / 2 ) and platelet - derived growth factor ( PDGF ) receptor beta ( P09619 - β ) , hypoxia - induced increased tissue permeability , occludin , zonula occludens protein 1 ( ZO - 1 ) , P15692 , and PDGF expression of human retinal pigment epithelial ( Q96AT9 ) cells and human umbilical vein endothelial cells ( HUVECs ) . Primary human Q96AT9 cells and HUVECs were exposed to hypoxia and axitinib . Viability of cells , tissue permeability , and expression of occludin , ZO - 1 , P15692 , PDGF , P17948 / 2 and P09619 - β , and their mRNAs , were investigated by reverse transcription - polymerase chain reaction , enzyme - linked immunosorbent assay , western blotting , and immunohistochemistry . Treatment with axitinib reduced expression of P17948 / 2 and P09619 - β . Hypoxia decreased cell viability , occludin , and ZO - 1 expression and increased tissue permeability , expression , and secretion of P15692 and PDGF . DB06626 significantly reduced hypoxia - induced effects on HUVEC and Q96AT9 cells . Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema .",
"P49767 promotes survival of retinal vascular endothelial cells via vascular endothelial growth factor receptor - 2 . AIM : To determine vascular endothelial growth factor C ( P49767 ) expression in retinal endothelial cells , its antiapoptotic potential and its putative role in diabetic retinopathy . METHOD : Cultured retinal endothelial cells and pericytes were exposed to tumour necrosis factor ( P01375 ) alpha and P49767 expression determined by reverse transcriptase - polymerase chain reaction . Secreted P49767 protein levels in conditioned media from endothelial cells were examined by western blotting analysis . The ability of P49767 to prevent apoptosis induced by TNFalpha or hyperglycaemia in endothelial cells was assessed by flow cytometry . The expression of P49767 in diabetic retinopathy was studied by immunohistochemistry of retinal tissue . RESULT : P49767 was expressed by both vascular endothelial cells and pericytes . TNFalpha up regulated both P49767 and vascular endothelial growth factor receptor - 2 ( VEGFR ) - 2 expression in endothelial cells in a dose - dependent manner , but had no effect on P35916 . Flow cytometry results showed that P49767 prevented endothelial cell apoptosis induced by TNFalpha and hyperglycaemia and that the antiapoptotic effect was mainly via P35968 . In pericytes , the expression of P49767 mRNA remained stable on exogenous TNFalpha treatment . P49767 immunostaining was increased in retinal vessels in specimens with diabetes compared with retinal specimens from controls without diabetes . CONCLUSION : In retinal endothelial cells , TNFalpha stimulates the expression of P49767 , which in turn protects endothelial cells from apoptosis induced by TNFalpha or hyperglycaemia via P35968 and thus helps sustain retinal neovascularisation .",
"Human endothelial progenitor cells isolated from P48444 patients are dysfunctional . Cardiovascular disease is the leading cause of morbidity and mortality in patients with moderate - to - severe chronic obstructive pulmonary disease ( P48444 ) . More than 44 % of these patients present with generalized atherosclerosis at autopsy . It is accepted that endothelial progenitor cells ( EPCs ) participate in the repair of dysfunctional endothelium and thus protects against atherosclerosis . However , whether P48444 affects the repairing capacity of EPCs is unknown . Therefore , the objective of this study was to determine whether and how EPCs are involved in the vascular repair process in patients with P48444 . In our study , EPCs from 25 P48444 and 16 control patients were isolated by Ficoll density - gradient centrifugation and identified using fluorescence activated cell sorting . Transwell Migratory Assay was performed to determine the number of EPC colony - forming units and the adherent capacity late - EPCs to human umbilical vein endothelial cells . Following arterial damage in NOD / SCID mice , the number of EPCs incorporated at the injured vascular site was determined using a fluorescence microscope . We found that the number of EPC clusters and cell migration , as well as the expression of P61073 , was significantly decreased in patients with P48444 . Additionally , the number of late - EPCs adherent to HUVEC tubules was significantly reduced , and fewer P35968 (+)- staining cells were incorporated into the injured site in P48444 patients . Our study demonstrates that EPC capacity of repair was affected in P48444 patients , which may contribute to altered vascular endothelium in this patient population .",
"The combination of axitinib followed by paclitaxel / carboplatin yields extended survival in advanced P15056 wild - type melanoma : results of a clinical / correlative prospective phase II clinical trial . BACKGROUND : Simultaneous chemotherapy with vascular endothelial growth factor ( P15692 ) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma . We tested administration of the potent P15692 inhibitor axitinib followed by paclitaxel / carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity . METHODS : We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0 - 1 and normal organ function . DB06626 5 mg PO b . i . d . was taken on days 1 - 14 of each 21 - day treatment cycle , and carboplatin ( AUC = 5 ) with paclitaxel ( 175 mg m (- 2 ) ) was administered on day 1 starting with cycle 2 . 3 '- Deoxy - 3 '-( 18 ) F - fluorothymidine ( ( 18 ) F - P17948 ) - PET scans were performed in five patients to assess tumour proliferation on days 1 , 14 , 17 , and 20 of cycle 1 . Molecular profiling for P15056 was performed for all patients with cutaneous , acral , or mucosal melanoma . RESULTS : The treatment was well tolerated . The most common grade 3 AEs were hypertension , neutropenia , and anaemia . Grade 4 non - haematologic AEs were not observed . Four of five patients completing ( 18 ) F - P17948 - PET scans showed increases ( 23 - 92 % ) in SUV values during the axitinib holiday . Of 36 evaluable patients , there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors . Overall , 20 patients had SD and 8 had PD as the best response . The median PFS was 8 . 7 months and the median overall survival was 14 . 0 months . Five P15056 ( V600E / K ) patients had significantly worse PFS than patients without these mutations . CONCLUSIONS : DB06626 followed by carboplatin and paclitaxel was well tolerated and effective in P15056 wild - type metastatic melanoma . 3 '- Deoxy - 3 '-( 18 ) F - fluorothymidine - PET scans showed increased proliferation during axitinib withdrawal .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK32___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK32___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse . Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy . In peripheral neuropathy , defects in neurofilament and microtubules have been demonstrated . In this study , we examined the effects of insulin deficiency within the brain in insulin knockout mice ( I -/- ) . The I -/- exhibited hyperphosphorylation of tau , at threonine 231 , and neurofilament . In addition , we showed hyperphosphorylation of c - Jun N - terminal kinase ( JNK ) and glycogen synthase kinase 3 beta ( P49841 ) at serine 9 . P27361 ( P29323 1 ) showed decrease in phosphorylation , whereas P29323 2 showed no changes . Ultrastructural examination demonstrated swollen mitochondria , endoplasmic reticulum , and Golgi apparatus , and dispersion of the nuclear chromatin . Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches . Thus , lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament , and ultrastructural cellular damage , that over time may induce decrease in cognition and learning disabilities .",
"Acute myeloid leukemia subgroups identified by pathway - restricted gene expression signatures . Acute myeloid leukemia ( AML ) is a heterogeneous group of disorders characterized by abnormal proliferation of myeloid precursors and a maturation block . Underlying genetic lesions determine an altered expression program ( transcriptosome ) that can be studied in depth by massive technologies . Alternatively , we selected a pathway profiling strategy based on the current knowledge in order to stratify de novo AML patients and identify those cases which would potentially benefit from the use of new chemotherapeutic agents . One hundred and thirty - two RNA samples obtained from de novo adult AML patients were tested for P36888 , P36888 - LG , P52848 , Q92769 , P46100 , P01100 , P26358 , Q9Y6K1 , Q9UBC3 , NBS1 , Q92878 , P49959 , Meis1 and Meis2 expression using quantitative PCR ( qPCR ) assays . Clinical and biologic findings were correlated with expression results . Cluster analysis was also performed . P36888 expression defined three subgroups of patients . The best outcome was found in the group with the lowest P36888 expression . Intermediate levels of P36888 were associated with the worst outcome . Patients with low levels of P46100 more frequently presented an adverse karyotype whereas cases with preserved P46100 levels showed an excellent outcome . In accordance with previous results , Meis1 downregulation is a useful surrogate marker indicating a good prognosis in AML patients . Simple qPCR platforms may help to identify different biologic subgroups in AML .",
"Prolonged high fat / alcohol exposure increases Q9HBA0 and its functional responses in pancreatic stellate cells . The present study investigated transient receptor potential vanilloid type 4 ( Q9HBA0 ) ion channels in pancreatic stellate cells ( PSCs ) isolated from rats with high - fat and alcohol diet ( HFA ) - induced chronic pancreatitis . Q9HBA0 is a calcium - permeable nonselective ion channel responsive to osmotic changes , alcohol metabolites arachidonic acid , anandamide , their derivatives , and injury - related lipid mediators . Male Lewis rats were fed HFA for 6 - 8 wk before isolation and primary culture of PSCs . Control PSCs were harvested from rats fed standard chow . Immunoreactivity for cytoskeletal protein activation product α - smooth muscle actin ( α - SMA ) and platelet - derived growth factor receptor - β subunit ( P09619 - β ) characterized the cells as PSCs . Q9HBA0 expression increased in PSCs of HFA - fed rats and control cultures after alcohol treatment ( 50 mM ) . Cell responses to activation of inducible Q9HBA0 were assessed with live cell calcium imaging . Threefold increased and sustained intracellular calcium mobilization responses occurred in 70 % of pancreatic stellate cells from HFA - fed rats in response to Q9HBA0 activators arachidonic acid , lipid second messenger , phorbol ester 4 α - phorbol 12 , 13 - didecanoate ( 4αPDD ) , and 50 % hypoosmotic media compared with relatively unresponsive PSCs from control rats . Activation responses were attenuated by nonselective TRPV channel blocker ruthenium red . P01375 - α ( P01375 - α , 1 ng / ml , 16 h ) increased responses to 4αPDD in control PSCs . These findings implicate Q9HBA0 - mediated calcium responses inducible after HFA exposure and inflammation in reactive responses of activated PSCs that impair pancreatic function , such as responsiveness to cytokines and the deposition of collagen fibrosis that precipitates ductal blockage and pain .",
"Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .",
"Selective inhibition of P01579 - induced autophagy by Mir155 - and Mir31 - responsive P41221 and SHH signaling . Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents . However , several pathogens have evolved strategies to evade autophagy . Here , we demonstrated that Mycobacteria , Shigella , and Listeria but not Klebsiella , Staphylococcus , and Escherichia inhibit P01579 - induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via P42345 . Utilization of gain - or loss - of - function analyses as well as mir155 - null macrophages emphasized the role of P42345 - responsive epigenetic modifications in the induction of Mir155 and Mir31 . Importantly , cellular levels of PP2A , a phosphatase , were regulated by Mir155 and Mir31 to fine - tune autophagy . Diminished expression of PP2A led to inhibition of P49841 , thus facilitating the prolonged activation of WNT and SHH signaling pathways . Sustained WNT and SHH signaling effectuated the expression of anti - inflammatory lipoxygenases , which in tandem inhibited P01579 - induced JAK - P35610 signaling and contributed to evasion of autophagy . Altogether , these results established a role for new host factors and inhibitory mechanisms employed by the pathogens to limit autophagy , which could be targeted for therapeutic interventions .",
"DB00762 synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo . AIMS : To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer . METHODS : Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer ( MIAPaCa - 2 , Capan - 1 ) cell lines exposed to SN - 38 , the active metabolite of irinotecan , axitinib , or their simultaneous combination for 72 hours . P27361 / 2 and Akt phosphorylation , the vascular endothelial growth factor ( P15692 ) , P15692 receptor - 2 , and thrombospondin - 1 ( P07996 - 1 ) concentration were measured by ELISAs . Q04656 and Q9UNQ0 gene expression was performed with real - time polymerase chain reaction and SN - 38 intracellular concentrations were measured by high - performance liquid chromatography . Capan - 1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination . RESULTS : A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib / SN - 38 combination on endothelial and cancer cells . P27361 / 2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines . DB06626 and SN - 38 combined treatment greatly inhibited the expression of the Q04656 and Q9UNQ0 genes in endothelial and cancer cells , increasing the SN - 38 intracellular concentration . Moreover , P07996 - 1 secretion was increased in cells treated with both drugs , whereas P35968 levels significantly decreased . In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization . CONCLUSIONS : In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells , suggesting a possible translation of this schedule into the clinics .",
"P28482 , but not P27361 , mediates acquired and \" de novo \" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .",
"DB06626 for renal cell carcinoma . BACKGROUND : The approval of sunitinib , sorafenib and temsirolimus has dramatically altered the management of renal cell carcinoma ( RCC ) . DB00112 plus IFN may also be added to the therapeutic armamentarium . DB06626 ( AG - 013736 ) is an oral and selective tyrosine kinase inhibitor . OBJECTIVE : Data supporting the development of axitinib for RCC are reviewed . METHODS : Preclinical and clinical data available for axitinib for RCC are presented . RESULTS : DB06626 inhibits P17948 , P35968 and P35916 with picomolar potencies , and P16234 , P09619 and c - kit with nanomolar potencies . Phase II clinical trials of axitinib in pretreated RCC following sorafenib or cytokine treatment have demonstrated promising activity accompanied by a favorable toxicity profile . Further development of axitinib for RCC is warranted .",
"Q02548 / P41212 acts as a transcriptional repressor causing down - modulation of P15391 , enhances migration to P48061 , and confers survival advantage in pre - BI cells . Q02548 is a transcription factor essential for B - cell development . Recently , it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia ( ALL ; 30 % of B cell ALL cases ) , showing monoallelic loss , point mutations , or chromosomal translocations . The role of these aberrancies is still poorly understood . We previously cloned the Q02548 / P41212 fusion gene in a patient affected by B - cell precursor ALL with a t ( 9 ; 12 ) translocation . This is the first report investigating the molecular and functional roles of Q02548 / P41212 protein in vitro from murine wild - type pre - BI cells . We showed that Q02548 / P41212 protein acts as an aberrant transcription factor with repressor function , recruiting mSin3A , down - regulating B220 , P15391 , Q8WV28 , MB - 1 , P36888 , and mu heavy chain expression , thus suggesting a block on B - cell differentiation . In a Q02548 - deficient context , the presence of Q02548 / P41212 did not replace Q02548 functions . Q02548 / P41212 protein enhances cell migration towards P48061 , with the overexpression of P61073 . Moreover , the presence of the fusion gene overcomes interleukin - 7 withdrawal and interferes with transforming growth factor - beta1 pathway , inducing resistance and conferring cells an advantage in proliferation and survival . Thus , in vitro , the Q02548 / P41212 protein has a dominant effect on wild - type Q02548 , interferes with the process of B - cell differentiation and migration , and induces resistance to apoptosis . Taken together , these phenomena likely represent key events in the process of B - cell transformation .",
"Inhibition of angiogenesis by vitamin D - binding protein : characterization of anti - endothelial activity of P02774 . Angiogenesis is a complex process involving coordinated steps of endothelial cell activation , proliferation , migration , tube formation and capillary sprouting with participation of intracellular signaling pathways . Regulation of angiogenesis carries tremendous potential for cancer therapy . Our earlier studies showed that vitamin D - binding protein - macrophage activating factor ( P02774 ) acts as a potent anti - angiogenic factor and inhibits tumor growth in vivo . The goal of this investigation was to understand the effect of P02774 on human endothelial cell ( O14777 ) and the mechanism of angiogenesis inhibition . P02774 inhibited human endothelial cell ( O14777 ) proliferation by inhibiting DNA synthesis ( IC ( 50 ) = 7 . 8 +/- 0 . 15 microg / ml ) . P02774 significantly induced S - and G0 / P55008 - phase arrest in O14777 in 72 h . P02774 potently blocked P15692 - induced migration , tube - formation of O14777 in a dose dependent manner . In addition , P02774 inhibited growth factor - induced microvessel sprouting in rat aortic ring assay . Moreover , P02774 inhibited P15692 signaling by decreasing P15692 - mediated phosphorylation of P35968 and P27361 / 2 , a downstream target of P15692 signaling cascade . However , Akt activation was not affected . These studies collectively demonstrate that P02774 inhibits angiogenesis by blocking critical steps such as O14777 proliferation , migration , tube formation and microvessel sprouting . P02774 exerts its effect by inhibiting VEGR - 2 and P27361 / 2 signaling cascades . Understanding the cellular and molecular mechanisms of anti - endothelial activity of P02774 will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy .",
"Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK100___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .",
"The expression level of P21554 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas . BACKGROUND : Cannabinoids represent unique compounds for treating tumors , including astrocytomas . Whether CB ( 1 ) and CB ( 2 ) receptors mediate this therapeutic effect is unclear . PRINCIPAL FINDINGS : We generated astrocytoma subclones that express set levels of CB ( 1 ) and CB ( 2 ) , and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to P27361 / 2 . In contrast , cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT . Remarkably , cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB ( 1 ) , CB ( 2 ) and AKT , but still through a mechanism involving P27361 / 2 . SIGNIFICANCE : The high expression level of CB ( 1 ) and CB ( 2 ) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics , unless AKT is concomitantly inhibited , or cannabinoids are applied at concentrations that bypass CB ( 1 ) and CB ( 2 ) receptors , yet still activate P27361 / 2 .",
"Kinome profiling of chondrosarcoma reveals P12931 - pathway activity and dasatinib as option for treatment . Chondrosarcomas are notorious for their resistance to conventional chemotherapy and radiotherapy , indicating there are no curative treatment possibilities for patients with inoperable or metastatic disease . We therefore explored the existence of molecular targets for systemic treatment of chondrosarcoma using kinome profiling . Peptide array was performed for four chondrosarcoma cell lines and nine primary chondrosarcoma cultures with GIST882 , MSCs , and colorectal cancer cell lines as controls . Activity of kinases was verified using immunoblot , and active Src - and platelet - derived growth factor receptor ( P09619 ) signaling were further explored using imatinib and dasatinib on chondrosarcoma in vitro . The P31749 / P49841 pathway was clearly active in chondrosarcoma . In addition , the P09619 pathway and the Src kinase family were active . P09619 and Src kinases can be inhibited by imatinib and dasatinib , respectively . Although imatinib did not show any effect on chondrosarcoma cell cultures , dasatinib showed a decrease in cell viability at nanomolar concentrations in seven of nine chondrosarcoma cultures . However , inhibition of phosphorylated Src ( Y419 ) was found both in responsive and nonresponsive cells . In conclusion , using kinome profiling , we found the Src pathway to be active in chondrosarcoma . Moreover , we showed in vitro that the inhibitor of the Src pathway , dasatinib , may provide a potential therapeutic benefit for chondrosarcoma patients who are not eligible for surgery .",
"P15941 and P04626 might be associated with invasive phenotype of intraductal papillary mucinous neoplasm . BACKGROUND / AIMS : The purpose of this study was to clarify the biomarkers which distinguish invasive Intraductal papillary mucinous neoplasms ( IPMNs ) from noninvasive IPMNs . METHODOLOGY : In tumor specimens from sixty patients with IPMNs ( 42 noninvasive IPMNs and 18 invasive IPMNs ) who underwent surgical resection at our institute , we analyzed the correlation between the immunohistochemical expression level of P15941 , Q02817 , Q99102 , P98088 , p53 , P35968 , P04626 , and P21860 . RESULTS : The 5 - year survival rate was 100 % in noninvasive IPMNs , while that of invasive IPMNs was only 36 . 5 % . P15941 , Q99102 , P04626 and P21860 were significantly associated with invasive IPMNs in univariate analysis . Multivariate analysis revealed that P15941 and P04626 were significantly associated with invasive IPMNs . The 5 - year survival of IPMN patients with either P15941 - positive and / or P04626 - positive ( 54 . 5 % ) is significantly poorer than that of IPMN patients with P15941 negative and P04626 negative ( 100 % ) . CONCLUSIONS : P15941 and P04626 might be closely associated with invasive phenotype of IPMNs .",
"The combination of rapamycin and MAPK inhibitors enhances the growth inhibitory effect on Nara - H cells . The inhibition of the mammalian target of rapamycin ( P42345 ) signaling pathway promotes the initiation of autophagy , and the mitogen - activated protein kinase ( MAPK ) / extracellular signal - regulated protein kinase ( P29323 ) is well known to induce autophagy . Autophagy is a self - defense mechanism of cancer cells that are subjected to antitumor agents , and blocking autophagy can trigger apoptosis . In the present study , we demonstrate that an P42345 inhibitor , rapamycin , induces autophagy in the Nara - H malignant fibrous histiocytoma ( Q9H334 ) cell line through the activation of P27361 / 2 . ___MASK82___ - induced apoptosis was enhanced following the inhibition of the MEK / P29323 pathway . In the Nara - H cells , we examined the effects of rapamycin treatment on cell proliferation and on the phosphorylation of the P42345 pathway components and autophagy by western blot analysis . Furthermore , we examined the effects of rapamycin with or without the MEK inhibitor , U0126 , on the induction of apoptosis by using fluorescence microscopy . ___MASK82___ inhibited Nara - H cell proliferation and decreased the phosphorylation of the P42345 pathway in the Nara - H cells . ___MASK82___ induced the apoptosis of Nara - H cells , and this apoptosis was enhanced by U0126 . Simultaneously , phospho - P27361 / 2 was activated by rapamycin . The present study demonstrates that rapamycin induces autophagy in Nara - H cells by activating the MEK / P29323 signaling pathway , and the rapamycin - induced apoptosis can be enhanced by the MEK inhibitor , U0126 . These results suggest that self ‑ protective mechanisms involving P42345 inhibitors in Nara - H cells are prevented by the inhibition of the MEK / P29323 pathway . The combination of an P42345 inhibitor ( e . g . , rapamycin ) and an MEK inhibitor ( e . g . , U0126 ) may offer effective treatment for Q9H334 , as this combination effectively activates apoptotic pathways .",
"Neutrophil apoptosis : selective regulation by different ligands of integrin alphaMbeta2 . Neutrophils undergo spontaneous apoptosis , but their survival can be extended during inflammatory responses . alpha ( M ) beta ( 2 ) is reported either to delay or accelerate neutrophil apoptosis , but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood . The abilities of closely related alpha ( M ) beta ( 2 ) ligands , plasminogen and angiostatin , derived from plasminogen , as well as fibrinogen and its two derivative alpha ( M ) beta ( 2 ) recognition peptides , P1 and P2 - C , differed markedly in their effects on neutrophil apoptosis . P00747 , fibrinogen , and P2 - C suppressed apoptosis via activation of Akt and P27361 / 2 kinases , while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis . Using cells transfected with alpha ( M ) beta ( 2 ) or its individual alpha ( M ) or beta ( 2 ) subunits , and purified receptors and its constituent chains , we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response . Hence , engagement of a single integrin by closely related ligands can induce distinct signaling pathways , which can elicit distinct cellular responses .",
"The selective P17948 - 3 inhibitor axitinib ( AG - 013736 ) shows antitumor activity in human neuroblastoma xenografts . Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high - risk disease . Within the KidsCancerKinome project , we evaluated the new oral selective pan - VEGFR tyrosine kinase inhibitor axitinib ( AG - 013736 ) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR - N91 derived from a primary bone marrow metastasis . DB06626 reduced cell proliferation in a dose - dependent manner with IC ( 50 ) doses between 274 and > 10 , 000 nmol / l . Oral treatment with 30 mg / kg P55957 for 2 weeks in advanced tumors yielded significant tumor growth delay , with a median time to reach five times initial tumor volume of 11 . 4 days compared to controls ( p = 0 . 0006 ) and resulted in significant reduction in bioluminescence . Simultaneous inhibition of VEGFR downstream effector P42345 using rapamycin 20 mg / kg q2d × 5 did not statistically enhance tumor growth delay compared to single agent activities . DB06626 downregulated P35968 phosphorylation resulting in significantly decreased microvessel density ( P53602 ) and overall surface fraction of tumor vessels ( OSFV ) in all xenografts as measured by P28906 immunohistochemical staining ( mean P53602 ± SD and OSFV at 14 days 21 . 27 ± 10 . 03 in treated tumors vs . 48 . 79 ± 17 . 27 in controls and 0 . 56 % vs . 1 . 29 % ; p = 0 . 0006 , respectively ) . We further explored the effects of axitinib on circulating mature endothelial cells ( CECs ) and endothelial progenitor cells ( CEPs ) measured by flow cytometry . While only transient modification was observed for CECs , CEP counts were significantly reduced during and up to 14 days after end of treatment . DB06626 has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma .",
"___MASK82___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK82___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .",
"___MASK74___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK74___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Inhibition of c - kit receptor tyrosine kinase activity by ___MASK32___ , a selective tyrosine kinase inhibitor . ___MASK32___ ( formerly known as CGP 57148B ) is a known inhibitor of the c - abl , bcr - abl , and platelet - derived growth - factor receptor ( P09619 ) tyrosine kinases . This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia . We sought to extend the activity profile of ___MASK32___ by testing its ability to inhibit the tyrosine kinase activity of c - kit , a receptor structurally similar to P09619 . We treated a c - kit expressing a human myeloid leukemia cell line , M - 07e , with ___MASK32___ before stimulation with Steel factor ( SLF ) . ___MASK32___ inhibited c - kit autophosphorylation , activation of mitogen - activated protein ( Q96HU1 ) kinase , and activation of Akt without altering total protein levels of c - kit , Q96HU1 kinase , or Akt . The concentration that produced 50 % inhibition for these effects was approximately 100 nmol / L . ___MASK32___ also significantly decreased SLF - dependent growth of M - 07e cells in a dose - dependent manner and blocked the antiapoptotic activity of SLF . In contrast , the compound had no effect on Q96HU1 kinase activation or cellular proliferation in response to granulocyte - macrophage colony - stimulating factor . We also tested the activity of ___MASK32___ in a human mast cell leukemia cell line ( HMC - 1 ) , which has an activated mutant form of c - kit . ___MASK32___ had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand - dependent activation of the wild - type receptor . These findings show that ___MASK32___ selectively inhibits c - kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival . This compound may be useful in treating cancers associated with increased c - kit kinase activity .",
"Improved effect of an antiangiogenic tyrosine kinase inhibitor ( SU5416 ) by combinations with fractionated radiotherapy or low molecular weight heparin . The effect of combining SU5416 with fractionated radiotherapy or with low molecular weight ( LMW ) heparin ( dalteparin ) was studied in U87 human glioblastoma xenografts in nude mice . SU5416 is antiangiogenic by a specific inhibition of the vascular endothelial growth factor receptor 2 ( P35968 ) , and heparins are assumed to bind P15692 . Both SU5416 ( 100 mg / kg every second day in 5 days ) and 3 Gyx5 produced moderate , yet significant , growth inhibition . Tumors treated with concomitant irradiation and short - term SU5416 maintained a lower growth rate during regrowth than the other treatment groups ( P =. 007 ) . ___MASK74___ ( 1000 IE / kg subcutaneously once a day ) had no growth - inhibitory effect on its own , but when this LMW heparin was added to the SU5416 schedule , a significantly enhanced growth inhibition was obtained . P15692 protein content in tumors was not significantly altered by SU5416 , but a significant decrease in P15692 levels was found in tumors treated with concomitant dalteparin and SU5416 compared with controls ( P =. 03 ) . We conclude that : 1 ) an additive growth - inhibitory effect is obtained by combining SU5416 and fractionated radiotherapy ; and 2 ) LMW heparin ( dalteparin ) , in combination with SU5416 , decreases the level of P15692 in tumors and increases the growth - inhibitory effect of SU5416 .",
"Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge - induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester - polyurethane sponges were implanted in C57Bl / 6j mice . Animals received doses ( 3 and 10 mg / kg / daily , s . c . ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N - acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 - α , P15692 , P09341 / KC , P13500 / JE , and P10147 / MIP - 1α levels , with increase in P13501 / RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge - induced inflammatory angiogenesis both via P21554 and CB2 receptors .",
"Q9UEF7 endows hepatoma cells with resistance to anoikis via P35968 / PAK1 activation in hepatocellular carcinoma . Q9UEF7 was originally characterized as an aging suppressor gene that predisposed Q9UEF7 - deficient mice to premature aging - like syndrome . Although Q9UEF7 was recently reported to exhibit tumor suppressive properties during various malignant transformations , the functional role and molecular mechanism of Q9UEF7 in hepatocarcinogenesis remains poorly understood . In our present study , immunohistochemical Q9UEF7 staining levels in a clinical follow - up of 52 hepatoma patients were significantly associated with liver cirrhosis , tumor multiplicity and venous invasion . The overall survival rate of hepatoma patients with high Q9UEF7 expression was significantly lower than those patients with low Q9UEF7 expression . Moreover , Q9UEF7 overexpression increased cellular migration , anchorage - independent growth , and anoikis resistance in hepatoma cells . Q9UEF7 overexpression elevated Q13153 ( PAK1 ) expression and shRNA - mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Q9UEF7 - overexpressed hepatoma cells . More importantly , the pivotal significance of upregulated P35968 protein levels mediated by Q9UEF7 expression was confirmed by P35968 inhibitor DB06626 and blocking antibody treatment in hepatoma cells . DB06626 treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Q9UEF7 - overexpressed hepatoma cells . Conversely , knockdown of Q9UEF7 reduced P35968 / PAK1 dependent anoikis resistance , which could be reversed by PAK1 T423E . These results revealed a novel oncogenic function of Q9UEF7 in promoting anoikis resistance via activating P35968 / PAK1 signaling , thus facilitating tumor migration and invasion during hepatoma progression , which could provide a putative molecular mechanism for tumor metastasis .",
"Feasibility of using molecular docking - based virtual screening for searching dual target kinase inhibitors . Multitarget agents have been extensively explored for solving limited efficacies , poor safety , and resistant profiles of an individual target . Theoretical approaches for searching and designing multitarget agents are critically useful . Here , the performance of molecular docking to search dual - target inhibitors for four kinase pairs ( P24941 - P49841 , P00533 - Src , Lck - Src , and Lck - P35968 ) was assessed . First , the representative structures for each kinase target were chosen by structural clustering of available crystal structures . Next , the performance of molecular docking to distinguish inhibitors from noninhibitors for each individual kinase target was evaluated . The results show that molecular docking - based virtual screening illustrates good capability to find known inhibitors for individual targets , but the prediction accuracy is structurally dependent . Finally , the performance of molecular docking to identify the dual - target kinase inhibitors for four kinase pairs was evaluated . The analyses show that molecular docking successfully filters out most noninhibitors and achieves promising performance for identifying dual - kinase inhibitors for P24941 - P49841 and Lck - P35968 . But a high false - positive rate leads to low enrichment of true dual - target inhibitors in the final list . This study suggests that molecular docking serves as a useful tool in searching inhibitors against dual or even multiple kinase targets , but integration with other virtual screening tools is necessary for achieving better predictions .",
"___MASK85___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"Imatinib inhibits P15692 - independent angiogenesis by targeting neuropilin 1 - dependent P00519 activation in endothelial cells . To enable new blood vessel growth , endothelial cells ( ECs ) express neuropilin 1 ( NRP1 ) , and NRP1 associates with the receptor tyrosine kinase P35968 after binding the vascular endothelial growth factor A ( P15692 ) to enhance arteriogenesis . We report that NRP1 contributes to angiogenesis through a novel mechanism . In human and mouse ECs , the integrin ligand fibronectin ( FN ) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin ( P49023 ) in a P15692 / P35968 - independent but NRP1 - dependent manner . NRP1 formed a complex with P00519 that was responsible for FN - dependent P49023 activation and actin remodeling . This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo . Accordingly , both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib , a small molecule inhibitor of P00519 which is widely used to prevent the proliferation of tumor cells that express P11274 - P00519 fusion proteins . The finding that NRP1 regulates angiogenesis in a P15692 - and P35968 - independent fashion via P00519 suggests that P00519 inhibition provides a novel opportunity for anti - angiogenic therapy to complement P15692 or P35968 blockade in eye disease or solid tumor growth .",
"Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor - 2 enzymatic activity , autophosphorylation , and inhibition by axitinib . The catalytic domains of protein kinases are commonly treated as independent modular units with distinct biological functions . Here , the interactions between the catalytic and juxtamembrane domains of P35968 are studied . Highly purified preparations of the receptor tyrosine kinase P35968 catalytic domain without ( P35968 - CD ) and with ( P35968 - CD / JM ) the juxtamembrane ( JM ) domain were characterized by kinetic , biophysical , and structural methods . Although the catalytic parameters for both constructs were similar , the autophosphorylation rate of P35968 - CD / JM was substantially faster than P35968 - CD . The first event in the autophosphorylation reaction was phosphorylation of JM residue Y801 followed by phosphorylation of activation loop residues in the CD . The rates of activation loop autophosphorylation for the two constructs were determined to be similar . The autophosphorylation rate of Y801 was invariant on enzyme concentration , which is consistent with an intramolecular reaction . In addition , the first biochemical characterization of the advanced clinical compound axitinib is reported . DB06626 was found to have 40 - fold enhanced biochemical potency toward P35968 - CD / JM ( K ( i ) = 28 pM ) compared to P35968 - CD , which correlates better with cellular potency . Calorimetric studies , including a novel ITC compound displacement method , confirmed the potency and provided insight into the thermodynamic origin of the potency differences . A structural model for the P35968 - CD / JM is proposed based on the experimental findings reported here and on the JM position in c - Kit , P36888 , and P09603 / cFMS . The described studies identify potential functions of the P35968 JM domain with implications to both receptor biology and inhibitor design .",
"Huge clusters of embryonic stem cells in human embryos : a morphologic study . BACKGROUND : Nothing is known about huge clusters ( HC ) of embryonic stem cells ( ESC ) in human fetal organs ( HFO ) . AIM : To know the status of HC - ESC in HFO . METHODS : Morphology and immunohistochemistry ( IHC ) in 32 HFO of 7 - 40 gestational weeks ( GW ) . RESULTS : HC - ESC were seen in many HFO including central nervous system , spinal cords , spine , soft tissue , bone , skin , thyroid , lung , liver , pancreas , gall bladder , extrahepatic bile duct , adrenal , kidney , bladder , foregut , midgut , hindgut , female and male genital organs , and neurons . HC - ESC ' s were composed of two populations depending on constituting cells . One were large cells with ample acidophilic cytoplasms with vesicular nuclei and nucleoli . The other were small cells with scant cytoplasm with hyperchromatic nuclei without nucleoli , resembling lymphocytes . The HC - ESC were frequently showed neuronal differentiation . HC - ESC were positive for P13591 , synaptophysin , P09104 , chromogranin , P16234 , AFP , ErbB2 , bcl - 2 , P10721 , MET . They were negative for P08575 , CD3 , P11836 , P15941 , P06731 , CA19 - 9 , cytokeratin ( CK ) 7 , CK8 , CK18 , CK19 , P15941 , Q02817 , P98088 , and Q6W4X9 . The mean Ki - 67 labeling index ( LI ) was 13 % ± 7 % . HC - ESC showed a little glycogen but lacked mucins . These HC - ESC were seen in 7 - 25 GW , and they were rarely seen in 26 - 40 GW . CONCLUSIONS : The morphology , IHC , and ontogeny of HC - ESC were described .",
"Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft . Neurofibromatosis type 1 ( P21359 ) patients are prone to the development of malignant tumors , the most common being Malignant Peripheral Nerve Sheath Tumor ( MPNST ) . P21359 - MPNST patients have an overall poor survival due to systemic metastasis . Currently , the management of MPNSTs includes surgery and radiation ; however , conventional chemotherapy is not very effective , underscoring the need for effective biologically - targeted therapies . Recently , the P21359 gene product , neurofibromin , was shown to negatively regulate the phosphoinositide - 3 - kinase ( PI3K ) / Protein Kinase - B ( Akt ) / mammalian Target Of ___MASK82___ ( P42345 ) pathway , with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of P42345 activity . We developed and characterized a human P21359 - MPNST explant grown subcutaneously in NOD - SCID mice , to evaluate the effect of the P42345 inhibitor rapamycin . We demonstrate that rapamycin significantly inhibited human P21359 - MPNST P42345 pathway activation and explant growth in vivo at doses as low as 1 . 0 mg / kg / day , without systemic toxicities . While rapamycin was effective at reducing P21359 - MPNST proliferation and angiogenesis , with decreased CyclinD1 and P15692 respectively , there was no increase in tumor apoptosis . ___MASK82___ effectively decreased activation of S6 downstream of P42345 , but there was accompanied increased Akt activation . This study demonstrates the therapeutic potential and limitations of rapamycin in P21359 - associated , and likely sporadic , MPNSTs .",
"___MASK55___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK30___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK82___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .",
"Transduction of P28906 + cells with lentiviral vectors enables the production of large quantities of transgene - expressing immature and mature dendritic cells . BACKGROUND : Genetically engineered dendritic cells ( DC ) presenting specific antigens to T cells may be of great interest for immunotherapy . For this reason , the production of transgene - expressing DC derived from P28906 + cells transduced either shortly after ex vivo purification or during their differentiation into DC were evaluated . METHODS : P28906 + cells were transduced with lentivectors encoding for GFP before or after 21 days of culture with P36888 - ligand , thrombopoietin and stem cell factor and induction into DC with GM - P04141 + P05112 ( G4 ) or G4 + P01375 ( GT4 ) . GFP and DC - specific marker expression was assessed by flow cytometry , and allostimulatory capacity was evaluated on GFP + and GFP - sorted cells . RESULTS : Immature ( G4 - induced ) DC obtained from amplified P28906 + cells were transducible by lentiviral vectors while mature ( GT4 - induced ) DC were rather refractory . Moreover , since differentiated DC did not proliferate , large quantities of vectors were required to generate transgene - expressing cells with this protocol . In contrast , greater numbers of both immature and mature GFP - expressing DC were obtained with P28906 + cells exposed to lentivector shortly after purification . By the time of DC induction , GFP + cells had increased by approximately 170 - fold . After DC induction with G4 , 32 % of CD1a + , HLA - DR + , or P25942 + cells expressed GFP . CD1a + P12830 + GFP + Langerhans - like DC were also obtained . Incubation with P01375 induced mature Q01151 + GFP + DC that displayed a higher allostimulatory capacity than cells induced with G4 alone . CONCLUSION : The transduction of a small number of P28906 + cells with minimal doses of lentivector may allow for the production of a large number of DC expressing selected antigens useful for immunotherapy .",
"ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .",
"Key predictive factors of axitinib ( AG - 013736 ) - induced proteinuria and efficacy : a phase II study in Japanese patients with cytokine - refractory metastatic renal cell Carcinoma . BACKGROUND : DB06626 ( AG - 013736 ) is an oral , selective and potent inhibitor of vascular endothelial growth factor receptors ( VEGFR ) - 1 , 2 and 3 . This phase II study investigated axitinib efficacy , safety and biomarkers in Japanese patients with cytokine - refractory metastatic renal cell carcinoma ( mRCC ) . PATIENTS AND METHODS : In an open - label , multicentre study , 64 patients received an axitinib starting dose of 5mg twice daily . RESULTS : Objective response rate ( ORR ) was 50 . 0 % and median progression - free survival ( PFS ) was 11 . 0 months per independent review committee . Common treatment - related adverse events were hypertension ( 84 % ; 70 % grade ≥ 3 ) , hand - foot syndrome ( 75 % ; 22 % grade ≥ 3 ) and diarrhoea ( 64 % ; 5 % grade ≥ 3 ) . Eighteen patients ( 28 % ) developed proteinuria ≥ 2g / 24h and required dose reduction or treatment interruption / discontinuation . Proteinuria was a major cause for treatment discontinuation . Baseline urine protein levels were associated with development of proteinuria ≥ 2g / 24h ( hazard ratio [ HR ]= 5 . 457 , P = 0 . 0035 in patients with baseline proteinuria ≥ 1 + versus < 1 + ) . Baseline urine protein levels correlated more strongly with axitinib - related proteinuria than other baseline renal function test values or blood pressure . Patients with greater decreases in soluble P35968 concentrations had significantly higher ORR and longer PFS than those with smaller decreases ( ORR : 64 . 5 % versus 37 . 5 % , P = 0 . 045 ; median PFS : 12 . 9 months versus 9 . 2 months , HR = 0 . 42 , P = 0 . 01 ) . CONCLUSIONS : DB06626 showed significant antitumour activity and was well tolerated in Japanese mRCC patients . Baseline proteinuria and soluble P35968 levels may be key indicators of axitinib - induced proteinuria and efficacy , respectively .",
"Combination of rapamycin and protein tyrosine kinase ( PTK ) inhibitors for the treatment of leukemias caused by oncogenic PTKs . Abnormal protein tyrosine kinases ( PTKs ) cause many human leukemias . For example , P11274 / P00519 causes chronic myelogenous leukemia ( CML ) , whereas P36888 mutations contribute to the pathogenesis of acute myelogenous leukemia . The P00519 inhibitor Imatinib ( Gleevec , STI571 ) has remarkable efficacy for treating chronic phase CML , and P36888 inhibitors ( e . g . , PKC412 ) show similar promise in preclinical studies . However , resistance to PTK inhibitors is a major emerging problem that may limit long - term therapeutic efficacy . Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders . Here , we report that the P42345 inhibitor rapamycin synergizes with Imatinib against P11274 / P00519 - transformed myeloid and lymphoid cells and increases survival in a murine CML model . ___MASK82___ / Imatinib combinations also inhibit Imatinib - resistant mutants of P11274 / P00519 , and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412 - sensitive or - resistant leukemogenic P36888 mutants . Biochemical analyses raise the possibility that inhibition of Q13541 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor / rapamycin combinations . Addition of a mitogen - activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy . Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and / or acute myelogenous leukemia caused by P36888 mutations . Similar strategies may be useful for treating solid tumors associated with mutant and / or overexpressed PTKs .",
"Ligand - specific dynamics of the progesterone receptor in living cells and during chromatin remodeling in vitro . P06401 ( PR ) , a member of the nuclear receptor superfamily , is a key regulator of several processes in reproductive function . We have studied the dynamics of the interaction of PR with a natural target promoter in living cells through the use of fluorescence recovery after photobleaching ( P42345 ) analysis and also have characterized the dynamics of the interaction of PR with the mouse mammary tumor virus ( MMTV ) promoter reconstituted into chromatin in vitro . In photobleaching experiments , PR in the presence of the agonist R5020 exhibits rapid exchange with the MMTV promoter in living cells . Two PR antagonists , ___MASK30___ and ZK98299 , have opposite effects on receptor dynamics in vivo . In the presence of ___MASK30___ , PR binds to the promoter and is exchanged more slowly than the agonist - activated receptor . In contrast , PR bound to ZK98299 is not localized to the promoter and exhibits higher mobility in the nucleoplasm than the agonist - bound receptor . Significantly , PR bound to R5020 or ___MASK30___ can recruit the SWI / SNF chromatin remodeling complex to the promoter , but PR activated with ZK98299 can not . Furthermore , we found ligand - specific active displacement of PR from the MMTV promoter during chromatin remodeling in vitro and conclude that the interaction of PR with chromatin is highly dynamic both in vivo and in vitro . We propose that factor displacement during chromatin remodeling is an important component of receptor mobility and that ligand - specific interactions with remodeling complexes can strongly influence receptor nuclear dynamics and rates of exchange with chromatin in living cells .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .",
"Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb . PURPOSE : We hypothesized that sustained delivery of vascular endothelial growth factor ( P15692 ) using a polymer [ 85 : 15 poly ( lactide - co - glycolide ) ( P00747 ) ] would enhance angiogenesis and improve perfusion of ischemic tissue . METHODS : C57BL / 6J mice ( n = 20 / group ) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation ( 0 - Implant ) , unloaded scaffold implantation ( Empty - P00747 ) , or implantation of scaffolds incorporating 3 microg of VEGF165 ( P00747 - P15692 ) . Endpoints included laser Doppler perfusion imaging ( LDPI , ischemic / nonischemic limb , % ) , local vessel counts , immunohistochemistry for CD31 , and alpha - smooth muscle actin . In vitro release kinetics of P15692 from P00747 was also measured . RESULTS : P00747 - P15692 resulted in improved lower extremity perfusion vs . controls as measured by LDPI % at 7 , 14 , 21 , and 28 days ( p < 0 . 05 ) . P00747 - P15692 was associated with significantly greater percentage of vessels staining for CD31 and alpha - smooth muscle actin compared to the Empty - P00747 or 0 - Implant ( p < 0 . 05 for both ) . CONCLUSIONS : The P00747 - P15692 scaffolds resulted in sustained P15692 delivery , improved tissue perfusion , greater capillary density , and more mature vasculature compared to the controls . The sustained - release P00747 polymer vehicle is a promising delivery system for therapeutic neovascularization applications .",
"Effect of axitinib ( AG - 013736 ) on fatigue , thyroid - stimulating hormone , and biomarkers : a phase I study in Japanese patients . DB06626 is an oral , potent , and selective inhibitor of vascular endothelial growth factor receptor ( VEGFR ) 1 , 2 , and 3 . This phase I study evaluated the safety , pharmacokinetics , pharmacodynamics , antitumor activity , and recommended starting dose of axitinib in patients with advanced solid tumors . Twelve patients received single - dose axitinib 5 mg and were monitored for > or = 48 h . Continuous 5 mg twice - daily dosing was then initiated . One patient had dose - limiting toxicity ( grade 3 proteinuria and fatigue ) . Common treatment - related adverse events were anorexia , fatigue , and diarrhea . Grade 3 treatment - related adverse events were fatigue and hypertension . Maximum axitinib plasma concentration occurred 1 - 4 h after steady - state dosing . Eleven patients experienced thyroid - stimulating hormone elevation ; time - course change and fatigue onset appeared to be related in some patients . Significant correlation was observed between thyroid - stimulating hormone change and area under the plasma concentration - time curve ( AUC ; r = 0 . 80 , P = 0 . 005 ) . DB06626 decreased plasma soluble vascular endothelial growth factor receptor 2 ( s - P35968 ) , with significant correlation between change in s - P35968 and AUC ( r = - 0 . 92 , P < 0 . 0001 ) . Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib . Tumor size decreased in nine patients . The time - course of thyroid - stimulating hormone change appeared correlated with fatigue . There were significant correlations between thyroid - stimulating hormone or s - P35968 and axitinib exposure . DB06626 5 mg twice - daily is the recommended starting dose for Japanese patients . This trial is registered with ClinicalTrials . gov , identifier NCT00447005 ."
] |
[
"___MASK100___",
"___MASK30___",
"___MASK32___",
"___MASK55___",
"___MASK68___",
"___MASK74___",
"___MASK82___",
"___MASK85___",
"___MASK93___"
] |
___MASK30___
|
MH_train_323
|
interacts_with DB01012?
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[
"___MASK33___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK33___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK33___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK33___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK33___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"Tp53 - associated growth arrest and DNA damage repair gene expression is attenuated in mammary epithelial cells of rats fed whey proteins . Dietary protection from mammary cancer is likely coordinated through multiple signaling pathways , based on the known heterogeneity of the disease and the distinct origins of mammary tumor cells . The present study examined the modulatory effects of dietary intake of whey protein hydrolysate ( WPH ) relative to casein ( CAS ) , on mammary epithelial cell resistance to endogenous DNA damage using Tp53 gene expression and signaling as a read - out , and on systemic proapoptotic and immune surveillance activity , in young adult female Sprague - Dawley rats . Rats were fed AIN - 93G diets made with CAS or WPH as the sole protein source beginning at gestation d 4 . At postnatal day ( P01160 ) 50 , mammary glands of rats fed WPH had lower levels of activated Tp53 and p38 mitogen - activated protein kinase proteins , and reduced transcript levels for Tp53 - associated DNA damage repair , growth arrest , and proapoptotic genes than those of CAS - fed rats . Serum from WPH - fed rats had greater apoptotic activity in MCF - 7 tumor cells than that from rats fed CAS . Serum levels of monocyte chemoattractant protein ( MCP ) - 1 were higher in WPH - than in CAS - fed rats . MCF - 7 cells treated with CAS serum + recombinant rat P13500 had apoptotic activity and Tp53 and P38936 gene expression levels comparable to those treated with WPH serum or recombinant P13500 . Results indicate that mammary glands of rats fed a WPH diet are more protected from endogenous DNA damage than are those of CAS - fed rats , and identify P13500 as a potential serum biomarker for the positive effects of healthy diets .",
"Attenuated translocation of group IVa phospholipase A2 and up - regulated annexin - 1 synthesis by glucocorticoid blocks beta 2 - integrin adhesion in neutrophils . We examined the effect of glucocorticoid stimulation in blocking beta 2 - integrin adhesion of polymorphonuclear leukocytes ( PMNs ) isolated from human subjects . Surface expression of CD11b and P27361 / 2 - mediated gIVaPLA2 phosphorylation , which are required for beta 2 - integrin adhesion , were not affected by treatment with < or = 10 (- 6 ) M fluticasone propionate ( FP ) for PMNs activated by either 10 (- 7 ) M LTB4 or 30 ng / ml P01375 and caused no significant blockade of beta 2 - integrin adhesion in vitro . Baseline expression of annexin - 1 ( P04083 ) synthesis was increased only after 10 (- 6 ) M FP for PMNs ; by contrast , comparable increase in P04083 expression was demonstrated in human eosinophils from the same subjects with 10 (- 8 ) M FP . Viability of PMNs was verified by propidium iodide and by the persistence of beta 2 - integrin adhesion in treated groups . Exogenous administration of P04083 mimetic peptide fragment blocked significantly and comparably the beta 2 - integrin adhesion in PMNs activated by LTB4 and P01375 and in eosinophils activated by P05113 . Translocation of gIVaPLA2 from the cytosol to the nucleus also was refractory for activated PMNs treated with > or = 10 (- 7 ) M FP ; by contrast , complete blockade of nuclear translocation of cytosolic gIVaPLA2 was effected by 10 (- 9 ) M FP in eosinophils . Our data indicate that the cell surface P04083 synthesis is capable of blocking beta 2 - integrin adhesion in both PMNs and eosinophils . However , in contrast to eosinophils , FP does not cause either substantial P04083 synthesis or nuclear transport of cytosolic gIVaPLA2 in PMNs and thus does not block beta2 - integrin adhesion , a necessary step for granulocyte cell migration in vivo .",
"Oxidative stress - induced p53 activity is enhanced by a redox - sensitive Q96A56 SUMOylation . Tumor Protein p53 - Induced Nuclear Protein 1 ( Q96A56 ) is a tumor suppressor that modulates the p53 response to stress . Q96A56 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes . Q96A56 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development . In this work , we report that redox - dependent induction of p53 transcriptional activity is enhanced by the oxidative stress - induced SUMOylation of Q96A56 at lysine 113 . This SUMOylation is mediated by Q9Y6X2 and O00257 , two SUMO ligases especially related to the p53 activation upon DNA damage . Importantly , this modification is reversed by three P63165 - specific proteases Q9P0U3 , 2 and 6 . Moreover , Q96A56 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions . Q96A56 mutation at lysine 113 prevents the pro - apoptotic , antiproliferative and antioxidant effects of Q96A56 by impairing the p53 response on its target genes P38936 , Bax and PUMA . We conclude that Q96A56 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress .",
"Prevention and treatment of pancreatic cancer by curcumin in combination with omega - 3 fatty acids . Pancreatic cancer BxPC - 3 cells were exposed to curcumin , docosahexaenoic acid ( DB01708 ) , or combinations of both and analyzed for proliferation and apoptosis . Pancreatic tumor xenografts were established by injecting BxPC - 3 cells into each flank of nude mice . After the tumors reached a size of approximately 190 - 200 mm ( 3 ) , animals were fed diets with or without 2 , 000 ppm curcumin in 18 % corn oil or 15 % fish oil + 3 % corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygeanse - 2 ( P35354 ) , 5 - lipoxinase ( 5 - P28300 ) , and P38936 . A synergistic effect was observed on induction of apoptosis ( approximately sixfold ) and inhibition of cell proliferation ( approximately 70 % ) when cells were treated with curcumin ( 5 microM ) together with the DB01708 ( 25 microM ) . Mice fed fish oil and curcumin showed a significantly reduced tumor volume , 25 % ( P < 0 . 04 ) and 43 % ( P < 0 . 005 ) , respectively , and importantly , a combination of curcumin and fish oil diet showed > 72 % ( P < 0 . 0001 ) tumor volume reduction . Expression and activity of P35228 , P35354 , and 5 - P28300 are downregulated , and P38936 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets . The preceding results evidence for the first time that curcumin combined with omega - 3 fatty acids provide synergistic pancreatic tumor inhibitory properties .",
"Rac1 controls Schwann cell myelination through DB02527 and P35240 / merlin . During peripheral nervous system development , Schwann cells ( SCs ) surrounding single large axons differentiate into myelinating SCs . Previous studies implicate RhoGTPases in SC myelination , but the mechanisms involved in RhoGTPase regulation of SC myelination are unknown . Here , we show that SC myelination is arrested in Rac1 conditional knock - out ( Rac1 - CKO ) mice . Rac1 knock - out abrogated phosphorylation of the effector P38936 - activated kinase and decreased P35240 / merlin phosphorylation . Mutation of P35240 / merlin rescued the myelin deficit in Rac1 - CKO mice in vivo and the shortened processes in cultured Rac1 - CKO SCs in vitro . Mechanistically , DB02527 levels and P12830 expression were decreased in the absence of Rac1 , and both were restored by mutation of P35240 / merlin . Reduced DB02527 is a cause of the myelin deficiency in Rac1 - CKO mice , because elevation of DB02527 by rolipram in Rac1 - CKO mice in vivo allowed myelin formation . Thus , P35240 / merlin and DB02527 function downstream of Rac1 signaling in SC myelination , and DB02527 levels control Rac1 - regulated SC myelination .",
"The human SWI / SNF complex associates with Q01196 to control transcription of hematopoietic target genes . The acute myeloid leukemia 1 ( Q01196 , Q01196 ) transcription factor is a key regulator of hematopoietic differentiation that forms multi - protein complexes with co - regulatory proteins . These complexes are assembled at target gene promoters in nuclear microenvironments to mediate phenotypic gene expression and chromatin - related epigenetic modifications . Here , immunofluorescence microscopy and biochemical assays are used to show that Q01196 associates with the human DB00171 - dependent SWI / SNF chromatin remodeling complex . The SWI / SNF subunits P51532 and Q12824 bind in vivo to Q01196 target gene promoters ( e . g . , P04141 , P08700 , P09603 - R , MIP , and P38936 ) . These interactions correlate with histone modifications characteristic of active chromatin , including acetylated H4 and dimethylated H3 lysine 4 . Downregulation of Q01196 by RNA interference diminishes the binding of P51532 and Q12824 at selected target genes . Taken together , our findings indicate that Q01196 interacts with the human SWI / SNF complex to control hematopoietic - specific gene expression .",
"Functional expression of the multimodal extracellular calcium - sensing receptor in pulmonary neuroendocrine cells . The Ca ( 2 +)- sensing receptor ( P41180 ) is the master regulator of whole - body extracellular free ionized [ Ca ( 2 +)] o . In addition to sensing [ Ca ( 2 +)] o , P41180 integrates inputs from a variety of different physiological stimuli . The P41180 is also expressed in many regions outside the [ Ca ( 2 +)] o homeostatic system , including the fetal lung where it plays a crucial role in lung development . Here , we show that neuroepithelial bodies ( NEBs ) of the postnatal mouse lung express a functional P41180 . NEBs are densely innervated groups of neuroendocrine epithelial cells in the lung representing complex sensory receptors in the airways and exhibiting stem cell characteristics . qRT - PCR performed on laser microdissected samples from Q99259 - GFP mouse lung cryosections revealed exclusive expression of the P41180 in the P20929 microenvironment . P41180 immunoreactivity was present at P20929 cells from postnatal day 14 onwards . Confocal imaging of lung slices revealed that P20929 cells responded to an increase of [ Ca ( 2 +)] o with a rise in intracellular Ca ( 2 +) ( [ Ca ( 2 +)] i ) ; an effect mimicked by several membrane - impermeant P41180 agonists ( e . g . the calcimimetic R - 568 ) and that was blocked by the calcilytic Calhex - 231 . Block of TRPC channels attenuated the P41180 - dependent increases in [ Ca ( 2 +)] i , suggesting that Ca ( 2 +) influx through TRPC channels contributes to the total [ Ca ( 2 +)] i signal evoked by the P41180 in NEBs . P41180 also regulated baseline [ Ca ( 2 +)] i in NEBs and , through paracrine signaling from Clara - like cells , coordinated intercellular communication in the P20929 microenvironment . These data suggest that the P20929 P41180 integrates multiple signals converging on this complex chemosensory unit , and is a key regulator of this intrapulmonary airway stem cell niche .",
"Clinical utilization of cinacalcet in hypercalcemic conditions . INTRODUCTION : DB01012 has recently been introduced as a treatment for secondary hyperparathyroidism in dialysis patients and for parathyroid carcinoma . However , there has been an increasing interest in finding out whether cinacalcet can be used as a treatment for other parathyroid hormone ( PTH ) - dependent hypercalcemic conditions also . AREAS COVERED : The article reports the most relevant recent contributions dealing with calcium sensing receptor ( P41180 ) physiology as well as cinacalcet pharmacokinetics and pharmacodynamics . It also looks at the different hypercalcemic conditions where the use of cinacalcet has been proposed . This article was researched using clinical trials , case reports and outstanding basic research published in the last 3 years ( MEDLINE database up to 31 November 2010 ) . It provides the reader with an insight into the many unaddressed issues regarding cinacalcet that need to be resolved before it can be used in newly proposed fields . EXPERT OPINION : Since cinacalcet may not only have an effect on parathyroid P41180 but also on P41180 expressed at bone and renal levels , it can currently only be considered a good alternative to parathyroidectomy in PTH - dependent hypercalcemic conditions when surgical intervention is burdened by a high failure rate or when it can be considered a risky procedure . At present , cinacalcet can not be considered the first choice treatment in asymptomatic primary hyperparathyroidism or in mild - to - moderate forms of familial hypocalciuric hypocalcemia .",
"The calcium - sensing receptor -- a driver of colon cell differentiation . Dietary Ca ( 2 +) reduces colon cell proliferation and carcinogenesis , but it becomes ineffective or even tumor - promoting during carcinogenesis . It appears that Ca ( 2 +) and the colon cell P41180 together brake the massive cell production in normal colon crypts . The rapid proliferation of the transit - amplifying ( TA ) progeny of the colon stem cells at the bases of the crypts is driven by the \" Wnt \" signaling mechanism that stimulates proliferogenic genes and prevents apoptogenesis . It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough external Ca ( 2 +) to stimulate the expression of CaSRs , the signals from which stimulate the expression of P12830 . At this point the P25054 ( adenomatous polyposis coli ) protein appears and some of it enters the nucleus . There it removes the apoptogenesis shield and stops the beta - cateninTcf - 4 complex from driving further TA cell proliferation by releasing beta - catenin from the nucleus , and delivering it to cytoplasmic APCaxinGSK - 3beta complexes for ultimate proteasomal destruction . Cytoplasmic beta - catenin is prevented from returning to the nucleus by destruction in APCaxinGSK - 3beta complexes or locked by the emerging P12830 into adherens junctions which link the cell to proliferatively shut - down functioning cells with P25054 - dependent cytoskeletons moving up and out of the crypt . A common first step in colon carcinogenesis is the loss of functional P25054 which results in the retention of proliferogenic nuclear beta - cateninTcf - 4 . This drives the eventual appearance of mutation accumulating , apoptosis - resistant clones the proliferation of which can not be inhibited by external Ca ( 2 +) because of P41180 - disabling gene mutations .",
"Cytological properties of stromal cells derived from giant cell tumor of bone ( GCTSC ) which can induce osteoclast formation of human blood monocytes without cell to cell contact . When human blood monocytes were cocultured with stromal cells derived from human giant cell tumor of bone ( GCTSC ) and a Millipore filter ( 0 . 4 microm ) was interposed between monocytes and GCTSC , multinucleated giant cell formation of monocytes was induced . The multinucleated giant cells have characters as osteoclast - like cells , indicating that a soluble osteoclast - inducing factor ( s ) is secreted from GCTSC expressing Q9Y6Q6 , O14788 / O14788 / O14788 and P78536 mRNA . Furthermore , O00300 / O00300 inhibited GCTSC - induced osteoclastogenesis , showing that the Q9Y6Q6 - O14788 system is involved in GCTSC - induced osteoclastogenesis and that soluble form of O14788 / O14788 induces osteoclasts from monocytes . GCTSC expressed the cytokine mRNAs such as P09603 , GM - P04141 , P08700 , P05112 , P05231 , and P01579 mRNAs . None of IL - 1ralpha , IL - 1alpha , IL - 1beta , P60568 , P05112 , P22301 , Q14116 , P01375 , G - P04141 and P01579 could be detected in all culture media . A significant amount of P05231 could be detected in the culture media of all GCTSC . P10145 was found in the culture media of two GCTSC and two osteosarcoma - derived cells . P09603 was detected in all culture media . GCTSC express P41180 , and stimulation of GCTSC with either extracellular Ca ( 2 +) or neomycin , agonist of P41180 , augmented the expression of O14788 . Some lines of GCTSC expressed alkaline phosphatase , osteocalcin and Cbfa1 , suggesting that GCTSC are intimately related to osteoblastic lineage .",
"[ Vascular Calcification - Pathological Mechanism and Clinical Application - . The effect of cinacalcet on vascular calcification ] . DB01012 acts on calcium receptors ( CaR ) expressed on chief cells of the parathyroid gland to inhibit the secretion of parathyroid hormone ( PTH ) . This drug inhibits PTH secretion without causing an elevation of serum calcium and phosphorus , unlike active vitamin D . Several experimental studies demonstrated an inhibitory effect of calcimimetics on the progression of vascular calcification in animals with chronic kidney disease ( CKD ) , in keeping with the expression of the calcium - sensing receptor ( P41180 ) in vascular tissue . The EVOLVE , evaluated in patients with CKD 5D the effects of the cinacalcet on the progression of vascular calcification and hard cardiovascular outcomes , respectively . The EVOLVE trials missed their respective primary end point by intent - to - treat analysis . However , recently , in order to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms , risk factors for these events , and the effects of cinacalcet , post hoc analysis using adjudicated data collected during the EVOLVE Trial were perfomed . In this trial , combining fatal and nonfatal cardiovascular events , randomization to cinacalcet reduced the rates of sudden death and heart failure . Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events , while the effect of cinacalcet on atherosclerotic events did not reach statistical significance .",
"Genetic aspects of pancreatitis . Acute pancreatitis and chronic pancreatitis are complex inflammatory disorders of the pancreas with unpredictable severity , complications , and clinical courses . Growing evidence for genetic risk and modifying factors , plus strong evidence that only a minority of patients with these disorders are heavy alcohol drinkers , has revolutionized our concept of these diseases . Once considered a self - inflicted injury , pancreatitis is now recognized as a complex inflammatory condition like inflammatory bowel disease . Genetic linkage and candidate gene studies have identified six pancreas - targeting factors that are associated with changes in susceptibility to acute and / or chronic pancreatitis , including cationic trypsinogen ( P07477 ) , anionic trypsinogen ( P07478 ) , serine protease inhibitor Kazal 1 ( P00995 ) , cystic fibrosis transmembrane conductance regulator ( P13569 ) , chymotrypsinogen C ( Q99895 ) and calcium - sensing receptor ( P41180 ) . Patients with mutations in these genes are at increased risk of pancreatitis caused by a variety of stresses including hyperlipidemia and hypercalcemia . Multiple studies are reporting new polymorphisms , as well as complex gene x gene and gene x environmental interactions .",
"DB01012 : pharmacological and clinical aspects . The calcium sensing receptor ( P41180 ) is expressed in cells secreting calcium - regulating hormones , in cells involved in calcium transport and in many other tissues , with an as yet not completely defined role . In parathyroid cells , the P41180 stimulation inhibits parathyroid hormone ( PTH ) secretion , synthesis and parathyroid cell proliferation . DB01012 belongs to calcimimetic type II compounds that can interact with P41180 , increasing its affinity for calcium . Clinical studies have proved cinacalcet to be effective in reducing calcium and PTH levels in primary hyperparathyroidism and in reducing PTH , calcium and phosphate in patients with secondary hyperparathyroidism owing to chronic renal failure , with a relatively safe profile , the only reported adverse events being hypocalcaemia and gastrointestinal symptoms . However , though calcimimetics do represent a real advancement in the field of the treatment of PTH secretion disturbances , there is a need for clinical trials , which should aim to demonstrate that a better control of biochemical parameters is also matched with better clinical outcomes .",
"Activation of P00533 promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT - like phenotype change and P14780 - mediated degradation of P12830 . P00533 is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas ( HNSCC ) . However , the mechanism by which P00533 may stimulate tumor cell invasion and metastasis still need to be elucidated . In this study , we showed that activation of P00533 by P01133 in HNSCC cell line SCC10A enhanced cell migration and invasion , and induced loss of epitheloid phenotype in parallel with downregulation of P12830 and upregulation of P19022 and vimentin , indicating that P00533 promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition ( EMT ) - like phenotype change . Interestingly , activation of P00533 by P01133 induced production of matrix metalloproteinase - 9 ( P14780 ) and soluble P12830 ( sE - cad ) , and knockdown of P14780 by siRNA inhibited sE - cad production induced by P01133 in SCC10A . Moreover , both P14780 knockdown and P12830 overexpression inhibited cell migration and invasion induced by P01133 in SCC10A . The results indicate that P00533 activation promoted cell migration and invasion through inducing P14780 - mediated degradation of P12830 into sE - cad . Pharmacologic inhibition of P00533 , MEK , and PI3K kinase activity in SCC10A reduced phosphorylated levels of P27361 / 2 and AKT , production of P14780 and sE - cad , cell migration and invasion , and expressional changes of EMT markers ( P12830 and P19022 ) induced by P01133 , indicating that P00533 activation promotes cell migration and invasion via P27361 / 2 and PI3K - regulated P14780 / P12830 signaling pathways . Taken together , the data suggest that P00533 activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT - like phenotype change and P14780 - mediated degradation of P12830 into sE - cad related to activation of P27361 / 2 and PI3K signaling pathways .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK35___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"DB01373 - sensing receptor in the T lymphocyte enhanced the apoptosis and cytokine secretion in sepsis . DB01373 - sensing receptor ( P41180 ) is a member of the G protein - coupled receptor superfamily that existed in lymphocytes and promoted cytokine secretion . Lymphocytes are also involved in sepsis . However , the role of P41180 in lymphocytes in sepsis is unclear . In this study , we want to examine whether the P41180 in lymphocytes in sepsis is involved in the cytokine secretions and apoptosis and make clear the relationship between NF - κB and MAPK signal transduction pathways . We investigated the issues mentioned earlier using Western blotting , ELISA , and Flow Cytometry . The sepsis was remodeled by cecal ligation and puncture ( CLP ) . We found that P41180 protein expression increased in the peripheral blood T lymphocytes in CLP rats . The calcimimetic R568 ( P0C0P6 R568 ) promoted , whereas the calcilytic P0C0P6 2143 attenuated , signaling pathways proteins P65 ( subunit of NF - κB ) , P27361 / 2 , and JNK ( one subgroup of MAPKs ) phosphorylation . However , P - O75791 and P - JAKs exhibit no significant changes . Furthermore , the production P01375 - α and P05112 was greater in CLP rats than in normal rats , and P0C0P6 R568 promoted secretion of these cytokines . Simultaneously , the apoptotic ratio of T cells in CLP increased , and P0C0P6 R 568 exacerbated the apoptosis degree . However , these effects could also be inhibited by U0126 or SP600125 ( MAPKs pathway inhibitor ) or Bay - 11 - 7082 or ( NF - κB pathway inhibitor ) . From these results , we can conclude that , in the sepsis , P41180 activation promoted T - cell apoptosis and the secretion of pro - inflammatory cytokine P01375 - α and anti - inflammatory cytokines P05112 probably through NF - κB and partial MAPK signal transduction pathways .",
"Mitochondrial fragmentation in cigarette smoke - induced bronchial epithelial cell senescence . Mitochondria are dynamic organelles that continuously change their shape through fission and fusion . Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species ( ROS ) production . Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease ( P48444 ) . Hence , we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract ( CSE ) - induced cellular senescence in human bronchial epithelial cells ( HBEC ) . Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy . Senescence - associated β - galactosidase staining and P38936 Western blotting of primary HBEC were performed to evaluate cellular senescence . Mitochondrial - specific superoxide production was measured by MitoSOX staining . Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins ( O60313 or Mitofusins ) by small - interfering RNA transfection . DB06151 and Mito - TEMPO were used as antioxidants . Mitochondria in bronchial epithelial cells were prone to be more fragmented in P48444 lung tissues . CSE induced mitochondrial fragmentation and mitochondrial ROS production , which were responsible for acceleration of cellular senescence in HBEC . Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells . HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants . CSE - induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production . Hence , disruption of mitochondrial dynamics may be a part of the pathogenic sequence of P48444 development .",
"Discovery of a calcimimetic with differential effects on parathyroid hormone and calcitonin secretion . Calcimimetics are positive allosteric modulators to the calcium - sensing receptor ( P41180 ) . Activation of the P41180 inhibits the secretion of parathyroid hormone ( PTH ) , stimulates the secretion of calcitonin , and decreases serum calcium ( Ca ( 2 +) ) . DB01012 , a second - generation calcimimetic , is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism . A calcimimetic that displays increased separation of PTH versus Ca ( 2 +) lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population . Toward this end , we developed a third - generation calcimimetic , determined the molecular pharmacological properties of it using an operation model of allosteric modulation / agonism , and measured the compound effects on PTH , serum ionized Ca ( 2 +) , and calcitonin levels in 5 / 6 nephrectomized rats . We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia . Furthermore , our third - generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3 -( 2 - chlorophenyl )- N - ( ( 1R ) - 1 -( 3 - methoxyphenyl ) ethyl ) - 1 - propanamine ( R - 568 ) , a first - generation calcimimetic . These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion .",
"Novel strategies in drug discovery of the calcium - sensing receptor based on biased signaling . A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention . Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone ( PTH ) , which causes renal osteodystrophy . PTH secretion from the parathyroid glands is controlled by the calcium - sensing receptor ( P41180 ) that senses extracellular calcium . High extracellular calcium activates the P41180 causing inhibition of PTH secretion through multiple signaling pathways . DB01012 is the first drug targeting the P41180 and can be used to effectively control and reduce PTH secretion in PTH - related diseases . DB01012 is a positive allosteric modulator of the P41180 and affects PTH secretion from parathyroid glands by shifting the calcium - PTH concentration - response curve to the left . One major disadvantage of cinacalcet is its hypocalcemic side effect , which may be caused by increased P41180 - mediated calcitonin secretion from the thyroid gland . However , multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways , and therefore it might be possible to develop a P41180 activating drug that selectively activates signaling pathways that inhibit PTH secretion while having no effect on signaling pathways involved in calcitonin secretion . Such a drug would have the same therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it not affecting calcitonin secretion . The present review will focus on recent advancements in understanding signaling and biased signaling of the P41180 , and how that may be utilized to discover new and smarter drugs targeting the P41180 .",
"Calcimimetics in the chronic kidney disease - mineral and bone disorder . Mineral and bone disorders ( MBD ) are both an early and very common complication of chronic kidney disease ( CKD ) . It is now accepted that they represent a significant risk factor , explaining the high cardiovascular morbidity and mortality in CKD patients . During the last decade , we have been witnessing many advances in the nomenclature , classification , pathophysiology , diagnosis , and treatment of CKD and some of its complications , such as CKD - MBD . The identification of the calcium - sensing receptor ( P41180 ) involvement in the pathogenesis of primary and secondary hyperparathyroidism ( SHPT ) and the availability of a new class of drugs called calcimimetics are two outstanding examples . DB01012 , the only available calcimimetic , has been shown to be a very effective therapeutic tool in CKD - MBD . Many clinical trials with cinacalcet in hemodialysis patients with SHPT have shown a reduction in parathyroid hormone , calcium ( Ca ) , phosphate ( P ) and Ca x P product levels , allowing far greater success in reaching therapeutic goals as recommended by international guidelines . Additionally , some studies have shown that the use of cinacalcet may improve other aspects of CKD - MBD , reducing the risk of vascular calcification and parathyroidectomy , among others . Prospective studies on dialysis patients , with hard endpoint data , are currently underway . This review summarizes the most significant aspects of calcimimimetics based on both experimental and clinical results , underlining their possibilities not only for the treatment of isolated SHPT but also for other CKD - MBD related conditions .",
"Comparative time - course study on pituitary and branchial response to salinity challenge in Mozambique tilapia ( Oreochromis mossambicus ) and Nile tilapia ( O . niloticus ) . The physiological response of Mozambique and Nile tilapia transferred from fresh to brackish ( 15 ppt ) water was compared during a one - week time course . Response in the pituitary was measured by the gene expression pattern of prolactin ( PRL I ) , growth hormone ( GH ) , and calcium - sensing receptor ( P41180 ) , while the response in the gills was measured by the gene expression pattern of the prolactin receptor ( PRL - R ) , Na (+)/ K (+)/ 2Cl (-) cotransporter ( NKCC ) and Na (+)/ Cl (-) cotransporter ( P55017 ) , and by activity and expression of Na (+)/ K (+)- ATPase ( P20366 ) . The time - course curves of plasma osmolality levels indicate a rapid elevation 24 h after transfer , which later decreased and maintained at stable level . PRL I expression decreased in both species , but with stronger response in the Nile tilapia , while no differences were found in the slightly elevated levels of GH mRNA . The branchial response demonstrated a faster up - regulation of P20366 and NKCC in the Mozambique tilapia , but similar levels after a week , while Nile tilapia had stronger and constant down - regulation of P55017 . The time - course response of the measured osmoregulatory parameters indicate that 24 h after transfer is a critical time point for brackish - water adaptation . The differences in responses to saltwater challenge between Mozambique and Nile tilapia shown in this study may be associated with the differences in saltwater tolerance between these two tilapiine species .",
"Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium - sensing receptor by positive and negative allosteric modulators . DB01012 is predominantly used to treat secondary hyperparathyroidism due to end - stage renal failure , but , more recently , its potential clinical efficacy in treating patients with loss - of - function mutations in the calcium - sensing receptor ( P41180 ) has been recognized . Many clinically relevant P41180 mutations are located in the heptahelical membrane spanning and extracellular loop regions of the receptor , where allosteric modulators are predicted to bind . The aim of the present study was to investigate the impact of such mutations on the pharmacoregulation of the P41180 by the positive and negative allosteric modulators , cinacalcet and P0C0P6 - 2143 , respectively . Both cinacalcet and P0C0P6 - 2143 effectively rescued mutants whose cell surface expression was substantially impaired , suggesting that both classes of drug can stabilize a receptor conformation that is trafficked more effectively to the cell surface . In addition , functional impairments in almost all mutant CaSRs were rescued by either cinacalcet or P0C0P6 - 2143 via restoration of intracellular signaling . There was a significantly greater ability of both compounds to modulate agonist - stimulated intracellular Ca ( 2 +) mobilization than P27361 / 2 phosphorylation , indicating that the allosteric modulators engender bias in agonist - stimulated P41180 signaling to different pathways . Three mutations ( G ( 670 ) R , P ( 748 ) R , and L ( 773 ) R ) altered the binding affinity of allosteric modulators to the P41180 , and 3 mutations ( V ( 817 ) I , L ( 773 ) R , and E ( 767 ) K ) altered the cooperativity between the allosteric modulator and Ca ( 2 +)( o ) . These findings have important implications for the treatment of diseases associated with P41180 mutations using allosteric P41180 modulators and for analyzing the effects of mutations on the function and pharmacoregulation of the P41180 .",
"Correlates of nurse practitioners ' diagnostic and intervention performance for domestic violence . The purposes of this research were to identify diagnosis and intervention performance accuracy , variables that influence this performance accuracy , and barriers that impede performance accuracy of adult nurse practitioners ( P01160 ) and family nurse practitioners ( FNP ) for domestic violence . Two measures were developed : the Nurse Practitioner Survey ( P0C0P6 ) and the Nurse Practitioner Performance Tool . A total of 118 ANPs and FNPs completed and returned mailed surveys . Of these , 22 individuals were interviewed by telephone regarding personal and professional experience with domestic violence and barriers in their clinical settings to addressing domestic violence .",
"Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Pharmacology of the calcium sensing receptor . DB01373 sensing receptor ( P41180 ) is a G - protein couple receptor which plays a key role in calcium homeostasis in vertebrates . Its extracellular domain is sensitive to divalent cations , aminoacids and polyamines . In parathyroid glands , P41180 activation causes parathyroid hormone ( PTH ) reduction and subsequently a decrease in blood calcium concentration . In PTH - dependent disorders , e . g . primary and secondary hyperparathyroidism ( Q9HD23 ) , the need for therapeutic options other than surgery led to the synthesis of various allosteric P41180 agonists ( calcimimetics ) , such as cinacalcet . DB01012 is the only calcimimetic approved for Q9HD23 secondary to chronic kidney disease ( CDK ) , parathyroid carcinoma , and , in some countries , primary Q9HD23 . Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary Q9HD23 , lowering the risk of bone fractures , surgery , and cardiovascular complications in the former patients . Long - term safety and pharmacoeconomics have to be fully tested yet . Few both in vitro and in vivo studies showed an association between Arg990Gly - P41180 polymorphism and cinacalcet sensitivity , though in patients with severe P41180 inactivating mutations the drug substantially retained its positive clinical effects . Recently , a new class of allosteric antagonists of P41180 , i . e . calcilytics , has been synthesized . Calcilytics are structurally similar to calcimimetics , but exert their effects acting on a different allosteric site . Infusion of calcilytics was followed by transient rise in PTH and calcium . One of these compounds , DB05255 , was able to increase femur BMD in post menopausal women , but with induction of mild hyperparathyroidism . In the future , calcilytics may contribute to the osteoporosis treatment choice .",
"[ DB01012 -- a new drug for the treatment of secondary hyperparathyroidism in patients with uraemia , parathyroid cancer or primary hyperparathyroidism ] . DB01012 is a new drug with antiparathyroid effects that belongs to the class of calcimimetics . It increases the sensitivity of the calcium - sensing receptor ( P41180 ) to calcium , thus inducing a decrease in plasma parathyroid ( PTH ) levels . In patients with uncontrolled secondary hyperparathyroidism due to uremia , cinacalcet has been shown to decrease the levels of PTH even in those optimally treated with calcium and 1 - ahydroxylated vitamin D . DB01012 decreases plasma calcium and plasma PTH levels in patients with primary hyperparathyroidism or parathyroid cancer .",
"Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .",
"Low calcium environment effects osteoprotegerin ligand / osteoclast differentiation factor . In coculture with osteoblastic cell line MC3T3 - E1 ( E1 ) and mouse bone marrow cells , we reported that numbers of osteoclasts rose significantly on exposure to a low - calcium environment . Here we examined how osteoblasts influence osteoclastogenesis under a low - calcium environment . Comparing low extracellular calcium with a regular calcium environment , osteoprotegerin ligand ( O14788 ) / osteoclast differentiation factor ( O14788 ) mRNA expression show more increase in the culture of low - calcium environment than in that of a regular calcium environment . DB01373 - sensing receptor ( P41180 ) , which was supposed as one of the mechanisms of recognizing extracellular calcium , existedon the surface of E1 cells . When E1 cells stimulated with agonists of P41180 , gadolinium , and neomycin , O14788 / O14788 mRNA expression decreased . Moreover , these agonists reduced osteoclast formation in coculture . Taken together , it is possible that osteoblasts may recognize extracellular calcium via P41180 and regulate osteoclastogenesis .",
"[ Medical treatment of primary hyperparathyroidism : role of calcimimetics ] . Primary hyperparathyroidism ( PHPT ) is a common endocrinological process , characterized by chronic elevation of serum concentrations of calcium and parathyroid hormone ( PTH ) . The only intervention able to cure the disease is parathyroidectomy . However , there are few valid medical alternatives for patients whose PHPT is unresolved by surgery , or in those with contraindications for surgery or who refuse the procedure . The discovery of calcium - sensing receptors ( CaSRs ) , which regulate PTH secretion according to extracellular calcium concentrations , has allowed specific anti - parathyroid drugs called calcimimetics to be designed . DB01012 is an allosteric modulator of P41180 that has demonstrated safety and efficacy in controlling serum calcium values and in reducing PTH levels in patients with PHPT . The exact role of calcimimetics in the overall management of PHPT is promising and should be considered in future clinical practice guidelines .",
"Transmitter neurochemistry of the efferent neuron system innervating the labyrinth . It is likely that several mechanisms contribute to the efferent control of cochlear and vestibular function . Different effects are probably mediated by different neuronal transmitters . In spite of a number of transmitter candidates , it is still widely assumed that the entire efferent system can be globally characterized as cholinergic . We attempted to label retrogradely identified efferent neurons in the brainstem with a monoclonal antibody against choline acetyltransferase ( P28329 ) , the acetylcholine ( ACh ) synthesizing enzyme . Only a portion of the vestibular efferents could thus be shown to be cholinergic in the rat . Medial cochlear efferents , terminating under outer hair cells , may also be cholinergic since they stain intensely for acetylcholine esterase ( P22303 ) after pre - treatment with the P22303 inhibitor diisopropylfluorophosphate ( ___MASK56___ ) . The lateral cochlear efferents terminating under inner hair cells , as well as more than half of the vestibular efferent neuron population , reacted negatively with either method designed to identify cholinergic neurons . Half of the lateral olivo - cochlear neuron population filled retrogradely with tritiated gamma - amino butyric acid [ ( 3H ] - GABA ) . These cells were similar in size and distribution to neurons staining for the GABA synthesizing enzyme glutamic acid decarboxylase ( Q99259 ) . Retrograde transport of [ 3H ] - aspartate from the inner ear to the brainstem was seen in half of the lateral olivocochlear population , as well as in part of the efferent vestibular population in group E and in the caudal pontine reticular nucleus ( P16435 ) . Since various peptides have also been located in efferent neurons , this system is chemically diversified . Several distinct mechanisms of efferent control with presumably differing functions must , therefore , exist .",
"Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism . Neonatal primary hyperparathyroidism ( NPHT ) is associated with an inactivating homozygous mutation of the calcium sensing receptor ( P41180 ) . The P41180 is expressed most abundantly in the parathyroid glands and the kidney and regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption . NPHT leads to life threatening hypercalcemia , nephrocalcinosis , bone demineralization , and neurologic disabilities . Surgery is the treatment of choice . While waiting for surgery , bisphosphonates offer a good alternative to deal with hypercalcemia . DB01012 is a class II calcimimetic that increases P41180 affinity for calcium , leading to parathormone suppression and increased calcium renal excretion . At present , there is little evidence as to whether cinacalcet could improve the function of mutant P41180 in NPHT . We report a case of NPHT , treated successfully with bisphosphonates and cinacalcet after surgery failure . To our knowledge , it is the first time cinacalcet has been used for NPHT .",
"Vitamin D increases plasma renin activity independently of plasma Ca2 + via hypovolemia and β - adrenergic activity . 1 , 25 - Dihydroxycholechalciferol ( calcitriol ) and 19 - nor - 1 , 25 - dihydroxyvitamin D2 ( paricalcitol ) are vitamin D receptor ( P11473 ) agonists . Previous data suggest P11473 agonists may actually increase renin - angiotensin activity , and this has always been assumed to be mediated by hypercalcemia . We hypothesized that calcitriol and paricalcitol would increase plasma renin activity ( P06703 ) independently of plasma Ca ( 2 +) via hypercalciuria - mediated polyuria , hypovolemia , and subsequent increased β - adrenergic sympathetic activity . We found that both calcitriol and paricalcitol increased P06703 threefold ( P < 0 . 01 ) . Calcitriol caused hypercalcemia , but paricalcitol did not . Both calcitriol and paricalcitol caused hypercalciuria ( 9 - and 7 - fold vs . control , P < 0 . 01 ) and polyuria ( increasing 2 . 6 - and 2 . 2 - fold vs . control , P < 0 . 01 ) . Paricalcitol increased renal calcium - sensing receptor ( P41180 ) expression , suggesting a potential cause of paricalcitol - mediated hypercalciuria and polyuria . Volume replacement completely normalized calcitriol - stimulated P06703 and lowered plasma epinephrine by 43 % ( P < 0 . 05 ) . β - Adrenergic blockade also normalized calcitriol - stimulated P06703 . P35354 inhibition had no effect on calcitriol - stimulated P06703 . Our data demonstrate that vitamin D increases P06703 independently of plasma Ca ( 2 +) via hypercalciuria , polyuria , hypovolemia , and increased β - adrenergic activity .",
"Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK92___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK92___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"Activation of Rac - 1 , Rac - 2 , and Cdc42 by hemopoietic growth factors or cross - linking of the B - lymphocyte receptor for antigen . P08700 ( P08700 ) - induced activation of endogenous Rac - 1 , Rac - 2 , and Cdc42 . Rac - 1 was also activated by colony - stimulating factor - 1 ( P09603 ) , Steel locus factor ( SLF ) , granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) , and P05113 or by cross - linking the B - lymphocyte receptor for antigen ( P11274 ) . The activation of Rac - 1 induced by cross - linking the P11274 or by P08700 stimulation was blocked only partially by Ly294002 , with about 25 % to 30 % of Rac - 1 activation still occurring in the absence of detectable increases in phosphatidyl - inositol - 3 kinase ( PI - 3K ) activity . Overexpression of constitutively active mutants of H - Ras , N - Ras , or M - Ras resulted in activation of coexpressed Rac - 1 through an Ly29402 - resistant , PI - 3K - independent mechanism . Overexpression of constitutively active mutants of P38936 Ras , or Rac - 1 , but not of PI - 3K , was sufficient for activation of p38 mitogen - activated protein kinase ( MAPK ) in cells of hemopoietic origin . Inhibition of increases in PI - 3K activity by Ly294002 had no effect on the P08700 - induced activation of p38 MAPK . In contrast , Ly294002 partially inhibited the activation of p38 MAPK induced by cross - linking of the P11274 , although some p38 MAPK activation occurred in the absence of increases in the activity of Rac - 1 or PI - 3K . The activation of Rac - 1 , Rac - 2 , and Cdc42 by P08700 and other hemopoietic growth factors is likely to be an important component of their actions in promoting growth , survival , and function .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Beta - arrestin - and G protein receptor kinase - mediated calcium - sensing receptor desensitization . Extracellular calcium rapidly controls PTH secretion through binding to the G protein - coupled calcium - sensing receptor ( P41180 ) expressed in parathyroid glands . Very little is known about the regulatory proteins involved in desensitization of P41180 . G protein receptor kinases ( GRK ) and beta - arrestins are important regulators of agonist - dependent desensitization of G protein - coupled receptors . In the present study , we investigated their role in mediating agonist - dependent desensitization of P41180 . In heterologous cell culture models , we found that the transfection of P32298 inhibits P41180 signaling by enhancing receptor phosphorylation and beta - arrestin translocation to the P41180 . In contrast , we found that overexpression of P25098 desensitizes P41180 by classical mechanisms as well as through phosphorylation - independent mechanisms involving disruption of Galphaq signaling . In addition , we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in beta - arrestin2 null mice , suggesting a functional role of beta - arrestin2 - dependent desensitization pathways in regulating P41180 function in vivo . We conclude that GRKs and beta - arrestins play key roles in regulating P41180 responsiveness in parathyroid glands .",
"Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .",
"DB01012 Treatment in an Adolescent With Concurrent 22q11 . 2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by P53680 Mutation . CONTEXT : The 22q11 . 2 deletion syndrome ( DS ) is a common multiple anomaly syndrome in which typical features include congenital heart defects , facial dysmorphism , and palatal anomalies . Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia , but hypercalcemia has not previously been reported in 22q11 . 2 DS . CASE DESCRIPTION : Our patient is a 16 - year - old adolescent male with dysmorphic facial features and delayed motor and speech development . At 2 years of age , 22q11 . 2 DS was confirmed by fluorescence in situ hybridization . In contrast to hypoparathyroidism that is usually seen in 22q11 . 2 DS , this patient had early childhood - onset hypercalcemia with inappropriately high PTH levels and hypocalciuria . Genomic DNA was obtained from the proband and screened for calcium - sensing receptor ( P41180 ) mutations with negative results . No parathyroid tissue could be localized by imaging or surgical exploration . As a result of symptomatic hypercalcemia , the patient was treated with a calcimimetic ( cinacalcet ) . During the treatment , plasma calcium normalized with mild symptoms of hypocalcemia . After discontinuation of cinacalcet , calcium returned to high pretreatment levels . Further DNA analysis of adaptor protein - 2 σ subunit ( P53680 ) showed a heterozygous missense mutation c . 44 G > T , resulting in a p . R15L substitution ; the mutation was absent in the healthy parents and two siblings . CONCLUSIONS : Hypercalcemia in our patient with 22q11 . 2 DS could be explained by the de novo mutation in P53680 . Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment .",
"Calcimimetic and calcilytic drugs for treating bone and mineral - related disorders . The calcium - sensing receptor ( P41180 ) plays a pivotal role in regulating systemic Ca ( 2 +) homeostasis and is a target for drugs designed to treat certain disorders of bone and mineral metabolism . Calcimimetics are agonists or positive allosteric modulators of the P41180 ; they inhibit parathyroid hormone ( PTH ) secretion and stimulate renal Ca ( 2 +) excretion . The first calcimimetic drug is cinacalcet , a positive allosteric modulator of the P41180 that is approved for treating secondary hyperparathyroidism ( Q9HD23 ) in patients on renal replacement therapy and for some forms of primary Q9HD23 characterized by clinically significant hypercalcemia . DB01012 is also being investigated as a therapy for other hypercalcemic conditions and certain hypophosphatemic disorders . Calcilytics are P41180 inhibitors that stimulate the secretion of PTH and decrease renal excretion of Ca ( 2 +) . Although calcilytics have failed thus far as anabolic therapies for osteoporosis , they are currently being evaluated as novel therapies for new indications involving hypocalcemia and / or hypercalciuria .",
"___MASK61___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK61___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) - mediated osteoclast differentiation from monocyte / macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate - resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264 . 7 cells suppressed O14788 - induced osteoclastogenesis by inhibiting the expression of c - Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia - associated transcription factor ( O75030 ) independent of sumoylation . Down - regulation of Q9Y6X2 markedly enhances O14788 - mediated osteoclastogenesis in RAW264 . 7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down - regulates O14788 expression induced by interleukin - 6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down - regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL - 6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts .",
"DB01012 HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD . BACKGROUND : Secondary hyperparathyroidism ( sHPT ) represents an adaptive response to progressively impaired control of calcium , phosphorus and vitamin D in chronic kidney disease ( CKD ) . It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone ( PTH ) . Parathyroid hyperplasia in uremic rats can be prevented by calcium - sensing receptor ( P41180 ) activation with the calcimimetic cinacalcet ( Sensipar ®/ Mimpara ® ) ; however , it is unknown , how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT . METHODS : We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT . RESULTS : Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia . In rats with established sHPT , cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia . The cinacalcet - mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin - dependent kinase inhibitor P38936 . Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium . CONCLUSIONS : The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating P41180 activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH .",
"Clinical utility of calcimimetics targeting the extracellular calcium - sensing receptor ( P41180 ) . Calcimimetics , which activate the extracellular calcium ( Ca ( o )( 2 +) ) - sensing receptor in the parathyroid and other tissues participating in Ca ( o )( 2 +) homeostasis , were the first described allosteric activators of a G - protein - coupled receptor . DB01012 , the only calcimimetic currently approved for human use , is used clinically for treating secondary hyperparathyroidism ( e . g . , overactivity of parathyroid glands ) in patients being dialyzed for chronic kidney disease . By sensitizing the parathyroids to Ca ( o )( 2 +) , cinacalcet lowers the circulating parathyroid hormone ( PTH ) level . It also reduces serum calcium and phosphate , changes increasing the percentage of patients achieving the guidelines recommended by the National Kidney Foundation ( NKF ) for these minerals . Studies are underway addressing whether better adherence to these guidelines in patients receiving cinacalcet reduces cardiovascular disease and related mortality , which are both common is the dialysis population . The second approved use of cinacalcet is for treating hypercalcemia in patients with inoperable parathyroid carcinoma . In this setting , it provides the first medical therapy chronically lowering serum calcium concentration in this condition , albeit not to normal in most patients . Its effect on the long - term prognosis of these patients , if any , is presently unclear . \" Off - label \" administration of cinacalcet [ i . e . , not yet approved by the US Food and Drug Administration ( FDA ) ] effectively lowers serum calcium and / or PTH in various other forms of hyperparathyroidism and increases serum phosphate in renal phosphate - wasting syndromes by reducing PTH - induced phosphaturia . In the future , the drug could conceivably be utilized to modulate the activity of the P41180 in other tissues ( i . e . , kidney , colon ) in therapeutically desirable ways .",
"The role of MAPK and Nrf2 pathways in ketanserin - elicited attenuation of cigarette smoke - induced P10145 production in human bronchial epithelial cells . Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease ( P48444 ) with chronic airway inflammation as a key feature . Blockade of serotonin receptor 2A ( 5 - HTR ( 2A ) ) with ketanserin has been found to improve lung function in P48444 patients . Furthermore , ketanserin has been shown to possess anti - inflammatory properties in vivo . In this study , we investigated the antioxidative and anti - inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke - induced interleukin ( IL ) - 8 release in vitro . Primary normal human bronchial epithelial cells and human bronchial epithelial cell line ( BEAS - 2B ) were treated with or without ketanserin prior to exposure to cigarette smoke medium ( CSM ) . Exposure to CSM caused elevation of both mRNA and release of P10145 with increased phosphorylation of p38 and extracellular signal - regulated kinases 1 and 2 ( P27361 / 2 ) . Consistently , CSM - induced P10145 release was blocked by SB203580 , U0126 , or Q02750 small interfering RNA ( siRNA ) but not SP600125 . On the other hand , CSM caused a dose - dependent decrease in the ratio of reduced glutathione to oxidized glutathione ( rGSH / GSSG ) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis . Knock down of Nrf2 by siRNA completely blocked CSM - induced P10145 release . Ketanserin suppressed CSM - induced P10145 release by inhibiting p38 , P27361 / 2 MAPK , and Nrf2 signaling pathways and partially inhibited CSM - induced reduction of rGSH / GSSG ratio . Our data demonstrated the novel antioxidative and anti - inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM - exposed human bronchial epithelial cells . This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke - related P48444 .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK47___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK47___ who were treated with a single dose of mifepristone .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK100___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .",
"Behind the curtain : cellular mechanisms for allosteric modulation of calcium - sensing receptors . DB01373 - sensing receptors ( P41180 ) are integral to regulation of systemic Ca ( 2 +) homeostasis . Altered expression levels or mutations in P41180 cause Ca ( 2 +) handling diseases . P41180 is regulated by both endogenous allosteric modulators and allosteric drugs , including the first Food and Drug Administration - approved allosteric agonist , DB01012 HCl ( Sensipar ® ) . Recent studies suggest that allosteric modulators not only alter function of plasma membrane - localized P41180 , but regulate P41180 stability at the endoplasmic reticulum . This brief review summarizes our current understanding of the role of membrane - permeant allosteric agonists in cotranslational stabilization of P41180 , and highlights additional , indirect , signalling - dependent role ( s ) for membrane - impermeant allosteric drugs . Overall , these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function , and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to P41180 abundance and signalling .",
"New insights into the role of calcium - sensing receptor activation . The discovery of the calcium - sensing receptor ( P41180 ) prompted the identification of substances that affect its function . DB01012 , for example , is a drug that allosterically modifies the receptor so as to increase its sensitivity to circulating calcium ( thus the name \" calcimimetic \" ) and in this way decreases parathyroid hormone secretion . Clinical use of cinacalcet is already approved for the treatment of primary and secondary hyperparathyroidism , but research is ongoing to identify further potential actions of this drug . The effects and functions of the P41180 have been evaluated in different systems and tissues , beyond parathyroid glands , such arterial walls . A complete understanding of the properties of calcimimetics are of obvious clinical interest , since therapeutic indications may be affected accordingly .",
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK70___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK1___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK61___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"DB01373 - sensing receptor activation in chronic kidney disease : effects beyond parathyroid hormone control . Secondary hyperparathyroidism ( SHPT ) is an important complication of advanced chronic kidney disease ( CKD ) . DB01012 , an allosteric modulator of the calcium - sensing receptor ( P41180 ) expressed in parathyroid glands , is the only calcimimetic approved to treat SHPT in patients on dialysis . By enhancing P41180 sensitivity for plasma extracellular calcium ( Ca ( 2 +) 0 ) , cinacalcet reduces serum parathyroid hormone , Ca ( 2 +) 0 , and serum inorganic phosphorous concentrations , allowing better control of SHPT and CKD - mineral and bone disorders . Of interest , the P41180 also is expressed in a variety of tissues where its activation regulates diverse cellular processes , including secretion , apoptosis , and proliferation . Thus , the existence of potential off - target effects of cinacalcet can not be neglected . This review summarizes our current knowledge concerning the potential role ( s ) of the P41180 expressed in various tissues in CKD - related disorders , independently of parathyroid hormone control .",
"Substance P induces rapid and transient membrane blebbing in U373MG cells in a P38936 - activated kinase - dependent manner . U373MG astrocytoma cells endogenously express the full - length neurokinin 1 receptor ( P25103 ) . Substance P ( SP ) , the natural ligand for P25103 , triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293 - P25103 cells . In both cell lines , the SP - induced morphological changes are Gq - independent , and they require the Rho , Rho - associated coiled - coil kinase ( ROCK ) signaling pathway . Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs . DB01394 , a tubulin polymerization inhibitor , blocked SP - induced blebbing in U373MG but not in HEK293 - P25103 cells . Although P38936 - activated kinase ( PAK ) is expressed in both cell lines , SP induced rapid phosphorylation of PAK in U373MG , but failed to phosphorylate PAK in HEK293 - P25103 cells . The cell - permeable Rho inhibitor P01024 transferase inhibited SP - induced PAK phosphorylation , but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation , suggesting that Rho activates PAK in a ROCK - independent manner . Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293 - P25103 cells .",
"Exposure to an organophosphate ( ___MASK56___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK56___ ( ___MASK56___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK56___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK56___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK56___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"DB01012 upregulates calcium - sensing receptors of parathyroid glands in hemodialysis patients . BACKGROUND : DB01012 hydrochloride ( cinacalcet ) , a calcimimetic , has been shown to upregulate calcium - sensing receptor ( P41180 ) expression in parathyroid glands of rats with chronic renal insufficiency . However , the effect of cinacalcet on the reduced P41180 expression in human parathyroid glands remains to be elucidated . METHODS : Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism ( SHPT ) treated with ( n = 10 ; cinacalcet group ) or without ( n = 8 ; conventional group ) cinacalcet were examined immunohistochemically with a specific antibody against P41180 . The expression level of P41180 was analyzed semiquantitatively . RESULTS : Compared with normal glands , the immunohistochemical expression of P41180 was decreased significantly in both the cinacalcet and conventional groups . In the cinacalcet group , the expression of P41180 was increased significantly compared with that in the conventional group ( 1 . 83 ± 0 . 14 vs . 0 . 87 ± 0 . 15 , p < 0 . 001 ) , even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups . The expression of P41180 was significantly decreased in the larger glands ( > 500 mg ) compared with that in the smaller glands ( < 500 mg ) in both groups ; furthermore , it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group . CONCLUSIONS : Our results indicate that cinacalcet upregulates the depressed expression of P41180 in hemodialysis patients with SHPT , and that insufficient expression of P41180 , especially in larger glands with advanced nodular hyperplasia , underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet .",
"DB01373 - sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl . DB01012 , a novel calcimimetic compound , is effective in reducing parathyroid hormone ( PTH ) levels in approximately 70 % of patients with secondary hyperparathyroidism . However , interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies . Our investigation examined the genetic polymorphisms of the calcium - sensing receptor ( P41180 ) gene as one possible cause of the different responses to cinacalcet . We report data on seven end - stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet . All patients had secondary hyperparathyroidism with baseline intact PTH ( iPTH ) levels greater than 600 pg / ml . Three patients were male and four female with a mean +/- SD age of 60 +/- 12 years . DNA was extracted from peripheral lymphocytes . An area in exon 7 of the P41180 gene was amplified by the polymerase chain reaction and sequenced . Mean +/- SD baseline iPTH was 1086 +/- 189 pg / ml . The five patients without Arg990Gly demonstrated a 29 . 7 +/- 4 . 0 % ( +/- SEM ) reduction in iPTH from individual baseline . One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles . The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients ( P = 0 . 003 ) with a 76 . 3 +/- 7 . 7 % reduction in iPTH from baseline . No polymorphisms were noted in codons 986 or 1011 . This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the P41180 may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location ."
] |
[
"___MASK100___",
"___MASK1___",
"___MASK33___",
"___MASK35___",
"___MASK47___",
"___MASK56___",
"___MASK61___",
"___MASK70___",
"___MASK92___"
] |
___MASK70___
|
MH_train_324
|
interacts_with DB00669?
|
[
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK75___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .",
"Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 / 1D receptor agonists , the triptans . P01258 gene - related peptide ( P80511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P80511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 and P28221 receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 receptors . Development of one or more such compound offers the exciting prospect of new non - vasoconstrictor treatments for migraine and cluster headache .",
"Inhibition of chondroitin - 4 - sulfate - specific adhesion of Plasmodium falciparum - infected erythrocytes by sulfated polysaccharides . Adhesion of Plasmodium falciparum - infected erythrocytes to placental chondroitin 4 - sulfate ( Q13216 ) has been linked to the severe disease outcome of pregnancy - associated malaria . Soluble polysaccharides that release mature - stage parasitized erythrocytes into the peripheral circulation may help elucidate these interactions and have the potential to aid in developing therapeutic strategies . We have screened a panel of 11 sulfated polysaccharides for their capacities to inhibit adhesion of infected erythrocytes to Q13216 expressed on CHO - P04264 cells and ex vivo human placental tissue . Two carrageenans and a cellulose sulfate ( CS10 ) were able to inhibit adhesion to Q13216 and to cause already bound infected erythrocytes to de - adhere in a dose - dependent manner . CS10 , like Q13216 and in contrast to all other compounds tested , remained bound to infected erythrocytes after washing and continued to inhibit binding . Both carrageenans and CS10 inhibited adhesion to placental tissue . Although highly sulfated dextran sulfate can inhibit Q13216 - mediated adhesion to CHO cells , this polysaccharide amplified adhesion to placental tissue severalfold , demonstrating the importance of evaluating inhibitory compounds in systems as close to in vivo as possible . Interestingly , and in contrast to all other compounds tested , which had a random distribution of sulfate groups , CS10 exhibited a clustered sulfate pattern along the polymer chain , similar to that of the undersulfated placental Q13216 preferred by placental - tissue - binding infected erythrocytes . Therefore , the specific anti - adhesive capacity observed here seems to depend not only on the degree of charge and sulfation but also on a particular pattern of sulfation .",
"The biology of serotonin receptors : focus on migraine pathophysiology and treatment . Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families ( 5 - HT1 - P34969 ) . With the exception of the 5 - Q9H205 which is a ligand - gated ion channel , all others are G - protein coupled receptors with each family sharing structural , pharmacological and transductional characteristics . 5 - HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission , and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache . In this respect , activation of vascular P41595 and / or P34969 receptors , possibly as a consequence of the sudden rise in 5 - HT levels reported at the onset of a migraine attack , would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents , hence initiating the manifestation of head pain . At this stage in the migraine process , activation of specific subtypes of 5 - HT1 receptors has proven clinically effective in relieving migraine pain . Neural P28221 and / or P30939 receptors localized pre - junctionally on trigeminovascular afferents appear to mediate the DB00669 - induced inhibition of the neurogenic inflammatory response , with possible additional sites of action for brain penetrant 5 - HT1 receptor agonists in inhibiting the transmission of pain centrally . In contrast , activation of vascular P28222 receptors would constrict meningeal vessels hence recovering their pre - migraine diameter . The recent availability of subtype selective P28221 and P30939 receptor agonists should allow a further test of the neural / vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile .",
"Glutamate release in human cerebral cortex and its modulation by 5 - hydroxytryptamine acting at h P28221 receptors . 1 . The release of glutamic acid and its modulation by 5 - hydroxytryptamine ( 5 - HT ) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours . 2 . The Ca2 +- dependent K + ( 15 mM ) - evoked overflow of glutamate was inhibited by 5 - HT in a concentration - dependent manner ( EC50 = 2 . 9 nM ; maximal effect approximately 50 % ) . The inhibition caused by 5 - HT was antagonized by the 5 - HT1 / 5 - HT2 receptor antagonist methiothepin . The P28222 / P28221 receptor agonist sumatriptan mimicked 5 - HT ( EC50 = 6 . 4 nM ; maximal effect approximately 50 % ) ; the effect of sumatriptan was also methiothepin - sensitive . Selective P08908 receptor antagonists could not prevent the inhibition of glutamate release by 5 - HT . 3 . The P28222 / P28221 receptor ligand GR 127935 and the P28335 / P28222 / P28221 receptor ligand metergoline were unable to prevent the 5 - HT effect ; instead they inhibited glutamate release , their effects being abolished by methiothepin . Some P08908 receptor antagonists also displayed intrinsic agonist activity . 4 . The effect of sumatriptan was prevented by ketanserin , a drug known to display much higher affinity for recombinant h P28221 than for h P28222 receptors . 5 . We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release - inhibiting presynaptic heteroreceptors that appear to belong to the h P28221 subtype .",
"[ ___MASK82___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK82___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"[ Treatments of migraine ] . During the 1980s , a new class of drugs for the acute treatment of migraine attacks was developed , the triptans . These agents are selective P28222 / 1D serotonin receptor agonists , and were developed in order to address the underlying biological mechanism of the migraine attack . French guidelines in migraine are available since 2002 . It is recommended to use a stratified treatment approach during the first consultation with the use of NSAID in first line acute treatment and DB00669 in second line . It is also recommended to use prophylactic treatment when the patient experience frequent and / or severe migraine attack with a bad quality of life and a real impairment .",
"The beta2 - adrenergic receptor specifically sequesters Gs but signals through both Gs and Gi / o in rat sympathetic neurons . Beta ( 2 )- adrenergic receptors ( beta ( 2 )- AR ) and P21554 cannabinoid receptors share the property of being constitutively active . The P21554 cannabinoid receptor can also sequester G ( i / o ) proteins ; however , it is not known whether the beta ( 2 )- AR can also sequester G proteins . Beta ( 2 )- ARs were heterologously expressed in rat superior cervical ganglion neurons by microinjection of cDNA and studied using the patch - clamp technique . The beta - AR agonist isoproterenol increased the Ca ( 2 +) current 25 . 9 +/- 1 . 6 % in neurons microinjected with 100 ng / microl beta ( 2 )- AR cDNA but was without effect on control neurons . Pretreatment with cholera toxin ( CTX ) abolished the effect of isoproterenol , indicating coupling via G ( s ) proteins . In neurons microinjected with 200 ng / microl beta ( 2 )- AR cDNA , isoproterenol had the opposite effect of inhibiting the Ca ( 2 +) current 36 . 5 +/- 2 . 0 % . Inhibition of the Ca ( 2 +) current was sensitive to pertussis toxin , indicating beta ( 2 )- AR coupling to G ( i / o ) proteins . Pretreatment with CTX resulted in a greater 54 +/- 3 . 8 % inhibition of the Ca ( 2 +) current , indicating that G ( s ) coupling masks the full effect of G ( i / o ) coupling . Expression of beta ( 2 )- ARs abolished signaling by G ( s )- coupled receptors for vasoactive intestinal polypeptide ( P01282 ) . P01282 inhibited the Ca ( 2 +) current 49 . 5 +/- 0 . 5 % in control neurons but had no effect in neurons expressing beta ( 2 )- ARs . In contrast , expression of beta ( 2 )- ARs had no effect on signaling by the G ( i / o )- coupled alpha ( 2 )- adrenergic receptor . This study demonstrates that the beta ( 2 )- AR couples to both G ( s ) and G ( i / o ) proteins but specifically sequesters G ( s ) proteins , preventing their interaction with another G ( s )- coupled receptor . beta ( 2 )- adrenergic receptors thus have the potential to prevent other G ( s )- coupled receptors from transducing their biological signals .",
"[ Triptans -- pivotal event in migraine treatment ] . Introducing serotonin P28222 / 1D agonists in the migraine treatment in the early 1990s had for the first time set guidelines for targeting a hypothetic physiologic source of the sequence of events in migraine , and results thus achieved were considerably better than those accomplished with earlier nonselective pharmacological approach . Triptans have revolutionized migraine management and inspired many epidemiological and public health surveys , strengthened efforts in understanding pathophysiology of migraine and initiated synthesis of many similar drugs in the DB00669 group , the first being sumatriptan . Triptans have risen to a therapeutic challenge posed by migraine , successfully thwarting the cycle of pain . In treating migraine sufferers , physicians can choose among seven triptans with different attributes . Each patient merits individualized approach in the treatment of migraine with triptans . Choosing the right DB00669 for a given patient is a matter of first matching the appropriate formulation to the patient , then deciding which agent will best meet the patient ' s needs . This process requires thorough understanding of the patient , careful and accurate assessment of the efficacy of previous medications used in acute care , and analysis of the individual features of the triptans being considered .",
"A review of rizatriptan , a quick and consistent P28222 / 1D agonist for the acute treatment of migraine . Rizatriptan is a second - generation DB00669 marketed as 5 and 10 mg tablets and rapidly disintegrating wafer formulations . In > 5000 acute migraine patients enrolled in short - term trials and almost 1800 patients in long - term , open - label trials treating approximately 47000 attacks , rizatriptan was effective and well - tolerated . Controlled head - to - head data and a meta - analysis of 53 randomised , placebo - controlled trials of oral triptans in > 24000 patients have shown that rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg and other oral triptans , both in terms of speed of onset of action and consistency . These advantages may reflect its improved pharmacological profile over sumatriptan in terms of higher oral bioavailability and a shorter time to maximum concentration . The wafer formulation offers the convenience of being administered without water . As a result of its superior efficacy profile and generally good tolerability , rizatriptan can be considered as a first - line treatment for acute migraine .",
"Identification of cellular pathways of \" type 1 , \" Th17 T cells , and P01375 - and inducible nitric oxide synthase - producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis . Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases . DB00091 A ( Q13216 ) is considered a \" gold standard \" therapy for moderate - to - severe psoriasis . We conducted a clinical trial with Q13216 and analyzed the treatment outcome in blood and skin of 11 responding patients . In the skin , as expected , Q13216 modulated genes from activated T cells and the \" type 1 \" pathway ( p40 , P01579 , and P35610 - 1 - regulated genes ) . However , Q13216 also modulated genes from the newly described Th17 pathway ( Q16552 , Q9GZX6 , and downstream genes P80511 , DEFB - 2 , IL - 1beta , SEPRINB3 , P80188 , and P78556 ) . Q13216 also affected dendritic cells , reducing P01375 and inducible NO synthase ( products of inflammatory P01375 - and inducible NO synthase - producing dendritic cells ) , Q01151 , and Q9NPF7 . We detected 220 early response genes ( day 14 posttreatment ) that were down - regulated by Q13216 . We classified > 95 % into proinflammatory or skin resident cells . More myeloid - derived than activated T cell genes were modulated by Q13216 ( 54 myeloid genes compared with 11 lymphocyte genes ) , supporting the hypothesis that myeloid derived genes contribute to pathogenic inflammation in psoriasis . In circulating mononuclear leukocytes , in stark contrast , no inflammatory gene activity was detected . Thus , we have constructed a genomic signature of successful treatment of psoriasis which may serve as a reference to guide development of other new therapies . In addition , these data also identify new gene targets for therapeutic modulation and may be applied to wide range of autoimmune diseases .",
"Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .",
"In vivo effects of a combined P28222 receptor / P31645 antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co - operation between the serotonin ( 5 - hydroxytryptamine , 5 - HT ) transporter and P28222 receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 receptor / serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over - expressing serotonin transporter ( P31645 + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin - induced vasoconstriction and P28222 receptor / serotonin transporter interactions in mouse isolated pulmonary artery . ___MASK27___ had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin - induced proliferation in IPAH hPASMCs . There is synergy between P28222 receptor and serotonin transporter inhibitors against serotonin - induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin - induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 receptor may be a novel therapeutic approach to PAH .",
"___MASK75___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK75___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .",
"Antidepressant effects on serotonin 1A / 1B receptors in the rat brain using a gene x environment model . A gene - environment ( GxE ) interaction is implicated in both the pathophysiology and treatment of major depressive disorder ( MDD ) . This study modeled the effects of genetic vulnerability by using the Flinders sensitive line ( FSL ) , a rat model of depression and its control counterpart - the Flinders resistant line ( FRL ) . The effects of environmental vulnerability ( e . g . , early - life stress ) were modeled by using maternal separation . Rats ( n = 105 ) were drawn from four groups reflecting experimental crossing of strain ( FSL vs . FRL ) and early - life stress ( high vs . low ) to assess the effects of two antidepressants ( escitalopram or nortriptyline ) compared to vehicle . Quantitative in vitro autoradiography was performed using [( 125 ) I ] MPPI ( P08908 ) and [( 125 ) I ] CYP ( P28222 ) in prefrontal cortex ( P27918 ) and hippocampus . Stringent , Bonferroni - corrected statistical analyses showed significant strain - by - rearing - by - treatment ( three - way ) interactions in P27918 P08908 and hippocampal P28222 receptors . Either vulnerability reduced serotonergic binding ; no additive effects were associated with the two vulnerabilities . Both antidepressants increased hippocampal P28222 receptor binding ; however , only nortriptyline selectively increased P27918 P08908 receptor binding . Taken together , our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a GxE interaction that depends on antidepressant class and brain region .",
"Identification of mRNA for 5 - HT1 and 5 - HT2 receptor subtypes in human coronary arteries . OBJECTIVE : Although pharmacological studies have indicated that serotonin ( 5 - HT ) - evoked contraction of the human coronary artery is mediated by 5 - HT1 - like and 5 - HT2 receptors , the gene expression of 5 - HT receptors is still unclear . We examined mRNA expression of 5 - HT1 and 5 - HT2 receptor subtypes in human coronary arteries . METHODS : Total RNA was extracted from human coronary arteries of 14 patients at autopsy by the guanidine method . Reverse transcription - polymerase chain reaction ( RT - PCR ) and ribonuclease protection assays were performed to identify 5 - HT1 and 5 - HT2 receptor mRNA expression in human coronary artery . RESULTS : By RT - PCR , 5 - HT1b , 5 - Q13049 and P41595 mRNAs were detected in all of the 14 patients . P08908 , P28221 , and P28566 mRNAs were detected in only some patients . However , neither P30939 mRNA nor P28335 mRNA was detected in any patient . By ribonuclease protection assay , P28222 and 5 - Q13049 signals were detected in all patients examined , but neither P08908 , P28221 nor P41595 signal was detected in any patient . CONCLUSIONS : Of 5 - HT1 / 2 receptor subtypes , P28222 and 5 - Q13049 receptor mRNAs were predominantly expressed in human coronary arteries . Our finding provides molecular evidence that the P28222 receptor may be the 5 - HT1 - like receptor which mediates constriction of human coronary arteries .",
"Sumatriptan ( P28221 receptor agonist ) does not exacerbate symptoms in obsessive compulsive disorder . The non - selective serotonin ( 5 - HT ) receptor agonist meta - chlorophenylpiperazine ( mCPP ) has been reported to elicit symptoms in patients with obsessive compulsive disorder ( OCD ) . MK - 212 , another non - selective 5 - HT receptor agonist , does not seem to induce obsessive compulsive symptoms in OCD patients . The major pharmacological difference between mCPP and MK - 212 is their affinity for the 5 - HT ( ID ) receptor . The aim of this study was to explore the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD , by using a challenge paradigm with the selective 5 - HT ( ID ) receptor agonist sumatriptan ( DB00669 ) . A randomized , double - blind , placebo - controlled crossover challenge with sumatriptan ( 100 mg PO ) was performed in 15 OCD patients . Neither the obsessive compulsive symptoms nor mood or anxiety symptoms changed significantly following sumatriptan administration as compared to placebo . Sumatriptan did induce a significant increase in plasma growth hormone ( GH ) levels . In the present study , no indication were found for the role of the 5 - HT ( ID ) receptor in the pathophysiology of OCD . It should be noted , however , that sumatriptan does not readily pass the blood - brain barrier . Selective 5 - HT ( ID ) receptors with better brain penetrating properties may shed more light on the role of this 5 - HT receptor subtype in OCD .",
"[ Rizatriptan : experience after 15 years of clinical use ] . We review the development of rizatriptan , one of the seven P28222 / 1D agonists available for the symptomatic treatment of migraine , emphasizing the most relevant contributions carried out from our country . Rizatriptan has shown the quickest onset of action , both in controlled studies and in the different metaanalyses , which translates in high efficacy levels at two hours . Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group . Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this DB00669 . Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents . This global profile places rizatriptan as a DB00669 of first choice for any kind of migraine attacks .",
"Colocalization of P80511 with P28222 / 1D receptors and DB05875 in trigeminal ganglion neurons in rats . Vasodilatation in the dura mater has been implicated in migraine pathogenesis . Anti - migraine DB00669 drugs block vasodilatation by binding to P28222 / 1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles . Previous studies suggest that calcitonin gene - related peptide ( P80511 ) released from Adelta - fibres plays a more important role than DB05875 ( SP ) released from C - fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of DB00669 drugs is inhibiting P80511 release . In the present study , the relationship between P80511 and P28222 / 1D receptors , and between P80511 and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining . P80511 , P28222 , P28221 and SP - positive trigeminal ganglion neurons were all predominantly small and medium - sized . In the trigeminal ganglia , approximately 50 % of P80511 - positive neurons were P28222 positive . Similarly , approximately 55 % of P80511 - positive neurons were P28221 immunoreactive . Approximately 50 % of P80511 - positive neurons were SP - positive , while 93 % of SP - positive neurons were P80511 - positive , suggesting that nearly all SP - positive neurons also contain P80511 . The fibre types of the P28222 - and P28221 - positive neurons were further investigated with an antibody against the A - fibre marker 200 - kDa neurofilaments ( NF200 ) . Approximately 46 % of the P28222 - positive and 43 % of the P28221 - positive trigeminal ganglion neurons were also NF200 positive , indicating that many A - fibre trigeminal neurons express P28222 or P28221 receptors . These results support the hypothesis that one important action of antimigraine drugs is the inhibition of P80511 release and that Adelta - fibres may play an important role in migraine pathogenesis .",
"___MASK10___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK10___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .",
"Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via P21554 and \" DB00669 \" receptors : implications in migraine . Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine . Endocannabinoids , as well as being physiologically analgesic , are known to inhibit dural trigeminovascular nociceptive responses . They are also involved in the descending modulation of cutaneous - evoked C - fiber spinal nociceptive responses from the brainstem . The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and / or cutaneous facial trigeminovascular nociceptive responses , from the brainstem ventrolateral periaqueductal gray ( vlPAG ) . P21554 receptor activation in the vlPAG attenuated dural - evoked Aδ - fiber neurons ( maximally by 19 % ) and basal spontaneous activity ( maximally by 33 % ) in the rat trigeminocervical complex , but there was no effect on cutaneous facial receptive field responses . This inhibitory vlPAG - mediated modulation was inhibited by specific P21554 receptor antagonism , given via the vlPAG , and with a P28222 / 1D receptor antagonist , given either locally in the vlPAG or systemically . These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ - fiber dural - nociceptive responses , which differs from the way the brainstem modulates spinal nociceptive transmission . Furthermore , our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information , suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG .",
"The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and P28222 receptors . Age - related changes in circadian rhythms , including attenuation of photic phase shifts , are associated with changes in the central pacemaker in the suprachiasmatic nucleus ( SCN ) . Aging decreases expression of mRNA for vasoactive intestinal peptide ( P01282 ) , a key neuropeptide for rhythm generation and photic phase shifts , and increases expression of serotonin transporters and 5 - HT ( 1B ) receptors , whose activation inhibits these phase shifts . Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin - releasing peptide , which also modulates photic phase resetting . Because serotonin innervation trophically supports SCN P01282 mRNA expression , and serotonin transporters decrease extracellular serotonin , we predicted that chronic administration of the serotonin - selective reuptake inhibitor , fluoxetine , would attenuate the age - related changes in SCN P01282 mRNA expression and 5 - HT ( 1B ) receptors . In situ hybridization studies showed that fluoxetine treatment does not alter SCN P01282 mRNA expression , in either age group , at zeitgeber time ( ZT ) 6 or 13 ( ZT12 corresponds to lights off ) . However , receptor autoradiographic studies showed that fluoxetine prevents the age - related increase in SCN 5 - HT ( 1B ) receptors at ZT6 , and decreases SCN 5 - HT ( 1B ) receptors in both ages at ZT13 . Therefore , aging effects on SCN P01282 mRNA and SCN 5 - HT ( 1B ) receptors are differentially regulated ; the age - related increase in serotonin transporter sites mediates the latter but not the former . The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm , in contrast to previous reports of phase resetting by acute fluoxetine treatment .",
"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .",
"Intramuscular gene transfer of P80511 inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta . P80511 is a well - known neuropeptide that has various protective effects on cardiovascular system . Our previous studies have shown that P80511 inhibits vascular smooth muscle cell ( VSMC ) proliferation in vitro . The present study aimed to explore the role of the P80511 in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism . Gene transfer of P80511 was performed with the use of intramuscular electroporation in a balloon - injured rat aorta model . Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase - mediated dUTP nick - end labeling assay . Overexpression of the P80511 gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer , as assessed by the intima - to - media ratio 14 days after balloon injury ( 29 . 2 +/- 3 . 7 % vs . 52 . 7 +/- 5 . 4 % ; n = 9 - 12 , P < 0 . 05 ) . In addition , P80511 gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury . Similarly , the addition of bioactive P80511 and the nitric oxide donor induced similar apoptosis in cultured VSMCs . The antagonist of the P80511 ( 1 ) receptor and inhibitors of DB02527 - PKA and nitric oxide blocked P80511 - mediated apoptosis . Furthermore , P80511 gene transfer increased inducible nitric oxide synthase and p53 but decreased P12004 and Bcl - 2 protein levels in balloon - injured rat aorta . Our data demonstrated that P80511 potently inhibited neointimal thickening in the rat aorta , at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro . Therefore , delivery of the P80511 gene may have therapeutic implications in limiting vascular restenosis .",
"Triptan use preceding life - threatening arrhythmias in charcot - marie - tooth : a case report and review of the literature . Charcot - Marie - Tooth ( CMT ) identifies a rare group of inherited disorders of the peripheral nervous system that share clinical features of sensory and motor defects , but rarely affect cardiac function . The few references that relate CMT to cardiac pathology of any sort are so rare that their finding was considered either fortuitous or suggestive of an erroneous diagnosis . The P28222 / 1D agonists or DB00669 drug class was introduced to the clinical practice arena in the early 1990s , and since then several cardiac adverse events have been associated with its use . The authors report the case of a 41 - year - old white woman with CMT who had been recently prescribed sumatriptan and who presented with sudden loss of consciousness associated with ventricular fibrillation . These findings have been reported in the literature , but the association of DB00669 - induced arrhythmias and degenerative neuropathies remains to be established . The authors propose , through this case report and review , that the relative rarity of CMT coupled with the lack of further investigation of their association with conduction abnormalities might have set the stage for underestimation of the potentially synergistic effect with triptans in their capacity to generate life - threatening arrhythmias .",
"___MASK100___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .",
"Is myofascial pain of the temporal muscles relieved by oral sumatriptan ? A cross - over pilot study . There is evidence that serotonin may be implicated in the pathophysiology of myofascial pain ( MFP ) . Because of this , we used oral sumatriptan ( DB00669 , Glaxo ) , a peripherally acting agonist of P28221 receptors , in a double - blind , randomized , placebo - controlled double crossover pilot study of 7 patients with episodic MFP of the temporalis muscles . The results showed that there was a significant reduction in pain intensity and increase in pain relief over time with both the active medication and the placebo , but no significant difference between treatments . All but 1 patient reported that they are not interested in retaking the same medication . These data suggest that oral sumatriptan may not be the drug of choice in the control of episodic MFP .",
"Individual DB00669 selection in migraine attack therapy . About 6 % of men and 18 % of women suffer migraine attacks . Migraine can induce a great impact in the quality of life of the patient and the costs of medical care and lost productivity can be also high . There are two therapeutic approaches in the treatment of migraine : preventive therapy and acute treatment of migraine attack . Immediate treatment with selective serotonin [ P28222 / 1T ] receptor agonists ( so - called triptans ) is the first - line option in the acute treatment of moderate - severe migraine attacks . The introduction in early nineties of triptans was a revolution in migraine therapy and evidences about their efficacy are at present irrefutable . At the moment , there are seven marketed molecules : sumatriptan , rizatriptan , zolmitriptan , eletriptan , naratriptan , almotriptan and frovatriptan . Obviously , every molecule has different pharmacokinetic and pharmacodinamic properties and , moreover , some triptans have several formulations : tablets , dissolvable tablets , nasal and injections . The prescription of one of these seven triptans for a specified patient is based in the drug profile : efficacy , safety , pharmacokinetics and pharmacodynamics . Despite there are a lot of published studies using triptans , no clinical trial has analyzed all the molecules at the same time . Other data to take account in the final prescription are clinical characteristics of the migraine attack and patient characteristics : labour aspects , style of life and the patient medical history . We present a state - of - the - art of the DB00669 selection in treatment of moderate - severe migraine attacks .",
"The pharmacological profile and clinical prospects of the oral P30939 receptor agonist lasmiditan in the acute treatment of migraine . More than 20 years have passed without the launch of a new substance class for acute migraine therapy . Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile . New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who can not tolerate triptans for attack treatment . Lasmiditan is a novel highly specific P30939 receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay . In both phase II randomized , placebo - controlled trials in acute migraine the primary endpoint was met . For the intravenous formulation a clear dose - dependent effect on headaches could be determined . Lasmiditan tablets in doses of 50 - 400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms . This substance is chemically clearly different from other antimigraine drugs , which is also reflected by its dose - dependent adverse event profile chiefly including dizziness , vertigo , paresthesia and fatigue . Adverse events are usually linked to the central nervous system . Future phase III clinical trials with an active DB00669 comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans . They will also determine whether lasmiditan will become available to the migraine patient .",
"Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \" pain - free \" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .",
"Migraine : current concepts and emerging therapies . Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . Migraine affects a substantial fraction of world population and is a major cause of disability in the work place . Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular ( due to cerebral vasodilatation ) , neurological ( abnormal neurological firing which causes the spreading depression and migraine ) and neurogenic dural inflammation ( release of inflammatory neuropeptides ) . The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder . The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention . The last decade has witnessed the advent of Sumatriptan and the ' DB00669 ' class of P28222 / 1D receptor agonists which have well established efficacy in treating migraine . Currently prophylactic treatments for migraine include calcium channel blockers , 5 - HT2 receptor antagonists , beta adrenoceptor blockers and gamma - amino butyric acid ( GABA ) agonists . Unfortunately , many of these treatments are non specific and not always effective . Despite such progress , in view of the complexity of the etiology of migraine , it still remains undiagnosed and available therapies are underused . In this article , the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed . Furthermore , the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine , with a special emphasis to calcitonin gene - related peptide , are critically evaluated .",
"No association between polymorphisms in four serotonin receptor genes , serotonin transporter gene and alcohol - related suicide . BACKGROUND : Serotonin ( 5 - HT ) is an important neurotransmitter with wide - ranging functions . Its disfunction in the central nervous system seems to play an important role in many psychiatric disorders and suicidal behavior . The objective of this study was to examine the association between polymorphisms in different serotonin receptor genes ( HTR ) : P08908 ( polymorphism - 1019C > G ) , P28222 ( polymorphisms 861G > C and - 161A > T ) , P30939 ( polymorphism - 78C > T ) and P28223 ( polymorphism - 1420C > T ) , and serotonin transporter gene ( 5 - HTT ) ( polymorphism LPR in promoter and VNTR in the second intron ) , and completed alcohol - related suicide , as well as between alcohol - dependent suicide victims . SUBJECTS AND METHODS : The study subjects were 373 Slovenian suicide victims ( mean age ± SD : 48 . 8 ± 17 . 7 years ) autopsied in the years 2002 through 2005 . During autopsy venous blood was drawn , and afterwards DNA extraction and alcoholimetric analysis were performed . Relatives of 79 suicide victims were interviewed using a semi - structured questionnaire designed according to Slovenian cultural and economic conditions . They provided information about the alcohol abuse of the suicide victims . Amongst the suicide victims were 25 alcohol misusers and 54 non - misusers . RESULTS : Association between polymorphisms in the selected serotonin receptor genes , transporter gene and completed alcohol - related suicide , as well as between alcohol - dependent suicide victims was not established . CONCLUSIONS : Present results suggest that selected polymorphisms of the 5 - HT receptor genes and transporter gene are not involved in genetic susceptibility to completed suicide under acute influence of alcohol or among alcohol - dependent individuals , but further studies in a larger sample are needed .",
"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .",
"[ Triptans and calcitonin gene - related peptide ( P80511 ) receptor antagonists ] . While triptans , the P28222 / 1D agonists , are effective and generally well - tolerated in many patients up to one - third of migraine patients either may not respond well to triptans , may not tolerate their side effects , or may have contraindications that preclude their use . Recurrence , DB00669 - related side effects , and cardiovascular constriction effects are demerits for acute migraine treatment . P80511 receptor antagonists , the so - called gepants , were clearely designed and expected to be better than triptans . P80511 is located in sensory nerve endings around cranial blood vessels . P80511 is a strong dilator of cerebral arteries and intravenous infusion of P80511 cause a migraine attack . DB04869 is the first selective P80511 receptor antagonist of proven efficacy in migraine . DB04869 could only be administered intravenously and never taken beyond Phase II . Telcagepant is orally available and several completed Phase III trials have revealed positive results . In several comparative studies of telcagepant and triptans , telcegepant did not appeared more effective than zolmitriptan or rizatriptan , although it had fewer DB00669 - related adverse events and drug - related adverse enents . A small number of patients taking olcegepant showed marked elevation in liver transaminase levels . It was decided to discontinue development of olcegepant . New P80511 receptor antagonists would be expected for acute migraine treatment .",
"Association study between clinical response to rizatriptan and some candidate genes . The aim of this study was to test genetic differences in the clinical response to rizatriptan in patients affected by migraine without aura . These genetic differences could be explained by various genes , the P28222 , encoding the 5 - HT ( 1 ) receptor subtype , P21397 gene that encodes the monoamino - oxidase , the main metabolic enzyme of this DB00669 , P31645 ( gene encoding the serotonin transporter ) and DRD ( 2 ) ( gene encoding the D ( 2 ) receptor ) , both involved in the pathogenesis of migraine . Fifty unrelated patients affected by migraine without aura ( IHS ) were included . Patients were divided into two groups ( responders and non - responders ) according to clinical response . Thirty - one out of fifty patients responded to rizatriptan . A significant difference among the two groups was observed in both allele ( p = 0 . 02 ) and genotype distribution ( p = 0 . 03 ) of P14416 / NcoI . The significant association with the P14416 / NcoI polymorphism in responders suggested that the P14416 / NcoI C allele may be considered a susceptibility factor heralding a good response to rizatriptan .",
"Rizatriptan in migraineurs with unilateral cranial autonomic symptoms : a double - blind trial . The objective and background is to confirm in a double - blind , placebo - controlled study the high DB00669 response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms . In this randomized , double - blind , placebo - controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo ( ratio 1 : 1 ) and treated for a single moderate or severe migraine attack . The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h . Secondary endpoints included pain relief , no associated symptoms and sustained pain freedom or relief . Significantly more patients reported pain freedom at 2 h after taking rizatriptan ( 54 % ) than after placebo ( 8 % ) ( therapeutic gain 46 % [ 28 % ; 64 % ] ; P < 0 . 001 ) . Similarly , significantly more patients reported total migraine freedom at 2 h after rizatriptan ( 51 % ) than after placebo ( 8 % ) ( therapeutic gain 43 % [ 26 % ; 61 % ] ; P < 0 . 001 ) . Rizatriptan was also more effective than placebo on most secondary endpoints . We confirm in a placebo - controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans , probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular P28222 / 1D receptors . Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients .",
"[ New DB00669 preparations can help the migraine patient . Pharmacodynamic and pharmacokinetic progresses ] . Migraine is an idiopathic , recurrent neurovascular headache disorder characterised by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . It is apparently a global disorder , occurring in all races , cultures and geographical locations . Migraine has a hereditary component , and its life - time prevalence is about 16 % . About a third of migraine patients in Sweden seem to be particularly sorely afflicted having 1 - 6 severe attacks a month and accounting for more than 80 per cent of the annual total of about 14 million attacks in the country as a whole . In general , these migraine sufferers do not obtain satisfactory relief from simple analgesice or NSAIDs ( non - sterodial antiinflammatory drugs only ) , and thus require additional migraine - specific treatment . Selective P28222 / 1D - agonists , the so - called triptans , have become an invaluable addition to the therapeutic arsenal for treating this category of patients .",
"The search for novel migraine therapies : experimental models . The identification and development of the potent P28222 / 1D agonist , sumatriptan has resulted in new therapeutic opportunities for the treatment of migraine and a number of chemically novel agents with a similar mechanism of action have been identified . Whilst these agents are optimised to enhance the therapeutic effect of sumatriptan , development of mechanistically novel therapies may provide new directions for the care of migraine sufferers . To develop new treatment paradigms , novel chemical entities should be evaluated in animal models which are predictive of therapeutic efficacy e . g . : in animal models where sumatriptan has shown activity , or the pathophysiological processes involved in the disease must be targeted . Therefore , investigation of mechanisms underlying cortical activity and its involvement in the activation of trigeminal vascular pathways may allow better understanding of the disease and result in the identification of new non - DB00669 - like therapies .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK70___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Mapping of the serotonin P28221 beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants . Abnormal brain serotonin function may be characteristic of several neuropsychiatric disorders . Thus , it is important to identify polymorphic genes and screen for functional variants at loci coding for genes that control normal serotonin functions . P28221 beta is a terminal serotonin autoreceptor which may play a role in regulating serotonin synthesis and release . Using an SSCP technique we screened for P28221 beta coding sequence variants in psychiatrically interviewed populations , which included controls , alcoholics , and alcoholic arsonists and alcoholic violent offenders with low P04141 concentrations of the main serotonin metabolite 5 - HIAA . A common polymorphism was identified in the P28221 beta gene with allele frequencies of 0 . 72 and 0 . 28 . The SSCP variant was caused by a silent G to C substitution at nucleotide 861 of the coding region . This polymorphism could also be detected as a HincII RFLP of amplified DNA . DNAs from informative CEPH families were typed for the HincII RFLP and analyzed with respect to 20 linked markers on chromosome 6 . Multipoint analysis placed the P28221 beta receptor gene between markers D6S286 and D6S275 . A maximum two - point lod score of 10 . 90 was obtained to D6S26 , which had been previously localized on 6q14 - 15 . Chromosomal aberrations involving this region have been previously shown to cause retinal anomalies , developmental delay , and abnormal brain development . This region also contains the gene for North Carolina - type macular dystrophy .",
"Effects of PNU - 109 , 291 , a selective P28221 receptor agonist , on electrically induced dural plasma extravasation and capsaicin - evoked c - fos immunoreactivity within trigeminal nucleus caudalis . We studied the effects of PNU - 109291 [ ( S ) -(-)- 1 -[ 2 -[ 4 -( 4 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N - methyl - isoc hroman - 6 - carboxamide ] , a receptor agonist showing 5000 - fold selectivity for primate P28221 versus P28222 receptors ( Ennis et al . , J . Med . Chem . 41 , 2180 - 2183 ) , on dural neurogenic inflammation and on c - fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents , respectively . Subcutaneous injection of PNU - 109291 in male guinea pigs dose - dependently reduced dural extravasation of [ 125I ] - labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4 . 2 nmol kg (- 1 ) . A dose of 73 . 3 nmol kg (- 1 ) blocked the response completely . The selective P28222 / 1D receptor antagonist GR - 127935 ( > or = 2 micromol kg (- 1 ) i . v . ) prevented this effect . In addition , the number of c - fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation ( intracisternally administered capsaicin ) was reduced by more than 50 % with PNU - 109291 ( > or = 122 . 2 nmol kg (- 1 ) administered s . c . 45 min before and 15 min after capsaicin ) . These data indicate that the P28221 receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models . Since P28221 receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle , the P28221 receptor subtype may become a useful therapeutic target for migraine and related headaches .",
"Role of endothelial cells in antihyperalgesia induced by a DB00669 and β - blocker . While blood vessels have long been implicated in diverse pain syndromes ( e . g . , migraine headache , angina pectoris , vasculitis , and Raynaud ' s syndrome ) , underlying mechanisms remain to be elucidated . Recent evidence supports a contribution of the vascular endothelium in endothelin - 1 - induced hyperalgesia , and its enhancement by repeated mechanical stimulation ; a phenomenon referred to as stimulus - induced enhancement of ( endothelin ) hyperalgesia ( SIEH ) . SIEH is thought to be mediated by release of DB00171 from endothelial cells , to act on P56373 receptors on nociceptors . In the present study we evaluated the ability of another vasoactive hyperalgesic agent , epinephrine , to induce endothelial cell - dependent hyperalgesia and SIEH . We found that epinephrine also produces hyperalgesia and SIEH . Both P56373 receptor antagonists , A317491 and octoxynol - 9 , which attenuate endothelial cell function , eliminated SIEH without affecting epinephrine hyperalgesia . We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache , whose receptors are present in endothelial cells - the triptans and β blockers - have a vascular component to their anti - hyperalgesic action . For this , we tested the effect of ICI - 118 , 551 , a β₂ - adrenergic receptor antagonist and sumatriptan , an agonist at P28222 and 5 - HT₁D receptors , on nociceptive effects of endothelin and epinephrine . ICI - 118 , 551 inhibited endothelin SIEH , and attenuated epinephrine hyperalgesia and SIEH . Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH , while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct - acting inflammatory mediator , prostaglandin E₂ . These results support the suggestion that triptans and β - blockers interact with the endothelial cell component of the blood vessel to produce anti - hyperalgesia .",
"A PET study with [ 11C ] AZ10419369 to determine brain P28222 receptor occupancy of zolmitriptan in healthy male volunteers . AIM : To investigate the occupancy at brain 5 - hydroxytryptamine ( 5 - HT ) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan . METHODS : Positron emission tomography ( PET ) studies were undertaken using the radioligand [( 11 ) C ] AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets . The subjects were examined after two consecutive administrations of 10 mg zolmitriptan , approximately 1 week apart . Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan . One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment . RESULTS : After administration of 10 mg zolmitriptan , mean receptor occupancy was 4 - 5 % . No consistent changes in P28222 receptor binding were observed for subjects who received 5 mg zolmitriptan . There was a statistically significant negative relationship between binding potential ( BP ND ) and plasma concentration of zolmitriptan and the active metabolite 183C91 , respectively . All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline . CONCLUSION : This is the first demonstration of CNS P28222 receptor occupancy of a DB00669 . The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK7___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK7___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK7___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK7___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK7___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK7___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK7___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK7___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK7___ in the treatment of changes in hypervigilance following severe stress .",
"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .",
"Q01094 - mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product . Previous studies have shown that the carboxyl - terminal region of Q01094 ( residues 368 - 437 ) can support transcriptional activation when linked to the DNA - binding domain of the yeast transcription factor GAL4 . This region also contains an 18 - residue retinoblastoma ( RB ) - binding sequence , raising the possibility that RB binding might inhibit the ability of Q01094 to form protein - protein contacts required for activation . Here we report a further analysis of the Q01094 activation domain . In addition , we show that overexpression of RB , but not the RB mutant , RBd22 , can inhibit GAL4 / Q01094 activity in vivo . Moreover , expression of the simian virus 40 large tumor antigen ( T antigen ) , but not the RB - binding defective T antigen point mutant , P04264 , can overcome this repression . Three different GAL4 / Q01094 mutants that activate transcription , but fail to bind to RB , are not significantly affected by overexpression of RB . These findings support a model wherein RB suppresses Q01094 - mediated transcriptional activation through direct physical association .",
"Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium . NO , produced by endothelial NO synthase ( P29474 ) , is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth . The capacity for NO production is maximal at term because pulmonary P29474 expression increases during late gestation . Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults , estrogen may upregulate P29474 in fetal pulmonary artery endothelium . Therefore , we studied the direct effects of estrogen on P29474 expression in ovine fetal pulmonary artery endothelial cells ( PAECs ) . ___MASK76___ caused a 2 . 5 - fold increase in NOS enzymatic activity in PAEC lysates . This effect was evident after 48 hours , and it occurred in response to physiological concentrations of the hormone ( 10 (- 10 ) to 10 (- 6 ) mol / L ) . The increase in NOS activity was related to an upregulation in P29474 protein expression , and P29474 mRNA abundance was also enhanced . P03372 antagonism with DB00947 completely inhibited estrogen - mediated P29474 upregulation , indicating that estrogen receptor activation is necessary for this response . In addition , immunocytochemistry revealed that fetal PAECs express estrogen receptor protein . Furthermore , transient transfection assays with a specific estrogen - responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen - induced transcriptional transactivation . Thus , estrogen upregulates P29474 gene expression in fetal PAECs through the activation of PAEC estrogen receptors . This mechanism may be responsible for pulmonary P29474 upregulation during late gestation , thereby optimizing the capacity for NO - mediated pulmonary vasodilation at birth .",
"17 ___MASK76___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"Overview of migraine treatment . SUMMARY Migraine is ranked as the 19th top cause of disability worldwide by WHO . Despite advancements in migraine - specific acute treatment , only a minority of patients utilize these medications . Specific pharmacologic treatments consist of the ergot alkaloids and triptans ( serotonin P28222 / 1D receptor agonists ) . Both classes are regarded as relatively safe and effective ; however , there is a greater concern for vasoconstrictive effects with the ergots , which limits their use . Triptans transformed migraine therapy , setting in motion revolutionary research that heightened our understanding of migraine mechanisms . However , one in three migraineurs may be DB00669 nonresponders and there is a group of migraine patients that remains ' refractory ' to conventional pharmacologic migraine therapy . This article discusses the approach to migraine management , reviews currently available acute and preventive pharmacologic and nonpharmacologic treatment options for migraine headache , as well as briefly focuses on novel and upcoming medicines presently under investigation .",
"Tissue injury regulates serotonin 1D receptor expression : implications for the control of migraine and inflammatory pain . The anti - migraine action of \" DB00669 \" drugs involves the activation of serotonin subtype 1D ( P28221 ) receptors expressed on \" pain - responsive \" trigeminal primary afferents . In the central terminals of these nociceptors , the receptor is concentrated on peptidergic dense core vesicles ( DCVs ) and is notably absent from the plasma membrane . Based on this arrangement , we hypothesized that in the resting state the receptor is not available for binding by a DB00669 , but that noxious stimulation of these afferents could trigger vesicular release of DCVs , thus externalizing the receptor . Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat , there is a significant increase of P28221 - immunoreactivity ( IR ) in the ipsilateral dorsal horn of the spinal cord . We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane , where it is more readily detected . We also observed divergent changes in P28221 - IR in inflammatory and nerve - injury models of persistent pain , occurring at least in part through the regulation of P28221 - receptor gene expression . Finally , we found that P28221 - IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide DB05875 . This result differs from that reported for the partial differential - opioid receptor , which is also sorted to DCVs , but is greatly reduced in preprotachykinin mutant mice . We suggest that a \" pain \" - triggered regulation of P28221 - receptor expression underlies the effectiveness of triptans for the treatment of migraine . Moreover , the widespread expression of P28221 receptor in somatic nociceptive afferents suggests that triptans could , in certain circumstances , treat pain in nontrigeminal regions of the body .",
"Effect of acetazolamide on aquaporin - 1 and fluid flow in cultured choroid plexus . ___MASK100___ ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill - defined . The drug reversibly inhibits aquaporin - 4 ( P55087 ) , the most ubiquitous \" water pore \" in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures . CP tissue culture from 10 - day Sprague - Dawley rats and a TRCSF - B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT - PCR ) were performed . Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels . Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently .",
"The pipeline in headache therapy . Migraine is a common , disabling , neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms . The advent of the DB00669 class of medication in the 1990s revolutionized the acute treatment of migraine , but many migraineurs do not respond optimally or at all to triptans , have intolerable adverse effects , or have contraindications to their use . Preventive pharmacotherapy has advanced mostly through serendipity , with new drugs being found effective while being used for other indications . There remains a significant need for new medications and devices that can provide effective , rapid , and sustained pain relief without adverse effects or recurrence . Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation . This article covers innovative delivery mechanisms , calcitonin gene - related peptide receptor antagonists , antibodies to calcitonin gene - related peptide and its receptor , P30939 receptor agonists , transient receptor potential vanilloid receptor modulators , orexin receptor antagonists , glial cell modulators , and neurostimulation .",
"[ Migraine - established concepts and new developments ] . Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering . Despite extensive research efforts in the recent years , many pathophysiological aspects remain unclear . An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a ( silent ) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache . Numerous studies in the last years have examined somatic , especially cerebrovascular and also psychological comorbidities . For attack therapy , P80511 antagonists have emerged as promising non - vasoconstrictive acting alternatives for triptans . However , they were so far not approved due to liver enzyme elevations in safety studies . Another new approach without vasoconstrictive action are the selective P30939 agonists ( especially Lasmiditan ) . Large placebo - controlled and DB00669 - controlled trials need to be awaited . For migraine prophylaxis , a comparable effect of sports and pharmacological prophylaxis using topiramate could be found . Particularly the combination of drug and non - drug therapies ( such as the combination of stress management training with a beta - blocker treatment ) achieves high efficacy . Also interdisciplinary , multimodal treatment approaches are important options . Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine . Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine .",
"P14416 mechanisms contribute to age - related cognitive decline : the effects of quinpirole on memory and motor performance in monkeys . The D2 dopamine ( DA ) receptor agonist , quinpirole , was characterized in young adult monkeys , young reserpine - treated monkeys and aged monkeys to assess the contribution of DA to age - related loss of prefrontal cortical ( P27918 ) cognitive function . Monkeys were tested on a delayed response memory task that depends on the P27918 , and a fine motor task that taps the functions of the motor cortex . In young adult monkeys , low quinpirole doses impaired performance of the P27918 and fine motor tasks , while higher doses improved memory performance and induced dyskinesias and \" hallucinatory - like \" behaviors . The pattern of the quinpirole response in reserpine - treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors , while the improvement in delayed response performance , dyskinesias and \" hallucinatory - like \" behaviors resulted from actions at postsynaptic receptors . In aged monkeys , low doses of quinpirole continued to impair fine motor performance , but lost their ability to impair delayed response performance . The magnitude of cognitive improvement and the incidence of \" hallucinatory - like \" behaviors were also reduced in the aged animals , suggesting some loss of postsynaptic D2 receptor function . The pattern of results is consistent with the greater loss of DA from the P27918 than from motor areas in aged monkey brain ( Goldman - Rakic and Brown , 1981 ; Wenk et al . , 1989 ) , and indicates that DA depletion contributes significantly to age - related cognitive decline .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK34___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"[ Cardiovascular side - effects of triptanes in migraine exist but are rare . 5 - HT receptor mediated extracranial vasoconstriction is the most common cause ] . Triptans , P28222 / 1D agonists used in migraine treatment , are rarely involved in serious coronary events due to vasospasm . 5 HT1 receptors mediate vasodilation and vasoconstriction of coronary arteries . Reports of serious coronary events mainly concern patients with known risk factors for coronary artery disease . It is prudent to obtain a thorough medical history before treatment with a DB00669 is started . If chest pain occurs , the possibility of coronary ischemia should be investigated . Stroke , a known complication to migraine , has also been reported in patients treated with triptans , but available data do not suggest that triptans , when correctly used , greatly increase the risk ."
] |
[
"___MASK100___",
"___MASK10___",
"___MASK27___",
"___MASK34___",
"___MASK70___",
"___MASK75___",
"___MASK76___",
"___MASK7___",
"___MASK82___"
] |
___MASK82___
|
MH_train_325
|
interacts_with DB00087?
|
[
"Antibody - based therapy of non - Hodgkin ' s lymphoma . Monoclonal antibodies ( mAb ) have dramatically advanced our ability to treat non - Hodgkin ' s lymphoma ( Q9NZ71 ) , and there has been a virtual explosion of clinical data regarding their use . DB00073 is a humanized anti - P11836 mAb and has significant single agent activity in follicular lymphoma , and to a lesser extent in mantle - cell and diffuse large B - cell lymphoma ( DLCL ) . DB00073 appears to have synergistic activity with cytotoxic chemotherapy and the combination has recently demonstrated improved rates of complete remission ( CR ) and overall survival in older patients with DLCL . DB00087 ( Campath - 1H ) is a humanized mAb targeting P31358 and has recently been approved in the USA for the treatment of fludarabine - refractory B - cell chronic lymphocytic leukaemia . Impressive activity has also been demonstrated in T - cell prolymphocytic leukaemia and mycosis fungoides . The radioconjugated anti - P11836 mAbs ibritumomab tiuxetan and I131 - tositumomab also have impressive clinical activity in low - grade B - cell Q9NZ71 , and the former has demonstrated superior CR rates to rituximab . Myelosuppression is more significant however , and their place in the treatment algorithm remains to be clearly defined . Other immunotoxins ( e . g . BL22 ) and mAb against alternate targets ( e . g . epratuzumab , humanized anti - P20273 ) are in development .",
"In vivo alemtuzumab enables haploidentical human leukocyte antigen - mismatched hematopoietic stem - cell transplantation without ex vivo graft manipulation . BACKGROUND : DB00087 , a humanized monoclonal antibody directed against human P31358 , has a strong lympholytic effect . This study evaluates the safety of unmanipulated peripheral blood stem - cell transplantation from two or three loci - mismatched related donors using alemtuzumab in vivo . METHODS : A total body irradiation - based regimen was used in young patients , whereas those 50 years or older received fludarabine - based conditioning . DB00087 was added to these regimens by intravenous infusion at 0 . 2 mg / kg per day for 6 days ( days - 8 to - 3 ) . RESULTS : We treated 12 patients with a median age of 49 . 5 years . Eight patients demonstrated active disease , and four patients demonstrated acute leukemia in high - risk remission . All achieved neutrophil engraftment a median of 17 . 5 days after transplantation with complete donor - type chimerism . The cumulative incidence of grades III to IV acute graft - versus - host disease was only 9 % . Infection - related deaths were not observed . CD3 +/ P01730 + and CD3 +/ CD8 + T cells were strongly suppressed within 2 months after transplantation , but recovered on day 90 . Relapse was observed in five of eight patients who underwent transplantation for active disease , whereas none of the three patients who underwent transplantation in first remission had a relapse . CONCLUSIONS : We conclude that in vivo alemtuzumab enables haploidentical hematopoietic stem - cell transplantation without ex vivo graft manipulation .",
"DB00087 in the treatment of chronic lymphocytic lymphoma . DB00087 was the first monoclonal antibody to be humanized , a process which embeds rodent sequence fragments in a human IgG framework . The antibody target is P31358 , an antigen expressed on normal lymphocytes as well as many T - and B - cell neoplasms . It therefore has a potential broad application across a spectrum of B - and T - cell malignancies as well as use as an immunosuppressant drug in , for example , bone marrow transplantation . The original licensing in the USA and Europe was for the treatment of fludarabine - refractory chronic lymphocytic leukemia ( CLL ) . However , recent trials using alemtuzumab as a first - line agent for CLL have shown superior response rates compared with traditional alkylator therapy and this has led to US FDA approval for first - line treatment for CLL . It seems to be particularly useful in patients with CLL who have deletion of the P04637 tumor suppressor gene , a subset of disease that responds poorly to other currently available chemotherapeutics .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Intravascularly administered RGD - displaying measles viruses bind to and infect neovessel endothelial cells in vivo . Systemically administered vectors must cross the endothelial lining of tumor blood vessels to access cancer cells . Vectors that interact with markers on the lumenal surface of these endothelial cells might have enhanced tumor localization . Here , we generated oncolytic measles viruses ( MVs ) displaying alpha ( v ) beta ( 3 ) integrin - binding peptides , cyclic arginine - glycine - aspartate ( RGD ) or echistatin , on the measles hemagglutinin protein . Both viruses had expanded tropisms , and efficiently entered target cells via binding to integrins , but also retained their native tropisms for P15529 and signaling lymphocyte activation molecule ( Q13291 ) . When fluorescently labeled and injected intravascularly into chick chorioallantoic membranes ( CAMs ) , in contrast to unmodified viruses , the integrin - binding viral particles bound to the lumenal surface of the developing chick neovessels and infected the P62158 vascular endothelial cells . In a mouse model of P15692 - induced angiogenesis in the ear pinna , the integrin - binding viruses , but not the parental virus , infected cells at sites of new blood vessel formation . When given intravenously to mice bearing tumor xenografts , the integrin - binding virus infected endothelial cells of tumor neovessels in addition to tumor parenchyma . To our knowledge , this is the first report demonstrating that oncolytic MVs can be engineered to target the lumenal endothelial surface of newly formed blood vessels when administered intravenously in living animals .",
"[ Moclobemide ( ___MASK51___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Nutlin - 3 up - regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells , as part of a negative feedback antiapoptotic mechanism . The small molecule inhibitor of the Q00987 / p53 interaction Nutlin - 3 significantly up - regulated the steady - state mRNA and protein levels of Notch1 in P04637 ( wild - type ) ( OCI , SKW6 . 4 ) but not in P04637 ( deleted ) ( HL - 60 ) or P04637 ( mutated ) ( BJAB ) leukemic cell lines . A direct demonstration that P46531 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53 . Moreover , inhibition of Notch1 expression using Notch1 - specific siRNA significantly increased cytotoxicity in P04637 ( wild - type ) leukemic cells . Of note , Nutlin - 3 up - regulated Notch1 expression also in primary P04637 ( wild - type ) B - chronic lymphocytic leukemia ( B - CLL ) cells and the combined use of Nutlin - 3 plus pharmacological gamma - secretase inhibitors of the Notch signaling showed a synergistic cytotoxicity in both P04637 ( wild - type ) leukemic cell lines and primary B - CLL cells . A potential drawback of gamma - secretase inhibitors was their ability to enhance osteoclastic maturation of normal circulating preosteoclasts induced by O14788 + P09603 . Notwithstanding , Nutlin - 3 completely suppressed osteoclastogenesis irrespective of the presence of gamma - secretase inhibitors . Taken together , these data indicate that the p53 - dependent up - regulation of Notch1 in response to Nutlin - 3 represents an antiapoptotic feedback mechanism able to restrain the potential therapeutic efficacy of Nutlin - 3 in hematologic malignancies . Therefore , therapeutic combinations of Nutlin - 3 + gamma - secretase inhibitors might potentiate the cytotoxicity of Nutlin - 3 in p53 ( wild - type ) leukemic cells .",
"___MASK37___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK37___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK37___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK37___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK37___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK37___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"DB00087 use in relapsed and refractory chronic lymphocytic leukemia : a history and discussion of future rational use . In this review , we outline the clinical experience with single - agent alemtuzumab as a treatment for relapsed and refractory chronic lymphocytic leukemia ( CLL ) in both prospective and retrospective trials and describe the multiagent use of the drug with the goal of updating clinicians on recent developments and possible future rational combinations . DB00087 , an antibody targeting the lymphocyte - specific surface marker P31358 , is an approved agent for the treatment of CLL . Despite its demonstrated efficacy , likely secondary to concerns regarding infectious complications , it is most commonly used in the relapsed and refractory setting . Given alemtuzumab ' s unique mechanism of action it has been demonstrated to have activity in disease that is refractory to both alkylating agents and purine analogs . Furthermore , it has activity in P04637 - mutated disease , which has the worst prognosis of any subset of CLL . DB00087 has greater efficacy on circulating disease relative to nodal disease . Rational combinations are attempting to use these attributes to increase response rates in patients with relapsed and refractory disease .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK1___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Serum osteoprotegerin and receptor activator of nuclear factor - kappaB ligand ( O14788 ) concentrations in allogeneic stem cell transplant - recipients : a role in bone loss ? PURPOSE : Osteoporosis is a long - term complication of allogeneic stem cell transplantation ( P09683 ) . Receptor activator of nuclear factor - kappaB ligand ( O14788 ) increases osteoclast activity , while osteoprotegerin ( O00300 ) neutralizes O14788 . A deficiency of O00300 or an excess of O14788 may contribute to post - P09683 bone loss . METHODS : Serum O00300 and soluble O14788 ( sRANKL ) concentrations were determined in 30 patients who received calcium , vitamin D and sex steroids -- with or without pamidronate -- prior to P09683 and 1 , 3 , 6 , and 12 months post - P09683 and compared to those in healthy controls . RESULTS : Despite all treatments patients lost bone at the hip . At baseline , serum O00300 was similar in patients and controls ; in the two patient groups it increased by 26 - 27 % at 6 months post - P09683 ( p = 0 . 002 - 0 . 028 ) and over the control level ( p = 0 . 002 ) . Serum sRANKL concentrations were also similar in patients and controls at baseline . In those patients receiving pamidronate sRANKL concentrations decreased by 42 % ( p = 0 . 0007 ) at 3 months post - P09683 . The findings on the effect of P09683 on O00300 and sRANKL serum levels were ascertained in 28 additional patients who did not receive pamidronate , at a median of 122 days after P09683 . In this latter group , O00300 but not sRANKL concentrations were clearly elevated ( p < 0 . 001 ) in comparison to healthy controls . In conclusion , the present study fails to support the view that an excess of sRANKL or a deficiency of O00300 would have a substantial impact on bone loss in P09683 - recipients . CONCLUSION : Serum sRANKL concentrations may be modulated by bisphosphonates .",
"NF - kappaB and FLIP in arsenic trioxide ( ATO ) - induced apoptosis in myelodysplastic syndromes ( MDSs ) . P01375 ( P01375 ) - alpha , a potent stimulus of nuclear factor - kappaB ( NF - kappaB ) , is up - regulated in myelodysplastic syndrome ( P43034 ) . Here , we show that bone marrow mononuclear cells ( BMMCs ) and purified P28906 + cells from patients with low - grade / early - stage P43034 ( refractory anemia / refractory anemia with ring sideroblasts [ RA / P54136 ] ) have low levels of NF - kappaB activity in nuclear extracts comparable with normal marrow , while patients with RA with excess blasts ( RAEB ) show significantly increased levels of activity ( P = . 008 ) . Exogenous P01375 enhanced NF - kappaB nuclear translocation in P43034 BMMCs above baseline levels . Treatment with arsenic trioxide ( ATO ; 2 - 200 microM ) inhibited NF - kappaB activity in normal marrow , primary P43034 , and ML1 cells , even in the presence of exogenous P01375 ( 20 ng / mL ) , and down - regulated NF - kappaB - dependent antiapoptotic proteins , B - cell leukemia XL ( Bcl - XL ) , Bcl - 2 , X - linked inhibitor of apoptosis ( P98170 ) , and Fas - associated death domain ( Q13158 ) - like interleukin - 1beta - converting enzyme ( Q14790 ) inhibitory protein ( FLIP ) , leading to apoptosis . However , overexpression of FLIP resulted in increased NF - kappaB activity and rendered ML1 cells resistant to ATO - induced apoptosis . These data are consistent with the observed up - regulation of FLIP and resistance to apoptosis with advanced P43034 , where ATO as a single agent may show only limited efficacy . However , the data also suggest that combinations of ATO with agents that interfere with other pathways , such as FLIP autoamplification via NF - kappaB , may have considerable therapeutic activity .",
"___MASK38___ for joints and bones . ___MASK38___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK38___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK38___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"High - density lipoprotein subfractions display proatherogenic properties in overweight and obese children . BACKGROUND : In adults , obesity - driven inflammation can lead to increased cardiovascular disease ( CVD ) . However , information regarding childhood obesity and its inflammatory sequelae is less well defined . Serum amyloid - A ( P0DJI8 ) is an inflammatory molecule that rapidly associates with high - density lipoproteins ( HDLs ) and renders them dysfunctional . Therefore , P0DJI8 may be a useful biomarker to identify increased CVD potential in overweight and obese children . METHODS : Young Hearts 2000 is a cross - sectional cohort study in which 92 children who were obese were matched for age and sex with 92 overweight and 92 lean children . HDL ( 2 ) and HDL ( 3 ) ( HDL ( 2 & 3 ) ) were isolated from plasma by a three - step rapid - ultracentrifugation procedure . P0DJI8 was measured in serum and HDL ( 2 & 3 ) by an enzyme - linked immunosorbent assay procedure , and the activities of cholesterol ester transfer protein ( P11597 ) and lecithin cholesteryl acyltransferase ( P04180 ) were measured by fluorimetric assays . RESULTS : Trends across the groups indicated that P0DJI8 increased in serum and HDL ( 2 & 3 ) as BMI increased , as did HDL ( 2 )- P11597 and HDL ( 2 )- P04180 activities . CONCLUSION : These results have provided evidence that overweight and obese children are exposed to an inflammatory milieu that impacts the antiatherogenic properties of HDL and that could increase CVD risk . This supports the concept that it is important to target childhood obesity to help minimize future cardiovascular events .",
"DB00099 - induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy : safety , feasibility and evidence for an efficient in vivo purging . Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia ( CML ) . Further , the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation ( P09683 ) reduces the number of therapeutic options in a number of patients . To assess the possibility of stem cell mobilization ( DB00919 ) during imatinib therapy we performed granulocyte colony - stimulating factor ( filgrastim )- induced DB00919 and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients . Aphaeresis was successful in 13 patients ( 72 % ) ( > or = 2 . 0 x 10 ( 6 ) P28906 + cells / kg body weight ) and five ( 28 % ) harvests could be obtained , which were negative for P11274 / P00519 mRNA as assessed by nested - reverse transcription polymerase chain reaction ( RT - PCR ) . All harvests , except one , were negative after first round RT - PCR , implicating a low level of CML cell contamination . There was no significant change in peripheral P11274 / P00519 transcript load after DB00919 as assessed by quantitative real - time RT - PCR . Fifteen patients remained stable in complete cytogenetic remission ( CCR ) during a median observation period of 9 . 3 months . One patient achieved a molecular remission shortly after DB00919 . Another patient who exhibited rising P11274 / P00519 mRNA levels before DB00919 achieved CCR after autologous P09683 with the generated harvest . One patient with a Philadelphia chromosome - negative , P11274 / P00519 - positive CML showed a cytogenetic relapse 6 months after DB00919 . We conclude that filgrastim - induced P28906 + cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients . Additionally , we found evidence that this procedure could generate stem cell harvests that exhibit non - detectable levels of P11274 / P00519 mRNA .",
"Allogeneic stem cell transplantation using alemtuzumab - containing regimens in severe aplastic anemia . DB00087 , a humanized anti - P31358 , IgG1 monoclonal antibody , is used to reduce graft - versus - host disease ( GVHD ) and aid engraftment after allogeneic haemopoietic stem cell transplant ( HSCT ) . Its associated low incidence of GVHD makes it an attractive alternative to anti - thymocyte globulin ( ATG ) in transplant conditioning regimen for severe aplastic anaemia ( P0DJI8 ) . We have reviewed the use of alemtuzumab - based conditioning regimen for HSCT in P0DJI8 and show that it results in sustained haematological engraftment , a very low incidence of chronic GVHD without an increase in viral infections . Intriguingly , alemtuzumab appears to induce tolerance post - HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD , and which persist on withdrawal of post - graft immunosuppression . Finally , its low toxicity profile may permit future application of HSCT to older patients with P0DJI8 who fail to respond to immunosuppressive therapy .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK39___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"A mechanistic rationale for combining alemtuzumab and rituximab in the treatment of ALL . B - lineage acute lymphoblastic leukemia ( ALL ) may express P31358 and P11836 . DB00087 ( ALM ) and rituximab ( RTX ) are therapeutic antibodies directed against P31358 and P11836 , respectively , but showed limited activity against ALL in clinical trials . The mechanisms for the impaired responses remained unclear . We studied expression of P31358 and P11836 on ALL cells and found that most cases coexpressed P31358 and P11836 . However , distinct P31358 - negative ( P31358 (-) ) subpopulations were detected in most cases as the result of defective glycophosphatidyl - inositol anchoring . Although ALM efficiently eradicated P31358 - positive ( P31358 (+) ) cells in NOD / scid mice engrafted with primary human ALL , P31358 (-) subclones escaped therapy . In the same model , RTX showed limited activity resulting from occurrence of P11836 down - modulation . However , P31358 (-) cells concurrently lacked the glycophosphatidyl - inositol - anchored complement regulators P08174 and P13987 and showed increased susceptibility to RTX - mediated complement - dependent cytotoxicity in vitro . At the same time , ALM was shown to inhibit down - modulation of P11836 in response to RTX by depleting the trogocytic capacity of phagocytic cells . Probably because of these complementary mechanisms , combined administration of ALM and RTX induced complete responses in vivo . Based on these data , we propose a mechanistic rationale for combined application of RTX and ALM in ALL .",
"Immunohistochemical analysis in ethinylestradiol - treated breast cancers after prior long - term estrogen - deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER - positive patients become resistant to hormone therapy after long - term hormone treatment . ___MASK61___ ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well - known breast cancer - related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down - regulated ER and up - regulated PgR while nuclear and cytosolic AR were oppositely down - and up - regulated , respectively . Cytosolic staining of P38398 was significantly up - regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non - responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non - genomic pathway and this may be reflected in their sensitivity to EE2 treatment .",
"___MASK38___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK38___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK38___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK37___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"DB00087 in peripheral T - cell malignancies . The humanized monoclonal antibody CAMPATH - 1H ( alemtuzumab ) binds to the P31358 antigen , a glycoprotein that is widely expressed on normal and malignant B - and T - lymphocytes . Over the past 5 years , a number of trials have demonstrated that alemtuzumab has clinical activity in mature T - cell diseases such as T - cell prolymphocytic leukemia ( T - PLL ) and cutaneous T - cell lymphoma ( CTCL ) . In heavily pretreated relapsed / refractory patients alemtuzumab induced responses in more than two thirds of T - PLL and more than 50 % of CTCL patients . Responding patients had improved survival compared to nonresponders . DB00087 is particularly effective in clearing malignant lymphocytes from peripheral blood and bone marrow and may therefore facilitate stem - cell transplantation ( P09683 ) in selected patients . The toxicity profile for the antibody is acceptable ; the major complications are infusional reactions , which generally subside after the first 1 - 2 weeks of therapy , and prolonged lymphopenia associated with reactivation of viruses . These can be minimized by careful monitoring and the use of prophylactic therapy . Future studies will be directed toward : alternative routes ( subcutaneous ) and schedules of administration ; use as first - line therapy ; combination strategies with conventional chemotherapy ; and use of alemtuzumab to purge minimal residual bone - marrow disease prior to P09683 .",
"Selective targeting of the repressive transcription factors P25490 and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 (+) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ). cMyc and P25490 are two transcription factors that are recruited as part of well - described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 , Q92769 , O15379 , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( ___MASK92___ ) enhanced the increase in LTR transcription in cells that were depleted of P25490 . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency .",
"In vivo cytokine responses to interleukin - 2 immunotherapy after autologous stem cell transplantation in children with solid tumors . The potent immunostimulatory cytokine interleukin - 2 ( P60568 ) has been extensively investigated for its potential to induce anti - tumor immunity in a number of tumor models . Only recently the complex interplay of mutually suppressive or supportive cytokines of the P60568 - induced network of cytokines has been better characterized . The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants ( P09683 ) , since in these patients long - lasting impairments in cytokine inducibility have been described . We have therefore studied the kinetics of putative modulators and mediators of P60568 - induced immune activation , namely IL - 1beta , P05112 , P05113 , P22301 , IL - 12 , soluble P48023 ( sFasL ) , and GM - P04141 during P60568 therapy . All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5 - day courses of high - dose intravenous P60568 as an adjuvant to their radio - chemotherapy and autologous P09683 . While IL - 1beta , P05112 and IL - 12 were not , and sFasL was only mildly affected by the P60568 therapy , we observed a consistent and early rise of P22301 , P05113 , and GM - P04141 . These increases were rapidly reversible after discontinuation of P60568 therapy . The inducibility of P22301 , P05113 and GM - P04141 was more pronounced with increasing time from the P09683 , and in the third cycle reached an order of magnitude as in high - dose P60568 patients without P09683 . Together with the abundant in vitro data , these findings may help devise a combination immunotherapy permitting stronger anti - tumor effects , but lesser adverse effects .",
"P02649 genotype , P01375 - α 308G / A and risk for cardiac surgery associated - acute kidney injury in Caucasians . OBJECTIVES : Acute kidney injury following cardiac surgery depicts a severe clinical problem that is strongly associated with adverse short - and long - term outcome . We analyzed two common genetic polymorphisms that have previously been linked to renal failure and inflammation , and have been supposed to be associated with cardiac surgery associated - acute kidney injury ( Q13216 - AKI ) . METHODS : A total of 1415 consecutive patients who underwent elective cardiac surgery with P15086 at our institution were prospectively enrolled . Patients were genotyped for P02649 ( ApoE E2 , E3 , E4 ) ( rs429358 and rs7412 ) and P01375 - α - 308 G > A ( rs1800629 ) . RESULTS : Demographic characteristics and procedural data revealed no significant differences between genotypes . No association between ApoE ( E2 , E3 , E4 ) and P01375 - α - 308 G > A genotypes and the RIFLE criteria could be detected . Several multiple linear regression analyses for postoperative creatinine increase revealed highly significant associations for aortic cross clamp time ( p < 0 . 001 ) , P15086 - time ( p < 0 . 001 ) , norepinephrine ( p < 0 . 001 ) , left ventricular function ( p = 0 . 004 ) and blood transfusion ( p < 0 . 001 ) . No associations were found for ApoE ( E2 , E3 , E4 ) and P01375 - α - 308 G > A genotypes or baseline creatinine . When the sample size is 1415 , the multiple linear regression test of R ( 2 )= 0 for seven covariates assuming normal distribution will have at least 99 % power with significance level 0 . 05 to detect an R ( 2 ) of 0 . 108 or 0 . 107 as observed in the data . CONCLUSIONS : ApoE ( E2 , E3 , E4 ) polymorphism and the P01375 - α - 308 G > A polymorphism are not associated with renal injury after P15086 .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK92___ ( ___MASK92___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK92___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK92___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .",
"P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK48___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \" good risk \" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK26___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Real life experience with alemtuzumab treatment of patients with lower - risk P43034 and a hypocellular bone marrow . Immunosuppressive therapy is a therapeutic option for selected low - risk myelodysplastic syndromes ( P43034 ) patients . Besides standard treatment protocols that include ATG and Q13216 , the humanized P31358 antibody alemtuzumab has been shown to have efficacy in P43034 treatment . We report our experience with alemtuzumab in nine P43034 RCMD patients . All patients had a hypocellular bone marrow with a blast count < 5 % and were classified as intermediate - 1 according to the IPSS . We found a response in five patients ( 60 % ) ; three patients achieved a complete remission 3 and 6 months after the treatment with alemtuzumab , and two patients showed a haematological improvement . DB00087 was administered in a 10 - mg dosage for 10 days . Treatment was well tolerated , and no severe side effects were observed . We could confirm the finding that the alemtuzumab is effective and save selected P43034 patients . Due to the promising results , further studies , especially with regard to long - term survival and risk of leucemic progression should be initiated .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK61___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .",
"Alternative immunosuppression in patients failing immunosuppression with ATG who are not transplant candidates : Campath ( DB00087 ) . Antithymocyte globulin ( ATG ) - based immunosuppression remains the standard immunosuppressive therapy ( IST ) for aplastic anemia ( AA ) patients lacking a sibling donor ; however , treatment failures are relatively frequent , including about one - quarter to one - third of patients who do not show any response to initial IST , and about half of the initial responders who may experience subsequent relapses or require continuous maintenance IST . For these patients , there is the option of further IST , which may include additional courses of ATG - based IST , or attempts with alternative IST regimens . DB00087 is a monoclonal anti - P31358 Ab , which has been recently investigated as novel IS agent for the treatment of AA patients . Recent data from different groups have clearly demonstrated the biological efficacy of DB00087 in AA patients , ruling out the initial concerns about possible unacceptable infectious risks secondary to its extremely powerful lympholytic effect . Preliminary data demonstrate a remarkable efficacy , especially in the context of relapsed and , to less extent , refractory patients , whereas data in naïve patients are still limited . On the basis of these results , DB00087 - based immunosuppression is a worthy option for AA and other marrow failure patients requiring a second - line IST . Here we describe a consensus regimen that the European Group for Blood and Marrow Transplantation Severe Aplastic Anemia Working Party suggests for AA patients failing initial IST who are not indicated for P09683 .",
"DB00087 ( Campath - 1H ) induction therapy and dendritic cells : Impact on peripheral dendritic cell repertoire in renal allograft recipients . Dendritic cells ( DC ) are the most potent antigen - presenting cells ( P25054 ) and are pivotal for initiating allograft immunity . Recently , particular DC subsets have been implicated also in allogeneic T cell hyporesponsiveness . DB00087 ( anti - P31358 , Campath - 1H ) is a novel T cell depleting antibody that is currently under investigation for the use in allogeneic organ transplantation . While recent studies demonstrated a conspicuous effect of alemtuzumab on peripheral DC in clinical graft - versus - host disease , its efficiency in patients receiving allogeneic organ transplants is still undefined . In the present study we assessed the peripheral DC repertoire in kidney transplant recipients after either alemtuzumab induction therapy followed by FK506 monotherapy or after conventional immunosuppression ( FK506 , mycophenolate mofetil and steroids ) without any induction agent . Induction with alemtuzumab caused a strong and sustained reduction of the total number of peripheral DC and a significant shift from myeloid to plasmacytoid DC subsets ( mDC / pDC ratio ) as early as 1 month post - transplantation . These data show that alemtuzumab induction targets the peripheral DC repertoire , which might add another mechanism allowing immunosuppressive drug minimization . Further studies are warranted to further elucidate the functional significance of these finding in the setting of allogeneic organ transplantation .",
"Use of the ImmuKnow assay to evaluate the effect of alemtuzumab - depleting induction therapy on cell - mediated immune function after renal transplantation . BACKGROUND : Good outcomes after renal transplantation are dependent on effective immunosuppression while minimizing infection . DB00087 ( Campath or Campath - 1H ) is an anti - P31358 humanized monoclonal IgG1 antibody which induces rapid and sustained depletion of circulating lymphocytes and has been effectively used as an immunosuppressant in post - transplant induction therapy . METHODS : We used the ImmuKnow assay to compare cell - mediated immune function in renal transplant patients treated with alemtuzumab or with conventional immunosuppressive tri - therapy . The ImmuKnow method determines the levels of adenosine triphosphate ( DB00171 ) released from P01730 cells following stimulation with a mitogen . RESULTS : We showed a statistically significant difference in the distribution of outcome after transplantation between the conventional and the Campath groups ( P = 0 . 010 ) . A significantly higher number of patients treated with alemtuzumab induction therapy were stable after transplantation compared to those treated with conventional immunosuppressive tri - therapy ( 96 . 6 vs . 75 . 7 % ) . DB00171 values were significantly higher in the conventional group compared to the Campath group at 180 days after transplantation ( P < 0 . 001 ) . DB00171 levels did not change significantly over time in clinically stable kidney recipients treated with alemtuzumab induction therapy ( P = 0 . 554 ) . CONCLUSIONS : The ImmuKnow assay is a useful tool for evaluating the global immune response in alemtuzumab - treated renal transplant patients . DB00087 - depleting induction therapy remains effective for at least 180 days .",
"Identification of new carbohydrate and membrane protein antigens in cardiac xenotransplantation . BACKGROUND : α1 , 3 - Galactosyltransferase gene knockout ( GTKO ) pigs reduced the significance of antibody to galactose alpha 1 , 3 - galactose ( Gal ) antigens but did not eliminate delayed xenograft rejection ( DXR ) . We hypothesize that DXR of GTKO organs results from an antibody response to a limited number of non - Gal endothelial cell ( EC ) membrane antigens . In this study , we screened a retrovirus expression library to identify EC membrane antigens detected after cardiac xenotransplantation . METHODS : Expression libraries were made from GT : P15529 and GTKO porcine aortic ECs . Viral stocks were used to infect human embryonic kidney cells ( P29320 ) that were selected by flow cytometry for IgG binding from sensitized cardiac heterotopic xenograft recipients . After three to seven rounds of selection , individual clones were assessed for non - Gal IgG binding . The porcine complementary DNA was recovered by polymerase chain reaction amplification , sequenced , and identified by homology comparisons . RESULTS : A total of 199 and 317 clones were analyzed from GT : P15529 and GTKO porcine aortic EC complementary DNA libraries , respectively . Sequence analysis identified porcine P21926 , P15529 , P13987 , and the EC protein C receptor . We also identified porcine annexin A2 and a glycosyltransferase with homology to the human β1 , 4 N - acetylgalactosaminyl transferase 2 gene . CONCLUSION : The identified proteins include key EC functions and suggest that non - Gal antibody responses may compromise EC functions and thereby contribute to DXR . Recovery of the porcine β1 , 4 N - acetylgalactosaminyl transferase 2 suggests that an antibody response to a SD - like carbohydrate may represent a new carbohydrate moiety involved in xenotransplantation . The identification of these porcine gene products may lead to further donor modification to enhance resistance to DXR and further reduce the level of xenograft antigenicity .",
"Quantitative methylation profiles for multiple tumor suppressor gene promoters in salivary gland tumors . BACKGROUND : Methylation profiling of tumor suppressor gene ( TSGs ) promoters is quickly becoming a powerful diagnostic tool for the early detection , prognosis , and even prediction of clinical response to treatment . Few studies address this in salivary gland tumors ( SGTs ) ; hence the promoter methylation profile of various TSGs was quantitatively assessed in primary O43765 tissue to determine if tumor - specific alterations could be detected . METHODOLOGY : DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence - based , quantitative methylation - specific PCR ( qMSP ) . The data were utilized in a binary fashion as well as quantitatively ( using a methylation quotient ) allowing for better profiling and interpretation of results . PRINCIPAL FINDINGS : The average number of methylation events across the studied genes was highest in salivary duct carcinoma ( P18827 ) , with a methylation value of 9 . 6 , compared to the normal 4 . 5 ( p < 0 . 0003 ) . There was a variable frequency and individual methylation quotient detected , depending on the Q9GZX9 and the tumor type . When comparing normal , benign , and malignant SGTs , there was a statistically significant trend for increasing methylation in P25054 , Mint 1 , P09936 , P10826 , and Timp3 . CONCLUSIONS / SIGNIFICANCE : Screening promoter methylation profiles in SGTs showed considerable heterogeneity . The methylation status of certain markers was surprisingly high in even normal salivary tissue , confirming the need for such controls . Several TSGs were found to be associated with malignant SGTs , especially P18827 . Further study is needed to evaluate the potential use of these associations in the detection , prognosis , and therapeutic outcome of these rare tumors .",
"Immunity 12 years after alemtuzumab in RA : CD5 ⁺ B - cell depletion , thymus - dependent T - cell reconstitution and normal vaccine responses . OBJECTIVES : Lymphocyte depleting therapies have been used to treat refractory autoimmune disease , including RA , but treatment may be associated with long - term lymphopenia . It is unclear whether delayed reconstitution preferentially affects lymphocyte subsets , how this modulates immune challenges and whether thymic function influences the outcome . These questions are now addressed in a detailed analysis of RA patients 12 years after alemtuzumab ( anti - P31358 ) treatment . METHODS : Blood was obtained from 20 RA patients 12 years after alemtuzumab treatment . Lymphocyte subsets were enumerated by flow cytometry . T - cell receptor excision circles ( TRECs ) / ml were determined to quantify thymic function , and serological responses to neoantigens and recall antigens were assessed . RESULTS : RA patients remained lymphopenic 12 years after their first dose of alemtuzumab . P06127 (+) B cells , which may be associated with autoantibody production , were significantly reduced in alemtuzumab - treated patients compared with age - matched disease controls . In addition , naïve and memory P01730 (+) T - cell subsets were present in altered proportions in patients who had received alemtuzumab , with increased effector memory P01730 (+) T cells , and decreased naïve and central memory P01730 (+) T cells . TRECs were detectable in alemtuzumab - treated patients and correlated with P01730 (+) lymphocyte counts . Vaccine responses to neoantigens and recall antigens fell within the normal range for an ageing population . CONCLUSIONS : DB00087 therapy resulted in long - term alterations in lymphocyte subsets . The significance of these changes remains uncertain but patients respond normally to antigenic challenges . Thymic function remains an important determinant of T - cell reconstitution even several years after lymphocytotoxic therapy .",
"DB00087 in the treatment of chronic lymphocytic leukemia . DB00087 is a humanized therapeutic monoclonal antibody ( MAb ) that recognizes the P31358 antigen , expressed on normal and neoplastic lymphocytes , monocytes , and natural killer cells . In 2001 , alemtuzumab was approved in the US and Europe to treat B - cell chronic lymphocytic leukemia ( CLL ) that had been treated previously with alkylating agents and was refractory to fludarabine . In heavily pretreated patients this MAb is able to produce response rates of about 40 % , and in symptomatic , previously untreated patients response rates of more than 80 % can be achieved . DB00087 can also be used in patients with CLL as a preparative regimen for stem cell transplantation ( P09683 ) and to prevent graft versus host disease . Moreover its in vivo use before or after P09683 may also potentially result in depletion of residual leukemia cells , especially in the autologous setting . Adverse events associated with alemtuzumab include acute first - dose reaction , hematologic toxicity , and infectious complications . Usually they are predictable , manageable , and acceptable in the context of CLL . However , in a significant percentage of patients , cytomegalovirus reactivation occurs during alemtuzumab therapy , and routine weekly monitoring with the polymerase chain reaction methodology is indicated . Moreover , antiviral and antibacterial prophylaxis is mandatory .",
"DB00087 as a bridge to allogeneic P09683 in atypical hemophagocytic lymphohistiocytosis . BACKGROUND : A 39 - year - old woman with no relevant medical or family history was admitted to hospital with episodic fever , which persisted despite antibiotic therapy . Other notable findings at admission were splenomegaly , pancytopenia , hyponatremia , elevated levels of liver enzymes , hyperferritinemia and hypofibrinogenemia . INVESTIGATIONS : Physical examination , laboratory tests , rheumatic marker serology , pathogen detection assays , complete blood counts , measurement of levels of ferritin , fibrinogen , triglycerides and soluble CD25 , natural killer cell functional studies , P14222 mutation analysis , renal biopsy , bone marrow biopsy , CT imaging of the chest and abdomen . DIAGNOSIS : Idiopathic , atypical hemophagocytic lymphohistiocytosis . MANAGEMENT : Initial treatment with antibiotics was followed by immunosuppressive therapy ( including intravenous immunoglobulin , ciclosporin , infliximab , corticosteroids and etoposide ) . Remission was achieved by treatment with the anti - P31358 monoclonal antibody , alemtuzumab , after which allogeneic stem - cell transplantation ( with reduced - intensity conditioning treatment and graft - versus - host disease prophylaxis ) resulted in a definitive cure .",
"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK48___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK48___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK48___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .",
"[ ___MASK39___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .",
"Ex vivo - expanded cynomolgus macaque regulatory T cells are resistant to alemtuzumab - mediated cytotoxicity . DB00087 ( Campath - 1H ) is a humanized monoclonal antibody ( Ab ) directed against P31358 that depletes lymphocytes and other leukocytes , mainly by complement - dependent mechanisms . We investigated the influence of alemtuzumab ( i ) on ex vivo - expanded cynomolgus monkey regulatory T cells ( Treg ) generated for prospective use in adoptive cell therapy and ( ii ) on naturally occurring Treg following alemtuzumab infusion . Treg were isolated from PBMC and lymph nodes and expanded for two rounds . P31358 expression , binding of alemtuzumab and both complement - mediated killing and Ab - dependent cell - mediated cytotoxicity ( ADCC ) were compared between freshly isolated and expanded Treg and effector T cells . Monkeys undergoing allogeneic heart transplantation given alemtuzumab were monitored for Treg and serum alemtuzumab activity . Ex vivo - expanded Treg showed progressive downregulation of P31358 expression , absence of alemtuzumab binding , minimal change in complement inhibitory protein ( P15529 ) expression and no complement - dependent killing or ADCC . Infusion of alemtuzumab caused potent depletion of all lymphocytes , but a transient increase in the incidence of circulating Treg . After infusion of alemtuzumab , monkey serum killed fresh PBMC , but not expanded Treg . Thus , expanded cynomolgus monkey Treg are resistant to alemtuzumab - mediated , complement - dependent cytotoxicity . Furthermore , our data suggest that these expanded monkey Treg can be infused into graft recipients given alemtuzumab without risk of complement - mediated killing .",
"EEG changes and serum anticholinergic activity measured in patients with delirium in the intensive care unit . The aim of this study was to examine whether serum anticholinergic activity ( P0DJI8 ) is a reliable indicator of delirium in the ICU , and whether there is a significant correlation between P0DJI8 and quantitative electroencephalographic ( EEG ) data in delirious patients . In a prospective cohort study , we assessed ICU patients diagnosed with delirium ( n = 37 ) . EEG measurements and blood analysis including P0DJI8 were performed 48 h following ICU admission . The presence of delirium was evaluated using the Confusion Assessment Method for critically ill patients in ICU ( P62158 - ICU ) . The P0DJI8 level was measured using a competitive radioreceptor binding assay for muscarinergic receptors and quantitative EEG was measured using the CATEEM system . We found that , under comparable conditions , patients in the delirium group showed a higher relative EEG theta power and a reduced alpha power ( n = 17 ) than did the non - delirious patients ( n = 20 ) . No difference in measured P0DJI8 levels were seen ; therefore , there was no correlation between P0DJI8 and EEG measurements in delirious patients . We conclude that , in contrast to the EEG , the P0DJI8 level can not be proposed as a tool for diagnosing delirium in ICU patients .",
"Amplification of human B cell activation by a monoclonal antibody to the B cell - specific antigen P20273 , Bp 130 / 140 . The B cell - specific antigen P20273 is a 130 / 140 - Kd complex and is unique among human B cell antigens , since its surface expression is restricted to a subpopulation of Ig + B cells . Here the function of the P20273 antigen was evaluated by using the mAb Q9UBN7 , directed against one of the epitopes on the molecule . The Q9UBN7 antibody was constimulatory with anti - Ig in inducing small , dense tonsillar cells to proliferate ; however , the antibody by itself was devoid of stimulatory activity . Anti - P20273 antibody also induced more anti - Ig - treated B cells to leave G0 and enter the P55008 phase of the cell cycle . It also was constimulatory with low - m . w . BCGF and with an antibody to a 50 - Kd polypeptide , P25942 , which mediates a BCGF - like activity . Results of kinetic experiments and analysis of different B cell fractions suggested that anti - P20273 acts during an early phase of B cell activation , probably by amplifying the anti - Ig signal . F ( ab ') 2 fragments of anti - P20273 Q9UBN7 were as effective as the whole antibody in inducing augmentation of B cell proliferation , showing that the Fc portion of the molecule was not required for the activity . The results of these experiments , together with the intriguing distribution of the Bp 130 / 140 antigen in B cell ontogeny , suggest that this molecule plays an important role in the process that leads to B cell activation and proliferation .",
"Killing tumour cells by alkylphosphocholines : evidence for involvement of CD95 . Many lipids act as cellular messengers and lead to a variety of different cellular responses . Out of the group of these compounds the ceramides are able to induce apoptosis , and some synthetic lipids can mimic this effect . Apoptosis is an important mechanism whereby chemotherapeutics exhibit their anti - oncogenic activity . Although , some lipid analogues were used in clinical trials , they exert severe side effects and their mechanism of action is widely unknown . We present here a new class of synthetic alkylphosphocholines ( P25054 ) that induce programmed cell death in leukaemia cells . The signs of apoptosis arise after 1 h of incubation with these compounds as shown by phosphatidylserine externalisation followed by caspase activation and DNA fragmentation . We demonstrate that the molecular target of these lipids is upstream of caspases and Bcl - 2 . Experiments with Q13158 dominant negative cells reveal that induction of apoptosis occurs on the level of CD95 and that these compounds can now be optimised for their capacity to activate the apoptosis - inducing receptor CD95 .",
"Dynamic immune cell accumulation during flow - induced atherogenesis in mouse carotid artery : an expanded flow cytometry method . OBJECTIVE : Inflammation plays a central role in atherosclerosis . However , the detailed changes in the composition and quantity of leukocytes in the arterial wall during atherogenesis are not fully understood in part because of the lack of suitable methods and animal models . METHODS AND RESULTS : We developed a 10 - fluorochrome , 13 - parameter flow cytometry method to quantitate 7 major leukocyte subsets in a single digested arterial wall sample . P02649 - deficient mice underwent left carotid artery ( LCA ) partial ligation and were fed a high - fat diet for 4 to 28 days . Monocyte / macrophages , dendritic cells , granulocytes , natural killer cells , and P01730 T cells significantly infiltrated the LCA as early as 4 days . Monocyte / macrophages and dendritic cells decreased between 7 and 14 days , whereas T - cell numbers remained steady . Leukocyte numbers peaked at 7 days , preceding atheroma formation at 14 days . B cells entered LCA by 14 days . Control right carotid and sham - ligated LCAs showed no significant infiltrates . Polymerase chain reaction and ELISA arrays showed that expression of proinflammatory cytokines and chemokines peaked at 7 and 14 days postligation , respectively . CONCLUSION : This is the first quantitative description of leukocyte number and composition over the life span of murine atherosclerosis . These results show that disturbed flow induces rapid and dynamic leukocyte accumulation in the arterial wall during the initiation and progression of atherosclerosis .",
"E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis .",
"Immunophenotypic profile and role of adhesion molecules in splenic marginal zone lymphoma with bone marrow involvement . Splenic Marginal Zone Lymphoma ( SMZL ) , with or without villous lymphocytes ( VL +/- ) , is a low - grade lymphoproliferative disorder with constant involvement of the bone marrow ( BM ) . Different BM infiltration patterns , mainly intra - sinusoidal , interstitial and nodular , have been described . Adhesion molecules ( AMs ) constitute a heterogeneous group of antigenic receptors playing a major role in leukocyte recruitment , in lymphocyte homing and in cellular - mediated immune response . Evolution and pattern of the BM infiltrate could be influenced by a variable expression of AM on SMZL lymphocytes . The degree and pattern of BM infiltration and the immunohistochemical expression of AM ( H - P62158 , P20273 , P14151 , Q14242 , P16581 , P05362 , P19320 and Beta - 1 integrin ) among the different infiltration patterns were evaluated in BM biopsies of 38 patients with SMZL and graded according to a semi - quantitative score ranging from 0 - 4 and based on the percentage of positive cells . An intra - sinusoidal infiltration was constantly observed , alone or in conjunction with other patterns . H - P62158 and P20273 showed a moderate - to - high degree of positivity in the intra - sinusoidal infiltrate ( median expression grade - 3 ) and were expressed in the neoplastic lymphocytes independently from the pattern . Q14242 was mostly expressed in the perisinusoidal region and in case of interstitial infiltration ( grade - 2 ) . P05362 and P19320 were selectively expressed in the nodules as a reticular meshwork located in the core region ( grade - 2 ) ; P19320 was also expressed in the perinodular endothelia . P16581 , P14151 and beta - 1 integrin proved constantly negative . These data suggest that different expression of AM can influence the modality of BM infiltration in SMZL .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"In vivo selection for human and murine hematopoietic cells transduced with a therapeutic P16455 lentiviral vector that inhibits HIV replication . We have developed an HIV - based lentiviral vector , DB05251 , which efficiently transduces human P28906 + progenitors and P01730 + T lymphocytes . DB05251 contains an antisense sequence against the HIV envelope and is currently being evaluated for safety in a clinical trial for treatment of HIV . Selective outgrowth of transduced hematopoietic cells in vivo is anticipated to increase the therapeutic efficacy of this treatment by maximizing the persistence of virus - resistant cells in the body . Although HIV resistance is selective , additional selection may aid in treatment efficacy due to the vast quantity of target cells . Therefore , we engineered DB05251 to express the P140K P16455 gene to drive potent drug - mediated in vivo selection for transduced hematopoietic long - term repopulating cells . Suboptimally transduced T cell cultures treated with O6 - benzylguanine and DB00262 were selected from 3 to 100 % , and after selection cultures did not support HIV replication . Primary P28906 + progenitors derived from G - P04141 - mobilized peripheral blood were transduced at 27 to 35 % efficiency . Approximate sixfold selection was observed for transduced P28906 + progenitors , colony - forming units , and long - term culture - initiating cells . Multilineage in vivo selection was demonstrated for transduced murine hematopoietic cells in human P28906 (+)- derived hematopoietic cells in NOD - SCID mice . These results establish efficient ex vivo and in vivo selection for hematopoietic cells transduced with lentiviral vectors and support the potential therapeutic benefit of this strategy in human gene therapy .",
"Sickle cell trait in Ivory Coast athletic throw and jump champions , 1956 - 1995 . In order to assess the performance of subjects with sickle cell trait ( P09683 ) during brief and explosive exercise involving mainly alactic anaerobic metabolism , the percentage of athletes with P09683 was determined in Ivory Coast track and field throw and jump champions , both men and women , for the period 1956 - 1995 . Thirty - four ( 27 . 8 % ) sickle cell trait carriers ( SCTC ) were identified among the 122 national champions that we were able to contact . These 34 SCTC had won 78 national titles ( 24 . 5 % ) and established 37 national records ( 43 . 5 % ) , distributed among the throw and jump events . These percentages were significantly higher than the prevalence of P09683 in the general Ivory Coast population ( 12 . 0 % ) . The women ' s high jump and men ' s shot put events had the highest percentages of SCTC record holders ( 90 . 9 % and 87 . 5 % , respectively ) . Moreover , the two top national record holders and title winners , one man and one woman , were SCTC athletes , and their hemoglobin S percentage ( HbS : Q04695 % and 39 . 4 % , respectively ) and mean corpuscular volume ( MCV ) excluded an associated alpha - thalassemia . We conclude that the significantly higher percentage of SCTCs among Ivory Coast track and field champions , as compared to the percentage in the general population suggests that P09683 may be a determinant factor for success in brief and explosive track and field events involving mainly alactic anaerobic metabolism .",
"DB00087 for the prevention and treatment of graft - versus - host disease . DB00087 is a humanized monoclonal antibody against the P31358 antigen , which is expressed on the surface of various hematopoietic cells such as B and T lymphocytes , and has been widely used for preventing acute graft - versus - host disease ( GVHD ) in allogeneic stem cell transplantation ( P09683 ) . Administration of 100 mg alemtuzumab before transplantation has resulted in a low incidence of acute GVHD in HLA - matched and mismatched transplantation from either related or unrelated donors . However , because alemtuzumab could remain in the blood at the lympholytic level 1 - 2 months after transplantation , immune reconstitution was substantially delayed , leading to a high incidence of viral infection and relapse . A dose reduction of alemtuzumab was attempted in a reduced - intensity conditioning setting to facilitate immune reconstitution , and this resulted in earlier immune reconstitution , but the clinical benefits were unclear . The dose of alemtuzumab and the timing of its administration should be optimized to maximize the benefit of acute GVHD suppression and minimize the risk of infection and relapse . Another strategy to facilitate immune reconstitution and augment anti - tumor effects is donor cell infusion of T and NK cells . Although there is accumulating evidence regarding the use of alemtuzumab for acute GVHD prevention , information on the salvage treatment for steroid - refractory acute and chronic GVHD is still limited .",
"Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV / HAART - associated dyslipidemia : further evidence for a unique form of metabolic syndrome in HIV patients . INTRODUCTION : Plasma triglycerides ( TG ) and HDL - C are inversely related in Metabolic Syndrome ( MetS ) , due to exchange of VLDL - TG for HDL - cholesteryl esters catalyzed by cholesteryl ester transfer protein ( P11597 ) . We investigated the relationship of TG to HDL - C in highly - active antiretroviral drug ( HAART ) - treated HIV patients . METHODS : Fasting plasma TG and HDL - C levels were compared in 179 hypertriglyceridemic HIV / HAART patients and 71 HIV - negative persons ( 31 normotriglyceridemic ( NL ) and 40 hypertriglyceridemic due to type IV hyperlipidemia ( HTG ) ) . P11597 mass and activity were compared in 19 NL and 87 HIV / HAART subjects . RESULTS : Among the three groups , a plot of HDL - C vs . TG gave similar slopes but significantly different y - intercepts ( 9 . 24 ± 0 . 45 , 8 . 16 ± 0 . 54 , 6 . 70 ± 0 . 65 , sqrt ( HDL - C ) for NL , HIV and HTG respectively ; P < 0 . 001 ) ; this difference persisted after adjusting HDL - C for TG , age , BMI , gender , glucose , P01730 count , viral load and HAART strata ( 7 . 18 ± 0 . 20 , 6 . 20 ± 0 . 05 and 4 . 55 ± 0 . 15 sqrt ( HDL - C ) for NL , HIV and HTG , respectively , P < 0 . 001 ) . P11597 activity was not different between NL and HIV , but P11597 mass was significantly higher in HIV ( 1 . 47 ± 0 . 53 compared to 0 . 93 ± 0 . 27μg / mL , P < 0 . 0001 ) , hence P11597 specific activity was lower in HIV ( 22 . 67 ± 13 . 46 compared to 28 . 46 ± 8 . 24nmol / μg / h , P = 0 . 001 ) . CONCLUSIONS : Dyslipidemic HIV / HAART patients have a distinctive HDL - C plasma concentration adjusted for TG . The weak inverse relationship between HDL - C and TG is not explained by altered total P11597 activity ; it could result from a non - P11597 - dependent mechanism or a decrease in P11597 function due to inhibitors of P11597 activity in HIV patients ' plasma .",
"Fanconi anemia : current management . Fanconi anemia ( FA ) is an autosomal recessive chromosomal instability disorder , characterized by congenital anomalies , defective hematopoiesis and a high risk of developing acute myeloid leukemia and certain solid tumors . All racial and ethnic groups are at risk , and at least 11 complementation groups have been identified and the genes defective in eight of these have been identified ( O15360 , C , D2 , E , F , G , L and P51587 ) . FA - A is the most common complementation group , accounting for approximately 65 % of all affected individuals . The gold - standard screening test for FA is based on the characteristic hypersensitivity of FA cells to the crosslinking agents , such as mitomicin C or diepoxybutane . Recent progress has been made in identifying the genes bearing pathogenetically relevant mutations , but slower progress has been made in defining the precise functions of the proteins in normal cells , in part because that the proteins are multifunctional . Molecular studies have established that a common pathway exist , both between the FA proteins and other proteins involved in DNA repair such as NBS1 , Q13315 , P38398 and P51587 . Stem cell transplantation ( P09683 ) is the only option for establishing normal hematopoiesis . To reduce undue toxicities due to inherent hypersensitivity , nonmyeloablative conditioning for transplants has been advocated . This review summarizes the general clinical and hematologic features and the current management of FA . Fanconi anemia ( FA ) is the commonest type of inherited bone marrow failure syndrome with the birth incidence of around three per million . The inheritance pattern is autosomal recessive with the estimated heterozygote frequency being one in 300 in Europe and the US .",
"P13987 underlines the antiatherosclerotic effects of C - phycocyanin on mice . The effects of C - phycocyanin ( C - PC ) on atherosclerosis and the regulatory effects of P13987 gene on anti - atherosclerotic roles of C - PC were investigated . P02649 knockout ( ApoE (-/-) ) mice were randomly divided into four groups : control group , C - PC treatment group , P13987 transfection group and C - PC + P13987 synergy group . The mice were fed with high - fat - diet and treated with drug intervention at the same time . Results showed the atherosclerotic mouse model was successfully established . P13987 was over - expressed in blood and tissue cells . Single P13987 or C - PC could reduce blood lipid levels and promote the expression of anti - apoptotic Bcl - 2 but inhibit pro - apoptotic Fas proteins in endothelial cells . The expression levels of cell cycle protein D1 ( P12004 D1 ) and mRNA levels of cyclin dependent protein kinase 4 ( P11802 ) in smooth muscle cells were restrained by P13987 and C - PC . P13987 or C - PC alone could inhibit the formation of atherosclerotic plaque by suppressing P08253 protein expression . In addition , C - PC could promote P13987 expression . So both P13987 and C - PC could inhibit the progress of atherosclerosis , and the anti - atherosclerotic effects of C - PC might be fulfilled by promoting P13987 expression , preventing smooth muscle cell proliferation and the apoptosis of endothelial cells , reducing blood fat levels , and at last inhibiting the development of atherosclerosis .",
"DB00087 induction of intracellular signaling and apoptosis in malignant B lymphocytes . The molecular changes induced by alemtuzumab following binding of P31358 on B tumor cells were investigated . DB00087 alone had no detectable impact on cell signaling but cross - linking of alemtuzumab on the surface of B tumor lines with anti - human Fc antibodies induced a transient Ca ( 2 +) flux followed by phosphorylation of several kinases involved in stress and survival pathways , and expression of associated proteins including P01375 - α . Cross - linking of alemtuzumab also induced capping and caspase - dependent apoptosis of the tumor lines . When using primary cells from B - CLL patients , alemtuzumab alone was capable of inducing protein phosphorylation and apoptosis through the cross - linking of alemtuzumab by FcγRIIb receptors on B - CLL cells . Apoptosis was prevented by blocking of FcγRIIb receptors with anti - CD32 antibody . Overall , our results indicate that cross - linking of alemtuzumab on B tumor cells can occur naturally through Fc receptor interaction and leads to the activation of specific cellular pathways and induction of apoptosis ."
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___MASK38___
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MH_train_326
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interacts_with DB00120?
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[
"Differential effects of placental restriction on P01344 , Q01718 and steroidogenic enzyme mRNA levels in the foetal sheep adrenal . We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for P01308 - like Growth Factor II ( P01344 ) , the IGF binding protein P18065 , Steroidogenic Factor 1 ( Q13285 ) and adrenocorticotrophic hormone ( ___MASK79___ ) receptor ( Q01718 ) and the steroidogenic cytochrome P - 450 enzymes : cholesterol side chain cleavage ( P05108 ) , 17alpha - hydroxylase ( P05093 ) and 21 - hydroxylase ( CYP21A1 ) ; and 3beta - hydroxysteroid dehydrogenase / Delta5Delta4 isomerase ( 3betaHSD ) . Endometrial caruncles were removed from non - pregnant ewes before mating ( placental restriction group ; PR ) . The total adrenal : foetal weight ratio was higher in PR ( n = 6 foetuses ) than in control foetuses ( n = 6 foetuses ) . There was no difference in plasma ___MASK79___ concentrations between the PR and control foetuses between 130 and 140 days gestation . Adrenal P01344 mRNA levels were lower ( P < 0 . 05 ) in the PR group , however , adrenal P18065 mRNA levels were not different between the PR and control groups . Adrenal Q01718 mRNA levels were also lower whilst P05108 mRNA levels were increased ( P < 0 . 005 ) in the PR group . We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ___MASK79___ are important in foetal adrenal activation during chronic , sustained hypoxaemia .",
"Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux .",
"___MASK1___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK1___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK70___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"___MASK42___ : kinetic and dynamic profile in the treatment of pain . ___MASK42___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK42___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK42___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK42___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .",
"P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .",
"[ Low doses of sulphonyluria as a successful replacement for insulin therapy in a patient with neonatal diabetes due to a mutation of Q14654 gene encoding Kir6 . 2 ] . Neonatal diabetes mellitus is a rare metabolic disorder with an estimated incidence of 1 : 300 . 000 to 400 . 000 newborns , and less than 50 % of the neonates have permanent neonatal diabetes mellitus ( PNDM ) . Recently , activating mutation in the Q14654 gene encoding Kir6 . 2 subunit of the adenosin triphosphate - sensitive potassium ( K ( DB00171 ) ) channel has been described as the most frequent cause of PNDM . Under physiological circumstances K ( DB00171 ) channel closure plays a central role in glucose - stimulated insulin secretion from pancreatic beta cells . Sulphonylurea drugs stimulate insulin secretion by binding to and closing K ( DB00171 ) channels and thus bypassing beta cell metabolism stimulate the same chain of reactions as glucose . We describe a boy diagnosed with PNDM at the age of 3 months when insulin therapy was started , and at the age of 4 . 5 years Q14654 gene was sequenced and found that the boy carried a de novo activating R201H mutation . P01308 therapy was successfully switched to low doses of oral glibenclamide . Accordingly , it is important to emphasize that every person diagnosed with diabetes before six months of life , however old they actually are , should be tested for K ( DB00171 ) mutations which is offered via the website www . diabetesgenes . org .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK49___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Identification of insulin - stimulated phosphorylation sites on calmodulin . P01308 enhances calmodulin phosphorylation in vivo . To determine the insulin - sensitive phosphorylation sites , phosphocalmodulin was immunoprecipitated from Chinese hamster ovary cells expressing human insulin receptors ( CHO / IR ) . P62158 was constitutively phosphorylated on serine , threonine , and tyrosine residues , and insulin enhanced phosphate incorporation on serine and tyrosine residues . Phosphocalmodulin immunoprecipitated from control and insulin - treated CHO / IR cells , and calmodulin phosphorylated in vitro by the insulin receptor kinase and casein kinase II were resolved by two - dimensional phosphopeptide mapping . Several common phosphopeptides were detected . The phosphopeptides from the in vitro maps were eluted and phosphoamino acid analysis , manual sequencing , strong cation exchange chromatography , and additional proteolysis were performed . This strategy demonstrated that DB00135 - 99 and DB00135 - 138 were phosphorylated in vitro by the insulin receptor kinase and DB00156 - 79 , DB00133 - 81 , DB00133 - 101 and DB00156 - 117 were phosphorylated by casein kinase II . In vivo phosphorylation sites were identified by comigration of phosphopeptides on two - dimensional maps with phosphopeptides derived from calmodulin phosphorylated in vitro and by phosphoamino acid analysis . This approach revealed that DB00135 - 99 and DB00135 - 138 of calmodulin were phosphorylated in CHO / IR cells in response to insulin . Additional sites remain to be identified . The identification of the insulin - stimulated in vivo tyrosine phosphorylation sites should facilitate the elucidation of the physiological role of phosphocal - modulin .",
"Interleukin 10 blocks matrix metalloproteinase - 2 and membrane type 1 - matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 - like growth factor ( IGF ) I has been shown previously to up - regulate matrix metalloproteinase - 2 ( P08253 ) production , whereas the interleukin ( IL ) 10 / P22301 receptor axis has been found to down - regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) - MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i . e . , P84074 - 10a and P84074 - 10c ) derived from high - grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0 . 001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5 ' promoter region of the P08253 gene ( - 1659 to - 555 bp ) additionally showed that P05019 stimulated p53 - dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 - induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein ( s ) binding to a putative \" silencer element \" ( - 1309 to - 555 fragment ) downstream of the p53 binding site ( - 1649 to - 1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK45___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK45___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK52___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK24___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Diminished phosphodiesterase - 8B potentiates biphasic insulin response to glucose . DB02527 activates multiple signal pathways , crucial for the pancreatic beta - cells function and survival and is a major potentiator of insulin release . A family of phosphodiesterases ( PDEs ) terminate the DB02527 signals . We examined the expression of PDEs in rat beta - cells and their role in the regulation of insulin response . Using RT - PCR and Western blot analyses , we identified Q14432 , Q13370 , Q07343 , Q08499 , and O95263 in rat islets and in P01308 - 1E cells and several possible splice variants of these PDEs . Specific depletion of Q14432 with small interfering ( si ) RNA ( siPDE3A ) led to a small ( 67 % ) increase in the insulin response to glucose in P01308 - 1E cells but not rat islets . siPDE3A had no effect on the glucagon - like peptide - 1 ( 10 nmol / liter ) potentiated insulin response in rat islets . Depletion in O95263 levels in rat islets using similar technology ( siPDE8B ) increased insulin response to glucose by 70 % , the potentiation being of similar magnitude during the first and second phase insulin release . The siPDE8B - potentiated insulin response was further increased by 23 % when glucagon - like peptide - 1 was included during the glucose stimulus . In conclusion , O95263 is expressed in a small number of tissues unrelated to glucose or fat metabolism . We propose that O95263 , an DB07954 - insensitive DB02527 - specific phosphodiesterase , could prove a novel target for enhanced insulin response , affecting a specific pool of DB02527 involved in the control of insulin granule trafficking and exocytosis . Finally , we discuss evidence for functional compartmentation of DB02527 in pancreatic beta - cells .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK58___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents ."
] |
[
"___MASK1___",
"___MASK24___",
"___MASK42___",
"___MASK45___",
"___MASK49___",
"___MASK52___",
"___MASK58___",
"___MASK70___",
"___MASK79___"
] |
___MASK52___
|
MH_train_327
|
interacts_with DB00642?
|
[
"Myocardial function and haemodynamics in extensive burn trauma : evaluation by clinical signs , invasive monitoring , echocardiography and cytokine concentrations . A prospective clinical study . BACKGROUND : The objectives of this study were to ( 1 ). describe the haemodynamic profile of patients with extensive burns during the early fluid resuscitation phase , ( 2 ). evaluate myocardial performance by invasive monitoring and echocardiography and ( 3 ). analyze the relations between serum cytokine ( P05231 , P10145 , P01375 ) and natriuretic peptide ( P01160 , DB04899 ) concentrations and myocardial function in these patients . METHODS : Prospective , clinical study in a tertiary care burn centre . Invasive haemodynamic measurements including a pulmonary artery catheter , echocardiography , blood samples for cytokine and atriopeptide analyses . The follow - up time was up to 72 h postinjury . RESULTS : According to echocardiography , patients were hypovolaemic despite aggressive ( median 7 , 9 ml kg (- 1 ) h (- 1 ) , range 3 . 3 - 11 . 7 ) fluid resuscitation and adequate urine output ( median 0 . 9 ml kg (- 1 ) h (- 1 ) , range 0 . 46 - 1 . 35 ) during the first day postinjury . There were no consistent findings of hyperlactatemia , metabolic acidosis or low mixed venous oxygen saturations . Daily highest and lowest values of cardiac index and stroke volume index increased and the lowest and highest values of systemic vascular resistance decreased . Cardiac performance ( stroke volume index ) improved during the study period even though there were no initial signs of myocardial depression in echocardiography . Three patients received a dobutamine infusion based on clinical judgement . There was no consistent association between haemodynamic changes and plasma cytokine concentrations . CONCLUSION : Persisting hypovolaemia is evident in the resuscitation phase of extensive burns despite aggressive fluid therapy and the lack of classic signs of hypoperfusion . Cardiac performance improves during the first days after extensive burn injury without association with plasma cytokine profile .",
"Charcot - Marie - Tooth neuropathy related to chromosome 1 . One family with documented male - to - male transmission of Charcot - Marie - Tooth ( CMT ) neuropathy was studied clinically and by genetic linkage . Patients had progressive distal weakness and atrophy , areflexia , and distal sensory loss , but early onset ( before age 3 years ) in all 5 cases , and phrenic nerve involvement in the propositus ( a 39 - year - old woman ) requiring Q9HC77 ventilator support during the night . Motor - nerve conduction velocities ( MNCVs ) were significantly slow , consistent with severe demyelinating neuropathy . Electromyography ( EMG ) data were normal . Two - point and multipoint linkage analyses strongly suggested the presence of a CMT gene on chromosome 1q . A maximum multipoint lod score of 2 . 70 was obtained at P15941 ( theta = 0 ) , with the locus order centromere - P15941 - P02549 - Fc gamma RII - P01008 - telomere . Multipoint linkage analysis excluded the CMT locus from chromosome 17 markers in this family .",
"Modulation of P15941 and blood group antigen expression in gastric adenocarcinoma cells by cytokines . Immunohistological studies demonstrated that P15941 expression in gastric cancer is associated with a poor prognosis . As a mediator of cell - cell interactions , P15941 may also be involved in metastasis . However , these aspects are of relevance since cytokine levels are locally increased as a consequence of peritumorous inflammatory response and coexisting chronic gastritis . Therefore we analyzed the potential influence of several cytokines on the expression of tumor - associated P15941 and Lewis blood group antigens in gastric carcinoma cells . Gastric cancer cell lines AGS and KATOIII were incubated with the cytokines interleukin - 1beta , interferon - gamma , tumor necrosis factor - alpha ( P01375 ) , and hepatocyte growth factor over a period of 72 h . Expressions of mucin antigens and cytokine secretion were measured by immunocytochemistry and / or enzyme - linked immunosorbent assay ( ELISA ) . Analysis by fluorescence - activated cell sorter ( FACS ) demonstrated that P15941 and sialyl Lewis A reactivities of AGS cells were increased significantly following P01375 stimulation but not by other cytokines . Expression of mucin - associated antigens by cell line KATOIII was not affected by any of the employed cytokines . These data provide evidence that P01375 can raise the expression of important mucin peptide as well as mucin - associated carbohydrate antigens and thereby potentially influence the progression of gastric carcinomas .",
"The role of pemetrexed in advanced non small - cell lung cancer : special focus on pharmacology and mechanism of action . DB00642 is a newer antifolate drug that has been approved as first - line treatment for patients with advanced non - squamous , non - small cell lung cancer ( NSCLC ) in combination with cisplatin , and as single agent for relapsed or chemotherapy refractory NSCLC after platinum - containing chemotherapy , at a dose of 500 mg / m ( 2 ) . DB00642 undergoes intracellular activation by poly - gamma - glutamylation , that is essential for its antiproliferative activity . Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism , i . e . thymidylates synthase ( P04818 ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) , with P04818 being the most relevant target . DB00642 undergoes rapid renal elimination as unchanged parent compound , with a terminal half - life of between two to five hours . In later clinical development , the usefulness of supplementation with folic acid and vitamin B ( 12 ) became evident , to control pemetrexed - related toxicity . The results from the phase III upfront registration study , a retrospective observational data , and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed , DB00642 is active in patients with non - squamous cell NSCLC while no benefit is seen in patients with squamous - cell histology , possibly as a result of different expression of intratumoral P04818 . These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC .",
"Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury . Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia , related in part to implantation injury . The cell - specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells ( EC ) and medial smooth muscle cells ( SMC ) from canine vein grafts , 2 hours ( H ) to 30 days ( D ) following surgery . Our results demonstrate a robust genomic response beginning at 2 H , peaking at 12 - 24 H , declining by 7 D , and resolving by 30 D . Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses , apoptosis , mitosis , and extracellular matrix reorganization in both cell types . Through backpropagation an integrated network was built , starting with genes differentially expressed at 30 D , followed by adding upstream interactive genes from each prior time - point . This identified significant enrichment of P05231 , P10145 , NF - κB , dendritic cell maturation , glucocorticoid receptor , and Triggering Receptor Expressed on Myeloid Cells ( Q9NP99 ) signaling , as well as PPARα activation pathways in graft EC and SMC . Interactive network - based analyses identified P05231 , P10145 , IL - 1α , and P01308 Receptor ( P06213 ) as focus hub genes within these pathways . Real - time PCR was used for the validation of two of these genes : P05231 and P10145 , in addition to Collagen 11A1 ( P12107 ) , a cornerstone of the backpropagation . In conclusion , these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury , and identifying novel targets for its prevention .",
"[ Effects of chronic fluoxetine treatment on catalepsy and immune response in mice genetically predisposed to freezing reaction : the role of P08908 and 5 - Q13049 receptors and tph2 and P31645 genes ] . ASC / Icg ( Antidepressant Sensitive Catalepsy ) mouse strain selected for high predisposition to pinch - induced catalepsy is characterized by depressive - like behavior and impaired immune response . Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette - forming cells ( P41440 ) in spleen in ASC mice . Chronic fluoxetine administration had no effect on catalepsy and P41440 number in mice of parental cataleptic CBA / Lac strain . DB00472 failed to alter P08908 receptor functional activity in mice of both strains and diminished 5 - Q13049 receptor functional activity in CBA but not in ASC mice . No effect on cortical P08908 and 5 - Q13049 receptor mRNA levels and on P08908 receptor , tph2 ( tryptophan hydroxylase - 2 ) and P31645 ( serotonin transporter ) mesencephalic gene expression was observed in ASC mice . Other possible serotonergic mechanisms of fluoxetine effect on catalepsy and immune response in mice with depressive - like state are discussed .",
"Effect of lipid - lowering strategies on tubular cell biology . BACKGROUND : Interstitial fibrosis and the development of renal cysts are crucial phenomena in renal disease progression . While 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors has been shown to reduce the progression of several experimental nephropathies , the mechanism of their potential protective effect remaines unclear . METHODS : The antiproliferative , apoptotic , and fibrinolytic effects of P04035 inhibitors were assessed in primary cultured rat ( rPTCs ) and mouse proximal tubule cells ( mPTCs ) , in isolated rat proximal tubules , and in vivo in 5 / 6 nephrectomized rats ( Nx ) . RESULTS : In vitro , lovastatin inhibited rPTC proliferation in a manner selectively prevented by mevalonate , farnesyl - , or geranylgeranyl - pyrophosphate ( FPP or GGPP ) . ___MASK73___ reduced membrane - bound P01112 and fetal calf serum - induced c - fos and c - jun protein expression . Gel shift assay showed that lovastatin reduced activated protein - 1 ( AP - 1 ) binding activity . In vivo , lovastatin inhibited tubular cell proliferation after Nx , as measured by proliferative cell nuclear antigen staining . ___MASK73___ - treated mPTCs displayed nucleus cleavage and DNA ladder formation , which were prevented by GGPP . Like P01024 exoenzyme , lovastatin induced actin filament disruption , which preceded evidence of apoptosis . ___MASK73___ increased tissue - type plasminogen activator ( PA ) and decreased PA inhibitor activities and antigens ; these effects were prevented by mevalonate and GGPP but not FPP , and were reproduced by P01024 exoenzyme in a manner insensitive to GGPP . CONCLUSIONS : P04035 inhibitors decreased proliferation , increased apoptosis , and enhanced fibrinolytic activity of renal tubular cells via modulation of different isoprenylated proteins . These effects could participate to reduce the progression of renal diseases .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK59___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Internalization and translocation of a new chimeric protein composed of Pseudomonas aeruginosa exotoxin A and mouse dihydrofolate reductase as a model system . In an attempt to introduce a large peptide that is not normally translocated across membranes into the cytosol of eukaryotic cells , we created a new chimeric protein termed CEDH between Pseudomonas aeruginosa exotoxin A ( P25101 ) and a variant enzyme of Mus musculus dihydrofolate reductase ( P00374 ) with reduced affinity for antifolates , P25101 ( 1 - 413 ). P00374 ( 1 - 187 ). P25101 ( 609 - 613 ) . We have defined , genetically constructed and expressed the chimeric protein in Escherichia coli . We showed that the CEDH chimeric protein , purified to homogeneity on an immunoaffinity resin , confers a methotrexate - resistant phenotype to Chinese hamster ovary cells . Furthermore , the chimeric protein allowed the growth of dihydrofolate reductase - deficient Chinese hamster ovary cells in the absence of hypoxanthine and thymidine . These results demonstrated that the chimeric protein exhibited enzyme activity and possessed the tightly folded native structure , and that the P00374 protein can be selectively internalized and translocated via domains of exotoxin A . These data show that the P25101 system is an efficient system for the delivery of a variety of large polypeptides into the cytosol without stress to the target cells , and extends the use of this delivery system to proteins that are not normally translocated across membranes .",
"Modulation of mitogen - activated protein kinase cascades by differentiation - 1 protein : acquired drug resistance of hormone independent prostate cancer cells . PURPOSE : The inhibitor of differentiation - 1 protein ( Id - 1 ) is over expressed in multidrug resistance prostate cancer cells . We determined the effect of Id - 1 expression and its underlying pathways on the development of multidrug resistance in prostate cancer . MATERIALS AND METHODS : P01008 cells were transfected with the Id - 1 gene or a blank vector . Id - 1 mRNA expression was determined by reverse transcriptase - polymerase chain reaction and Id - 1 protein content was detected by immunoblot and flow cytometry . Cellular cytotoxicity was determined by MTT ( microculture 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ) assay ( Sigma Chemical Co . , St . Louis , Missouri ) . The activation and expression of mitogen - activated protein kinase ( MAPK ) were measured by transactivation assay and Western blotting , respectively . RESULTS : Id - 1 overproduction drove P01008 cells to become resistant to chemotherapeutic agents but did not induce mdr - 1 gene expression . The p38MAPK and c - jun N - terminal kinase ( JNK ) pathways were suppressed , which correlated with increased Id - 1 expression . No significant change in extracellular signal - regulated kinase ( P29323 ) activation was observed in Id - 1 transfectants compared with that of P01008 or vector control . Treatment of Id - 1 expressing cells with p38MAPK and JNK inhibitors resulted in decreased doxorubicin induced apoptosis . In contrast , Id - 1 expressing cells treated with P29323 inhibitor made cells more sensitive to drug induced apoptosis . CONCLUSIONS : Up - regulation of Id - 1 was found in prostate cancer multidrug resistant cells . Sustained P29323 activation , and JNK and p38MAPK inhibition by Id - 1 in cells may confer drug resistance . These changes in MAPKs could be a mechanism for the acquisition of multidrug resistance in prostate cancer .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK35___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK35___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK35___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK35___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"An improved effect size for single - case research : nonoverlap of all pairs . Nonoverlap of All Pairs ( Q8WYA6 ) , an index of data overlap between phases in single - case research , is demonstrated and field tested with 200 published AB contrasts . Q8WYA6 is a novel application of an established effect size known in various forms as Area Under the Curve ( AUC ) , the Common Language Effect Size ( CL ) , the Probability of Superiority ( PS ) , the Dominance Statistic ( DS ) , Mann - Whitney ' s U , and Sommers D , among others . Q8WYA6 was compared with 3 other non - overlap - based indices : P01160 ( percent of nonoverlapping data ) , P15941 ( percent of data points exceeding the median ) , and PAND ( percent of all nonoverlapping data ) , as well as Pearson ' s R ( 2 ) . Five questions were addressed about Q8WYA6 : ( a ) typical Q8WYA6 values , ( b ) its ability to discriminate among typical single - case research results , ( c ) its power and precision ( confidence interval width ) , ( d ) its correlation with the established effect size index , R ( 2 ) , and ( e ) its relationship with visual judgments . Results were positive , the new index equaling or outperforming the other overlap indices on most criteria .",
"Establishment of pemetrexed - resistant non - small cell lung cancer cell lines . DB00642 ( P15941 ) , a multitargeted antifolate with manageable toxicity , is active against non - squamous non - small cell lung cancer ; however , most patients eventually acquire resistance to P15941 . To elucidate the resistant mechanism , we established P15941 - resistant lung adenocarcinoma cell lines . Two parental cell lines , PC - 9 and A549 , were treated with step - wise increasing concentrations of P15941 . Growth inhibition was determined by the 3 -[ 4 , 5 - dimethyl - thizol - 2 - yl ]- 2 , 5 - diphenyltetrazolium bromide assay . Expression of the genes encoding thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) was analyzed by quantitative real - time reverse transcriptase polymerase chain reaction . The four PC - 9 sublines were more resistant than the PC - 9 cell line to P15941 ( 2 . 2 - , 2 . 9 - , 8 . 4 - , and 14 . 3 - fold , respectively ) . The four A549 sublines also showed more resistance to P15941 ( 7 . 8 - , 9 . 6 - , 42 . 3 - , and 42 . 4 - fold , respectively ) than the parent cell line . All resistant sublines showed cross - resistance to cisplatin , but not to docetaxel , vinorelbine , 5 - fluorouracil , or the active metabolite of irinotecan , SN - 38 . All P15941 - resistant sublines expressed more TS than the parental cells , by polymerase chain reaction and Western blotting . P00374 was significantly increased in the four P15941 - resistant A549 sublines . GARFT did not correlate with resistance to P15941 . In summary , P15941 - resistant cells remained sensitive to docetaxel , vinorelbine , 5 - fluorouracil , and irinotecan . TS expression appeared to be associated with resistance to P15941 .",
"DB00563 induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . DB00563 ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .",
"Spline - fitting with a genetic algorithm : a method for developing classification structure - activity relationships . Classification methods allow for the development of structure - activity relationship models when the target property is categorical rather than continuous . We describe a classification method which fits descriptor splines to activities , with descriptors selected using a genetic algorithm . This method , which we identify as SFGA , is compared to the well - established techniques of recursive partitioning ( RP ) and soft independent modeling by class analogy ( SIMCA ) using five series of compounds : cyclooxygenase - 2 ( P35354 ) inhibitors , benzodiazepine receptor ( BZR ) ligands , estrogen receptor ( ER ) ligands , dihydrofolate reductase ( P00374 ) inhibitors , and monoamine oxidase ( MAO ) inhibitors . Only 1 - D and 2 - D descriptors were used . Approximately 40 % of compounds in each series were assigned to a test set , \" cherry - picked \" from the complete set such that they lie outside the training set as much as possible . SFGA produced models that were more predictive for all but the P00374 set , for which SIMCA was most predictive . RP gave the least predictive models for all but the MAO set . A similar trend was observed when using training and test sets to which compounds were randomly assigned and when gradually eliminating compounds from the ( designed ) training set . The stability of models was examined for the random and reduced sets , where stability means that classification statistics and the selected descriptors are similar for models derived from different sets . Here , SIMCA produced the most stable models , followed by SFGA and RP . We show that a consensus approach that combines all three methods outperforms the single best model for all data sets .",
"DB06594 in the treatment of major depressive disorder : an assessment of benefits and risks . DB06594 ( AGM ) was approved for the treatment of major depressive disorder ( MDD ) in adults by the European Medicines Agency ( P15941 ) in February 2009 . It is an analogue of melatonin and features a unique pharmacodynamic profile with agonism on both types of melatonergic receptors ( MT1 / P02795 ) and antagonism at serotonergic P28335 receptors . There is , however , an ongoing debate regarding the efficacy and safety of this novel antidepressant agent , originally evoked by claims of a significant publication bias underlying the assessment of AGM being an effective antidepressant . Indeed , two recent comprehensive metaanalyses of published and unpublished clinical trials found evidence for a relevant publication bias . However , due to its statistically significant advantage over placebo based on the results of these metaanalyses AGM must be referred to as an effective antidepressant agent in the acute phase of MDD . However , the effect sizes of AGM in the treatment of MDD were evaluated as being small in comparison to other antidepressant agents . In addition , there is insufficient evidence for the efficacy of AGM in relapse prevention of MDD . Apart from efficacy issues , AGM appears to have the potential to exhibit severe hepatotoxicity ( the P15941 has identified AGM - associated \" hepatotoxic reactions \" as a new safety concern in September 2013 ) that is currently poorly understood . Considering these aspects , it seems inappropriate to evaluate AGM as an antidepressant agent of first choice . Nevertheless , its unique mechanism of action with particular sleep modulating effects may represent a specific treatment strategy for patients with particular characteristics ; further studies with thorough characterization of patients are needed to test this hypothesis .",
"Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .",
"Tyrosine phosphorylation of Shc proteins and formation of Shc / Grb2 complex correlate to the transformation of NIH3T3 cells mediated by the point - mutation activated neu . P98160 - gamma , ras - P20936 and Shc have been proposed to be in vivo substrates for the neu - encoded p185neu receptor tyrosine kinases . We compared the tyrosine phosphorylation levels of P98160 - gamma , ras - P20936 and Shc in two NIH3T3 derived cell lines , transformed B104 - 1 - 1 and non - transformed P00374 / Q9UBA6 cells in which point - mutation activated and normal rat neu genes were transfected and expressed , respectively . We found that tyrosine phosphorylation of Shc and formation of Shc / Grb2 complex were more significant in B104 - 1 - 1 cells than in P00374 / Q9UBA6 cells , while no obvious difference could be detected for the tyrosine phosphorylation levels of ras - P20936 and P98160 - gamma between these two cell lines . Furthermore , we observed that association with Shc was severely impaired by deletion of most of the major autophosphorylation sites of the point - mutated neu . The truncated neu product , however , fully retained its ability to transform NIH3T3 cells , induce Shc tyrosine phosphorylation and Shc / Grb2 complex formation . Our results suggest that tyrosine phosphorylation of Shc which allows formation of Shc / Grb2 complex may play an important role for cell transformation induced by the point mutation - activated neu , and that stable binding to mutant p185neu may not be necessary for Shc to mediate this signaling pathway .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"In vitro and in vivo biological activities of a novel nonpolyglutamable anti - folate , MX - 68 . MX - 68 is a newly synthesized anti - folate , chemically designed not to undergo intracellular polyglutamation and to have increased affinity to dihydrofolate reductase ( P00374 ) . In the present study , we examined the in vitro and in vivo biological activities of MX - 68 compared with methotrexate ( MTX ) which forms several polyglutamates intracellularly . MX - 68 dose - dependently inhibited the proliferation of PHA - , anti - CD3 - , or PMA plus ionomycin - stimulated peripheral blood mononuclear cells ( PBMC ) and endothelial cells ( EC ) from normal subjects as well as P01584 - or P01375 alpha - stimulated synovial fibroblastic cells ( SC ) from rheumatoid arthritis ( RA ) patients . Coaddition of folinic acid completely reversed the anti - proliferative effects of both MX - 68 and MTX . Although the anti - proliferative activities of MX - 68 were almost comparable to those of MTX , the washout study clearly showed the characteristic nature of MX - 68 . When drugs were removed during culture , the suppressive effect of MX - 68 completely disappeared , whereas suppression by MTX was merely weakened . MX - 68 dramatically suppressed the onset of collagen - induced arthritis ( CIA ) in mice when the drug was orally administered three times a week . starting from the day of first immunization . In this model , 2 mg / kg of MX - 68 was sufficient to completely suppress arthritis , whereas suppression by the same dose of MTX was partial . These lines of evidence suggest that polyglutamation is not always a prerequisite in the anti - rheumatic effects of anti - folate . In addition , since intracellular accumulation of polyglutamates is thought to have adverse effects , MX - 68 may become a more potent and less toxic anti - rheumatic drug than MTX .",
"Discovery and structure - activity relationship of ( 1R ) - 8 - chloro - 2 , 3 , 4 , 5 - tetrahydro - 1 - methyl - 1H - 3 - benzazepine ( ___MASK13___ ) , a selective serotonin P28335 receptor agonist for the treatment of obesity . The synthesis and SAR of a novel 3 - benzazepine series of P28335 agonists is described . Compound 7d ( lorcaserin , APD356 ) was identified as one of the more potent and selective compounds in vitro ( pEC50 values in functional assays measuring [( 3 ) H ] phosphoinositol turnover : P28335 = 8 . 1 ; 5 - Q13049 = 6 . 8 ; P41595 = 6 . 1 ) and was potent in an acute in vivo rat food intake model upon oral administration ( ED50 at 6 h = 18 mg / kg ) . ___MASK13___ was further characterized in a single - dose pharmacokinetic study in rat ( t1 / 2 = 3 . 7 h ; F = 86 % ) and a 28 - day model of weight gain in growing Sprague - Dawley rat ( 8 . 5 % decrease in weight gain observed at 36 mg / kg b . i . d . ) . ___MASK13___ was selected for further evaluation in clinical trials for the treatment of obesity .",
"DB00642 : its promise in treating non - small - cell lung cancer . The use of chemotherapy in the treatment of early and advanced non - small - cell lung cancer ( NSCLC ) has increased during the past decade . One of the main reasons for the increased acceptance of chemotherapy is the development of several new cytotoxic agents with a unique mechanism ( s ) of action and high single - agent activity , combined with a favorable toxicity profile . DB00642 ( Alimta ) is a novel antifolate that inhibits several enzymes involved in DNA synthesis ( thymidylate synthase [ TS ] , dihydrofolate reductase [ P00374 ] , and glycinamide ribonucleotideformyltransferase [ GARFT ] ) . DB00642 ' s toxicity is markedly reduced by folic acid and vitamin B12 supplementation . The compound has been studied extensively in various tumor types , including NSCLC . In NSCLC , pemetrexed at 500 mg / m2 , every 3 weeks , given i . v . over 10 minutes , has shown promising activity , and can safely be administrated with vitamin supplementation . After registration , single - agent pemetrexed will certainly add to the chemotherapeutic options available for pretreated patients and will most likely change significantly chemotherapy prescriptions in second - line chemotherapy . In first - line chemotherapy , the role of platinum - based and - free combination doublet chemotherapy with pemetrexed still needs to be defined . Phase II data indicate high efficacy combined with favorable toxicity for pemetrexed in combination with cisplatin , carboplatin ( DB00958 ) , oxaliplatin ( Eloxatin ) , gemcitabine ( Gemzar ) , and vinorelbine ( Navelbine ) . This review summarizes the clinical experience obtained thus far during the early clinical development of pemetrexed in NSCLC .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Recent advances in classical and non - classical antifolates as antitumor and antiopportunistic infection agents : Part II . Antifolates that inhibit the key enzymes thymidylate synthase ( TS ) and dihydrofolate reductase ( P00374 ) have found clinical utility as antitumor and antiopportunistic agents . DB00563 { MTX , ( 1 ) } and 5 - fluorouracil ( DB00544 ) were among the first clinically useful P00374 and TS inhibitors , respectively . The development of resistance to DB00544 , its occasional unpredictable activity and toxicity resulted in the search of novel antifolates . DB00642 ( 4 ) and raltitrexed ( 5 ) are newer antifolates that specifically inhibit TS , and are clinically useful as antitumor agents . A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly - gamma - glutamate synthetase ( Q05932 ) . Recently , classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed ( 6 ) and GW1843 ( 7 ) . Nolatrexed ( 8 ) , trimethoprim { P54849 , ( 11 ) } and piritrexim { PTX , ( 12 ) } are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on Q05932 or the reduced folate carrier ( P41440 ) . Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS , P00374 , Q05932 , and P41440 have been proposed . This two - part review discusses the design , synthesis and structural requirements for TS and P00374 inhibition and their relevance to antitumor and parasitic chemotherapy , since 1996 . Monocyclic and 6 - 5 fused bicyclic antifolates were discussed in Part I . The 6 - 6 bicyclic and tricyclic antifolates will be discussed here in Part II .",
"NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .",
"Serotonin increases P27361 / 2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 ( 1 / 2 ) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5 - HT ( 2B ) receptors ( Li et al . , 2008b ) . This raises the question whether this is also the case for serotonin ( 5 - HT ) itself . In the present study serotonin was found to induce P29323 ( 1 / 2 ) phosphorylation by stimulation of 5 - HT ( 2B ) receptors with high affinity ( EC ( 50 ) : 20 - 30 pM ) , and by stimulation of 5 - HT ( 2C ) receptor with low affinity ( EC ( 50 ) : 1 microM or higher ) . P29323 ( 1 / 2 ) phosphorylation induced by stimulation of either 5 - HT ( 2B ) or 5 - HT ( 2C ) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al . , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn - dependent metalloproteinases , and thus of 5 - HT ( 2B ) receptor - mediated P01133 receptor agonist release . It is discussed that the high potency of the 5 - HT ( 2B )- mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5 - HT ( 2B ) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality - dependent increase in specific brain areas to activate 5 - HT ( 2B ) receptors . In contrast the relevance of the observed 5 - HT ( 2C ) receptors on astrocytes is questioned .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK24___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"DB00642 alters folate phenotype and inflammatory profile in EA . hy 926 cells grown under low - folate conditions . Elevated homocysteine is a risk marker for several major human pathologies . Emerging evidence suggests that perturbations of folate / homocysteine metabolism can directly modify production of inflammatory mediators . DB00642 acts by inhibiting thymidylate synthetase ( P04818 ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) . EA . hy 926 cells grown under low ( \" Lo \" ) and high ( \" Hi \" ) folate conditions were treated with pemetrexed . The concentrations of several intracellular folate derivatives were measured using LC - MRM / MS . Lo cells had lower total folate concentrations and a different distribution of the intracellular folate derivatives than Hi cells . Treatment with pemetrexed caused a decrease in individual folate analytes . Microarray analysis showed that several genes were significantly up or down - regulated in pemetrexed treated Lo cells . Several of the significantly up - regulated transcripts were inflammatory . Changes in transcript levels of selected targets , including P01024 , P10145 , and P00374 , were confirmed by quantitative RT - PCR . P01024 and P10145 transcript levels were increased in pemetrexed - treated Lo cells relative to Lo controls ; P00374 transcript levels were decreased . In Lo cells , P10145 and P01024 protein concentrations were increased following pemetrexed treatment . DB00642 drug treatment was shown in this study to have effects that lead to an increase in pro - inflammatory mediators in Lo cells . No such changes were observed in Hi cells , suggesting that pemetrexed could not modify the inflammatory profile in the context of cellular folate sufficiency .",
"Ductal adenocarcinoma of the pancreas usually retained Q13485 and p53 protein status as well as expression of epithelial - to - mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis . There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma ( PDAC ) . The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues . Thirty - two stains ( corresponding to proteins encoded by 31 genes : Q13485 , P04637 , P62736 , CDH1 , P38936 , O95832 , O14493 , O95471 , P35222 , P00533 , P04626 , P02751 , P08727 , P28482 / P27361 , Q16539 , P46013 , P08253 , P14780 , P15941 ( 3 antibodies ) , P98088 , Q6W4X9 , P42345 , MYC , P48681 , P35354 , P62753 , P23443 , P01137 , P36897 , P08670 ) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases . There were no significant differences in expression levels of examined proteins between primary and secondary lesions . In particular , metastatic PDAC retained the primary tumour ' s Q13485 protein status in all and p53 protein status in all but one case . This surprising homogeneity also involved expression levels of markers of epithelial - to - mesenchymal transition as well as cell cycle regulators studied . In conclusion , the biological profiles of primary PDACs and their liver metastases seemed to be similar . Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Interaction of plasma proteins with heparinized gel particles studied by high - resolution two - dimensional gel electrophoresis . In order to further the understanding of protein - surface interactions in the coagulation system , we have chosen to study plasma protein adsorption onto heparin - immobilized surfaces . DB01109 - binding proteins are abundant in plasma : a search of amino acid sequences revealed that many plasma proteins have possible heparin binding sites . Plasma protein adsorption to the heparinized surfaces is monitored by a novel technique in which the solution depletion of proteins is analytically determined using quantitative two - dimensional polyacrylamide gel electrophoresis ( 2 - D PAGE ) . This method enables simultaneous , quantitative detection of the majority of plasma proteins before , during , and after their adsorption onto high surface area adsorbents . Using computerized densitometry of silver - stained 2 - D PAGE gels , the amount of each protein can be determined from the integrated optical density of each protein \" spot . \" Kinetics of adsorption and adsorption isotherms of four important heparin binding proteins , antithrombin III ( P01008 ) , complement factor P01024 ( P01024 ) , apolipoprotein AI ( P02647 ) and apolipoprotein AIV ( P06727 ) are reported in this paper . From the adsorption isotherms , the apparent binding constants of each protein - immobilized heparin complex , Ka , were calculated . The surface binding constants were of the same order of magnitude as the respective solution binding constants in the literature . The surface binding constants followed the same order as the respective solution binding constants : Ka ( P01008 ) greater than Ka ( P06727 ) greater than Ka ( P01024 ) greater than Ka ( P02647 ) , indicating that protein binding to the immobilized heparin used is not essentially different from solution binding .",
"___MASK52___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK52___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .",
"Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone - induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( ___MASK35___ ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 +] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 +] i were significantly attenuated in cells pretreated with ___MASK35___ in a dose - dependent manner . P06401 antagonists prevented the attenuated Ca2 + transients induced by ___MASK35___ . P25101 and ETB receptor subtypes were expressed in myometrial cells , and treatment with ___MASK35___ resulted in significant downregulation of P25101 and ETB receptor binding . ___MASK35___ did not alter ionomycin - stimulated increases in [ Ca2 +] i and had no effect on inositol trisphosphate - dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone - induced modification of receptor - mediated increases in [ Ca2 +] i .",
"Down - regulation of P15941 in cancer cells inhibits cell migration by promoting P12830 / catenin complex formation . P15941 , a tumor associated glycoprotein , is over - expressed in most cancers and can promote proliferation and metastasis . The objective of this research was to study the role of P15941 in cancer metastasis and its potential mechanism . Pancreatic ( PANC1 ) and breast ( MCF - 7 ) cancer cells with stable ' knockdown ' of P15941 expression were created using RNA interference . beta - Catenin and P12830 protein expression were upregulated in PANC1 and MCF - 7 cells with decreased P15941 expression . Downregulation of P15941 expression also induced beta - catenin relocation from the nucleus to the cytoplasm , increased P12830 / beta - catenin complex formation and P12830 membrane localization in PANC1 cells . PANC1 cells with ' knockdown ' P15941 expression had decreased in vitro cell invasion . This study suggested that P15941 may affect cancer cell migration by increasing P12830 / beta - catenin complex formation and restoring P12830 membrane localization .",
"___MASK59___ improves hippocampal neurogenesis and depression - like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . ___MASK59___ is a non - competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer ' s disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression - like behaviors , we chronically administered rivastigmine ( 0 . 1 - 1 . 0mg / kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0 . 3 or 1 . 0mg / kg dose dependently and significantly improved depression - like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty - suppressed feeding ( NSFT ) tests . Importantly , co - administration with WAY - 100635 ( 1 . 0mg / kg ) , a P08908 receptor antagonist , but not ketanserin ( 1 . 0mg / kg , ) , a 5 - Q13049 receptor antagonist , completely blocked rivastigmine - induced anti - depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor - dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal - regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY - 100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5 - Q13049 receptor stimulation by specific agonists mimicked rivastigmine - induced anti - depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients .",
"Inhibitory effects of botulinum toxin on P28335 receptor - induced Cl - current in Xenopus oocytes . Several low molecular weight G proteins have been identified , but their functional roles remain unclear . To clarify the involvement of low molecular weight G protein in receptor - stimulated turnover of polyphosphoinositide ( PI ) turnover , influences of botulinum toxins on serotonin ( 5 - HT ) - stimulated Cl - current mediated by PI turnover were investigated using Xenopus oocytes injected with rat brain mRNA . Treatment with botulinum toxin C , D or purified ADP - ribosyltransferase of botulinum toxin ( botulinum toxin P01024 enzyme ) inhibited the 5 - HT - induced Cl - current in oocytes , and ADP - ribosylated 23 kDa proteins . Both botulinum toxin P01024 enzyme - induced inhibition of the current and ADP - ribosylation were suppressed by pretreatment with antibotulinum toxin P01024 enzyme antibody . Botulinum toxin D treatment of oocytes was ineffective in the response of Cl - current induced by injection of 50 pmol inositol 1 , 4 , 5 - trisphosphate and 50 pmol Ca2 + . It is suggested that low molecular weight G proteins ADP - ribosylated by botulinum toxin P01024 enzyme are involved in phospholipase C activation in Xenopus oocytes .",
"Protection of lung epithelial cells from protease - mediated injury by trappin - 2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP - mediated inflammatory events . We have examined the capacity of trappin - 2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin - 2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight - junction proteins , P12830 , β - catenin and ZO - 1 , induced by each individual NSP and by activated neutrophils . Trappin - 2 A62L also decreased the release of the pro - inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin - 2 A62D / M63L , a trappin - 2 variant that has no antiprotease activity , has similar properties , suggesting that the anti - inflammatory action of trappin - 2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin - 2 A62L , as well as wild - type trappin - 2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti - inflammatory effects . We have also demonstrated that trappin - 2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin - 2 A62L is a powerful anti - protease and anti - inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases .",
"Antithrombin can modulate coagulation , cytokine production , and expression of adhesion molecules in abdominal aortic aneurysm repair surgery . We investigated the effects of antithrombin on coagulation , fibrinolysis , and production of cytokines and adhesion molecules in abdominal aortic aneurysm repair surgery . Sixteen patients for Y - shaped graft replacement of abdominal aortic aneurysm were divided into an antithrombin group and a control group . In the antithrombin group , 3000 U antithrombin was infused over 30 min before heparin administration and 24 h later . White blood cell counts , platelet counts , prothrombin time ratio , and serum concentrations of antithrombin , polymorphonuclear leukocyte elastase , interleukin ( IL ) - 1beta , P05231 , P10145 , tumor necrosis factor - alpha , and adhesion molecules , and variables of coagulation and fibrinolysis were measured before surgery , at the end of surgery , and 1 and 2 days after surgery . The antithrombin concentration decreased in the control group , whereas it increased in the antithrombin group with significant differences between the groups . P00734 time ratio , concentrations of d - dimer , thrombin - antithrombin complex , and intercellular adhesion molecule - 1 increased only in the control group and polymorphonuclear leukocyte elastase , P05231 , tumor necrosis factor - alpha , and vascular cell adhesion molecule - 1 increased in both groups . They were significantly less in the antithrombin group except for intercellular adhesion molecule - 1 . In conclusion , antithrombin could decrease hypercoagulation and inflammatory activation during abdominal aortic aneurysm surgery , which may decrease adverse events .",
"Effects of pemetrexed , gefitinib , and their combination on human colorectal cancer cells . PURPOSE : The study investigated the effects of pemetrexed , gefitinib , and their combination on human colorectal cancer cells . METHODS : Six human colorectal cancer cells were exposed to pemetrexed , gefitinib , and their combination . Antitumor effects were measured by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay . P04818 ( TS ) mRNA expression and P00533 mutation were studied by real - time RT - PCR and DNA sequence determination . Pharmacological interaction was studied using the combination index method . Cell cycle distribution and apoptosis were determined by flow cytometry . Activity assay was performed to assess the effects of drugs on TS activity , and Western blot was performed to assess the protein expression of pEGFR , pAKT , and pERK 1 / 2 . RESULTS : Six colorectal cancer cells are all sensitive to pemetrexed , and TS gene expression of cells was negatively related to pemetrexed sensitivity . The cytotoxic synergism was observed in concurrent pemetrexed combined with gefitinib and sequential pemetrexed followed by gefitinib . The combination of pemetrexed and gefitinib modulated cell cycle and induced apoptosis . DB00642 combined with gefitinib decreased TS mRNA expression and in situ activity . DB00642 induced an P00533 - mediated activation of the phosphatidylinositol 3 - kinase / AKT and P29323 pathway , which was inhibited by gefitinib . CONCLUSIONS : DB00642 is a promising agent , and pemetrexed combined with gefitinib has a significantly synergistic effect on colorectal cancer cells , which seems to present a strategy of pemetrexed combined with P00533 - TKIs in colorectal cancer treatment .",
"P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .",
"Cathepsin - D , adiponectin , P01375 - α , P05231 and hsCRP plasma levels in subjects with diabetic foot and possible correlation with clinical variables : a multicentric study . Diabetic foot , characterized by a pronounced inflammatory reaction , decreased collagen content and biosynthesis and accelerated degradation are crucial in wound healing . P07339 , an aspartic endopeptidases implicated in cell growth , apoptosis , and its inhibitor has been reported to reverse the inhibition of collagen biosynthesis in wounded rat skin with diabetes . To date , the increased proteolytic activity of P07339 in diabetic foot has not been evaluated and the pathogenic significance of the inflammation has received little attention . Of the patients [ with ulcer ( n = 211 ) and without ulcer ( n = 208 ) ] , 89 . 73 % had type 2 diabetes . Subjects with diabetic foot ulcer showed higher median plasma level of P07339 [ 556 . 3 ( 312 . 6 - 587 . 3 ) P41440 / ml vs 306 . 3 ( 92 . 6 - 337 . 3 ) P41440 / ml ] , P01375 - α [ 96 . 6 ( 79 . 9 - 121 . 5 ) ng / ml vs 8 . 4 ( 7 . 1 - 9 . 20 ) ng / ml ] , P05231 [ 32 . 2 ( 8 . 52 - 48 . 4 ) ng / ml vs 4 . 9 ( 4 . 5 - 5 . 6 ) ng / ml ] , hsCRP [ 12 . 6 ( 11 . 2 - 14 . 1 ) mg / ml vs 3 . 90 ( 3 . 50 - 4 . 60 ) mg / ml ] and lower median plasma levels of adiponectin [ 8 . 50 ( 7 . 10 - 9 . 5 ) ng / ml vs 13 . 3 ( 12 . 1 - 14 . 2 ) ng / ml ] . A positive correlation was found between grades of ulcer , BMI , A1c and retinopathy for P07339 , for adiponectin , between grades of ulcer , BMI , retinopathy , nephropathy & smoking , for P05231 , between grades of ulcer , BMI , nephropathy , CAD & smoking , for hsCRP , grades of ulcer , BMI , LDL - C , nephropathy & smoking , while total cholesterol , nephropathy , PAD , smoking and neuropathy for P01375 - α .",
"Identification and analysis of specific chromosomal region adjacent to exogenous Dhfr - amplified region in Chinese hamster ovary cell genome . Chinese hamster ovary ( CHO ) cells are widely used for the stable production of recombinant proteins . Gene amplification techniques are frequently used to improve of protein production , and the dihydrofolate reductase ( P00374 ) gene amplification system is most widely used in the CHO cell line . We previously constructed a CHO genomic bacterial artificial chromosome ( BAC ) library from a mouse Dhfr - amplified CHO DR1000L - 4N cell line and one BAC clone ( Cg0031N14 ) containing the CHO genomic DNA sequence adjacent to Dhfr was selected . To identify the specific chromosomal region adjacent to the exogenous Dhfr - amplified region in the CHO cell genome , we performed further screening of BAC clones to obtain other Dhfr - amplified regions in the CHO genome . From the screening by high - density replica filter hybridization using a digoxigenin - labeled pSV2 - dhfr / hGM - P04141 probe , we obtained 8 new BAC clones containing a Dhfr - amplified region . To define the structures of the 8 BAC clones , Southern blot analysis , BAC end sequencing and fluorescence in situ hybridization ( Q5TCZ1 ) were performed . These results revealed that all the selected BAC clones contained a large palindrome structure with a small inverted repeat in the junction region . This suggests that the obtained amplicon structure in the Dhfr - amplified region in the CHO genome plays an important role in exogenous gene amplification .",
"P01308 - like growth factor - 1 receptor inhibitor , Q99217 - 479 , in cetuximab - refractory head and neck squamous cell carcinoma . BACKGROUND : Recurrent head and neck squamous cell carcinoma ( HNSCC ) remains a difficult cancer to treat . Here , we describe a patient with HNSCC who had complete response to methotrexate ( MTX ) after progressing on multiple cytotoxic agents , cetuximab , and Q99217 - 479 ( monoclonal antibody against insulin - like growth factor - 1 receptor [ IGF - 1R ] ) . METHODS : The clinical information was collected by a retrospective medical record review under an Institutional Review Board - approved protocol . From 4 tumors and 2 normal mucosal epithelia , global gene expression , and IGF - 1R and dihydrofolate reductase ( P00374 ) protein levels were determined . RESULTS : Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho - IGF - 1R after treatment with Q99217 - 479 . Decreased level of P00374 and conversion of a gene expression profile associated with cetuximab - resistance to cetuximab - sensitivity were also observed . CONCLUSION : This suggests that the combination of Q99217 - 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"Translational research with pemetrexed in breast cancer . DB00642 ( Alimta ) is a novel folate antimetabolite that primarily inhibits the enzymes thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyl transferase ( GARFT ) , all of which are involved in pyrimidine and purine synthesis . In a phase II trial of patients with DB00279 / 4 , N0 - 2 breast cancer , expression of thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , glycinamide ribonucleotide formyltransferase ( GARFT ) , p53 , and c - erb - B2 ( at the mRNA or protein level ) was examined in tumor biopsy specimens before and 24 hours after the first dose of pemetrexed and after three cycles of single - agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity . Although final data are not available , initial indications are that clinical response may correlate with decreased or low TS expression . The results obtained from clinical data are supported by laboratory results in three cell lines ( MDA - 231 , MCF - 7 , and ZR - 75 ) . These results suggest that in vitro transcript profiling to identify which genes are important predictors of successful cytotoxic chemotherapy , followed by a focused clinical trial to confirm the in vitro results , may be the best approach for translational research .",
"DB00642 : mRNA expression of the target genes TS , GARFT and P00374 correlates with the in vitro chemosensitivity of human solid tumors .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK43___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK43___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK43___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK43___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK43___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK43___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK43___ .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK77___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"___MASK73___ overcomes gefitinib resistance in human non - small cell lung cancer cells with K - Ras mutations . ___MASK73___ is a 3 - hydroxy - 3 - methylglutaryl - coenzyme A ( HMG - DB01992 ) reductase inhibitor . Its inhibitory action on P04035 leads to depletion of isoprenoids , which inhibits post - translational modification of DB01367 . In this study , we investigated the effect of combining lovastatin with gefitinib on gefitinib - resistant human non - small cell lung cancer ( NSCLC ) cell lines with K - Ras mutations . Antitumor effects were measured by growth inhibition and 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay . Effects on apoptosis were determined by flow cytometry , DNA fragmentation , and immunoblots . Protein levels of DB01367 , AKT / pAKT , and RAF / P27361 / 2 in cancer cells were analyzed by immunoblot . Compared with gefitinib alone , a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib - resistant A549 and NCI - H460 human NSCLC cells . In addition , lovastatin combination treatment significantly increased gefitinib - related apoptosis , as determined by fluorescence microscopy and flow cytometric analysis . These effects correlated with up - regulation of cleaved caspase - 3 , poly ( ADP - ribose ) polymerase ( PARP ) , and Bax and down - regulation of Bcl - 2 . The combination of lovastatin and gefitinib effectively down - regulated DB01367 protein and suppressed the phosphorylation of RAF , P27361 / 2 , AKT , and P00533 in both cell lines . Taken together , these results suggest lovastatin can overcome gefitinib resistance , in NSCLC cells with K - Ras mutations , by down regulation of DB01367 protein , which leads to inhibition of both RAF / P29323 and AKT pathways .",
"New data integrating multitargeted antifolates into treatment of first - line and relapsed non - small - cell lung cancer . Non - small - cell lung cancer ( NSCLC ) represents approximately 80 % of all lung cancers . With modern platinum - based combination regimens , overall median survival has reached 9 - 12 months . Antifolates are active against several solid tumors and hematologic malignancies . The cytotoxic action of antifolates is mainly related to their ability to inhibit several different folate - dependent enzymes involved in DNA synthesis . DB00642 is a novel multitargeted antifolate that inhibits at least 3 of the enzymes involved in purine and pyrimidine synthesis : thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) . DB00642 was approved for the treatment of relapsed NSCLC as it produced equivalent response and survival rates and less toxicity compared with docetaxel . DB00642 in combination with platinum analogues or with gemcitabine showed equivalent clinical impact compared with standard combinations of platinum plus third - generation agents . We analyze the potential implications of pemetrexed ' s role in first - line chemotherapy of NSCLC as well as hints of differential cytotoxic action according to histology , new schedules of vitamin supplementation , and target enzymes expression levels . Issues of pharmacogenomics are becoming relevant in defining pemetrexed efficacy . Chemosensitivity was significantly linked to low levels of TS , GARFT , and P00374 in preclinical models . Consequently , the differential expression of TS according to histology might explain the different activity of pemetrexed according to histology , as recently postulated .",
"Activation of the MyD88 signaling pathway inhibits ischemia - reperfusion injury in the small intestine . Toll - like receptors ( TLRs ) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity . Recent studies have shown that the activation of TLR - dependent signaling pathways plays important roles in the pathogenesis of ischemia - reperfusion ( I / R ) injuries in many organs . All TLRs , except O15455 , use a common adaptor protein , MyD88 , to transduce activation signals . We investigated the role of MyD88 in I / R injury of the small intestine . MyD88 and cyclooxygenase - 2 ( P35354 ) knockout and wild - type mice were subjected to intestinal I / R injury . I / R - induced small intestinal injury was characterized by infiltration of inflammatory cells , disruption of the mucosal epithelium , destruction of villi , and increases in myeloperoxidase activity and mRNA levels of P01375 - α and the P10145 homolog KC . MyD88 deficiency worsened the severity of I / R injury , as assessed using the histological grading system , measuring luminal contents of hemoglobin ( a marker of intestinal bleeding ) , and counting apoptotic epithelial cells , while it inhibited the increase in mRNA expression of P01375 - α and KC . I / R significantly enhanced P35354 expression and increased PGE ( 2 ) concentration in the small intestine of wild - type mice , which were markedly inhibited by MyD88 deficiency . P35354 knockout mice were also highly susceptible to intestinal I / R injury . Exogenous PGE ( 2 ) reduced the severity of injury in both MyD88 and P35354 knockout mice to the level of wild - type mice . These findings suggest that the MyD88 signaling pathway may inhibit I / R injury in the small intestine by inducing P35354 expression .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK13___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK13___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK13___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK13___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Repair of benzo ( a ) pyrene diol epoxide - and UV - induced DNA damage in dihydrofolate reductase and adenine phosphoribosyltransferase genes of CHO cells . Using Uvr proteins we have quantified benzo ( a ) pyrene diol epoxide ( BPDE ) - DNA adduct formation and repair at the dihydrofolate reductase ( P00374 ) and adenine phosphoribosyltransferase ( P07741 ) genes in two Chinese hamster ovary cell lines : B - 11 cells , which are 50 - fold amplified for P00374 , and P01008 - 2 cells , which are diploid for P00374 . We have found that : 1 ) BPDE - DNA adduct formation in different regions of the P00374 gene is proportional to the concentration of BPDE . 2 ) There is no significant difference in the repair of BPDE - DNA adducts between the coding and noncoding regions in either amplified or nonamplified P00374 gene domains . 3 ) Repair in the nonamplified P00374 gene is more efficient ( 30 - 40 % ) than in the amplified P00374 genes . 4 ) There are no significant differences of repair in the transcribed or nontranscribed strands of the P00374 gene . 5 ) BPDE - DNA adduct formation and repair in the P07741 gene in B - 11 and P01008 - 2 cells are the same . These results contrast those for the repair of cyclobutane pyrimidine dimers , which occurs preferentially in the transcribed strand of the P00374 gene and in which gene amplification appears to play no role .",
"P01308 - like growth factor - binding protein - 5 induces pulmonary fibrosis and triggers mononuclear cellular infiltration . We have recently shown that insulin - like growth factor - binding protein ( IGFBP ) - 5 is overexpressed in idiopathic pulmonary fibrosis lung tissues and increases collagen and fibronectin deposition . Here , we further examined the effect of P24593 in vivo by intratracheal administration of replication - deficient adenovirus expressing human P24593 ( Ad5 ) , P17936 ( Ad3 ) , or no cDNA ( cAd ) to wild - type mice . Increased cellular infiltration and extracellular matrix deposition were observed in mice after Ad5 administration compared with Ad3 and cAd . Mononuclear cell infiltration consisted predominantly of T lymphocytes at day 8 . By day 14 , the number of infiltrating T cells decreased , whereas that of B cells and monocytes / macrophages increased . P24593 also induced migration of peripheral blood mononuclear cells in vitro , suggesting that in vivo mononuclear cell infiltration may be the direct result of P24593 expression . alpha - Smooth muscle actin and P15941 co - localized in cells of mice treated with Ad5 , suggesting that P24593 induced epithelial - mesenchymal transition . In addition , exogenous P24593 induced alpha - smooth muscle actin expression in primary fibroblasts and epithelial - mesenchymal transition of pulmonary epithelial cells in vitro . In conclusion , our results suggest that overexpression of P24593 in mouse lung results in fibroblast activation , increased extracellular matrix deposition , and myofibroblastic changes . Thus , the P24593 - induced fibrotic phenotype in vivo may represent a novel model to better understand the pathogenesis of fibrosis .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK65___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"___MASK73___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer ."
] |
[
"___MASK13___",
"___MASK24___",
"___MASK35___",
"___MASK43___",
"___MASK52___",
"___MASK59___",
"___MASK65___",
"___MASK73___",
"___MASK77___"
] |
___MASK43___
|
MH_train_328
|
interacts_with DB00398?
|
[
"DB00398 ( BAY 43 - 9006 ) in hepatocellular carcinoma patients : from discovery to clinical development . Angiogenesis and signaling through the DB01367 / RAF / mitogen - activated protein / extracellular signal - regulated kinase ( P29323 ) kinase ( MEK ) / P29323 cascade have been reported to play important roles in the development of hepatocellular carcinoma ( HCC ) . DB00398 ( Nexavar ) , a novel bi - aryl urea BAY 43 - 9006 , is an orally administered multikinase inhibitor with activity against DB01367 / RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases , including vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) , P36888 , Ret , and c - Kit . It is involved in angiogenic pathway and cell proliferation . DB00398 has demonstrated potent anti - tumor activity in in vitro studies , preclinical xenograft models of different tumor types and human clinical trials . This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans - arterial chemoembolization ( P78536 ) in HCC patients .",
"1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats : possible role of serotonin receptors . 1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) , a serotonin1 ( 5 - HT1 ) receptor agonist , injected i . p . in doses of 0 . 1 and 0 . 6 mg / kg , did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg / kg per day desipramine ( ___MASK37___ ) . A similar effect was found on infusing 1 and 5 micrograms / microliters TFMPP bilaterally into the ventral tegmental area ( VTA ) . Infusion of 5 micrograms / microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of ___MASK37___ . The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i . p . administration of 5 mg / kg metergoline , a non - selective serotonin receptor antagonist . Infusion of 5 micrograms / microliters 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , a specific P08908 receptor agonist , into the VTA did not modify the effect of ___MASK37___ . Besides acting as a P28222 receptor agonist , TFMPP may also act on other 5 - HT receptor types , but available evidence suggests that its former action is more important . It thus appears that 5 - HT1 receptors in the VTA , presumably of the P28222 type , act by preventing the anti - immobility effect of ___MASK37___ . The role of VTA dopamine and non - dopamine cells in the effect of TFMPP is discussed .",
"P07949 fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation . Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase ( TK ) activity resulting from chimaeric fusion genes or point mutations such as P11274 - P00519 or O60674 V617F . We report here the cloning and functional characterization of two novel fusion genes P11274 - P07949 and O95684 - P07949 in chronic myelomonocytic leukemia ( CMML ) cases generated by two balanced translocations t ( 10 ; 22 )( q11 ; q11 ) and t ( 6 ; 10 )( q27 ; q11 ) , respectively . The two P07949 fusion genes leading to the aberrant activation of P07949 , are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic / macrophage lineage . The P07949 fusion genes seem to constitutively mimic the same signaling pathway as DB01367 mutations frequently involved in CMML . One patient was treated with DB00398 , a specific inhibitor of the P07949 TK function , and demonstrated cytological and clinical remissions .",
"[ Strategy for patients with GIST after failure of imatinib ] . DB01268 malate ( SU11248 ) is an oral multitargeted receptor tyrosine kinase inhibitor ( MTI ) that has antitumor activities for patients with gastrointestinal stromal tumor ; GIST after failure of Imatinib . DB01268 has demonstrated significant clinical benefits , including PFS , RR and OS in the USA and Japan . However , cis - mutations in the activation loop of the P10721 gene tend to develop DB01268 - resistant GIST . Two clinical trials revealed that new multitargeted receptor tyrosine kinase inhibitors , DB00398 and DB04868 , had antitumor activities for DB01268 - resistant GIST with longer PFS and a different spectrum . Now , clinical trials of several new MTIs are ongoing in Western countries . Inhibition of the P10721 gene cis - mutations and antiangiogenesis activities may be essential for the strategy for Imatinib / Sunitinibresistant GIST .",
"DB00398 in patients with advanced biliary tract carcinoma : a phase II trial . BACKGROUND : Advanced biliary tract carcinoma has a very poor prognosis , with chemotherapy being the mainstay of treatment . DB00398 , a multikinase inhibitor of P35968 /- 3 , P09619 , B - Raf , and C - Raf , has shown to be active in preclinical models of cholangiocarcinoma . METHODS : We conducted a phase II trial of single - agent sorafenib in patients with advanced biliary tract carcinoma . DB00398 was administered at a dose of 400 mg twice a day . The primary end point was the disease control rate at 12 weeks . RESULTS : A total of 46 patients were treated . In all , 26 ( 56 % ) had received chemotherapy earlier , and 36 patients completed at least 45 days of treatment . In intention - to - treat analysis , the objective response was 2 % and the disease control rate at 12 weeks was 32 . 6 % . Progression - free survival ( PFS ) was 2 . 3 months ( range : 0 - 12 months ) , and the median overall survival was 4 . 4 months ( range : 0 - 22 months ) . Performance status was significantly related to PFS : median PFS values for ECOG 0 and 1 were 5 . 7 and 2 . 1 months , respectively ( P = 0 . 0002 ) . The most common toxicities were skin rash ( 35 % ) and fatigue ( 33 % ) , requiring a dose reduction in 22 % of patients . CONCLUSIONS : DB00398 as a single agent has a low activity in cholangiocarcinoma . Patients having a good performance status have a better PFS . The toxicity profile is manageable .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK71___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"P01308 / FGF - binding ciliary membrane glycoprotein from Tetrahymena . Triton X - 100 extracted ciliary membrane protein from isolated cilia , prepared from the protozoon Tetrahymena thermophila , were fractionated by affinity chromatography on columns with covalently bound fibroblast growth factor ( FGF ) , insulin , or concanavalin A ( ConA ) , respectively . The eluted proteins were further analyzed by electrophoresis on sodium dodecyl sulfate polyacrylamide gels , isoelectric focusing , and by immunoblotting techniques using antibodies against the FGF receptor , platetelet derived growth factor ( PDGF ) receptor alpha - subunit , and insulin receptor beta - subunit . The particular antibodies were chosen because the peptides PDGF , FGF , insulin , and ConA are chemoattractants in this organism and corresponding binding ( receptor ) proteins could be expected to be identified . A 66 kDa protein fraction was eluted from the FGF - MiniLeak agarose , insulin - MiniLeak agarose and ConA sepharose . This fraction responded in Western immunoblots to an antibody against the beta - subunit of the human insulin receptor , to an antibody against the PDGF receptor ( P09619 ) and also to an antibody against the bovine FGF receptor ( FGFR ) that is known , in other systems , to inhibit FGF binding to its receptor . When analyzed by SDS - PAGE and stained with Coomassie blue the 66 kDa fraction appeared as a single component . However , in some experiments it appeared more heterogeneous when stained with silver indicating the presence of minor components that may be a procedural artifact or isoforms of the same glycoprotein . The 66 kDa protein ( s ) migrated in isoelectric focusing with a pI of 7 . 4 . The results are discussed in terms of the possible role of the 66 kDa glycoprotein as a protein involved in peptide - mediated cell signalling .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK69___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Algorithm for the management of metastatic cutaneous melanoma . Over the last 4 years , various drugs have been approved for the treatment of metastatic cutaneous melanoma . DB06186 , an anti - P16410 inhibitor that stimulates antitumor immunity , was the first agent to improve overall survival both in first line and in previously treated patients . DB06186 results in long term disease control in approximately 20 % of the patients . DB08881 was the first P15056 inhibitor ( BRAFi ) approved and also resulted in improved overall survival compared with dacarbazine in patients with P15056 mutated metastatic melanoma . More recently , another BRAFi , dabrafenib , and a MEK inhibitor , trametinib , were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy . The major feature of such tumor targeted therapy is its high response rate ( 40 - 70 % ) and the rapidity of the responses , resulting in prompt clinical improvement . However , unlike immunotherapy , targeted therapy does not result in long - term treatment free survival . In this paper , we discuss how best to integrate the currently available treatment options including high - dose interleukin - 2 ( HD P60568 ) , systemic chemotherapy , ipilimumab and tumor targeted therapy in various clinical scenarios .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK81___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"P55042 001 ( everolimus ) prevents P42345 and Akt late re - activation in response to imatinib in chronic myeloid leukemia . The mammalian target of rapamycin ( P42345 ) is one target of P11274 - P00519 fusion gene of chronic myeloid leukemia ( CML ) . Moreover , it drives a compensatory route to Imatinib mesylate ( IM ) possibly involved in the progression of leukemic progenitors towards a drug - resistant phenotype . Accordingly , P42345 inhibitors are proposed for combined therapeutic strategies in CML . The major caveat in the use of P42345 inhibitors for cancer therapy comes from the induction of an P42345 - phosphatidylinositol 3 kinase ( PI3k ) feedback loop driving the retrograde activation of Akt . Here we show that the rapamycin derivative P55042 001 ( everolimus , Novartis Institutes for Biomedical Research ) inhibits P42345 and , more importantly , revokes P42345 late re - activation in response to IM . P55042 001 interferes with the assembly of both P42345 complexes : mTORC1 and mTORC2 . The inhibition of mTORC2 results in the de - phosphorylation of Akt at DB00133 ( 473 ) in the hydrophobic motif of C - terminal tail required for Akt full activation and precludes Akt re - phosphorylation in response to IM . Moreover , P55042 001 - induced inhibition of Akt causes the de - phosphorylation of tuberous sclerosis tumor suppressor protein P49815 at 14 - 3 - 3 binding sites , P49815 release from 14 - 3 - 3 sigma ( restoring its inhibitory function on mTORC1 ) and nuclear import ( promoting the nuclear translocation of cyclin - dependent kinase [ CDK ] inhibitor p27 ( Kip1 ) , the stabilization of p27 ( Kip1 ) ligand with P24941 , and the G ( 0 )/ G ( 1 ) arrest ) . P55042 001 cytotoxicity on cells not expressing the P11274 - P00519 fusion gene or its Q92817 protein tyrosine kinase ( TK ) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect .",
"A phase I , dose - finding study of sorafenib in combination with gemcitabine and radiation therapy in patients with unresectable pancreatic adenocarcinoma : a Grupo Español Multidisciplinario en Cáncer Digestivo ( GEMCAD ) study . PURPOSE : DB00398 , an oral inhibitor of B - raf , P35968 , and P16234 - beta , acts against pancreatic cancer in preclinical models . Due to the radio - sensitization activity of both sorafenib and gemcitabine , we designed a multicenter , phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy . METHODS : Patients with biopsy - proven , unresectable pancreatic adenocarcinoma ( based on vascular invasion detected by computed tomography ) were treated with gemcitabine ( 300 mg / m2 i . v . weekly × 5 weeks ) concurrently with radiation therapy ( 45 Gy in 25 fractions ) and sorafenib ( escalated doses in a 3 + 3 design , from 200 to 800 mg / day ) . Radiation portals included the primary tumor but not the regional lymph nodes . Patients with planning target volumes ( PTV ) over 500 cc were excluded . Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression . RESULTS : Twelve patients were included . Three patients received 200 mg / day , 6 received 400 mg / day , and 3 received 800 mg / day ; PTVs ranged from 105 to 500 cc . No dose - limiting toxicities occurred . The most common grade 2 toxicities were fatigue , neutropenia , nausea , and raised serum transaminases . Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy . There were no treatment - related deaths . CONCLUSION : The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma . A dose of 800 mg / day is recommended for phase II evaluation . TRIAL REGISTRATION : EudraCT 2007 - 003211 - 31 ClinicalTrials . gov 00789763 .",
"Differential involvement of Galpha16 in CC chemokine - induced stimulation of phospholipase Cbeta , P29323 , and chemotaxis . Chemokines are known to regulate the chemotaxis of leukocytes and play an important role in immunological processes . Chemokine receptors are widely distributed in hematopoietic cells and are often co - localized with the hematopoietic - specific G ( 16 ) and its close relative , G ( 14 ) . Yet , many chemokine receptors utilize pertussis toxin - sensitive G ( i ) proteins for signaling . Given that both G ( 16 ) and G ( 14 ) are capable of linking G ( i )- coupled receptors to the stimulation of phospholipase Cbeta , we examined the capacity of six CC chemokine receptors ( P32246 , CCR2a , CCR2b , P51677 , P51681 and P32248 ) to interact with G ( 14 ) and G ( 16 ) in a heterologous expression system . Among the CC chemokine receptors tested , P32246 , CCR2b , and P51677 were capable of mediating chemokine - induced stimulation of phospholipase Cbeta via either G ( 14 ) or G ( 16 ) . The G ( 14 )/ G ( 16 )- mediated responses exhibited CC chemokine dose - dependency and were resistant to pertussis toxin ( PTX ) treatment . In contrast , CCR2a , P51681 and P32248 were unable to interact with G ( 14 ) and G ( 16 ) . Under identical experimental conditions , all six CC chemokine receptors were fully capable of inhibiting adenylyl cyclase via G ( i ) as well as stimulating phospholipase Cbeta via 16z44 , a G ( 16 / z ) chimera that possesses increased promiscuity toward G ( i )- coupled receptors . Moreover , P32246 - mediated P27361 / 2 phosphorylation was largely PTX - insensitive in THP - 1 monocytic cells that endogenously express Galpha ( 16 ) . In addition , P32246 agonist was less efficacious in mediating chemotaxis of THP - 1 cells following the knockdown of Galpha ( 16 ) by overexpressing siRNA , indicating the participation of Galpha ( 16 ) in P32246 - induced cell migration . These results show that different CC chemokine receptors can discriminate against G ( 14 ) and G ( 16 ) for signal transduction .",
"[ Hand - foot syndrome and sorafenib ] . DB00398 ( Nexavar ) is a targeted therapy acting as VEGFR and P09619 tyrosine - kinase inhibitor that has been approved in France in the treatment of metastatic renal cell carcinoma and hepatocarcinoma . Hand - foot syndrome is one of the more frequent toxicity related to sorafenib . This paper up lights the main points concerning this toxicity in the view of specialists working together in the care of these patients : a pharmacologist , a dermatologist and a medical oncologist . The clinic and symptoms of hand - foot syndrome as the biological interpretation , the symptomatic treatment and the impact on the specific treatment of sorafenib are developed .",
"Identification and characterization of novel oncogenes in chronic eosinophilic leukemia and T - cell acute lymphoblastic leukemia . Research conducted in my group in the period 2006 - 2009 has led to a better understanding of the oncogenic mechanisms of the Q6UN15 - P16234 and P35658 - P00519 oncogenes . Insights into these mechanisms may help us to design novel strategies to treat leukemia . In addition , we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the Q6UN15 - P16234 and its T674I imatinib resistant mutant . DB00398 was originally developed as a P15056 inhibitor , but our work demonstrates that sorafenib can also be used to treat Q6UN15 - P16234 positive leukemia , demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases . Finally , using genome - wide screening approaches , we have identified the P10242 gene as a novel oncogene implicated in the pathogenesis of T - ALL , and we suggest that P10242 may represent a novel target for therapy in T - ALL as well as in other cancers .",
"DB00398 inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice . Anaplastic thyroid carcinoma ( ATC ) remains one of the most lethal human cancers . We hypothesized that sorafenib , a multikinase inhibitor of the BRaf , vascular endothelial growth factor receptor - 2 , and platelet - derived growth factor receptor - beta kinase , would decrease tumor growth and angiogenesis in an orthotopic model of ATC . The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined . To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice , sorafenib was given p . o . at 40 or 80 mg / kg daily . Intratumoral effects were studied using immunohistochemical analysis . The effect of sorafenib on survival of the mice was also studied . DB00398 inhibited the in vitro proliferation of ATC cell lines . DB00398 also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer . As result , the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved . DB00398 exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect . The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the P15056 mutational status of thyroid tumors . Given the lack of curative options for patients with ATC , sorafenib warrants further study as a therapeutic agent against ATC .",
"Optimized protocols for generation of cord blood - derived cytokine - induced killer / natural killer cells . The efficacy of various combinations of stem cell factor ( P21583 ) , P36888 ligand , interleukin ( IL ) - 2 , P13232 and P40933 to induce and expand cord blood - derived cytokine - induced killer ( CIK ) cells was investigated . There were three treatment groups : group A : P21583 combined with P60568 , P13232 and P40933 ; group B : P21583 , P36888 ligand combined with P60568 , P13232 and P40933 , and group C : P60568 , P13232 and P40933 , the control group . Proliferation rates of CD3 (+) CD56 (+) CIK cells and CD3 (-) CD56 (+) natural killer ( NK ) cells were highest in group B ; expansion of CIK cells increased 796 . 1 ± 278 . 5 - fold , and that of NK cells increased 36 . 6 ± 3 . 5 - fold . All expanded cord blood - derived CIK / NK cells showed cytotoxic activity against the K562 cell line . Interestingly , the cytotoxicity of group A was highest and significantly higher than that of other groups . These protocols might provide an alternative choice for CIK / NK cell expansion .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK24___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK23___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"Cribriform - morular variant of papillary thyroid carcinoma in an 8 - year - old girl : a case report with immunohistochemical and molecular testing . The description of the histological features and the immunohistochemical and molecular analyses of a case of cribriform - morular variant of papillary thyroid carcinoma in an 8 - year - old girl with a family history of adenomatous polyposis is presented . The neoplasm was multifocal and bilateral , with a mixed pattern of solid , trabecular , and morular areas . The neoplasm showed angioinvasive behavior , extracapsular infiltration with extension to the perythyroidal muscles , and lymph node metastases . Tumor cells were positive for P62158 5 . 2 , cytokeratins 5 / 6 , Q15669 - 1 , HBME - 1 , galectin - 3 , and β - catenin . In addition , the molecular tests did not reveal P15056 mutations , P07949 / PTC rearrangement , P25054 mutation , or P01116 mutation .",
"Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor - sensitive and kinase inhibitor - resistant forms of P36888 and P11274 / P00519 . Previous studies have shown that activation of the signal transducer and activator of transcription 5 ( P42229 ) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases ( PTK ) . Because PIM - 1 is a P42229 target gene , we analyzed the role of the family of PIM serine / threonine kinases ( PIM - 1 to PIM - 3 ) in PTK - mediated transformation of hematopoietic cells . Ba / P13726 cells transformed to growth factor independence by various oncogenic PTKs ( P41212 / O60674 , P41212 / Q16288 , P41212 / P00519 , P11274 / P00519 , P36888 - ITD , and H4 / PDGFbetaR ) show abundant expression of PIM - 1 and PIM - 2 . Suppression of PIM - 1 activity had a negligible effect on transformation . In contrast , expression of kinase - dead PIM - 2 mutant ( PIM - 2KD ) led to a rapid decline of survival in Ba / P13726 cells transformed by P36888 - ITD but not by other oncogenic PTKs tested . Coexpression of PIM - 1KD and PIM - 2KD abrogated growth factor - independent growth of Ba / P13726 transformed by several PTKs , including P11274 / P00519 . Targeted down - regulation of PIM - 2 by RNA interference ( RNAi ) selectively abrogated survival of Ba / P13726 cells transformed by various P36888 ( P36888 ) - activating mutants [ internal tandem duplication ( ITD ) and kinase domain ] and attenuated growth of human cell lines containing P36888 mutations . Interestingly , cells transformed by P36888 and P11274 / P00519 mutations that confer resistance to small - molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM - 2 , or PIM - 1 and PIM - 2 by RNAi . Our observations indicate that combined inactivation of PIM - 1 and PIM - 2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK - mediated leukemia . Targeting the PIM kinase family could provide a new avenue to overcome resistance against small - molecule tyrosine kinase inhibitors .",
"Clinical outcome , role of P15056 ( V600E ) , and molecular pathways in papillary thyroid microcarcinoma : is it an indolent cancer or an early stage of papillary thyroid cancer ? Most human thyroid cancers are differentiated papillary carcinomas ( PTC ) . Papillary thyroid microcarcinomas ( PTMC ) are tumors that measure 1 cm or less . This class of small tumors has proven to be a very common clinical entity in endocrine diseases . PTMC may be present in 30 - 40 % of human autopsies and is often identified incidentally in a thyroid removed for benign clinical nodules . Although PTMC usually has an excellent long - term prognosis , it can metastasize to neck lymph nodes ; however deaths related to this type of thyroid tumor are very rare . Few data exist on molecular pathways that play a role in PTMC development ; however , two molecules have been shown to be associated with aggressive PTMC . P26447 ( calcium - binding protein ) , which plays a role in angiogenesis , extracellular matrix remodeling , and tumor microenvironment , is over - expressed in metastatic PTMC . In addition , the P15056 ( V600E ) mutation , the most common genetic alteration in PTC , is present in many PTMC with extra thyroidal extension and lymph node metastasis . Importantly , recently developed selective [ e . g . , PLX4720 , PLX4032 ( DB08881 , also called RG7204 ) ] or non - selective ( e . g . , DB00398 ) inhibitors of P15056 ( V600E ) may be an effective treatment for patients with P15056 ( V600E )- expressing PTMCs with aggressive clinical - pathologic features . Here , we summarize the clinical outcome , cancer genetics , and molecular mechanisms of PTMC .",
"Somatic Q06124 mutations in childhood acute myeloid leukaemia . Somatic mutations in Q06124 , the gene encoding the transducer Q06124 , have emerged as a novel class of lesions that upregulate DB01367 signalling and contribute to leukaemogenesis . In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia ( AML ) , we documented a non - random distribution of Q06124 mutations among French - American - British ( FAB ) subtypes . Lesions were restricted to FAB - M5 cases , where they were relatively common ( four of 12 cases ) . Here , we report on the results of a molecular screening performed on 181 additional unselected patients , enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica - AML Study Group , to provide a more accurate picture of the prevalence , spectrum and distribution of Q06124 mutations in childhood AML and to investigate their clinical relevance . We concluded that Q06124 defects do not represent a frequent event in this heterogeneous group of malignancies ( 4 . 4 % ) , although they recur in a considerable percentage of patients with FAB - M5 ( 18 % ) . Q06124 lesions rarely occur in other subtypes . Within the FAB - M5 group no clear association of Q06124 mutations with any clinical variable was evident . Nearly two third of the patients with this subtype were found to harbour an activating mutation in Q06124 , P01111 , P01116 or P36888 .",
"Serotonin transporter interacts with the PDGFβ receptor in DB00102 - induced signaling and mitogenesis in pulmonary artery smooth muscle cells . The serotonin transporter ( P31645 ) and the platelet - derived growth factor receptor ( P09619 ) have been implicated in both clinical and experimental pulmonary hypertension ( PH ) and the facilitation of pulmonary artery smooth muscle cell ( PASMC ) growth . To gain a better understanding of the possible relationship of these two cell surface molecules we have explored interactions between P31645 and P09619 . We have previously demonstrated that P31645 transactivates PDGFRβ in serotonin - stimulated PASMC proliferation . We now provide evidence for a role for P31645 in DB00102 signaling and PASMC proliferation by using pharmacological inhibitors , genetic ablation , and construct overexpression of P31645 . The results show that four tested P31645 blockers dose dependently inhibit PDGF - stimulated human and bovine PASMC proliferation with comparable efficacy to that of P09619 inhibitors , whereas P28222 or 5 - Q13049 receptor inhibitors had no effect . Combinations of the P31645 and P09619 inhibitors led to synergistic / additive inhibition . Similarly , PDGF - induced PASMC proliferation was attenuated by small interfering RNA downregulation of P31645 . Inhibition of P31645 in PASMCs attenuated PDGF - induced phosphorylation of PDGFRβ , Akt , and p38 but not Erk . Overexpression of P31645 in HEK293 cells led to enhanced Akt phosphorylation by PDGF , which was blunted by a P31645 PDZ motif mutant , indicating the mechanistic need for the PDZ motif of P31645 in PDGF signaling . Furthermore , coimmunoprecipitation experiments showed that P31645 and PDGFRβ become physically associated upon PDGF stimulation . In total , the data show for the first time an important interactive relationship between P31645 and the PDGFRβ in the production of PASMC proliferation triggered by PDGF that may be important in PH .",
"DB02709 inhibits PDGF receptor mitogenic signaling in mesangial cells : role of P18031 . Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction . We show that the phytoalexin resveratrol dose dependently inhibits PDGF - induced DNA synthesis in mesangial cells with an IC ( 50 ) of 10 microM without inducing apoptosis . Remarkably , the increased Q96EB6 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect . DB02709 significantly blocked PDGF - stimulated c - Src and Akt kinase activation , resulting in reduced cyclin D1 expression and attenuated P06400 phosphorylation and cyclin - dependent kinase - 2 ( P24941 ) activity . Furthermore , resveratrol inhibited P09619 phosphorylation at the PI 3 kinase and Grb - 2 binding sites tyrosine - 751 and tyrosine - 716 , respectively . This deficiency in P09619 phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1 / 2 MAPK activity . Interestingly , resveratrol increased the activity of protein tyrosine phosphatase P18031 , which dephosphorylates PDGF - stimulated phosphorylation at tyrosine - 751 and tyrosine - 716 on P09619 with concomitant reduction in Akt and Erk1 / 2 kinase activity . P18031 significantly inhibited PDGF - induced DNA synthesis without inducing apoptosis . These results for the first time provide evidence that the stilbene resveratrol targets P18031 to inhibit P09619 mitogenic signaling .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK71___ GITS , Diaprel MR ) . One daily dose of ___MASK71___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"DB00398 induces sustained molecular remission in P36888 - ITD positive AML with relapse after second allogeneic stem cell transplantation without exacerbation of acute GVHD : a case report .",
"Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .",
"___MASK48___ induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase - 5 ( O76074 ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1 - 20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin - 1 ( P10599 - 1 ) , hemeoxygenase - 1 ( P09601 ) and P15692 . ___MASK48___ induced P15692 and angiopoietin specific receptors such as P35968 , Tie - 1 and Tie - 2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 enzyme activity . ___MASK48___ below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . ___MASK48___ along with SnPP inhibited both P15692 and Q15389 ( Ang - 1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro - angiogenic factor .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK94___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK94___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Initial testing ( stage 1 ) of the multi - targeted kinase inhibitor sorafenib by the pediatric preclinical testing program . BACKGROUND : DB00398 is an inhibitor of multiple kinases ( e . g . , P15692 receptors , P09619 , P36888 , P07949 , P15056 , P10721 ) and is approved by FDA for treatment of two adult cancers . The activity of sorafenib was evaluated against the PPTP ' s in vitro and in vivo panels . PROCEDURES : DB00398 was evaluated against the PPTP in vitro panel using 96 - hr exposure at concentrations ranging from 1 . 0 nM to 10 . 0 µM . It was tested against the PPTP in vivo panels at a dose of 60 mg / kg administered by oral gavage daily for 5 days per week , repeated for 6 weeks . RESULTS : In vitro sorafenib demonstrated cytotoxic activity , with a median IC ( 50 ) value of 4 . 3 µM . Twenty of 23 cell lines had IC ( 50 ) values between 1 . 0 and 10 . 0 µM . A single cell line ( Kasumi - 1 ) with an activating P10721 mutation had an IC ( 50 ) value < 1 . 0 µM ( IC ( 50 ) = 0 . 02 µM ) . In vivo sorafenib induced significant differences in event - free survival ( O43281 ) distribution compared to control in 27 of 36 ( 75 % ) of the evaluable solid tumor xenografts and in 1 of 8 ( 12 . 5 % ) of the evaluable ALL xenografts . DB00398 induced tumor growth inhibition meeting criteria for intermediate activity ( O43281 T / C ) in 15 of 34 ( 44 % ) evaluable solid tumor xenografts . No xenografts achieved an objective response . CONCLUSIONS : The primary in vitro activity of sorafenib was noted at concentrations above 1 µM , with the exception of a more sensitive cell line with an activating P10721 mutation . The primary in vivo effect for sorafenib was tumor growth inhibition , which was observed across multiple histotypes .",
"5 - hydroxytryptamine 2B receptor regulates cell - cycle progression : cross - talk with tyrosine kinase pathways . In this paper , we present evidence that activation of 5 - hydroxytryptamine 2B ( P41595 ) receptors by serotonin ( 5 - HT ) leads to cell - cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1 / cdk4 and cyclin E / cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels . The induction of cyclin D1 expression , but not that of cyclin E , is under mitogen - activated protein kinase ( MAPK ) control , indicating an independent regulation of these two cyclins in the P41595 receptor mitogenesis . Moreover , by using the specific platelet - derived growth factor receptor ( P09619 ) inhibitor AG 1296 or by overexpressing a kinase - mutant P09619 , we show that P09619 kinase activity is essential for P41595 - triggered MAPK / cyclin D1 , but not cyclin E , signaling pathways . P41595 receptor activation also increases activity of the Src family kinase , c - Src , Fyn , and c - Yes . Strikingly , c - Src , but not Fyn or c - Yes , is the crucial molecule between the G ( q ) protein - coupled P41595 receptor and the cell - cycle regulators . Inhibition of c - Src activity by 4 - amino - 5 -( 4 - methylphenyl )- 7 -( t - butyl ) pyrazolo [ 3 , 4 - d ] pyrimidine ( P50391 ) or depletion of c - Src is sufficient to abolish the 5 - HT - induced ( i ) P09619 tyrosine kinase phosphorylation and MAPK activation , ( ii ) cyclin D1 and cyclin E expression levels , and ( iii ) thymidine incorporation . This paper elucidates a model of P41595 receptor mitogenesis in which c - Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase P09619 to induce cyclin D1 expression via the MAPK / P29323 pathway .",
"Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator - activated receptors , Q9HAZ2 , transforming growth factor - β2 and P36888 in hematopoiesis . Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells . One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains . We previously showed that TGF - β2 is a genetically determined positive regulator of hematopoiesis . In the presence of unknown nonprotein serum factors TGF - β2 , but not TGF - β1 or - β3 , enhances progenitor proliferation in vitro , an effect that is subject to mouse strain - dependent variation mapping to a locus on chr . 4 , Tb2r1 . TGF - β2 - deficient mice show hematopoietic defects , demonstrating the physiologic role of this cytokine . Here , we show that TGF - β2 specifically and predominantly cell autonomously enhances signaling by P36888 in vitro and in vivo . A coding polymorphism in Prdm16 ( PR - domain - containing 16 ) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator - activated receptor - γ ( PPARγ ) , identifying lipid Q07869 ligands as the serum factors required for regulation of P36888 signaling by TGF - β2 . We furthermore show that PPARγ agonists play a P36888 - dependent role in stress responses of progenitor cells . These observations identify a novel regulatory axis that includes PPARs , Prdm16 , and TGF - β2 in hematopoiesis .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK92___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Clinical Response to DB00398 in a Patient with Metastatic Colorectal Cancer and P36888 Amplification . BACKGROUND : A considerable number of patients with metastatic colorectal cancer progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment . We aim at reviewing our experience with sorafenib treatment of a patient with P36888 mutation in refractory metastatic colorectal cancer . METHODS : Treatment with sorafenib of a patient with metastatic colorectal cancer and P36888 translocation who had previously been heavily treated . RESULTS : The patient with metastatic colorectal cancer , aged 51 years , showed significant symptomatic and laboratory improvement with sorafenib treatment ( 400 mg twice daily ) . CONCLUSION : The presented case illustrates how an aggressive and refractory colorectal tumor may respond well to targeted therapy .",
"DB00398 . PURPOSE OF REVIEW : DB00398 is an oral , multikinase inhibitor that was recently approved for use in metastatic renal cancer . It is currently undergoing investigation in locally advanced renal cancer and in other tumor types . RECENT FINDINGS : DB00398 was initially developed as an inhibitor of Raf kinase ; however , it has broad spectrum activity against multiple tyrosine kinases , including angiogenic factors VEGFR and P09619 . Common toxicities experienced with sorafenib include hypertension , hand - foot syndrome , rash , diarrhea and fatigue . Early clinical trials suggested that sorafenib acts as a cytostatic agent , as many patients experienced prolonged disease stabilization but insufficient tumor shrinkage to meet RECIST criteria for response . To assess whether sorafenib ' s growth inhibition translated into a clinical benefit , a phase II randomized discontinuation trial was designed . This trial demonstrated that sorafenib increased progression - free survival in patients with metastatic renal cell cancer ; the phase II data were confirmed in a large international phase III trial . SUMMARY : In this review , we will discuss the clinical development of sorafenib and its role in the treatment of renal cancer . Additionally , we will highlight critical methods of clinical trial design and biomarker development that contribute to the development of sorafenib .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK37___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK37___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"DB00398 for the treatment of hepatocellular carcinoma across geographic regions . DB00398 is an oral multikinase inhibitor targeting Raf , P15692 receptor , PDGF receptor , c - kit , Flt - 3 and rearranged during transfection ( P07949 ) . Two randomized , placebo - controlled trials for Western and Asian patients , respectively , demonstrated that sorafenib significantly prolongs overall survival and time to progression in patients with advanced hepatocellular carcinoma ( HCC ) . These have become the reference treatment for future clinical trials of advanced HCC . DB00398 is well tolerated in patients with Child - Pugh liver function class A , but limited data are available in Child - Pugh class B and C patients . Clinical trials are ongoing to test the efficacy of sorafenib - based combination therapy and sorafenib adjuvant therapy for HCC .",
"Combination of the P29323 inhibitor AZD6244 and low - dose sorafenib in a xenograft model of human renal cell carcinoma . DB00398 , a multikinase inhibitor , is currently used as monotherapy for advanced renal cell carcinoma ( RCC ) . However , adverse effects associated with its use have been experienced by some patients . In this study , we examined the antitumor and antiangiogenic activities of low - dose sorafenib in combination with the MEK inhibitor AZD6244 ( sorafenib / AZD6244 ) in a preclinical model of RCC . Primary RCC 08 - 0910 and RCC 786 - 0 cells as well as patient - derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib / AZD6244 . Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting . Microvessel density , apoptosis and cell proliferation were analyzed by immunohistochemistry . Treatment of RCC 786 - 0 cells with sorafenib / AZD6244 resulted in P55008 cell cycle arrest and blockade of serum - induced cell migration . DB00398 / AZD6244 induced apoptosis in primary RCC 08 - 0910 cells at low concentrations . In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity . DB00398 / AZD6244 potently inhibited angiogenesis and phosphorylation of P35968 , P09619 - β and P29323 , p90RSK , p70S6K , cdk - 2 and retinoblastoma . DB00398 / AZD6244 also caused upregulation of p27 , Bad and Bim but downregulation of survivin and cyclin B1 . These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis . Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth . This study provides sound evidence for the clinical investigation of low - dose sorafenib in combination with AZD6244 in patients with advanced RCC .",
"Peroxisome proliferator - activated receptor - gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells . Vascular endothelial growth factor ( P15692 ) , expressed in a variety of mesenchymal cells including vascular smooth muscle cells ( VSMC ) , is a potent mitogen for endothelial cells , and is used clinically applied for ischemic disease of peripheral vessels . To determine whether peroxisome proliferator - activated receptor gamma ( PPARgamma ) regulates P15692 production in VSMC , we examined P15692 secretion from VSMC treated with Q07869 agonists . DB00197 increased P15692 secretion in a time - and dose - dependent manner ( 261 +/- 35 % with 25 mM of troglitazone for 24 h ) , and also increased levels of P15692 mRNA . P15692 secretion was also increased by other PPARgamma agonists , pioglitazone , LY171883 , and 15d - PGJ2 ( 224 +/- 17 . 1 % , 247 +/- 36 . 8 % and 171 +/- 7 . 8 % , respectively ) , but not the PPARgamma agonists bezafibrate and Wy14643 ( 85 . 2 +/- 1 . 5 % , 94 . 6 +/- 3 . 2 , respectively ) . Our findings suggest that thiazolidinediones might be useful for the therapeutic angiogenesis for ischemic artery disease .",
"Amniotic DB05914 with robust chemotactic properties are effective in the treatment of a myocardial infarction model . BACKGROUND : We previously reported that amniotic DB05914 ( AMMs ) possess high angio - vasulogenic properties . In this study , we investigated the chemotactic abilities of AMMs for improved cardiac function and regenerative angiogenesis . METHODS : The expressions of chemotactic and angiogenic genes were determined by qRT - PCR . Myocardial infarction ( MI ) was induced in NOD / SCID mice and cells were directly transplanted into the border regions of ischemic heart tissue . Immunohistochemical analysis was also conducted . RESULTS : AMMs significantly expressed the representative chemotactic factor P04001 - 2 , Q99733 as well as angiogenic factor Hif - 1a . AMMs also highly expressed the chemokine receptors P41597 , P51677 and P51681 . AMM transplantation improved left ventricular function , capillary density , angiogenic cytokine levels , angiopoetin ( Ang ) - 1 and vascular endothelial growth factor ( P15692 ) levels in affected tissue . Immunohistochemical assaying also revealed increased engraftment and endothelial phenotypes . CONCLUSION : Our findings suggest that due to elevated survival and related chemotactic potential , AMMs are a promising stem cell source for the treatment of ischemic cardiovascular disease .",
"[ Angiogenesis and renal cell carcinoma ] . Developments in the knowledge of molecular biology of renal cell carcinoma ( RCC ) over the past 20 years have been identified . Angiogenesis is playing a key role in the physiopathology of RCC . Von Hippel - Lindau ( P40337 ) alterations , HIFalpha accumulation and vascular endothelial growth factor ( P15692 ) overexpression are important mediators of this process . Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC . These include inhibition of P15692 receptors ( inhibition of the tyrosine kinase activity ) or binding to the P15692 protein . Several additional kinases inhibitions including PDGF receptors are also targeted . DB01268 ( SU11248 ) is an orally biovailable small molecule that has demonstrated superiority over interferon - alpha for the treatment of metastatic RCC . In a recent randomized phase III study conducted in 750 patients , the response rate to sunitinib was 31 % and to interferon 6 % . The median of progression free survival ( PFS ) was 11 months for sunitinib and 5 months for interferon ( p < 0 . 001 ) . DB00398 ( BAY43 - 9006 ) was found to inhibit Raf1 , but also P35968 and 3 , Flt3 , P09619 - a and b and c - kit , has been tested in a phase III study against placebo after one prior systemic therapy . The median of the time to progression ( TTP ) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm ( p = 0 , 01 ) . Other molecules tested in metastatic RCC will be presented including axitinib , pazopanib and bevacizumab .",
"Sustained response following sorafenib therapy in an older adult patient with advanced renal cancer on hemodialysis : a case report . The prognosis for patients with renal cell carcinoma is very poor , with a five - year survival rate of less than 10 % . DB00398 is an orally administered multikinase inhibitor that blocks intracellular kinases in the Raf / MEK / P29323 pathway involved in tumor proliferation , and also kinases responsible for angiogenesis , including VEGFr - 2 , VEGFr - 3 , Flt - 3 , PDGFr - β and c - P10721 . As a consequence of its limited renal clearance , sorafenib appears to be suitable for patients with advanced kidney cancer and terminal renal failure . The case of a 72 - year - old male patient on hemodialysis and receiving sorafenib treatment for mRCC is reported .",
"P37231 agonists induce the expression of P15692 and its receptors in cultured cardiac myofibroblasts . OBJECTIVES : Myofibroblasts ( myoFb ) are the major cell types that appear at the site of myocardial infarction ( MI ) in response to injury and play a vital role in tissue repair / remodeling . Since vascular endothelial growth factor ( P15692 ) plays a crucial role in the infarcted / ischemic heart , we hypothesized that activation of the peroxisome proliferator - activated receptor ( Q07869 ) - gamma by its agonists induces P15692 expression while simultaneously decreasing inflammation ( NF - kappaB ) . Such an increase in myoFb P15692 expression by P37231 agonists may play a role in angiogenesis . METHODS : Rat myoFb were treated with P37231 agonists and P15692 expression was measured by ELISA . The effect of these agonists on P15692 receptors was determined by qRT - PCR and flow - cytometric analysis . P15692 produced by these cells was also used for analysis of in vitro tubule formation ( Matrigel assay ) . RESULTS : The P37231 activators troglitazone ( TZ ) and 15 - deoxy - prostaglandin J2 ( 15J2 ) induced the expression of P15692 and its receptors ( Flt - 1 and P35968 ) in myoFb . TZ and 15J2 elicited a significant increase in the expression of P35968 ( 14 . 7 +/- 1 . 0 % and 9 . 6 +/- 2 . 1 % respectively ) and Flt - 1 ( 24 . 5 +/- 2 . 0 % , and 14 . 0 +/- 2 . 2 % respectively ) when compared to untreated myoFb . MyoFb treated with P37231 agonists increased extracellular P15692 , augmenting tubule formation on a Matrigel . The P37231 activator 15J2 significantly decreased the NF - kappaB activity in myoFb . CONCLUSION : This study demonstrates the induction of the P15692 accompanied by a reduction of NF - kappaB activity ( inflammatory signaling ) by P37231 agonists in cardiac myoFb . These results may further the understanding of the beneficial effects of P37231 agonists on infarcted tissue repair and angiogenesis .",
"DB00398 is tolerable and improves clinical outcomes in patients with P36888 - ITD acute myeloid leukemia prior to stem cell transplant and after relapse post - transplant .",
"Discovery of potent , orally active compounds of tyrosine kinase and serine / threonine - protein kinase inhibitor with anti - tumor activity in preclinical assays . Traditional medicines have become the most productive source of leads for drugs development , particularly as anti - cancer agents . Various screening approaches are being applied . DB00398 , a multikinase inhibitor , is used to treat primary kidney cancer ( advanced renal cell carcinoma ) and advanced primary liver cancer . A small library of compounds analogous to sorafenib were designed and screened for the treatment of liver cancer . Multiple members of the family in an assay panel of tyrosine kinase family and serine / threonine - protein kinase family , including VEGFR , Abl , Aurora A , p 38 , Lck , Src , P09619 , Flt3 , c - RAF , c - P10721 , MEK ( MAPKK ) were selected to test these compounds . Analysis of the selectivity patterns for these compounds shows specificity for many kinase families . IC₅₀ were measured for the selected compounds . Multiple compounds have very similar kinase inhibition profiles of VEGFR , Flt3 , FGFR to that of sorafenib . The IC₅₀ of c - RAF of BB1 is lower than sorafenib . The IC₅₀ of c - RAF of BB3 - 12 is higher than that of sorafenib . For Flt3 , IC₅₀ of BB1 - 4 is less than sorafenib . The IC₅₀ value of P35968 of BB1 - 10 is less than sorafenib . especially against c - RAF , P09619 , c - P10721 , P35968 compared to sorafenib . These compounds are potent Raf1 and Flt4 kinase inhibitors .",
"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK92___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .",
"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .",
"___MASK48___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .",
"Two cases of recurrent ovarian clear cell carcinoma treated with sorafenib . DB00398 is an oral multikinase inhibitor targeting Raf and other kinases . The anti - tumor effect of sorafenib is thought to be mediated through its inhibition of the DB01367 - Raf - Erk pathway , as well as its inhibition of VEGFR and P09619 . DB00398 has been effective at treating patients with renal cell carcinoma ( RCC ) . Ovarian clear cell carcinoma ( OCCC ) is a chemoresistant subtype of ovarian cancer . OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC . Using a microarray database , the gene expression profile of OCCC was similar to that of RCC . The effects of sorafenib against human OCCC are unknown . Therefore , we used sorafenib to treat two patients with recurrent chemoresistant OCCC , and observed good effect in both of them without severe side effects . We believe that sorafenib is an effective agent against OCCC . Given the chemoresistant nature of this tumor , this drug appears to be very valuable .",
"Indicators for the exposure assessment of transformation products of organic micropollutants . Environmental transformation products of organic micropollutants have the potential to be similarly or even more mobile , persistent , ortoxic than their parent compounds . They should , therefore , be included in chemical hazard and risk assessment procedures as well as in the assessment of soil and water quality . To fulfill this requirement most efficiently , screening approaches that select relevant transformation products for detailed assessment are needed . This paper presents two process - based multimedia , multispecies models that allow us to quantitatively estimate the environmental fate of transformation products . The resulting exposure patterns are assessed with two indicators : joint persistence ( JP ) , which describes the temporal extent of environmental exposure to a parent compound and its transformation products , and the predicted relative aquatic concentrations ( P31749 ) , which estimate the relative concentrations of parent compounds and their transformation products in surface water bodies . As a case study , JP and P31749 are calculated for 16 pesticides and their relevant transformation products . The results for the JP indicator confirm the importance of considering transformation products in the assessment of overall persistence ; for example , in the context of P10721 assessments . Comparison of P31749 results with monitoring data on herbicides and their transformation products shows the suitability of our approach for estimating relative concentrations in surface water , and as a consequence , its usefulness in identifying transformation products for future water quality monitoring programs . Transformation products of triketones and other highly used acidic herbicides are specifically identified as targets .",
"SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .",
"DB00398 and thyroid cancer . DB00398 ( Nexavar ) is a multikinase inhibitor , which has demonstrated both anti - proliferative and anti - angiogenic properties in vitro and in vivo , inhibiting the activity of targets present in the tumor cell [ c - RAF ( proto - oncogene serine / threonine - protein kinase ) , P15056 , ( V600E ) P15056 , c - P10721 , and P07333 - like tyrosine kinase 3 ] and in tumor vessels ( c - RAF , vascular endothelial growth factor receptor - 2 , vascular endothelial growth factor receptor - 3 , and platelet - derived growth factor receptor β ) . For several years , sorafenib has been approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma . After previous studies showing that sorafenib was able to inhibit oncogenic P07949 mutants , ( V600E ) P15056 , and angiogenesis and growth of orthotopic anaplastic thyroid cancer xenografts in nude mice , some clinical trials demonstrated the effectiveness of sorafenib in advanced thyroid cancer . Currently , the evaluation of the clinical safety and efficacy of sorafenib for the treatment of advanced thyroid cancer is ongoing . This article reviews the anti - neoplastic effect of sorafenib in thyroid cancer . Several completed ( or ongoing ) studies have evaluated the long - term efficacy and tolerability of sorafenib in patients with papillary and medullary aggressive thyroid cancer . The results suggest that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies .",
"N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .",
"A novel tissue model for angiogenesis : evaluation of inhibitors or promoters in tissue level . A novel tissue model for angiogenesis ( TMA ) is established for effective evaluation of angiogenesis inhibitors or promoters in vitro . Lung tissues were cultured in fibrinogen \" sandwich \" structure which resembled the formation of neovessels in vivo . The cells and capillary - like structures grew from the lung tissues were identified as endothelial cells and neovessels . Both immunohistochemisty and western blot results indicated that autocrine P15692 bound to the P35968 and induced P35968 autophosphorylation that could induce the proliferation of endothelial cells and their migration as well as the formation of microvessels on the lung tissue edge . With addition of the TMA , the murine P15692 and cultured medium produced by A549 tumor cells apparently promoted the increase of neovessels . DB00398 as a tumor angiogenesis inhibitor and Tongxinluo as an angiogenesis promoter were both used to evaluate the TMA performance and they exhibited a good effect on neovessels in the TMA . The model established imitated angiogenesis in vivo and could well serve as an effective method in evaluating the angiogenesis inhibitors or promoters , and could also be practical for screening small molecules that affect blood vessel formation .",
"The important roles of P07949 , P35968 and the RAF / MEK / P29323 pathway in cancer treatment with sorafenib . AIM : To elucidate the roles of receptor tyrosine kinases P07949 and P35968 and the RAF / MEK / P29323 signaling cascade in cancer treatment with sorafenib . METHODS : The cell lines A549 , HeLa , and HepG2 were tested . The enzyme activity was examined under cell - free conditions using 384 - well microplate assays . Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay . Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system . Protein expression analysis was performed using Western blotting . RESULTS : DB00398 potently suppressed the activities of cRAF , P35968 , and P07949 with IC ( 50 ) values of 20 . 9 , 4 and 0 . 4 nmol / L , respectively . DB00398 inhibited cRAF , P35968 , and P07949 via non - DB00171 - competitive , DB00171 - competitive and mixed - type modes , respectively . In contrast , sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines . The IC ( 50 ) values for inhibition of A549 , HeLa , and HepG2 cells were 8572 , 4163 , and 8338 nmol / L , respectively . In the 3 cell lines , sorafenib suppressed the cell proliferation mainly by blocking the MEK / P29323 downstream pathway at the posttranscriptional level , which in turn regulated related gene expression via a feed - back mechanism . CONCLUSION : This study provides novel evidence that protein kinases P07949 and P35968 play crucial roles in cancer treatment with sorafenib .",
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"Toxicity of sorafenib : clinical and molecular aspects . IMPORTANCE OF THE FIELD : DB00398 is a novel oral bis - aryl urea compound originally developed as an inhibitor of RAF kinase for its anti - proliferative property . DB00398 also inhibits receptor tyrosine kinases of multiple pro - angiogenic factors such as P17948 / 2 / 3 , Flt - 3 and P09619 . The combination of both its anti - proliferative and anti - angiogenic properties makes sorafenib an attractive agent in cancer treatment . DB00398 has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer . Despite its inherent selectivity , sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists . AREAS COVERED IN THIS REVIEW : Relevant literature was identified using a Pubmed search of articles published up to June 2009 . Search terms included ' sorafenib ' and ' toxicity ' . Original articles were reviewed and relevant citations from these articles were also considered . WHAT THE READER WILL GAIN : The clinical aspect of sorafenib - induced adverse events and the molecular basis behind this toxicity are discussed . Finally , recommendations for the management of these adverse events are proposed . TAKE HOME MESSAGE : Although not life - threatening , toxicity of sorafenib can severely impact the physical , psychological and social well - being of patients . The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist , cardiologist and dermatologist .",
"Peripheral medulloepithelioma : a rare tumor with a potential target therapy . BACKGROUND : Medulloepithelioma ( ME ) is a rare embryonal tumor predominantly located in the eye or in the central nervous system without an established treatment . CASE PRESENTATION : We report of a case of a localized peripheral ME treated with conventional and high dose chemotherapy , surgery and local radiotherapy . At relapse , the tumor tissue revealed a different molecular signature compared to the initial tumor mass . This molecular signature revealed a high expression of platelet derived growth factor receptor ( P09619 ) . DB00398 plus irinotecan and temozolomide was started with a 5 month progression free survival . CONCLUSION : Our experience suggests a possible role of sorafenib or different P09619 inhibitors in ME . Targeting treatment could represent an adjuvant and / or alternative therapy for ME and other rare tumors .",
"The role of HIV - related chemokine receptors and chemokines in human erythropoiesis in vitro . In order to better define the role of HIV - related chemokines in human erythropoiesis we studied : A ) the expression of chemokine receptors , both on human P28906 (+) cells which include erythroid progenitors and on more mature erythroid cells ; B ) the functionality of these receptors by calcium flux , chemotaxis assay and phosphorylation of mitogen - activated protein kinases ( MAPK ) Q8NFH3 / 44 ( P27361 / P28482 ) and AKT , and finally C ) the influence of chemokines on BFU - E formation . We found that HIV - related chemokine receptor P61073 , but not P51681 , is detectable on human P28906 (+) BFU - E cells . P61073 surface expression decreased during erythroid maturation , although P61073 mRNA was still present in cells isolated from differentiated erythroid colonies . P48061 , a P61073 ligand , induced calcium flux and phosphorylation of MAPK ( Q8NFH3 / 44 ) and AKT in P28906 (+) P10721 (+) bone marrow mononuclear cells which contain BFU - E , as well as chemotactic activity of both human P28906 (+) BFU - E progenitors and erythroid cells isolated from day 2 - 6 BFU - E colonies . Responsiveness to P48061 decreased when the cells differentiated to the point of surface expression of the erythroid - specific marker P02724 . In contrast , the P51681 ligands ( macrophage inflammatory protein - 1alpha [ MIP - 1alpha ] , MIP - 1beta , and RANTES ) did not activate calcium flux , MAPK and AKT phosphorylation or chemotaxis of P28906 (+) P10721 (+) cells or cells isolated from the BFU - E colonies . Interestingly , none of the chemokines tested in this study had any effect on BFU - E colony formation . In conclusion , only P61073 is functional , and its specific ligand P48061 may therefore play an important role in the homing and / or retention of early erythroid precursors in the bone marrow environment .",
"Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC ."
] |
[
"___MASK23___",
"___MASK24___",
"___MASK37___",
"___MASK48___",
"___MASK69___",
"___MASK71___",
"___MASK81___",
"___MASK92___",
"___MASK94___"
] |
___MASK48___
|
MH_train_329
|
interacts_with DB06719?
|
[
"Identification of the amino acid sequence motif of alpha - synuclein responsible for macrophage activation . P37840 ( Syn ) is implicated in the pathogenesis of PD and related neurodegenerative disorders . Recent studies have also shown that alpha - synuclein can activate microglia and enhance dopaminergic neurodegeneration . The mechanisms of microglia activation by alpha - synuclein , however , are not well understood . In this study , we found that not only alpha - synuclein but also beta - and gamma - synucleins activated macrophages ( RAW 264 . 7 ) in vitro . Macrophages treated with synuclein proteins secreted P01375 in a dose - dependent manner . Synuclein family proteins also increased mRNA transcription of P35354 and P35228 . Two alpha - synuclein deletion mutants , SynDeltaNAC and Syn61 - 140 , activated macrophages , while deletion mutants Syn1 - 60 and Syn96 - 140 did not significantly activate them . Finally , we demonstrated that macrophage activation by alpha - synuclein was accompanied by phosphorylation of P29323 . These results suggest that synuclein family proteins can activate macrophages , and that macrophage activation needs both the N - terminal and C - terminal domains of alpha - synuclein , but not the central Q9C000 region .",
"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK99___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Signaling and antiproliferative effects of type I and II gonadotropin - releasing hormone receptors in breast cancer cells . DB00644 receptors ( DB00644 - Rs ) mediate direct antiproliferative effects on hormone - dependent cancer cells . DB00644 - Rs can be grouped according to ligand specificity ( for DB00644 and - II ) , and there is evidence that type II DB00644 ligands and / or receptors can inhibit proliferation . Type I DB00644 - Rs ( e . g . human and sheep ) lack the C - terminal tails found in other G protein - coupled receptors including type II DB00644 - Rs ( e . g . Xenopus ; XGnRH - R ) . This underlies the remarkable resistance of type I DB00644 - Rs to desensitization and may be important for chronic effects on proliferation . To test this , we have compared the antiproliferative effects of DB00644 - Rs expressed in MCF7 breast cancer cells using recombinant adenovirus ( Ad ) . Endogenous DB00644 - Rs were not detected , but infection with Ad - expressing sheep DB00644 - Rs ( sGnRH - R ) facilitated proliferation inhibition by DB06719 , and maximum inhibition required only 10 , 000 - 20 , 000 sGnRH - Rs . XGnRH - Rs were much less efficient at inhibiting proliferation and were internalized faster than sGnRH - Rs . Thus , the type II P30968 is less efficient at inhibiting proliferation , presumably because it is rapidly desensitized and / or internalized . Moreover , comparisons of human P30968 , sGnRH - R , and XGnRH - R , as well as chimeric receptors ( type I DB00644 - Rs with C - terminal tails from XGnRH - Rs ) , revealed that C - terminal tail addition increases receptor expression and thereby increases the efficiency with which the vector facilitates the antiproliferative effect .",
"Translational research in bipolar disorder : emerging insights from genetically based models . Bipolar disorder ( BPD ) is characterized by vulnerability to episodic depression and mania and spontaneous cycling . Because of marked advances in candidate - gene and genome - wide association studies , the list of risk genes for BPD is growing rapidly , creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment . However , genetic findings are associated with major unresolved issues , including whether and how risk variance leads to behavioral abnormalities . Although animal studies are key to resolving these issues , consensus is needed regarding how to define and monitor phenotypes related to mania , depression and mood swing vulnerability in genetically manipulated rodents . In this study we discuss multiple facets of this challenging area , including theoretical considerations , available tests , limitations associated with rodent behavioral modeling and promising molecular - behavioral findings . These include O15516 , glycogen synthase kinase 3beta ( GSK - 3beta ) , glutamate receptor 6 ( Q13002 ) , extracellular signal - regulated kinase - 1 ( P27361 ) , p11 ( or P60903 ) , vesicular monoamine transporter 2 ( Q05940 or Q05940 ) , glucocorticoid receptors ( GRs ) , Bcl - 2 - associated athanogene - 1 ( Q99933 ) and mitochondrial DNA polymerase - gamma ( P54098 ) . Some mutant rodent strains show behavioral clusters or activity patterns that cross - species phenocopy objective / observable facets of mood syndromes , and changes in these clustered behaviors can be used as outcome measures in genetic - behavioral research in BPD .",
"___MASK86___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Q9H4A3 activates large - conductance Ca2 +- activated K + channels through modulation of P27361 / 2 signaling . With no lysine ( WNK ) kinases are members of the serine / threonine kinase family . We previously showed that Q96J92 inhibits renal large - conductance Ca ( 2 +)- activated K (+) ( BK ) channel activity by enhancing its degradation through a lysosomal pathway . In this study , we investigated the effect of Q9H4A3 on Q12791 activity . In HEK293 cells stably expressing the α subunit of BK ( P29320 - BKα cells ) , siRNA - mediated knockdown of Q9H4A3 expression significantly inhibited both BKα channel activity and open probability . Knockdown of Q9H4A3 expression also significantly inhibited BKα protein expression and increased P27361 / 2 phosphorylation , whereas overexpression of Q9H4A3 significantly enhanced BKα expression and decreased P27361 / 2 phosphorylation in a dose - dependent manner in HEK293 cells . Knockdown of P27361 / 2 prevented Q9H4A3 siRNA - mediated inhibition of BKα expression . Similarly , pretreatment of P29320 - BKα cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of Q9H4A3 siRNA on BKα expression in a dose - dependent manner . Knockdown of Q9H4A3 expression also increased the ubiquitination of BKα channels . Notably , mice fed a high - K (+) diet for 10 days had significantly higher renal protein expression levels of BKα and Q9H4A3 and lower levels of P27361 / 2 phosphorylation compared with mice fed a normal - K (+) diet . These data suggest that Q9H4A3 enhances Q12791 function by reducing P27361 / 2 signaling - mediated lysosomal degradation of the channel .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK71___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"___MASK65___ block of cloned human T - type voltage - gated calcium channels . ___MASK65___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"Phospholipase C not protein kinase C is required for the activation of Q9UL62 channels by cholecystokinin . Cholecystokinin ( CCK ) is one of the most abundant neuropeptides in the brain where it interacts with two G protein - coupled receptors ( CCK1 and CCK2 ) . Both types of CCK receptors are coupled to G ( q / 11 ) proteins resulting in increased function of phospholipase C ( P98160 ) pathway . Whereas CCK has been suggested to increase neuronal excitability in the brain via activation of cationic channels , the types of cationic channels have not yet been identified . Here , we co - expressed CCK2 receptors and Q9UL62 channels in human embryonic kidney ( P29320 ) 293 cells and studied the effects of CCK on Q9UL62 channels using patch - clamp techniques . Our results demonstrate that activation of CCK2 receptors robustly potentiates the function of Q9UL62 channels . CCK - induced activation of Q9UL62 channels requires the functions of G - proteins and P98160 and depends on extracellular Ca ( 2 +) . The activation of Q9UL62 channels mediated by CCK2 receptors is independent of IP ( 3 ) receptors and protein kinase C . CCK - induced opening of Q9UL62 channels is not store - operated because application of thapsigargin to deplete intracellular Ca ( 2 +) stores failed to alter CCK - induced Q9UL62 channel currents significantly . Bath application of CCK also significantly increased the open probability of Q9UL62 single channel currents in cell - attached patches . Because CCK exerts extensive effects in the brain , our results may provide a novel mechanism to explain its roles in modulating neuronal excitability .",
"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .",
"Wheat germ agglutinin behaves as a DB00644 antagonist but induces gonadotrope desensitization . Preincubation of cultured rat pituitary cells with 10 micrograms / ml of either wheat germ agglutinin ( WGA ) or concanavalin A inhibited LH release stimulated with DB00644 ( 0 . 5 nM ) by 55 % and 40 % , respectively . WGA - inhibition of LH release stimulated by DB00644 was dose - dependent , reaching a plateau of 75 % inhibition at 50 micrograms / ml . Concomitantly , WGA induced a dose - dependent inhibition of 125I - DB06719 specific binding to pituitary cells , with a maximal inhibition of 45 % . The inhibition of 125I - DB06719 binding by WGA is due to P30968 internalization and not to persistent occupancy of the receptors . In addition to the effect of WGA on receptor internalization , WGA also induced partial desensitization of pituitary cells but was ineffective in modulating DB00644 - induced desensitization . These findings indicate that WGA has all the characteristics of a DB00644 antagonist , nevertheless , it does induce desensitization of cultured rat pituitary cells to further stimulation with DB00644 .",
"Large - scale association study for structural soundness and leg locomotion traits in the pig . BACKGROUND : Identification and culling of replacement gilts with poor skeletal conformation and feet and leg ( FL ) unsoundness is an approach used to reduce sow culling and mortality rates in breeding stock . Few candidate genes related to soundness traits have been identified in the pig . METHODS : In this study , 2066 commercial females were scored for 17 traits describing body conformation and FL structure , and were used for association analyses . Genotyping of 121 SNPs derived from 95 genes was implemented using Sequenom ' s MassARRAY system . RESULTS : Based on the association results from single trait and principal components using mixed linear model analyses and false discovery rate testing , it was observed that P02649 , P34820 , P30988 , P08123 , P20849 , DKFZ , P35555 and VDBP were very highly significantly ( P < 0 . 001 ) associated with body conformation traits . The genes P09917 , P34820 , P30988 , O00300 , P30559 and Q9UBV4 were very highly significantly ( P < 0 . 001 ) associated with FL structures , and P02649 , P30988 , P08123 , P30968 , Q14623 , P42898 and Q9UBV4 were highly significantly ( P < 0 . 01 ) associated with overall leg action . Strong linkage disequilibrium between P30988 and P08123 on SSC9 was detected , and haplotype - ACGACC - was highly significantly ( P < 0 . 01 ) associated with overall leg action and several important FL soundness traits . CONCLUSION : The present findings provide a comprehensive list of candidate genes for further use in fine mapping and biological functional analyses .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"Tunicamycin and neuraminidase effects on luteinizing hormone ( LH ) - releasing hormone binding and LH release from rat pituitary cells in culture . We have studied the effects of tunicamycin ( TM ) and neuraminidase on the binding of 125I - labeled DB06719 , a DB00644 agonist , and on DB00644 - stimulated LH release in cultured rat pituitary cells . Treatment with TM , an antibiotic which inhibits protein glycosylation , abolished the development of elongated cell processes without any effect on cell viability . Concomitantly , TM caused a time - and dose - dependent inhibition of specific binding of DB06719 and of DB00644 - stimulated LH release . The inhibition of binding was due to a decrease in the number of DB00644 receptors without any significant effect on binding affinity . Protein synthesis was not affected under these experimental conditions , suggesting that the aglycosylated DB00644 receptors are probably intracellularly accumulated and are not expressed on the cell surface . Treatment with neuraminidase inhibited only 50 % of DB00644 agonist binding and did not affect DB00644 - stimulated LH release . These results indicate that the oligosaccharide portion is essential for the functional properties of the P30968 .",
"P01308 augments gonadotropin - releasing hormone induction of translation in LbetaT2 cells . The integrated signaling of insulin and gonadotropin - releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function , although the cross - receptor signaling mechanisms are unclear . We demonstrate that the insulin receptor is constitutively localized to non - caveolar lipid raft microdomains in the pituitary gonadotrope cell line LbetaT2 . The localization to rafts is consistent with similar localization of the P30968 . P06213 phosphorylation occurs in raft domains and activates the downstream signaling targets P01308 Receptor Substrate1 and Akt / Protein Kinase B . Although insulin alone does not strongly activate the extracellular signal - regulated kinase second messenger cascade , co - stimulation potentiates the phosphorylation of the extracellular signal - regulated kinase by gonadotropin - releasing hormone . The co - stimulatory effect of insulin and gonadotropin - releasing hormone is also evident in increased activation of cap - dependent translation . In contrast , co - stimulation attenuates Akt / Protein Kinase B activation . Our results show that both gonadotropin - releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades . We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function .",
"The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane . The mammalian type I gonadotropin releasing hormone receptor ( P30968 ) is a structurally unique G protein - coupled receptor ( GPCR ) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression ( PME ) . Compared to its murine counterparts , the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum ( ER ) leading to a further reduction in PME . The decrease in PME and concomitant increase in intracellular localization of the mammalian DB00644 - RI led us to characterize the spatial distribution of the human and mouse DB00644 receptors in two human cell lines , P29320 293 and HTR - 8 / SVneo . In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane . A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence ( NLS ) in the first intracellular loop of DB00644 - RI . Surprisingly , however , neither the deletion of the NLS nor the addition of the Xenopus P30968 cytoplasmic tail sequences to the human receptor altered its spatial distribution . Finally , we demonstrate that DB00644 treatment of nuclei isolated from P29320 293 cells expressing exogenous DB00644 - RI triggers a significant increase in the acetylation and phosphorylation of histone H3 , thereby revealing that the nuclear - localized receptor is functional . Based on our findings , we conclude that the mammalian DB00644 - RI is an intracellular GPCR that is expressed on the nuclear membrane . This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor .",
"Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .",
"Effects of gonadotropin - releasing hormone agonist on steroidogenesis in the rat ovary . To assess the regulatory roles of gonadotropin - releasing hormone ( DB00644 ) in ovarian function , the kinetics of the ovarian P30968 and the effects of the DB00644 superagonist buserelin on steroidogenesis in ovarian cell culture were examined . Scatchard analysis of buserelin - binding to crude ovarian cell membrane revealed a specific high - affinity P30968 . DB06719 together with follicle - stimulating hormone stimulated estradiol ( E2 ) production in immature follicles in hypophysectomized and DES - treated rats . On the other hand , applied to developing follicles of rats treated with pregnant - mare - serum gonadotropin buserelin suppressed E2 production to terminate follicle maturation and simultaneously stimulated progesterone ( P4 ) production to induce luteinization . With ovarian cells luteinized by human chorionic gonadotropin in vitro , buserelin suppressed production of both P4 and E2 , leading to luteolysis . DB06719 affected steroid production by modulating activities of key enzymes in steroid synthesis . These findings indicate that buserelin action depended on the gonadotropin priming of ovarian cells , and suggest the possible involvement of DB00644 in the regulation of steroidogenesis throughout the ovulatory cycle .",
"Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .",
"P30968 concentration differentially regulates intracellular signaling pathways in GGH3 cells . Pituitary cell lines ( GGH3 ) expressing the P30968 ( GnRHR ) were used to investigate the effect of GnRHR concentration on the ability of a DB00644 agonist to activate second messenger systems . Four different strategies were utilized to generate cells expressing functionally different concentrations of receptors : ( 1 ) transient transfection with different concentrations of wild type GnRHR into GH3 cells , ( 2 ) utilization of two cell lines derived from a common stably transfected line expressing high ( 4 , 209 +/- 535 receptors / cell ) or low ( 1 , 031 +/- 36 receptors / cell ) concentrations of GnRHR , ( 3 ) co - incubation of GGH3 - 1 ' cells with a DB00644 agonist ( DB06719 ) and a DB00644 antagonist to compete for binding sites , and ( 4 ) photo - affinity binding to GnRHR with a DB00644 antagonist to change effective receptor concentration . A range of receptor concentrations ( 1 , 000 - 8 , 000 receptors / cell ) were generated by these techniques . Inositol phosphate ( IP ) and DB02527 accumulation were quantified to assess the effect of receptor concentration on receptor - effector coupling . Under all four paradigms , the efficacy and potency of DB06719 stimulated IP production was dependent on receptor concentration . In contrast , DB06719 stimulated DB02527 release was relatively unchanged at varying concentrations of GnRHR . This suggests that the cellular concentration of GnRHR affects the induction of cell signaling pathways . These results demonstrate that a single ligand - receptor - complex can differentially activate second messenger systems and present a mechanism by which multiple physiological endpoints can be differentially regulated by a single hormone / receptor interaction .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"DB00644 II ( DB00644 II ) mediates the anorexigenic actions of α - melanocyte - stimulating hormone ( α - MSH ) and corticotropin - releasing hormone ( P06850 ) in goldfish . Intracerebroventricular ( ICV ) administration of gonadotropin - releasing hormone II ( DB00644 II ) , which plays a crucial role in the regulation of reproduction in vertebrates , markedly reduces food intake in goldfish . However , the neurochemical pathways involved in the anorexigenic action of DB00644 II and its interaction with other neuropeptides have not yet been identified . Alpha - melanocyte - stimulating hormone ( α - MSH ) , corticotropin - releasing hormone ( P06850 ) and P06850 - related peptides play a major role in feeding control as potent anorexigenic neuropeptides in goldfish . However , our previous study has indicated that the DB00644 II - induced anorexigenic action is not blocked by treatment with melanocortin 4 receptor ( P32245 ) and P06850 receptor antagonists . Therefore , in the present study , we further examined whether the anorexigenic effects of α - MSH and P06850 in goldfish could be mediated through the P30968 neuronal pathway . ICV injection of the P32245 agonist , melanotan II ( 80 pmol / g body weight ; BW ) , significantly reduced food intake , and its anorexigenic effect was suppressed by ICV pre - administration of the DB00644 type I receptor antagonist , antide ( 100 pmol / gBW ) . The P06850 - induced ( 50 pmol / gBW ) anorexigenic action was also blocked by treatment with antide . ICV injection of P06850 ( 50 pmol / gBW ) induced a significant increase of the DB00644 II mRNA level in the hypothalamus , while ICV injection of melanotan II ( 80 pmol / gBW ) had no effect on the level of DB00644 II mRNA . These results indicate that , in goldfish , the anorexigenic actions of α - MSH and P06850 are mediated through the DB00644 type I receptor - signaling pathway , and that the DB00644 II system regulates feeding behavior .",
"Role of mitochondrial DNA variants and copy number in diabetic atherogenesis . Hyperglycemia - induced reactive oxygen species production can cause diabetes and its complications , including atherosclerosis . The role of mitochondrial DNA variants and mitochondrial copy number in the pathogenesis of diabetic atherogenesis is not well understood . We examined 36 diabetic patients who had undergone amputation for diabetic foot and seven non - diabetic patients who had undergone amputation after traumatic injury . Mitochondrial DNA was extracted and used for sequencing . Single nucleotide polymorphisms ( SNPs ) relative to the Cambridge reference sequence were analyzed . Mitochondrial DNA copy number was quantified by real - time PCR . Twenty - one novel variants were detected in 29 diabetic patients with arterial stenosis ; six of the variants were heteroplasmic , and most occurred in highly evolutionarily conserved residues . These variants were more prevalent in patients with arterial stenosis than in those without stenosis . The novel variants included four in complex I ( P03886 : C3477A / C , A3523A / G ; P03915 : C13028A / C , C13060A / C ) , one in complex IV ( P23219 : T6090A / T ) , and one in rRNA ( 12srRNA : G857G / T ) . Compared with non - diabetic patients , the diabetic patients had significantly less mitochondrial DNA . Furthermore , among diabetic patients with arterial stenosis , there was a significant positive correlation between mitochondrial DNA copy number and the number of total SNPs . In conclusion , we identified six novel heteroplasmic mitochondrial DNA variants among diabetic patients with arterial stenosis , and we found that diabetic atherogenesis is associated with decreased amounts of mitochondrial DNA .",
"Biphasic action of cyclic adenosine 3 ', 5 '- monophosphate in gonadotropin - releasing hormone ( DB00644 ) analog - stimulated hormone release from GH3 cells stably transfected with P30968 complementary deoxyribonucleic acid . GH3 cells are a PRL - secreting adenoma cell line derived from pituitary lactotropes . These cells have been stably transfected with rat P30968 complementary DNA to produce four cell lines : Q92820 ( 3 ) 1 ' , Q92820 ( 3 ) 2 ' , Q92820 ( 3 ) 6 ' , and Q92820 ( 3 ) 12 ' . In response to either DB00644 or DB06719 ( a metabolically stable DB00644 agonist ) , these cell lines synthesize PRL in a DB02527 - dependent manner . Only Q92820 ( 3 ) 6 ' cells desensitize in response to persistent treatment with 10 (- 7 ) g / ml DB06719 . Q92820 ( 3 ) 1 ' , Q92820 ( 3 ) 2 ' , and Q92820 ( 3 ) 12 ' cells , however , can be made refractory to DB06719 stimulation by raising DB02527 levels either by the addition of ( Bu ) 2cAMP to the medium or by treatment with cholera toxin . In Q92820 ( 3 ) cells , low levels of DB02527 fulfill the requirements for a second messenger , whereas higher levels appear to mediate the development of desensitization . The observation that in Q92820 ( 3 ) 6 ' cells , DB02527 production persists after the onset of desensitization is consistent with the view that the mechanism responsible for desensitization is distal to the production of DB02527 . Moreover , the absence of any significant difference in the amount of DB02527 produced per cell in Q92820 ( 3 ) 2 ' , Q92820 ( 3 ) 6 ' , or Q92820 ( 3 ) 12 ' cells suggests that elevated DB02527 production per cell does not explain the development of desensitization in Q92820 ( 3 ) 6 ' cells . We suggest that DB06719 - stimulated PRL synthesis in Q92820 ( 3 ) 6 ' cells is mediated by a different DB02527 - dependent protein kinase pool ( s ) than that in nondesensitizing Q92820 ( 3 ) cells . Such a protein kinase A pool ( s ) may be more susceptible to degradation via DB02527 - mediated mechanisms than the protein kinase pools mediating the DB06719 response in nondesensitizing Q92820 ( 3 ) cells . A similar mechanism has been reported in other systems .",
"Hormonal regulation of human trophoblast differentiation : a possible role for 17beta - estradiol and DB00644 . We have examined the role of 17beta - estradiol and gonadotropin releasing hormone ( DB00644 ) in the regulation of functional differentiation in human trophoblasts . In contrast to its recognized functions as a proliferation - promoting hormone in a variety of cell types , we found that 17beta - estradiol induced terminal differentiation in human trophoblastic cells , and that this event was estrogen - receptor - mediated . This process involved a loss in expression of Cyclins A2 and E , and a coincident increase in p27 ( Kip1 ) . The anti - proliferative effects of 17beta - estradiol were annulled by specific transforming growth factor - beta 1 ( TGFbeta1 ) - neutralizing antibody , suggesting that 17beta - estradiol may mediate its growth - inhibitory actions , through TGFbeta1 activity . Following exposure to DB06719 , cultured human trophoblastic cells stopped proliferating and formed functionally mature syncytiotrophoblasts . This differentiation event , that involved a drastic loss in expression of proliferating - cell - nuclear - antigen , could be blocked by DB00050 , suggesting the involvement of functional DB00644 receptors . Preliminary studies on the characterization of the human placental P30968 , indicate the presence of multiple receptor isoforms across human gestation .",
"Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .",
"P28482 , but not P27361 , mediates acquired and \" de novo \" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .",
"The basal subcellular distribution of beta - adrenergic receptor kinase is independent of G - protein beta gamma subunits . beta - Adrenergic receptor kinase ( beta O14965 or P25098 ) is a key regulatory protein involved in the regulation of G - protein - coupled receptors which associates with microsomal and plasma membranes . beta gamma Subunits of G - proteins have been suggested to mediate agonist - dependent membrane translocation of beta ARK , but their possible role in maintaining the complex subcellular distribution of the kinase is not known . In this study we show that lovastatin - mediated inhibition of G gamma subunits isoprenylation in P29320 - 293 cells stably transfected with beta O14965 leads to a significant release of G beta subunits to the cytosol without causing changes in total particulate beta ARK or in the association of this kinase to plasma or microsomal membrane fractions . In addition , transient overexpression of mutant forms of G gamma unable to become isoprenylated resulted in a marked sequestration of G beta to the soluble compartment , but caused no rearrangement in the distribution of cotransfected beta ARK . These results indicate that anchoring of beta ARK to cellular membranes under basal conditions is independent of the availability of heterotrimeric G - protein subunits .",
"Evolution of subterranean diving beetles ( Coleoptera : Dytiscidae : Hydroporini , Bidessini ) in the arid zone of Australia . Calcrete aquifers in arid inland Australia have recently been found to contain the world ' s most diverse assemblage of subterranean diving beetles ( Coleoptera : Dytiscidae ) . In this study we test whether the adaptive shift hypothesis ( ASH ) or the climatic relict hypothesis ( P06850 ) is the most likely mode of evolution for the Australian subterranean diving beetles by using a phylogeny based on two sequenced fragments of mitochondrial genes ( CO1 and 16S - tRNA - P03886 ) and linearized using a relaxed molecular clock method . Most individual calcrete aquifers contain an assemblage of diving beetle species of distantly related lineages and / or a single pair of sister species that significantly differ in size and morphology . Evolutionary transitions from surface to subterranean life took place in a relatively small time frame between nine and four million years ago . Most of the variation in divergence times of the sympatric sister species is explained by the variation in latitude of the localities , which correlates with the onset of aridity from the north to the south and with an aridity maximum in the Early Pliocene ( five mya ) . We conclude that individual calcrete aquifers were colonized by several distantly related diving beetle lineages . Several lines of evidence from molecular clock analyses support the P06850 , indicating that all evolutionary transitions took place during the Late Miocene and Early Pliocene as a result of aridification .",
"Functional polymorphisms associated with disease - free survival in resected carcinoma of the esophagus . PURPOSE : The aim of this study was to determine whether clinical outcome after surgical resection of esophageal adenocarcinoma ( EAC ) or esophageal squamous cell carcinoma ( ESCC ) could be predicted by functional polymorphisms in different proto - oncogenes and tumor suppressor genes . EXPERIMENTAL DESIGN : Six single nucleotide polymorphisms ( SNPs ) in the O14965 ( rs2273535 ) , P04626 ( rs1136201 ) , Q00987 ( rs2279744 ) , CDH1 ( rs5030625 ) , CDKN2A ( rs11515 ) , and O15350 ( rs2273953 ) genes were genotyped in a consecutive cohort of 346 esophageal cancer patients , who had underwent surgical resection with curative intent . Associations with disease - free survival ( DFS ) were analyzed with Kaplan - Meier curves and Cox regression , adjusting for potential confounders . RESULTS : Univariate analysis showed no significant associations between the tested polymorphisms and DFS in patients with EAC or ESCC . However , in a multivariate analysis , patients with EAC carrying the heterozygous Q00987 ( rs2279744 ) T / G genotype had significantly improved DFS compared with patients carrying the wild - type genotype ( adjusted hazard ratio ( P35869 ) , 0 . 63 ; 95 % confidence interval ( CI ) [ 0 . 45 - 0 . 88 ] ) . Patients with EAC harboring the homozygous CDH1 ( rs5030625 ) GA / GA genotype had a significantly reduced survival as compared with patients carrying the wild - type genotype P35869 4 . 0 , 95 % CI [ 1 . 4 - 11 ] . CONCLUSIONS : In a large cohort of esophageal cancer patients , the Q00987 T / G and CDH1 GA / GA genotype confer risk of death in patients with EAC . These data suggest that inter - individual differences in germ - line DNA have an impact on DFS in patients with EAC .",
"Androgen - targeted therapy - induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer : an opportunity for intervention . Androgens regulate biological pathways to promote proliferation , differentiation , and survival of benign and malignant prostate tissue . P10275 ( AR ) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression . Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function . Although targeting the androgen axis has clear therapeutic benefit , its effectiveness is temporary , as prostate tumor cells adapt to survive and grow . The removal of androgens ( androgen deprivation ) has been shown to activate both epithelial - to - mesenchymal transition ( EMT ) and neuroendocrine transdifferentiation ( NEtD ) programs . EMT has established roles in promoting biological phenotypes associated with tumor progression ( migration / invasion , tumor cell survival , cancer stem cell - like properties , resistance to radiation and chemotherapy ) in multiple human cancer types . NEtD in prostate cancer is associated with resistance to therapy , visceral metastasis , and aggressive disease . Thus , activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression . Brachyury , Axl , MEK , and O14965 are molecular drivers of these programs , and inhibitors are currently in clinical trials to determine therapeutic applications . Understanding tumor cell plasticity will be important in further defining the rational use of androgen - targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer .",
"Therapeutic targeting of CPT - 11 induced diarrhea : a case for prophylaxis . CPT - 11 ( irinotecan ) , a P11387 inhibitor is one of the main treatments for colorectal cancer . The main dose limiting toxicities are neutropenia and late onset diarrhea . Though neutropenia is manageable , CPT - 11 induced diarrhea is frequently severe , resulting in hospitalizations , dose reductions or omissions leading to ineffective treatment administration . Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT - 11 induced late onset diarrhea . It is predicted that prophylaxis of CPT - 11 induced diarrhea will reduce sub - therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates . This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity . Covered topics include schedule / dose modification , intestinal alkalization , structural / chemical modification , genetic testing , anti - diarrheal therapies , transporter ( P08183 , Q92887 , Q96JK2 ) inhibitors , enzyme ( β - glucuronidase , P22309 , P08684 , carboxylesterase , P35354 ) inducers and inhibitors , probiotics , antibiotics , adsorbing agents , cytokine and growth factor activators and inhibitors and other miscellaneous agents .",
"[ The effects of DB00644 agonist on steroidogenesis in the rat ovary ] . The effects of DB00644 agonist ( buserelin ) on in vitro ovarian steroidogenesis were studied using DES - treated immature rats and PMS - treated immature rats . The estradiol and progesterone secreted by the cultured ovarian cells and the activities of various enzymes of steroid - metabolism were examined with or without gonadotropins ( DB00094 or hCG ) , and the effects of 10 (- 6 )- 10 (- 12 ) M of buserelin on those indices were observed for 3 - 72 hours . In addition , the kinetic study of ovarian P30968 was performed using 125I - labelled buserelin and crude ovarian cell membrane fraction of PMS - treated rats . The Scatchard analysis revealed the specific high affinity and low capacity ovarian P30968 ( Kd = 0 . 92 nM and Bmax = 0 . 57 fmol / mg tissue ) . The DB00094 - stimulated cholesterol side chain cleavage enzyme ( CSCC ) activity of the DES - treated rats was suppressed in a dose - dependent manner by buserelin . Estradiol release and aromatase activity were increased by 10 (- 8 ) M buserelin within 48 hours from the beginning of the incubation of the PMS - treated rat ovarian cells , but were suppressed after 48 hours . DB06719 increased basal progesterone secretion and both activities of CSCC and of 3 beta - hydroxysteroid dehydrogenase of PMS - treated rat ovarian cells incubated without hCG , which were suppressed by buserelin co - incubated with 100 IU / ml of hCG . These results suggested that DB00644 plays a physiological role in ovarian steroidogenesis binding the specific receptor and that DB00644 promotes the development of the follicle through increased estrogen synthesis in the early stage of the folliculogenesis and the luteinization in the late stage of the follicular development through increased progesterone and decreased estradiol production and the luteolysis in the luteinized cells by hCG through decreased progesterone secretion .",
"Transcriptional regulation of the gonadotropin - releasing hormone receptor gene is mediated in part by a putative repressor element and by the cyclic adenosine 3 ', 5 '- monophosphate response element . The levels of the P30968 ( GnRHR ) and its messenger RNA depend on the pattern of administration of DB00644 . In this study , internal deletion mutants in a luciferase reporter gene vector ( GnRHR - pXP2 ) containing a 1226 - bp promoter fragment of mouse GnRHR gene were used to examine the regulation of GnRHR gene transcription in GGH3 cells . Our results indicate that the mouse GnRHR promoter contains one putative repressor element located at position - 343 /- 335 . When this sequence was deleted , the GnRHR promoter activity was significantly increased in both basal and DB00644 agonist ( DB06719 ) - , phorbol ester - , and forskolin - stimulated cells . Gel mobility shift assay showed that the sequence - 343 /- 335 is capable of binding GGH3 nuclear proteins . With deletion of the DB02527 response element ( - 107 /- 100 ) , basal and DB06719 - stimulated transcription was decreased . The same response was observed after stimulation with forskolin . Stimulation with ( Bu ) 2cAMP did not alter transcription above basal levels . The stimulation with phorbol ester resulted in an attenuated increase in transcriptional activity , suggesting that this sequence of the GnRHR promoter is a DB02527 response element . These results suggest that the transcriptional activity of the GnRHR gene is mediated in part by a putative repressor element and by the DB02527 response element .",
"Expression of type I P01148 receptor and in vivo and in vitro P01148 - I effects in corpora lutea of pseudopregnant rabbits . The expression of type I P01148 receptor ( P30968 - I ) and the direct role of P01148 - I on corpora lutea ( CL ) function were studied in the pseudopregnant rabbit model . Immunohistochemistry evidenced P30968 - I and P01148 - I in luteal cells at early ( day 4 pseudopregnancy ) - , mid ( day 9 ) - , and late ( day 13 ) - luteal stages . Real - time RT - PCR and western blotting revealed P30968 - I mRNA and protein at the three luteal stages . DB06719 in vivo treatment at days 9 and 13 decreased plasma progesterone levels for 48 and 24 h respectively . In in vitro cultured CL , buserelin reduced progesterone secretion , increased prostaglandin F ( 2α ) ( P49763 ( 2α ) ) secretion and cyclo - oxygenase - 2 ( P35354 ) and nitric oxide synthase ( NOS ) activities at days 9 and 13 , and decreased PGE₂ at day 13 . Co - incubation with antagonists for P01148 - I ( antide ) , inositol 1 , 4 , 5 - trisphosphate ( IP₃ , 2 - amino - ethoxydiphenylborate ) , and diacylglycerol ( DAG , 1 - hexadecyl - 2 - acetyl glycerol ) or inhibitors for phospholipase C ( P98160 , compound 48 / 80 ) , and protein kinase C ( PKC , staurosporine ) counteracted the buserelin effects . DB06719 co - incubated with P36551 inhibitor ( acetylsalicylic acid ) increased progesterone and decreased P49763 ( 2α ) and NOS activity at days 9 and 13 , whereas co - incubation with NOS inhibitor ( DB04223 methyl ester ) increased progesterone at the same luteal stages . These results suggest that P30968 - I is constitutively expressed in rabbit CL independently of luteal stage , whereas P01148 - I down - regulates directly CL progesterone production via P49763 ( 2α ) at mid - and late - luteal stages of pseudopregnancy , utilizing its cognate type I receptor with a post - receptorial mechanism that involves P98160 , IP₃ , DAG , PKC , P35354 , and NOS .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK80___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .",
"Human prostate carcinoma cell lines secrete GM - P04141 and express GM - P04141 - receptor on their cell surface . Using specific ELISA kits , we investigated the secretion of cytokines in five human prostate carcinoma cell lines : ALVA 31 , DU145 , LNCaP , P03886 and PC3 . Three of the five cell lines investigated secreted granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) ; GM - P04141 was not identified in ALVA31 or LNCaP . In addition , we have shown that conditioned media of DU145 , P03886 and PC3 stimulated proliferation of the GM - P04141 - dependent cell line MO7e indicating that these cells secrete biologically active GM - P04141 . By flow cytometric analysis we determined that all five cell lines expressed the alpha - subunit of the GM - P04141 receptor on the cell surface but only ALVA31 expressed both the alpha - and beta - subunits of the GM - P04141 receptor . Varying concentrations of GM - P04141 did not stimulate the proliferation rate of any of the prostate carcinoma cell lines . Thus , there does not appear to be autocrine loop of GM - P04141 - induced proliferation . However , the expression of P12830 and endoglin ( CD105 ) was modulated under GM - P04141 treatment in ALVA31 . In addition , GM - P04141 decreased the level of soluble P16070 in P03886 . These results suggest that the GM - P04141 receptor alpha - subunit may play a role in metabolic activity of prostate cancer .",
"DB00644 specific binding sites in uterine leiomyomata . DB00644 ( DB00644 ) analogs can cause regression of uterine leiomyomata . This effect is thought to be mediated by the inhibition of gonadotropin release and steroid synthesis . In the present study we examined the possibility that these analogs may also act directly on uterine leiomyomata . Specific binding sites for DB00644 are present in myoma membranes , as 125I - DB06719 binding was displaced with equal efficiency by the superagonists , DB06719 and D - Trp6 - DB00644 , and by the antagonist Organon 30276 , but not by unrelated peptides such as thyrotropin releasing hormone and oxytocin . A nonlinear Scatchard curve obtained for DB06719 specific binding suggests the presence of at least two binding sites , one of which exhibits a relatively high affinity for DB00644 analogs ( Kd of approximately 10 (- 8 ) M ) . Western blotting with a specific P30968 antibody revealed the presence of a 60 kDa protein in myoma membranes . This protein has a similar molecular weight to the purified pituitary P30968 . These results indicate , for the first time , the presence of specific binding sites for DB00644 in uterine leiomyomata , suggesting a direct effect of DB00644 analogs on this tissue .",
"Improvement of chloride transport defect by gonadotropin - releasing hormone ( DB00644 ) in cystic fibrosis epithelial cells . Cystic fibrosis ( CF ) , the most common autosomal recessive disease in Caucasians , is due to mutations in the P13569 gene . F508del , the most frequent mutation in patients , impairs P13569 protein folding and biosynthesis . The F508del - P13569 protein is retained in the endoplasmic reticulum ( ER ) and its traffic to the plasma membrane is altered . Nevertheless , if it reaches the cell surface , it exhibits a Cl (-) channel function despite a short half - life . Pharmacological treatments may target the F508del - P13569 defect directly by binding to the mutant protein or indirectly by altering cellular proteostasis , and promote its plasma membrane targeting and stability . We previously showed that annexine A5 ( AnxA5 ) directly binds to F508del - P13569 and , when overexpressed , promotes its membrane stability , leading to the restoration of some Cl (-) channel function in cells . Because Gonadotropin - Releasing Hormone ( DB00644 ) increases AnxA5 expression in some cells , we tested it in CF cells . We showed that human epithelial cells express DB00644 - receptors ( P30968 ) and that DB00644 induces an AnxA5 overexpression and an increased Cl (-) channel function in F508del - P13569 cells , due to an increased stability of the protein in the membranes . Beside the numerous physiological implications of the P30968 expression in epithelial cells , we propose that a topical use of DB00644 is a potential treatment in CF .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK99___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK99___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK93___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Salmon DB00644 and its analogues bind the human placental receptor . OBJECTIVE : The presence of DB00644 receptors in the human placenta has been recognized for a number of years . However , mammalian DB00644 , which is expressed in placental tissues , has limited affinity for the chorionic receptor . On the basis of immunological and bioactivity data , we have previously proposed that the chorionic DB00644 may differ from mammalian DB00644 . METHODS : We have studied the affinity of another isoform of DB00644 ( ie , salmon DB00644 and stable analogues of this DB00644 isoform ) , and compared their receptor affinity to that of mammalian DB00644 and its analogues . RESULTS : Using our receptor assay method with the labeled mammalian DB00644 analogue DB06719 , salmon DB00644 had a twofold greater affinity for the placental P30968 than did mammalian DB00644 and for the stable salmon DB00644 analogue the affinity was increased tenfold . Using a homologous receptor assay method with a stable salmon DB00644 analogue as label , the affinity for this salmon DB00644 analogue had a K ( d ) of 101 nmol / L . CONCLUSION : The presence of these higher affinity receptors for non - mammalian DB00644 in the human placenta has led us to propose that the chorionic tissues may express more than one isoform of DB00644 and that non - mammalian DB00644 , such as salmon DB00644 , may be potent regulators of placental functions .",
"Agonists and antagonists of DB00644 and - II reduce metastasis formation by triple - negative human breast cancer cells in vivo . Metastasis to bone is a frequent problem of advanced breast cancer . Particularly breast cancers , which do not express estrogen and progesterone receptors and which have no overexpression / amplification of the P04626 - neu gene , so called triple - negative breast cancers , are considered as very aggressive and possess a bad prognosis . About 60 % of all human breast cancers and about 74 % of triple - negative breast cancers express receptors for gonadotropin - releasing hormone ( DB00644 ) , which might be used as a therapeutic target . Recently , we could show that bone - directed invasion of human breast cancer cells in vitro is time - and dose - dependently reduced by DB00644 analogs . In the present study , we have analyzed whether DB00644 analogs are able to reduce metastases of triple - negative breast cancers in vivo . In addition , we have evaluated the effects of DB00644 analogs on tumor growth . To quantify formation of metastasis by triple - negative MDA - MB - 435 and MDA - MB - 231 human breast cancers , we used a real - time PCR method based on detection of human - specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs . To analyze tumor growth , the volumes of breast cancer xenotransplants into nude mice were measured . We could demonstrate that DB00644 analogs significantly reduced metastasis formation by triple - negative breast cancer in vivo . In addition , we could show that DB00644 analogs significantly inhibited the growth of breast cancer into nude mice . Side effects were not detectable . In conclusion , DB00644 analogs seem to be suitable drugs for an efficacious therapy for triple - negative , P30968 - positive human breast cancers to prevent metastasis formation .",
"___MASK93___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .",
"Transient transfection of GGH3 - 1 ' cells [ GH3 cells stably transfected with the gonadotropin - releasing hormone ( DB00644 ) receptor complementary deoxyribonucleic acid ] with the carboxyl - terminal of beta - adrenergic receptor kinase 1 blocks prolactin release : evidence for a role of the G protein beta gamma - subunit complex in DB00644 signal transduction . G proteins consist of heterotrimeric alpha - , beta - , and gamma - subunits . To assess the role of the beta gamma - subunit complex in P30968 - mediated signal transduction , GGH3 - 1 ' cells were transfected with plasmids PRK5 - beta O14965 ( 495 - 689 ) containing complementary DNA ( cDNA ) of the carboxyl - terminal ( Gly495 - Leu689 ) of beta - adrenergic receptor kinase 1 ( beta O14965 ) . GGH3 - 1 ' cells are GH3 cells that have been stably transfected with rat P30968 cDNA . The carboxyl region of beta O14965 ( Gly495 - Leu689 ) binds to the beta gamma complex and thereby inhibits its action . Twenty - four hours after stimulation , PRL release , DB02527 release , and inositol phosphate ( IP ) production were measured in these cells and in control cells transfected with vector PRK5 cDNA alone . In cells expressing the beta O14965 -( 495 - 689 ) sequence there was inhibition of basal PRL release ( 69 . 3 % ) , DB02527 release ( 61 . 2 % ) , and IP production ( 75 . 5 % ) compared to cells containing vector only . When cells expressing the beta O14965 fragment were stimulated with a DB00644 analog ( DB06719 ; 10 (- 7 ) M ) , maximal responses were inhibited ( 66 . 1 % for PRL release , 52 . 3 % for DB02527 release , and 79 . 1 % for IP production ) . Scatchard analysis of DB00644 analog binding was also performed in the two groups of transfected cells . No significant differences in Kd or receptor numbers were found between beta O14965 -( 495 - 689 )- transfected cells and control cells containing the vector alone . These data suggest a role for the beta gamma complex in mediation of DB02527 release , IP production , and hormone release in response to agonist occupancy of the P30968 .",
"In vitro effects of gonadotropin - releasing hormone ( DB00644 ) analogue on cancer cell sensitivity to cis - platinum . Six endometrial cancer cell lines ( Ishikawa , EIIL , HEC1A , 6 , 50 and 59 ) , one breast cancer cell line ( MCF - 7 ) and two ovarian cancer cell lines ( OVHS - 1 , HRA ) were treated for 24 or 168 h with a gonadotropin - releasing hormone ( DB00644 ) analogue , DB06719 acetate , and the cellular growth profile was studied . All these cell lines except for the HRA line had positive P30968 mRNA expression detected by reverse transcriptase polymerase chain reaction . GnRHa suppressed cell growth after 168 h of exposure , but not after 24 h . Suppression of cell growth by the exposure to cis - platinum ( DB00515 , 10 nM for 24 h ) was significantly increased in the presence of GnRHa for 168 h . The mechanism of this growth inhibition was tested by examining both RNA components of human telomerase ( hTR ) expression and telomerase activity . The results showed that GnRHa inhibits telomerase activity without altering the RNA component of telomerase expression . The present data suggest that DB00644 analogue may modulate endometrial , breast and ovarian cancer cell growth through modifying the telomerase activity . Since GnRHa increased the cytotoxic effects of DB00515 and GnRHa is a compound of high patient compliance , the value of GnRHa as a tumor sensitizer to DB00515 should be further tested in clinical trials .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK99___ ) in castrated male and female mice subjected to ___MASK99___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK99___ in mice CPs .",
"___MASK99___ interacts with P00533 / MAPK signalling and modulates P00533 levels in androgen receptor - positive LNCaP prostate cancer cells . P10275 ( AR ) signalling plays a pivotal role in prostate cancer pathogenesis and progression . However , androgen - mediated AR signalling is yet to be fully understood . P00533 and Q96HU1 kinase signalling pathways play predominant roles in AR function . Therefore , we investigated the interaction of P00533 signalling and AR activity in AR - positive LNCaP cells . We found that 5alpha - dihydrotestosterone ( ___MASK99___ ) and P01133 had a synergistic effect on AR activity as detected by a luciferase reporter system , although P01133 alone did not activate AR . Both P27361 / 2 and p38 were involved in ___MASK99___ and ___MASK99___ / P01133 - induced AR activation as detected by specific MEK and p38 inhibitors . Furthermore , 24 - h treatment of the cells with ___MASK99___ resulted in ubiquitination and down - regulation of the P00533 . This effect could be inhibited by the anti - androgen flutamide , suggesting an androgen - dependent mechanism . On the other hand , ___MASK99___ - treatment strongly increased AR levels in LNCaP cells . These data suggest a complex regulatory loop between activated AR and P00533 . In conclusion , activation of AR by both ___MASK99___ and P01133 / ___MASK99___ involves the Q96HU1 kinase pathway . Long - term activation of AR results in increase of AR levels , which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the P00533 .",
"Targeting hormonal signaling pathways in castration resistant prostate cancer . It is now well established that hormonal pathways are involved in the development of prostate cancer towards the castration resistant ( CRPC ) stage and can be effective molecular targets for novel treatment strategies . Most CRPC are sensitive to androgens and this can be due to the intratumoral production of androgens , androgen receptor ( AR ) amplification / mutations and epigenetic modifications of AR expression / signaling . Based on these observations , potent agents targeting the AR axis were developed : 1 ) inhibitors of P05093 ( a key enzyme in the production of androgens ) , such as abiraterone and orteronel ; 2 ) AR antagonists that bind to AR and impair AR activation , such as enzalutamide and ARN - 509 . Moreover , gonadotropin - releasing hormone receptors ( P30968 ) , associated with a strong antitumor activity , are expressed in CRPC cells , indicating that they might represent an important target for DB00644 analog - based therapeutic strategies . In addition to DB00644 agonists and antagonists ( i . e . , degarelix ) , cytotoxic DB00644 - based bioconjugates , delivering chemotherapeutic drugs to cancer cells expressing the P30968 , were developed and reported to exert antitumor effects on CRPC cells ; some of them ( i . e . , AN - 152 ) have already entered clinical trials . This review discusses the most relevant patents and recent observations on the anti - cancer efficacy of novel drugs targeting the AR and the P30968 pathways in CRPC .",
"P35354 predicts adverse effects of tamoxifen : a possible mechanism of role for nuclear P04626 in breast cancer patients . P35354 ( P35354 ) is associated with breast tumour progression . Clinical and molecular studies implicate human epidermal growth factor receptor 2 ( P04626 ) in the regulation of P35354 expression . Recent reports raise the possibility that P04626 could mediate these effects through direct transcriptional mechanisms . The relationship between P04626 and P35354 was investigated in a cohort of breast cancer patients with or without endocrine treatment . A tissue microarray comprising tumours from 560 patients with 10 - year follow - up was analysed for P04626 , P27361 / 2 , polyoma enhancer activator 3 ( P43268 ) and P35354 expression . Subcellular localisation of P04626 was assessed by immunofluorescence and confocal microscopy . Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease - free survival in the presence and absence of tamoxifen . P35354 expression associated with both membranous and nuclear expression of P04626 ( P = 0 . 0033 and P < 0 . 00001 respectively ) . No association was detected between P35354 and either P27361 / 2 or P43268 ( P = 0 . 7 and P = 0 . 3 respectively ) . None of the markers were found to be independently prognostic . Membrane P04626 , nuclear P04626 and P35354 , however , were all found to predict poor disease - free survival in patients on endocrine treatment ( P = 0 . 0017 , P = 0 . 0003 and P = 0 . 0202 respectively ) . Moreover , patients who were positive for P35354 predicted adverse effects of tamoxifen ( P = 0 . 0427 ) . These clinical ex vivo data are consistent with molecular observations that P04626 can regulate P35354 expression through direct transcriptional mechanisms . P35354 expression correlates with disease progression on endocrine treatment . This study supports a role for P35354 as a predictor of adverse effects of tamoxifen in breast cancer patients .",
"Q96RP3 is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation : potential role of the type - 2 corticotropin - releasing hormone receptor in the control of myometrial contractility . The family of P06850 - related peptides are suggested to play important roles in the control of myometrial contractility during pregnancy and labor . In this study we investigated the expression of urocortin II ( P55089 II ) in human myometrium and its ability to phosphorylate intracellular components that can be involved in modulating myometrial contractility . Using RT - PCR and fluorescent in situ hybridization , we demonstrated that P55089 II and type - 2 P06850 receptor ( Q13324 ) mRNAs were expressed in human nonpregnant and pregnant myometrium . Immunofluorescent studies confirmed protein expression of P55089 II in human pregnant myometrial cells , whereas chemical cross - linking studies with radiolabeled P55089 II confirmed the presence of Q13324 sites with an apparent molecular mass of 50 kDa . Treatment of primary human myometrial cells with P55089 II to specifically activate Q13324 resulted in a dose - dependent increase of myosin light chain ( MLC ( 20 ) ) phosphorylation . Activation of protein kinase C ( PKC ) and P27361 / 2 was required for the P55089 II - induced activation of MLC ( 20 ) , because treatment of myometrial cells with inhibitors of MAPK kinase 1 ( U0126 ) and PKC ( bisindolylmaleimide ) inhibited the P55089 II - induced phosphorylation of MLC ( 20 ) . Furthermore , the P55089 II effect on MLC ( 20 ) was dependent on RhoA translocation to the membrane and subsequent activation of RhoA - associated kinase , as shown by the use of the specific inhibitors exoenzyme P01024 and Y27632 . Collectively , our data suggest a distinctive role for Q13324 - specific agonists like P55089 II in the control of myometrial contractility during human pregnancy involving sequential activation of PKC , MAPK kinase 1 , P27361 / 2 , RhoA , and RhoA - associated kinase , leading to the MLC ( 20 ) phosphorylation .",
"Production and characterization of antibodies to gonadotropin - releasing hormone receptor . Antibodies to the gonadotropin - releasing hormone ( DB00644 ) receptor of bovine pituitary membranes have been raised in rabbits by immunization with affinity - purified receptor preparations . These antibodies did not compete with 125I - labeled DB00644 analog ( DB06719 ) for binding to the receptors but did precipitate rat and bovine solubilized receptors labeled with 125I - DB06719 . Binding of the antibodies to the receptors was also demonstrated by immunoprecipitation of 125I - labeled purified receptors and photoaffinity - labeled receptors . The antibodies did not have a DB00644 - like activity but rather inhibited , in a dose - dependent manner , DB00644 - stimulated luteinizing hormone release from cultured rat pituitary cells . In addition , the antibodies did not inhibit luteinizing hormone release stimulated by high K + concentration . This suggests that the antibodies recognize domains of the receptor other than the binding site of the hormone and thereby inhibit the biological response . These P30968 antibodies provide a useful tool for studying P30968 structure , function , localization , and biosynthesis .",
"Cyclic adenosine 3 ', 5 '- monophosphate ( DB02527 ) and DB02527 responsive element - binding protein are involved in the transcriptional regulation of gonadotropin - releasing hormone ( DB00644 ) receptor by DB00644 and mitogen - activated protein kinase signal transduction pathway in Q92820 ( 3 ) cells . Stimulation of mouse P30968 promoter by a DB00644 agonist ( DB06719 ) , or by a DB02527 analogue , significantly increased reporter ( luciferase ) activity . Overexpression of P04049 , P27361 , or P28482 partially blocked DB06719 - stimulated luciferase activity . In contrast , treatment with a mitogen - activated protein kinase ( MAPK ) kinase inhibitor ( PD 98059 ) activated basal and DB06719 - stimulated luciferase activity in a dose - dependent manner . Transient transfection of the deleted DB02527 response element expression vector followed by pretreatment with PD98059 prior to DB06719 stimulation showed that the transcriptional response was decreased compared to wild - type promoter . A gel - mobility shift assay using a probe containing the DB02527 response element showed the presence of two specific protein - DNA complexes that contain one or more members of the DB02527 responsive element - binding ( CREB ) protein family . These results suggest that DB02527 and CREB participate in the DB00644 activation of P30968 promoter activity and that the MAPK cascade is involved in the negative regulation of basal and DB00644 - stimulated P30968 transcriptional activity .",
"DB00644 induction of extracellular - signal regulated kinase is blocked by inhibition of calmodulin . Our previous studies demonstrate that DB00644 - induced P29323 activation required influx of extracellular Ca2 + in alphaT3 - 1 and rat pituitary cells . In the present studies , we examined the hypothesis that calmodulin ( Cam ) plays a fundamental role in mediating the effects of Ca2 + on P29323 activation . Cam inhibition using W7 was sufficient to block DB00644 - induced reporter gene activity for the c - Fos , murine glycoprotein hormone alpha - subunit , and MAPK phosphatase ( MKP ) - 2 promoters , all shown to require P29323 activation . Inhibition of Cam ( using a dominant negative ) was sufficient to block DB00644 - induced P29323 but not c - Jun N - terminal kinase activity activation . The Cam - dependent protein kinase ( CamK ) II inhibitor KN62 did not recapitulate these findings . DB00644 - induced phosphorylation of Q02750 and c - Raf kinase was blocked by Cam inhibition , whereas activity of phospholipase C was unaffected , suggesting that Ca2 +/ Cam modulation of the P29323 cascade potentially at the level of c - Raf kinase . Enrichment of Cam - interacting proteins using a Cam agarose column revealed that c - Raf kinase forms a complex with Cam . Reconstitution studies reveal that recombinant c - Raf kinase can associate directly with Cam in a Ca2 +- dependent manner and this interaction is reduced in vitro by addition of W7 . Cam was localized in lipid rafts consistent with the formation of a Ca2 +- sensitive signaling platform including the P30968 and c - Raf kinase . These data support the conclusion that Cam may have a critical role as a Ca2 + sensor in specifically linking Ca2 + flux with P29323 activation within the DB00644 signaling pathway .",
"___MASK74___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Adrenal and gonadal function in hypothyroid adult male rats . The functional relationship between thyroid , adrenal and gonadal hormones was investigated using adult male rats . Hypothyroidism was produced by the administration of 4 - methyl - 2 - thiouracil ( thiouracil ) in the drinking water for 2 weeks . Plasma concentrations of DB00024 dramatically increased , whereas plasma concentrations of tri - iodothyronine and thyroxine decreased in thiouraciltreated rats as compared with euthyroid rats . Hypothyroidism increased basal levels of plasma DB01285 and pituitary content of DB01285 . The pituitary responsiveness to P06850 for DB01285 release markedly increased , whereas the adrenal responsiveness to DB01285 for corticosterone release decreased . These results indicated that hypothyroidism causes adrenal dysfunction in adult male rats . Pituitary contents of LH and prolactin decreased in hypothyroid rats as compared with euthyroid rats . In addition , hypothyroidism lowered pituitary LH responsiveness to P01148 . Testicular responsiveness to human chorionic gonadotrophin for testosterone release , however , was not different between euthyroid and hypothyroid animals . These results indicated that hypothyroidism causes adrenal dysfunction and results in hypersecretion of DB01285 from the pituitary gland . Adrenal dysfunction may contribute to the inhibition of P01148 secretion from the hypothalamus , possibly mediated by excess P06850 .",
"Selective cyclooxygenase - 2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration - triggered c - DB00134 / hepatocyte growth factor receptor induction and extracellular signal - regulated kinase 2 activation . Nonsteroidal anti - inflammatory drugs , both nonselective and cyclooxygenase - 2 ( P35354 ) selective , delay gastric ulcer healing . Whether they affect esophageal ulcer healing remains unexplored . We studied the effects of the P35354 selective inhibitor , celecoxib , on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process . Esophageal ulcers were induced in rats by focal application of acetic acid . Rats with esophageal ulcers were treated intragastrically with either celecoxib ( 10 mg / kg , once daily ) or vehicle for 2 or 4 days . Esophageal ulceration triggered increases in : esophageal epithelial cell proliferation ; expression of P35354 ( but not P23219 ) ; hepatocyte growth factor ( P14210 ) and its receptor , c - DB00134 ; and activation of extracellular signal - regulated kinase 2 ( P28482 ) . Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration - triggered increases in esophageal epithelial cell proliferation , c - DB00134 mRNA and protein expression , and P28482 activity . In an ex vivo organ - culture system , exogenous P14210 significantly increased P28482 phosphorylation levels in esophageal mucosa . A structural analog of celecoxib , SC - 236 , completely prevented this effect . These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration - induced esophageal epithelial cell proliferation . These actions are associated with , and likely mediated by , down - regulation of the P14210 / c - DB00134 - P28482 signaling pathway .",
"Effects of Asn318 and Asp87Asn318 mutations on signal transduction by the gonadotropin - releasing hormone receptor and receptor regulation . P30968 ( P30968 ) contains Asn87 and Asp318 instead of the more frequently observed Asp87 and Asn318 found in other G protein - coupled receptors . In the present study , site - directed mutagenesis was used to introduce Asn318 and Asp87Asn318 into P30968 . The effect on coupling and regulation of P30968 was studied by stable expression of wild and mutant mouse P30968 in the lactotropic GH3 cells ; these normally release PRL in response to TRH stimulation . The responses to DB06719 ( a metabolically stable DB00644 analog ) in three different cell lines , M1 , N8 , and P03886 ( expressing wild - type , Asn318 mutant , and Asp87Asn318 mutant mouse P30968 , respectively ) were compared with that observed in the previously characterized GGH3 - 1 ' cells , which stably express rat P30968 . The Asn318 and Asp87Asn318 mutations had no measurable effect on ligand binding , but abolished the initial down - regulation of receptor that was observed in M1 and GGH3 - 1 ' cells , suggesting that the normal location of Asn87 and Asp318 in P30968 is involved in the regulation of P30968 . In N8 and P03886 cells , DB06719 - stimulated inositol phosphate ( IP ) production was attenuated , but the release of both DB02527 and PRL was stimulated in a dose - and time - dependent manner . These mutations apparently impaired the coupling between P30968 and G proteins involved in IP production , but not those involved in DB02527 release . In M1 cells , DB06719 stimulation produced a significant increase in IP production , but neither DB02527 nor PRL release was significantly stimulated . These findings are consistent with the previous suggestion that DB00644 - stimulated PRL release is mediated by a DB02527 second messenger system in transfected GGH3 cells .",
"In vitro effects of gonadotropin - releasing hormone ( DB00644 ) on Leydig cells of adult alpaca ( Lama pacos ) testis : P30968 immunolocalization , testosterone and prostaglandin synthesis , and cyclooxygenase activities . The main objective of this study was to examine the modulatory in vitro effects of gonadotropin - releasing hormone ( DB00644 ) on isolated Leydig cells of adult alpaca ( Lama pacos ) testis . We first evaluated the presence of P30968 ( GnRHR ) and cyclooxygenase ( P36551 ) 1 and P35354 in alpaca testis . We then studied the in vitro effects of buserelin ( DB00644 analogue ) , antide ( DB00644 antagonist ) , and buserelin plus antide or inhibitor of phospholipase C ( compound 48 / 80 ) and COXs ( acetylsalicylic acid ) on the production of testosterone , PGE ( 2 ) , and P49763 ( 2α ) and on the enzymatic activities of P23219 and P35354 . Immunoreactivity for GnRHR was detected in the cytoplasm of Leydig cells and in the acrosomal region of spermatids . P23219 and P35354 immunosignals were noted in the cytoplasm of spermatogonia , spermatocytes , spermatids , Leydig cells , and Sertoli cells . Western blot analysis confirmed the GnRHR and P23219 presence in alpaca testis . The in vitro experiments showed that buserelin alone increased ( P < 0 . 01 ) and antide and buserelin plus acetylsalicylic acid decreased ( P < 0 . 01 ) testosterone and P49763 ( 2α ) production and P23219 activity , whereas antide and compound 48 / 80 counteracted buserelin effects . Prostaglandin E ( 2 ) production and P35354 activity were not affected by buserelin or antide . These data suggest that DB00644 directly up - regulates testosterone production in Leydig cells of adult alpaca testis with a postreceptorial mechanism that involves P98160 , P23219 , and P49763 ( 2α ) .",
"___MASK97___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK97___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK64___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients ."
] |
[
"___MASK64___",
"___MASK65___",
"___MASK71___",
"___MASK74___",
"___MASK80___",
"___MASK86___",
"___MASK93___",
"___MASK97___",
"___MASK99___"
] |
___MASK80___
|
MH_train_330
|
interacts_with DB00013?
|
[
"Thrombolysis for intravascular thrombosis in neonates and children . PURPOSE OF REVIEW : P00747 activators stimulate the fibrinolytic pathway to accelerate thrombus resolution and can be used to treat serious and life - threatening arterial and venous thrombosis in neonates and children . The main disadvantage of these drugs is the risk of bleeding associated with their use . This article reviews the fibrinolytic pathway and discusses the current agents available for thrombolytic therapy , as well as indications for their use , dosing regimens , safety , and efficacy . RECENT FINDINGS : There is great variation in the drug dosing regimens used for thrombolysis and in the incidence of bleeding complications that have been reported in pediatric series . Increased experience with these drugs , appropriate patient selection , and careful monitoring appear to have reduced the risk of major bleeding over time . The use of thrombolysis for occlusive deep vein thrombosis , in attempt to reduce the long - term complication of postthrombotic syndrome , is controversial and deserves further investigation . SUMMARY : The use of thrombolytic therapy in pediatrics has increased over the past two decades . DB00013 and recombinant tissue plasminogen activator are the currently available thrombolytic agents . Catheter - related arterial thrombi that threaten life , organ or limb are the most common indication for their use . There is a tremendous need for well designed clinical studies to improve the safety and efficacy of these drugs in neonates and children .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK7___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"DB00013 - catalysed cleavage of the urokinase receptor requires an intact glycolipid anchor . DB00013 ( uPA ) has the striking ability to cleave its receptor , Q03405 , thereby inactivating the binding potential of this molecule . Here we demonstrate that the glycosylphosphatidylinositol ( P06744 ) anchor of Q03405 , which is attached to the third domain , is an important determinant in governing this reaction , even though the actual cleavage occurs between the first and second domains . Purified full - length P06744 - anchored Q03405 ( P06744 - Q03405 ) proved much more susceptible to uPA - mediated cleavage than recombinant truncated soluble Q03405 ( suPAR ) , which lacks the glycolipid anchor . This was not a general difference in proteolytic susceptibility since P06744 - Q03405 and suPAR were cleaved with equal efficiency by plasmin . Since the amino acid sequences of P06744 - Q03405 and suPAR are identical except for the C - terminal truncation , the different cleavage patterns suggest that the two Q03405 variants differ in the conformation or the flexibility of the linker region between domains 1 and 2 . This was supported by the fact that an antibody to the peptide AVTYSRSRYLE , amino acids 84 - 94 in the linker region , recognizes P06744 - Q03405 but not suPAR . This difference in the linker region is thus caused by a difference in a remote hydrophobic region . In accordance with this model , when the hydrophobic lipid moiety was removed from the glycolipid anchor by phospholipase C , low concentrations of uPA could no longer cleave the modified P06744 - Q03405 and the reactivity to the peptide antibody was greatly decreased . Naturally occurring suPAR , purified from plasma , was found to have a similar resistance to uPA cleavage as phospholipase C - treated P06744 - Q03405 and recombinant suPAR .",
"P00747 activator inhibitor - 1 regulates LPS induced inflammation in rat macrophages through autophagy activation . BACKGROUND : The mechanisms by which plasminogen activator inhibitor - 1 ( P05121 ) regulates inflammation , especially in acute respiratory distress syndrome ( ARDS ) , are largely unknown . OBJECTIVE : To assess the relationship between P05121 and autophagy in inflammatory reactions induced by LPS in rat NR8383 cells . METHODS : ELISA was used to assess the amounts of P01375 - α , IL - 1β , and P05121 in cell culture supernatants ; O00206 , MyD88 , P05121 , LC3 , Beclin1 , and P42345 protein and mRNA levels were determined by western blot and quantitative RT - PCR , respectively ; western blot was used to determine NF - κB protein levels . To further evaluate the role of P05121 , the P05121 gene was downregulated and overexpressed using the siRNA transfection technology and the pCDH - P05121 , respectively . Finally , the GFP Positive Expression Rate Method was used to determine the rate of GFP - LC3 positive NR8383 cells . RESULTS : In LPS - induced NR8383 cells , P01375 - α , IL - 1β , and P05121 expression levels increased remarkably . Upon P05121 knockdown , P01375 - α , IL - 1β , P05121 , O00206 , MyD88 , NF - κB , LC3 , and Beclin1 levels were decreased , while P42345 increased . Conversely , overexpression of P05121 resulted in increased amounts of P01375 - α , IL - 1β , P05121 , O00206 , MyD88 , NF - κB , LC3 , and Beclin1 . However , no significant change was observed in P42345 expression . CONCLUSIONS : In NR8383 cells , P05121 contributes in the regulation of LPS - induced inflammation , likely by promoting autophagy .",
"P00749 potentiates lipopolysaccharide - induced neutrophil activation . DB00013 plasminogen activator ( uPA ) is a serine protease that catalyzes the conversion of plasminogen to plasmin . Although increased circulating levels of uPA are present in endotoxemia and sepsis , conditions in which activated neutrophils contribute to the development of acute organ dysfunction , the ability of uPA to participate directly in LPS - induced neutrophil activation has not been examined . In the present experiments , we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS . In particular , uPA increased LPS - induced activation of intracellular signaling pathways , including Akt and c - Jun N - terminal kinase , nuclear translocation of the transcriptional regulatory factor NF - kappa B , and expression of proinflammatory cytokines , including P01584 , macrophage - inflammatory protein - 2 , and P01375 . There was no effect of uPA on LPS - induced activation of p38 mitogen - activated protein kinase in neutrophils . Transgenic mice unable to produce uPA ( uPA (-/-) ) were protected from endotoxemia - induced lung injury , as determined by development of lung edema , pulmonary neutrophil accumulation , lung P01584 , macrophage - inflammatory protein - 2 , and P01375 cytokine levels . These results demonstrate that uPA can potentiate LPS - induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil - mediated inflammatory responses , such as the development of acute lung injury .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK45___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"High expression levels of P48061 and P61073 predict recurrence of adamanti - nomatous craniopharyngiomas in children . BACKGROUND : Adamantinomatous craniopharyngioma ( O14561 ) is a benign but maldevelopmental tumor with a high recurrence rate . OBJECTIVE : Theaim of this study was to investigate the dysregulated biological molecules that play important roles in the recurrence of O14561 . METHODS : We first performed microarray analysis on tumor samples from two pediatric patients with recurrent O14561 and from two pediatric O14561 patients without recurrence after a one - year follow - up . The expression of P48061 and P61073 in 45 specimens of pediatric O14561 was further evaluated by immunohistochemistry . These results were correlated with the clinicopathological parameters and survival of the patients . RESULTS : Four downregulated genes ( P25054 , ITGA , P43121 , and Q99727 ) and 16 upregulated genes ( O76096 , P43235 , P07711 , P48061 , P61073 , P02751 , Q96DB9 , P05106 , P08253 , P08254 , P09237 , P14780 , Q92570 , Q03405 , P16035 , and P15692 ) were found in the recurrent patients . P48061 and P61073 were highly expressed in 13 patients ( 28 . 9 % ) and 14 patients ( 31 . 1 % ) , respectively . High levels of P48061 and P61073 expression were significantly associated with a poor recurrence - free survival and were the prognostic factors for O14561 recurrence in pediatric patients . CONCLUSIONS : High levels of P48061 and P61073 expression were associated with O14561 recurrence . The role of P48061 and P61073 in the development of brain tumors requires further research .",
"[ P00747 activator system and its clinical significance in patients with a malignant disease ] . DB00013 ( uPA ) plays an essential role in the activation of plasminogen to plasmin , a serine protease participating in the activation of matrixmetaloproteinases , latent elastases , growth factors and cytokines involved in the degradation of extracellular matrix elements . Together with its receptor ( Q03405 ) , tissue activator ( tPA ) and urokinase inhibitors ( P05121 , P05120 , P05154 and protease nexin ) , it forms the plasminogen activator system ( DB00233 ) , a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours . P05121 inhibits uPA - dependent invasiveness of some cancer cell lines . The vitronectin - P05121 complex inhibits migration of smooth muscle cells by binding alpha ( v ) beta3 integrin to vitronectin . P05121 or its deficiency interferes with signalling pathways such as PI3K / Akt and JAK / P35610 and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death . P05121 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways . The individual components of DB00233 undoubtedly play an important role in angiogenesis and metastasising of malignant tumours . In the near future , results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and , at the same time , could serve as the goal for targeted therapies .",
"Characterization of the insulin and insulin - like growth factor receptors and responsitivity of a fibroblast / adipocyte cell line before and after differentiation . Q96RJ0 cells , like 3T3 - Q9NUQ9 cells , undergo a differentiation process in vitro from a fibroblast to an adipocyte phenotype . The Q96RJ0 pre - adipocytes were found to have low numbers of insulin receptors but high numbers of receptors for insulin - like growth factors ( IGF ) I and II . Also , the pre - adipocytes were more responsive to IGF than insulin as measured by either stimulation of glucose or amino acid uptake . After differentiation , the adipocytes had higher numbers of insulin receptors and a better responsitivity to insulin than to P05019 . These results indicate that insulin - like growth factors are the primary regulators of the pre - adipocytes whereas insulin regulates the adipocytes .",
"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .",
"Regulation of cell migration and invasion by specific modules of uPA : mechanistic insights and specific inhibitors . DB00013 ( uPA ) is a 411 residues serine protease originally identified for its ability to activate plasminogen and generate plasmin , a broad - spectrum matrix - and fibrin - degrading enzyme . Later , this protease has been shown to possess also a clear - cut ability to stimulate cell migration and survival in a catalytic - independent manner . This activity turned out to be exerted through the growth factor - like domain ( GFD - like , residues 1 - 49 ) of the protease binding to a GPIanchored membrane receptor ( Q03405 ) , in complex with transmembrane receptors such as integrins , the epidermal growth factor and the formyl - peptide receptors . Direct binding of uPA to integrins through its kringle ( residues 50 - 131 ) and connecting peptide ( residues 132 - 158 ) regions results in enhanced migration . The dual function of uPA in promoting migration while reducing the physical resistance of extracellular matrix underlies its crucial role in the invasion of malignant tumours . Consolidated evidence emerging from animal models and clinical studies shows that the overexpression of uPA is a causal determinant to tumour metastasis and is associated to a poor prognosis . Therefore , pinpointing the molecular interactions and identifying novel agents to interfere with the diverse activities of uPA is a goal of basic and applied research . In this review , we discuss the general theme of cell migration and invasion . A description of the uPA structure - function relationship and the functional effects of isolated domains is presented . Current information on molecular agonistic as well as antagonistic compounds , including the compounds which have reached clinical trials , is provided .",
"P00747 activator dependent pathways in the dissemination of human tumor cells in the chick embryo . We have previously shown that inhibition of uPA activity of a human tumor - HEp3 - results in a drastic reduction of its metastasis in the chick embryo . Using 125IUdR - labeled tumor cells , we have now studied the role of uPA in individual steps of tumor metastasis . We found that , 48 hr after inoculation of tumor cells on the P62158 , the organs of the embryos , inoculated with cells in which uPA was inhibited , contained 4 - fold less cells than the controls . Neither the initial advance of the tumor mass into the P62158 nor the process of extravasation was affected by the inhibition of tumor uPA . However , the infiltration of the P62158 mesenchyme by individual tumor cells was blocked when tumor uPA activity or production was inhibited . In addition , indirect evidence implicated uPA as an essential factor in the tumor cell intravasation .",
"The urokinase receptor ( CD87 ) facilitates CD11b / P05107 - mediated adhesion of human monocytes . DB00013 receptors ( Q03405 ; CD87 ) from complexes with complement receptor 3 ( CR3 ) ( CD11b / P05107 ) , a beta2 integrin . In this study , we sought to determine if this association modulates the adhesive function of CR3 . Both CR3 and Q03405 concentrate at the ventral surface of fibrinogen - adherent human monocytes , and CR3 - Q03405 coupling increases substantially upon adhesion to fibrinogen . Pretreatment with anti - Q03405 monoclonal antibody reduced adhesion to CR3 counterligands ( fibrinogen and DB05299 ) by 50 % , but did not affect adhesion to fibronectin , a beta1 integrin counterligand . Antisense ( AS ) oligonucleotides were used to determine if selectively suppressing Q03405 expression also modulates CR3 adhesive function . AS - Q03405 oligo reduced CR3 - dependent adhesion by 43 +/- 9 % ( P < 0 . 01 ) , but did not affect CR3 - independent adhesion . To determine if the effects of Q03405 are mediated through its ligand , monocytes were pre - treated with AS oligo to block uPA expression . Unlike the effects of blocking Q03405 expression , AS - uPA oligo increased adhesion by 46 % ( P < 0 . 005 ) , and exogenous intact uPA , but not uPA fragments , reversed this effect . We conclude that complex formation with Q03405 facilitates the adhesive functions of CR3 . This function of Q03405 is not dependent upon its occupancy with uPA , which negatively influences adhesion .",
"Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats . BACKGROUND : Sepsis and endotoxemia are associated with concurrent activation of inflammation and the hemostatic mechanism , which both contribute to organ dysfunction and death . Electrical vagus nerve stimulation ( VNS ) has been found to inhibit tumor necrosis factor ( P01375 ) - alpha release during endotoxemia in rodents . OBJECTIVE : To determine the effect of VNS on activation of coagulation and fibrinolysis . METHODS : Rats received a sublethal i . v . dose of lipopolysaccharide ( LPS ) after electrical VNS or sham stimulation . Activation of coagulation and fibrinolysis , as well as cytokine release , was measured before LPS injection and 2 , 4 and 6 h thereafter . RESULTS : LPS induced activation of the coagulation system ( increases in the plasma concentrations of thrombin - antithrombin complexes and D - dimer , and a decrease in antithrombin ) and biphasic changes in the fibrinolytic system [ early rises of plasminogen activator activity and tissue - type plasminogen activator , followed by a delayed increase in plasminogen activator inhibitor type 1 ( P05121 ) ] . VNS strongly inhibited all LPS - induced procoagulant responses and more modestly attenuated the fibrinolytic response . In addition , VNS attenuated the LPS - induced increases in plasma and splenic concentrations of the proinflammatory cytokines P01375 and interleukin - 6 ( P05231 ) , while not influencing the release of the anti - inflammatory cytokine P22301 . CONCLUSION : These data illustrate a thus far unrecognized effect of VNS and suggest that the cholinergic anti - inflammatory pathway not only impacts on inflammation but also on the coagulant - anticoagulant balance .",
"[ Results of in situ arterial thrombolysis by the combination of urokinase and lysyl plasminogen in acute arterial occlusive diseases of the lower limbs ] . 35 patients with acute arterial occlusions [ 27 ] and graft thromboses [ 8 ] , responsible for severe and recent ischemia , were treated by fibrinolytic therapy ( DB00013 : 1 000 units / kg / hour , and Lys P00747 ) . These drugs were delivered at the site of occlusions using a 5 French catheter . Angiographically , initial success was obtained in 30 patients ( 85 % ) and a significant clinical benefit persisted 5 months later , in 20 patients ( 57 % ) . 4 distal embolisms during the treatment were noted , and one woman died a few hours after the withdrawal of an axillary catheter of a cerebellar infarction . Only two minor ( 6 % ) and one severe ( 3 % ) groin hematoma were encountered . No patient had at any moment a fibrinogen concentration lower than 1 g / l . Thus , the thrombolytic treatment used in the study appears as effective as locally administered DB00086 but better tolerated .",
"Activated human neutrophils rapidly release the chemotactically active D2D3 form of the urokinase - type plasminogen activator receptor ( Q03405 / CD87 ) . The urokinase - type plasminogen activator receptor ( Q03405 / CD87 ) exists both in cell - bound and soluble forms . Neutrophils contain extensive intracellular pools of Q03405 that are translocated to the plasma membrane upon activation . In the present study , we investigated the ability of human neutrophils to shed Q03405 from cell surface following activation and addressed the possible involvement of the released receptor in the inflammatory response . We first observed that the spontaneous release of suPAR by resting neutrophils was strongly and rapidly ( within minutes ) enhanced by calcium ionophore ionomycin and to a lesser extent when cells were primed with P01375 and then stimulated with fMLP or P10145 . We demonstrated that suPAR is produced by resting and activated neutrophils predominantly as a truncated form devoid of N - terminal D1 domain ( D2D3 form ) that lacks P06744 anchor . Migration of formyl peptide receptor - like 1 ( P25090 ) - transfected human embryonic kidney ( P29320 ) 293 cells toward the supernatants harvested from activated neutrophils was significantly diminished when D2D3 form of suPAR was immunodepleted from the supernatants . We conclude that activated neutrophils release the chemotactically active D2D3 form of suPAR that acts as a ligand of P25090 . Interestingly , we present evidence that P80108 ( P80108 ) that has previously been shown to shed Q03405 in cancer cells is not involved in suPAR release from human neutrophils . We suggest that production of the chemotactically active D2D3 form of suPAR by activated human neutrophils in vivo could contribute to the recruitment of monocytes and other formyl peptide receptors - expressing cells to the sites of acute inflammation where neutrophil accumulation and activation occur .",
"Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet - derived growth factor . During liver fibrogenesis , hepatic stellate cells ( P19526 ) proliferate and migrate under the influence of growth factors , including platelet - derived growth factor ( PDGF ) and basic - fibroblast growth factor ( b - FGF ) . The plasminogen activation system regulates extracellular matrix ( Q13201 ) catabolism and cell movement . We evaluated the expression and biological functions of the plasminogen activation system in human P19526 and its interaction with PDGF and b - FGF . DB00013 - plasminogen activator receptors ( u - PAR ) were measured by radioligand binding , cell cross - linking , immunoassay , and RNAse protection assay . u - PA and plasminogen activator inhibitors ( PAIs ) expression and activities were analyzed by zymography , immunoassay , and RNase protection assay . Cell migration and proliferation , studied in Boyden chambers and by microscopic counting , were evaluated after the addition of PDGF , b - FGF , and blockade with anti - u - PA , anti - u - PAR antibodies , and antisense oligodeoxynucleotides ( aODN ) against u - PAR mRNA . We have shown that P19526 produce u - PAR , u - PA , and P05121 . PDGF and b - FGF up - regulate u - PA and u - PAR , but not P05121 , and exogenous addition of u - PA stimulates P19526 proliferation , chemotaxis , and chemoinvasion . Inhibition of u - PA / u - PAR with antibodies against u - PA or u - PAR and with u - PAR aODN inhibit the proliferative , chemotactic , and chemoinvasive activity of PDGF and b - FGF . These findings indicate that u - PA and u - PAR are required for the mitogenic and chemoinvasive activity of PDGF and b - FGF on P19526 .",
"DB00013 induces its own expression in Beas2B lung epithelial cells . The urokinase - type plasminogen activator ( uPA ) interacts with its receptor ( Q03405 ) to promote local proteolysis as well as cellular proliferation and migration . These functions contribute to the pathogenesis of lung inflammation and remodeling as well as the growth and invasiveness of lung neoplasms . In this study , we sought to determine if uPA alters its own expression in lung epithelial cells . Using immunoprecipitation and Western and Northern blotting techniques , we found that uPA treatment enhanced uPA expression in Beas2B lung epithelial cells in a time - and concentration - dependent manner . The induction of uPA expression is mediated through its cell surface receptor Q03405 and does not require uPA enzymatic activity . The amino - terminal fragment of uPA , lacking the catalytic domain , is sufficient to induce uPA expression . The serine protease plasmin and the protease inhibitor aprotinin failed to alter uPA - mediated uPA expression , whereas alpha - thrombin potentiated the response . Pretreatment of Beas2B cells with a tyrosine kinase inhibitor , herbimycin , suggests that activation of tyrosine kinase ( s ) is involved in the uPA - mediated uPA expression . Induction of uPA expression by exposure of lung - derived epithelial cells to uPA is a newly defined pathway by which this protease could influence expression of local fibrinolytic activity and other uPA - dependent cellular responses germane to lung inflammation or neoplasia .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK46___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"Liver regeneration induced by a designer human P05231 / sIL - 6R fusion protein reverses severe hepatocellular injury . The cytokine P05231 plays a significant role in liver regeneration in conjunction with additional growth factors ( P14210 , P01375 , and TGF - alpha ) . Many P05231 effects depend on a naturally occurring soluble P05231 receptor ( sIL - 6R ) . Here , the chimeric protein hyper - P05231 , constructed from the human P05231 protein fused to a truncated form of its receptor , was found to have superagonistic P05231 properties , and as such , enhanced liver cell regeneration . Hyper - P05231 reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D - galactosamine administration . The hyper - P05231 protein has a significant potential for use in the treatment of severe human liver diseases .",
"Possible role of P30086 in cytotrophoblast migration : immunohistochemical and in vitro studies . P30086 ( P30086 ) regulates growth and differentiation signaling of mitogen - activated protein kinases ( MAPK ) , P25098 and NF - kappaB pathways each of which regulates cytotrophoblast differentiation and normal placental development . We show here that P30086 is expressed in human normal and preeclampic placentas as detected by immunostaining . P30086 was detected in villous cytotrophoblast in normal placenta and switched to syncytiotrophoblast in pre - eclampsia ( PE ) - complicated pregnancies . P30086 was also localized in extravillous cytotrophoblast of cell islands and cell columns both in normal and in PE placentas , although staining was less uniform in the latter specimens . In order to test P30086 involvement in cytotrophoblast function , we performed in vitro studies on HTR - 8 / SVneo cells , a first trimester cytotrophoblast cell line . We show that the P30086 inhibitor locostatin reduces P29323 phosphorylation and impairs HTR - 8 / SV neo cells motility in wound closure experiments . We also document the presence of P25098 mRNA , the reduction of phosphorylated P30086 expression by locostatin and the induction of P05121 mRNA expression in HTR - 8 / SV neo cells , suggesting the involvement of P25098 and NF - kappaB pathways in these cells . In conclusion , our work provides evidence that P30086 is a novel factor expressed in cytotrophoblast cells where it likely regulates cell migration .",
"Fibrinolytic parameters in spermatozoas and seminal plasma . DB00013 - type ( u - PA ) and tissue - type plasminogen activator antigen ( t - PA ) as well as plasminogen activator - inhibitor activity were determined in seminal plasma and lysates of the respective spermatozoas in 67 ejaculate of males in infertile marriage without genito urinary pathology . U - PA was determined by a competition RIA , t - PA by an ELISA and P05121 by a spectrophotometric assay . 15 patients showed normozoospermia , 11 azoospermia and 41 oligoasthenoteratozoospermia ( P04181 - syndrome ) . In lysates of spermatozoas , significantly higher levels of both plasminogenactivators and P05121 were found in patients with P04181 syndrome as compared to those exhibiting normozoospermia . Whereas P05121 was absent in the seminal plasma of normozoospermic ejaculate , patients with azoospermia ( 180 +/- 13 mU / ml . ) and P04181 - syndrome ( 60 +/- 5 mU / ml . ) showed high P05121 levels . The similarly high values of t - PA ( 190 . 8 - 227 . 8 ng ./ ml . ) and u - PA ( 19 . 4 - 32 ng ./ ml . ) in the same compartment confirm their predominantly prostatic origin and seem to have no influence on the quality of the ejaculate .",
"Induction of c - fos Gene Expression by DB00013 - Type P00747 Activator in Human Ovarian Cancer Cells . The ability to fractionate nucleic acids and to determine which of them has sequences complementary to an array of DNA or RNA molecules is one of the most powerful tools of molecular biology . The Southern blot , named for its inventor , is a method for transferring size - fractionated DNA from a gel matrix to a solid support followed by hybridization to a labeled probe ( 1 . The identical process for RNA became known as ) the Northern blot i2 1i The identical process for RNA became known as the Northern blot ( 2 ) . Both are , then , often key elements in establishing the identity of nucleic acids of interest . Northern blot analysis was used by us as a tool in order to answer the question whether or not the nuclear transcripitional apparatus of human ovarian cancer cells might be activated in response to the urokinase .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"P00747 potentiates thrombin cytotoxicity and contributes to pathology of intracerebral hemorrhage in rats . Thrombin and plasmin are serine proteases involved in blood coagulation and fibrinolysis , whose precursors are circulating in blood stream . These blood - derived proteases might play important roles in the pathogenesis of intracerebral hemorrhage by acting on brain parenchymal cells . We previously reported that thrombin induced delayed neuronal injury through extracellular signal - regulated kinase ( P29323 ) - dependent pathways . Here , we investigated potential cytotoxic actions of plasminogen , a precursor protein of plasmin , using slice cultures prepared from neonatal rat brain and intracortical microinjection model in adult rats . Although plasminogen alone did not evoke prominent neuronal injury , plasminogen caused significant neuronal injury when combined with a moderate concentration of thrombin ( 30 U / mL ) in the cerebral cortex of slice cultures . The cortical injury was prevented by tranexamic acid and aprotinin . The combined neurotoxicity of thrombin and plasminogen was also prevented by PD98059 , an inhibitor of P29323 pathway , as well as by other agents that have been shown to prevent cortical injury induced by a higher concentration ( 100 U / mL ) of thrombin alone . Extracellular signal - regulated kinase phosphorylation after plasminogen exposure was localized in cortical astrocytes . Moreover , microinjection of plasminogen in vivo potentiated thrombin - induced cortical injury , and inhibition of plasmin ameliorated hemorrhage - induced neuronal loss in the cerebral cortex . These results suggest that plasminogen / plasmin system augmenting thrombin neurotoxicity participates in hemorrhagic cortical injury .",
"DB00013 expression and binding activity associated with the transforming growth factor beta1 - induced migratory and invasive phenotype of mouse epidermal keratinocytes . Transforming growth factor beta1 ( TGF - beta1 ) is a stimulator of malignant progression in mouse skin carcinogenesis . TGF - beta1 exerts a differential effect on cultured nontumorigenic ( MCA3D cell line ) and transformed ( PDV cell line ) keratinocytes . Whereas MCA3D cells are growth arrested and committed to die in the presence of the factor , it induces a reversible epithelial - fibroblastic conversion in PDV cells . This conversion is associated in vivo with a squamous - spindle cell carcinoma transition . Here we have investigated the role of urokinase ( uPA ) during malignant progression of transformed epidermal keratinocytes . We show that the levels of uPA expression / secretion , and the uPA binding activity to the cell surface , correlate with the invasive and malignant potentials of mouse epidermal cell lines . TGF - beta1 enhanced uPA production , the number of uPA cell surface binding sites , and the expression of the plasminogen activator inhibitor P05121 , in transformed PDV cells , but had no major effect on nontumorigenic MCA3D keratinocytes . Increased uPA production depended on the presence of the factor in the culture medium and occurred concomitantly to the stimulation of the migratory and invasive abilities of PDV cells . Synthetic peptides containing the amino terminal sequence of the mature mouse uPA inhibited the binding of uPA to the cell surface and decreased TGF - beta1 - induced cell motility and invasiveness . These results demonstrate that the uPA system mediates at least part of the migratory and invasive phenotype induced by TGF - beta1 in transformed keratinocytes , and suggest a role for uPA on the changes that lead to the appearance of spindle carcinomas .",
"Simvastatin and atorvastatin attenuate P19320 and Q03405 expression on human endothelial cells and platelet surface expression of P29965 . BACKGROUND : In addition to their cholesterol lowering ability , statins have proven pleiotropic effects in the cardiovascular system . Chronic inflammation with interactions between platelets and endothelial cells leads to an upregulation of activity markers of atherosclerosis . The purpose of this study was to investigate the effects of simvastatin and atorvastatin on platelets and endothelial cells in an in vitro endothelial cell model . METHODS AND RESULTS : After a 24 h incubation period with either simvastatin or atorvastatin ( 1 μmol / L ) , human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide ( LPS ) , and were then incubated in direct contact with activated platelets . Platelet surface expression of P29965 and CD62P and expression of P05362 , P19320 , Q03405 and P50281 on endothelial cells were measured by flow cytometry . Supernatants were analyzed by ELISA for soluble P03956 . The increased expression of P19320 and Q03405 on endothelial cells by stimulation with LPS and by direct contact with activated platelets was significantly reduced to a similar extent through pre - incubation with both atorvastatin and simvastatin ( p < 0 . 05 ) . Platelets without endothelial cell contact , but in direct contact with either statin , showed similar significant reductions in surface expression of P29965 ( p < 0 . 005 ) . CONCLUSIONS : These effects may explain the ability of statins to reduce the progression of atherosclerosis in addition to their cholesterol - lowering properties .",
"Chemotactic effect of urokinase plasminogen activator : a major role for mechanisms independent of its proteolytic or growth factor domains . DB00013 type plasminogen activator ( uPA ) converts plasminogen to plasmin and is highly chemotactic for many cell types . We examined , using recombinant wild type and mutated forms of uPA , the extent to which its proteolytic properties , its growth - like domain ( GFD ) and / or interactions with the specific receptor ( Q03405 ) contribute to the chemotactic activity towards vascular smooth muscle cells ( SMC ) . Recombinant wild type uPA ( r - uPA ) stimulated cell migration nearly 5 . 8 - fold , inactive r - uPA , with a mutation in the catalitic domain ( r - uPA ( H / Q ) ) , 3 - fold , uPA without growth factor like domain ( r - uPA ( GFD ) ) , 2 . 6 - fold , and a form containing both mutations ( r - uPA ( H / Q , GFD ) , 3 . 3 - fold . All recombinant forms of uPA , wild type and those with mutations were equally and highly effective ( IC50 approximately 20 nM ) in displacing 125I - r - uPA bound to SMC . These results indicate that additional mechanisms , not dependent on uPA ' s proteolytic activity or the binding ability of its GFD to Q03405 , are the major contributors to its chemotactic action on SMC .",
"___MASK71___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK71___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"P00747 activation activity of urokinase determined via a cascade enzymatic reaction system . A method for determining the plasminogen activation rate by urokinase via a cascade enzymatic reaction system is presented . A procedure of parameter estimation has been proposed for the determination of the activity of urokinase and the kinetic constants . DB00013 from urine has been successfully assayed through use of a plasminogen concentration lower than its saturating level . The methodology presented in this work may be adopted for the analysis of other cascade enzymatic reaction systems .",
"___MASK78___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .",
"DB00013 receptor and resistance to targeted anticancer agents . The urokinase receptor ( Q03405 ) is a P06744 - anchored membrane protein , which regulates protease activity at the cell surface and , in collaboration with a system of co - receptors , triggers cell - signaling and regulates gene expression within the cell . In normal tissues , Q03405 gene expression is limited ; however , in cancer , Q03405 is frequently over - expressed and the gene may be amplified . Hypoxia , which often develops in tumors , further increases Q03405 expression by cancer cells . Q03405 - initiated cell - signaling promotes cancer cell migration , invasion , metastasis , epithelial - mesenchymal transition , stem cell - like properties , survival , and release from states of dormancy . Newly emerging data suggest that the pro - survival cell - signaling activity of Q03405 may allow cancer cells to \" escape \" from the cytotoxic effects of targeted anticancer drugs . Herein , we review the molecular properties of Q03405 that are responsible for its activity in cancer cells and its ability to counteract the activity of anticancer drugs .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"DB00013 receptor is necessary for adequate host defense against pneumococcal pneumonia . Cell recruitment is a multistep process regulated by cytokines , chemokines , and growth factors . Previous work has indicated that the urokinase plasminogen activator receptor ( Q03405 ) may also play a role in this mechanism , presumably by an interaction with the beta ( 2 ) integrin CD11b / P05107 . Indeed , an essential role of Q03405 in neutrophil recruitment during pulmonary infection has been demonstrated for beta ( 2 ) integrin - dependent respiratory pathogens . We investigated the role of Q03405 and urokinase plasminogen activator ( uPA ) during pneumonia caused by a beta ( 2 ) integrin - independent respiratory pathogen , Streptococcus pneumoniae . Q03405 - deficient ( Q03405 (-/-) ) , uPA - deficient ( uPA (-/-) ) , and wild - type ( Wt ) mice were intranasally inoculated with 10 ( 5 ) CFU S . pneumoniae . Q03405 (-/-) mice showed reduced granulocyte accumulation in alveoli and lungs when compared with Wt mice , which was associated with more S . pneumoniae CFU in lungs , enhanced dissemination of the infection , and a reduced survival . In contrast , uPA (-/-) mice showed enhanced host defense , with more neutrophil influx and less pneumococci in the lungs compared with Wt mice . These data suggest that Q03405 is necessary for adequate recruitment of neutrophils into the alveoli and lungs during pneumonia caused by S . pneumoniae , a pathogen eliciting a beta ( 2 ) integrin - independent inflammatory response . This function is even more pronounced when Q03405 is unoccupied by uPA .",
"Changes in coagulation and fibrinolysis of post - P49591 osteonecrosis in a Chinese population . The purpose of this study was to detect changes in coagulation and fibrinolysis of post - severe acute respiratory syndrome ( P49591 ) Chinese patients with osteonecrosis , investigate the aetiology of post - P49591 osteonecrosis ( ON ) , and select the sensitive molecular markers for identifying the susceptible population . For this study , blood samples were collected from 88 patients with post - P49591 ON and 52 healthy people . Activated partial thromboplastin time ( APTT ) , protein C ( PC ) , antithrombin III ( DB11598 ) , plasminogen activator inhibitor ( P05121 ) , activated protein C resistance ( P25054 - R ) , plasminogen ( P00747 ) , von Willebrand ' s factor ( P04275 ) , D - dimer ( D - D ) , fibrinogen ( Fib ) , and homocysteine ( HCY ) were examined by enzyme - linked immunosorbent assay ( ELISA ) . We noted that blood agents of patients with ON changed obviously . APTT , PC , DB11598 , P05121 , P25054 - R , and P00747 were significantly different between the two groups . Hypercoagulation and hypofibrinolysis were found in patients with post - P49591 ON . Therefore , these examinations can be used to screen a population susceptible to ON . Measurements of APTT , PC , DB11598 , P05121 , P25054 - R , and P00747 are sensitive blood tests for screening purposes .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK57___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy . Concomitant expression of urokinase type plasminogen activator ( uPA ) and its surface receptor ( Q03405 ) has been shown to correlate strongly with a more invasive tumor cell phenotype . A highly malignant human epidermoid carcinoma cell line ( HEp3 ) was transfected with a vector capable of expressing an antisense transcript complementary to 300 bases of the 5 ' end of Q03405 , including the ATG codon . Six stably transfected antisense ( AS - 2 , 3 , 5 , 9 , 10 , 12 ) and eight control clones were characterized . All clones produced high levels of uPA activity . Examination of collagenase production and doubling time showed that all of the clones tested produced similar activities . The antisense clones showed a 20 - 74 % reduction in the Q03405 sites ; the Q03405 mRNA level was also reduced . A test of the invasive ability of all clones in a modified chorioallantoic membrane ( P62158 ) showed that invasiveness of the antisense - inhibited clones was directly proportional to the density of surface Q03405 . The AS - 2 clone , which expressed the lowest number of uPARs showed a significantly reduced level of invasion . The invasiveness of additional AS - inhibited clones was also reduced . Seven control and four AS - inhibited clones were tested for tumorigenicity on CAMs of chick embryos . Inoculation of control cells produced large tumors , while the As clones were non - tumorigenic . AS - 2 did not produce tumors even if kept in vivo for up to 10 weeks . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Myosin light chain kinase functions downstream of Ras / P29323 to promote migration of urokinase - type plasminogen activator - stimulated cells in an integrin - selective manner . P00749 ( uPA ) activates the mitogen activated protein ( Q96HU1 ) kinases , extracellular signal - regulated kinase ( P29323 ) 1 and 2 , in diverse cell types . In this study , we demonstrate that uPA stimulates migration of MCF - 7 breast cancer cells , HT 1080 fibrosarcoma cells , and Q03405 - overexpressing MCF - 7 cells by a mechanism that depends on uPA receptor ( Q03405 ) - ligation and P29323 activation . Ras and Q96HU1 kinase kinase ( MEK ) were necessary and sufficient for uPA - induced P29323 activation and stimulation of cellular migration , as demonstrated in experiments with dominant - negative and constitutively active mutants of these signaling proteins . Myosin light chain kinase ( MLCK ) was also required for uPA - stimulated cellular migration , as determined in experiments with three separate MLCK inhibitors . When MCF - 7 cells were treated with uPA , MLCK was phosphorylated by a MEK - dependent pathway and apparently activated , since serine - phosphorylation of myosin II regulatory light chain ( P19105 ) was also increased . Despite the transient nature of P29323 phosphorylation , MLCK remained phosphorylated for at least 6 h . The uPA - induced increase in MCF - 7 cell migration was observed selectively on vitronectin - coated surfaces and was mediated by a beta1 - integrin ( probably alphaVbeta1 ) and alphaVbeta5 . When MCF - 7 cells were transfected to express alphaVbeta3 and treated with uPA , P29323 was still phosphorylated ; however , the cells did not demonstrate increased migration . Neutralizing the function of alphaVbeta3 , with blocking antibody , restored the ability of uPA to promote cellular migration . Thus , we have demonstrated that uPA promotes cellular migration , in an integrin - selective manner , by initiating a Q03405 - dependent signaling cascade in which Ras , MEK , P29323 , and MLCK serve as essential downstream effectors .",
"Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .",
"P00747 activator inhibitor type 1 ( P05121 ) is a valuable biomarker for predicting the metabolic syndrome ( MS ) in institutionalized elderly residents in Taiwan . Circulating levels of inflammatory and prothrombotic factors are elevated in the metabolic syndrome ( MS ) and linked with the occurrence of cardiovascular events . The aim of our study was to investigate the relationship between inflammatory and prothrombotic markers and the MS in elderly institutionalized residents . A total of 326 non - diabetic residents of Chuang - Hua Veterans Care Home ( age : 79 . 9 +/- 4 . 1 years ; 100 % males ) were enrolled . MS was diagnosed according to the DB00551 / NHLBI Scientific Statement criteria . Body fat percentage was measured by bioelectrical impedance analysis . P01308 resistance was calculated by homeostasis model assessment for insulin resistance ( HOMA - IR ) . Inflammatory markers , including tumor necrosis factor - a ( P01375 ) , high sensitivity P02741 ( hsCRP ) , and plasminogen activator inhibitor - 1 ( P05121 ) , were determined using ELISA . Elderly residents with the MS had higher systolic and diastolic blood pressures ( both p < 0 . 001 ) and higher HOMA - IR ( p < 0 . 001 ) , hsCRP ( p = 0 . 008 ) , and P05121 levels ( p < 0 . 001 ) than those without the MS . On multivariate logistic regression analysis , P05121 was an independent risk factor for the MS . Of the MS components , elderly residents with higher waist circumferences and higher levels of plasma fasting glucose , and triglyceride ( TG ) , and lower levels of high density lipoprotein ( HDL ) had higher P05121 levels than those without the above components .",
"DB00013 signal transduction and its role in cell migration . DB00013 and its receptor Q03405 play a role in cell migration that is being actively characterized . We previously reported that urokinase potentiates cell migration in human airway smooth muscle cells only where there is some primary migratory stimulus such as PDGF or recent exposure to growth medium . In this study , we examined the signaling of urokinase through its receptor , which lacks an intracellular domain and is presumed to act through associations with other membrane proteins . Whereas PDGF ( 30 min ) and PDGF with urokinase increased the amount of the tyrosine dephosphorylase SHP2 in the membrane fraction , urokinase alone ( 30 min ) decreased membrane SHP2 . Analysis of the time course of urokinase stimulation showed that SHP2 was brought into association with the urokinase receptor Q03405 between 2 . 5 and 20 min of urokinase , and later dissociated from it . Focal adhesion kinase was steadily lost from association with Q03405 during urokinase stimulation , but its phosphorylation state increased and it became cleaved to smaller molecules . Association of Q03405 with caveolin also decreased during urokinase stimulation . In contrast , the tyrosine kinase Src increased in the membrane fraction in response to urokinase stimulation . Disruption of raft structures by cyclodextrin treatment led to potentiation of PDGF chemotaxis , similar to urokinase action . Blocking of dephosphorylase activity with vanadate reduced basal cell migration and blocked the action of urokinase on PDGF chemotaxis . These observations support a role for urokinase in altering the phosphorylation state of focal adhesions , leading to breakdown of their structure and facilitation of cell motility .- Carlin , S . M . , Resink , T . J . , Tamm , M . , Roth , M . DB00013 signal transduction and its role in cell migration .",
"Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine - induced hyperlocomotion . DB00133 proteases in the nervous system have functional roles in neural plasticity . Among them , urokinase - type plasminogen activator ( uPA ) exerts a variety of functions during development , and is involved in learning and memory . Furthermore , psychostimulants strongly induce uPA expression in the mesolimbic dopaminergic pathway . In this study , doxycycline - regulatable lentiviruses expressing either uPA , a dominant - negative form of uPA , or non - regulatable lentiviruses expressing small interfering RNAs ( siRNAs ) targeted against uPA have been prepared and injected into the ventral tegmental area ( VTA ) of rat brains . Over - expression of uPA in the VTA induces doxycycline - dependent expression of its receptor , Q03405 , but not its inhibitor , plasminogen activator inhibitor - 1 ( P05121 ) . Q03405 expression in the VTA is repressed upon silencing of uPA with lentiviruses expressing siRNAs . In addition , over - expression of uPA in the VTA promotes a 15 - fold increase in locomotion activity upon cocaine delivery . Animals expressing the dominant - negative form of uPA did not display such hyperlocomotor activity . These cocaine - induced behavioural changes , associated with uPA expression , could be suppressed in the presence of doxycycline or uPA - specific siRNAs expressing lentiviruses . These data strongly support the major role of urokinase in cocaine - mediated plasticity changes .",
"The receptor for urokinase regulates O60603 mediated inflammatory responses in neutrophils . The urokinase - type plasminogen activator receptor ( Q03405 ) , a glycosylphosphatidylinositol ( P06744 ) anchored membrane protein , regulates urokinase ( uPA ) protease activity , chemotaxis , cell - cell interactions , and phagocytosis of apoptotic cells . Q03405 expression is increased in cytokine or bacteria activated cell populations , including macrophages and monocytes . However , it is unclear if Q03405 has direct involvement in the response of inflammatory cells , such as neutrophils and macrophages , to Toll like receptor ( TLR ) stimulation . In this study , we found that Q03405 is required for optimal neutrophil activation after O60603 , but not O00206 stimulation . We found that the expression of P01375 - α and P05231 induced by O60603 engagement in Q03405 -/- neutrophils was less than that in Q03405 +/+ ( WT ) neutrophils . Pretreatment of neutrophils with PI - P98160 , which cleaves P06744 moieties , significantly decreased O60603 induced expression of P01375 - α in WT neutrophils , but demonstrated only marginal effects on P01375 - α expression in PAM treated Q03405 -/- neutrophils . IκB - α degradation and NF - κB activation were not different in Q03405 -/- or WT neutrophils after O60603 stimulation . However , Q03405 is required for optimal p38 MAPK activation after O60603 engagement . Consistent with the in vitro findings that Q03405 modulates O60603 engagement induced neutrophil activation , we found that pulmonary and systemic inflammation induced by O60603 , but not O00206 stimulation is reduced in Q03405 -/- mice compared to WT counterparts . Therefore , our data suggest that neutrophil associated Q03405 could be a potential target for treating acute inflammation , sepsis , and organ injury related to severe bacterial and other microbial infections in which O60603 engagement plays a major role .",
"MEK / P29323 - dependent Q03405 expression is required for motility via phosphorylation of P70S6K in human hepatocarcinoma cells . Motility and invasiveness events require specific intracellular signaling cascade activations . In cancer liver cells , one of these mechanisms could involve the MAPK MEK / P29323 cascade activation which has been shown over expressed and activated in hepatocellular carcinoma . To study whether the MEK / P29323 cascade is involved in the motility of HCC , we examined the effect of MEK inhibitor and P28482 silencing using monolayer wound - healing assays and fluoroblock invasion systems . Evidence was provided that the MAPK cascade is a key transduction pathway which controls HCC cells motility and invasiveness . We could disconnect proliferation to motility using mitomycin C and we established that RNAi - mediated inhibition of P28482 led to strongly reduced cell motility . To improve our understanding , we analysed the regulation and the role of urokinase receptor ( Q03405 ) in this process . We provided evidence that Q03405 was under a MEK / P29323 dependent mechanism and blocking Q03405 activity using specific antagonist or inhibiting its expression by RNA interference which resulted in complete inhibition of motility . Moreover , we found in MAPK inhibited cultures and in Q03405 silencing cells that p70S6K phosphorylation on residue DB00156 - 389 was significantly reduced , whereas DB00133 - 421 / DB00156 - 424 phosphorylation did not change . We highlighted that the P42345 / P42345 pathway did not affect motility and DB00156 - 389 phosphorylation . Furthermore , we demonstrated that p70S6K inhibition by RNA interference completely inhibited hepatocarcinoma cell motility . Therefore , targeting Q03405 and / or MEK / P29323 / S6K by RNA interference could be a major therapeutic strategy for the future treatment of invasive hepatocarcinoma cells .",
"___MASK75___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK75___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK75___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK75___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Dermatological adverse events from P15056 inhibitors : a growing problem . The development of targeted therapies has ushered in a new era in the management of melanoma . Inhibitors of the DB01367 - RAF - MEK - P29323 pathway have taken the center stage with development at a rapid pace . ___MASK57___ was recently approved by regulatory agencies , and other agents ( e . g . dabrafenib ) are in various stages of clinical testing . These agents are producing remarkable results for patients , but are also presenting new challenges . Clinical toxicities and drug resistance are topmost issues . Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations . Published trials and initial observations reflect a toxicity profile ( e . g . squamous cell carcinomas / keratoacanthomas , maculopapular rashes , hyperkeratosis ) that is distinct from cutaneous toxicities from P00533 and P42345 inhibitors ( acneiform rash , paronychia , xerosis ) . Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities , skill sets unique to dermatologists . All these pose significant challenges to clinicians , and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life . In this manuscript , we provide an overview of the emerging scientific literature on dermatological adverse events arising out of P15056 inhibition .",
"[ P00747 activators : general aspects and recent developments ] . Considerable interest in plasminogen activators as human thrombolytic drugs has stimulated rapid biotechnologic progresses . These enzymes have been classified in two immunochemically distinct groups : \" urokinase - like \" activators or u - PA which do not interact with fibrin and \" tissue activator - like \" activators or t - PA which interact with fibrin . P00747 activators are widely distributed in normal and malignant tissues and they are implicated in various physiological and pathological processes . They maintain the functional integrity of the vascular system and their presence may be of importance in tissue remodeling and cell migration . DB00013 and streptokinase are used in human thrombolytic therapy . However , the properties displayed by t - PA suggest that this enzyme may be a superior fibrinolytic agent . The primary structures of urokinase and t - PA are known ; both enzymes have been synthesized by DNA technology . In order to produce t - PA in large quantities by gene cloning , intensive studies are conducted by pharmaceutical industries . Clinical trials using t - PA for dissolving thrombi in coronary heart disease , strokes and pulmonary embolism are in progress . This review presents the molecular and structural properties of plasminogen activators , as well as related physiological , pathological and therapeutic aspects .",
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .",
"Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia . Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia . Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor ( Q03405 ) . DB00013 plasminogen activator ( uPA ) , or a 7 - residue peptide derived from this protein ( u7 - peptide ) , bound the receptor and stimulated apical endocytosis . Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno - associated virus vectors and by a modified adenovirus vector that had been coupled to the u7 - peptide . These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia . Thus , the uPA / Q03405 system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia .",
"The urokinase - type plasminogen activator and the generation of inhibitors of urokinase activity and signaling . DB00013 ( uPA ) was originally identified in human urine for its ability to catalyse the transformation of plasminogen into its active form , plasmin which degrades fibrin and extracellular matrix components . Two major , functionally independent regions have been identified in the uPA molecule : a non - catalytic N - terminal region ( residues 1 - 135 ) and a large catalytic region ( residues 159 - 411 ) spaced by the \" connecting peptide \" ( residues 136 - 158 ) . Binding of uPA to its specific surface receptor ( Q03405 ) amplifies cell surface plasminogen activation , thus enhancing pericellular proteolysis . The Q03405 , linked to the lipid bilayer via a glycosylphosphatidylinositol anchor , mediates signaling through the assembly of a multiprotein complex with transmembrane receptors , like the integrins , P00533 , GPCRs . Receptor engagement with uPA results in a variety of cell responses , including increased proliferation , survival , migration and invasion . These responses may be enhanced by the concomitant binding of the uPA \" connecting peptide \" region to αvβ5 integrin , thus favoring Q03405 - integrin association . Receptors engaged with uPA exhibit a high affinity for vitronectin , stimulating cell adhesion . The uPA / Q03405 system is regarded as one of the key systems driving tumour invasion and metastases . Different strategies to prevent the activity of the protease , as well as the interactions of Q03405 with integrins and GPCRs have been designed . Many preclinical studies are ongoing and , at least , two uPA - related compounds have reached Phase II clinical trials . The aim of this review is to provide a comprehensive picture of the functionally relevant interactions , together with a description of the promising compounds and strategies to control uPA activity and signaling in human pathologies .",
"Reduced plasminogen activator content of the endometrium in oral contraceptive users . Human endometrium was found to contain two different plasminogen activators , urokinase and tissue activator . DB00013 was released in higher amounts from endometrial tissue explants obtained in the midcycle phase than from those obtained in the luteal phase . P00747 activator activity of the culture medium followed the same pattern . Treatment of postmenopausal patients with ethinylestradiol resulted in liberation of urokinase and tissue activator from endometrial explants in concentrations similar to those found in the normal midcycle phase . In contrast , treatment with oral contraceptives ( OCs ) , containing ethinylestradiol and a progestagen , resulted in lowered release of both activators , even lower than was found during the normal luteal phase . Also the amounts of extractable urokinase from endometrial tissue samples were significantly lower in OC - users than in non - users . Estradiol seems to have a stimulatory effect on the release of plasminogen activators from the endometrium ; whereas , gestagens depress the content and release of activators . The low content of plasminogen activators in the endometrium explains the reduced menstrual bleedings found in OC - users .",
"P00749 : a paracrine factor regulating the bioavailability of IGFs in PA - III cell - induced osteoblastic metastases . The transplantation of PA - III rat prostate cancer cells onto rat skeleton produces osteoblastic metastases . Therefore w e studied the paracrine interactions between the PA - III cells and osteoblast - derived osteosarcoma cells ( UMR 106 cells ) . A serine protease secreted by PA - III cells hydrolyzed IGF - binding protein - 1 and IGF - binding protein - 2 ( P08833 and P18065 ) detected in the cell culture media ( CM ) of OMR 106 cells by western ligand blotting . The serine protease of PA - III cell CM was purified using a benzamidine affinity column . This protease was a protein of 45 - 50 kDa on polyacrylamide gel electrophoresis under non - reducing conditions but generated two protein bands under reducing conditions ; a ) one of 33 - 35 kDa possessing protease activity and b ) another of 20 - 25 kDa which was proteinolytically inactive . Sequence analysis identified the amino acid sequence of the a - chain ( 20 - 25 kDa band ) and of the b - chain ( 33 - 35 kDa band ) of rat urokinase - type plasminogen activator molecule . DB00013 purified from PA - III cell CM hydrolyzed IGFBPs of UMR 106 cells and stimulated the proliferation of UMR 106 cells in serum - free cultures . Its protease activity was abolished by benzamidine and aprotinin . Its mitogenic activity for osteoblasts was inhibited by anti - P05019 monoclonal antibody . Northern blot analysis documented the expression of the urokinase - type plasminogen activator gene in the mRNA extracted from PA - III cells . DB00013 expression was inhibited by dexamethasone . Therefore , we conclude that urokinase - type plasminogen activator stimulates osteoblasts via an P05019 dependent mechanism . Hydrolysis of the IGFBOPs at the sites of PA - III cell - induced bone tumors account for an increased bioavailability of IGFs . This may facilitate the development and the growth of PA - III cell - induced bone tumor and can also mediate the subsequent local osteoblastic reaction .",
"Soluble DB00013 Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion . Genomic heterogeneity is characteristic of glioblastoma ( GBM ) . In many GBMs , the P01133 receptor gene ( P00533 ) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII . P00533 gene amplification and EGFRvIII are associated with GBM progression , even when only a small fraction of the tumor cells express EGFRvIII . In this study , we show that EGFRvIII - positive GBM cells express significantly increased levels of cellular urokinase receptor ( Q03405 ) and release increased amounts of soluble Q03405 ( suPAR ) . When mice were xenografted with human EGFRvIII - expressing GBM cells , tumor - derived suPAR was detected in the plasma , and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII - negative GBM cells . suPAR also was increased in plasma from patients with EGFRvIII - positive GBMs . Purified suPAR was biologically active when added to cultures of EGFRvIII - negative GBM cells , activating cell signaling and promoting cell migration and invasion . suPAR did not significantly stimulate cell signaling or migration of EGFRvIII - positive cells , probably because cell signaling was already substantially activated in these cells . The activities of suPAR were replicated by conditioned medium ( CM ) from EGFRvIII - positive GBM cells . When the CM was preincubated with Q03405 - neutralizing antibody or when Q03405 gene expression was silenced in cells used to prepare CM , the activity of the CM was significantly attenuated . These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII - positive GBMs , inducing an aggressive phenotype in tumor cells that are EGFRvIII - negative .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK50___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .",
"uPA receptor expression in benign and malignant thyroid tumors . BACKGROUND : DB00013 type plasminogen activator receptor ( Q03405 ) plays an important role in cancer invasion and metastasis . However , the Q03405 expression has been rarely investigated in thyroid carcinomas . The aim of this study was to evaluate the clinical relevance of Q03405 in thyroid tumors . MATERIALS AND METHODS : Samples included 53 benign tumors ( follicular adenoma 34 , Graves ' disease 8 , adenomatous goiter 7 and others 4 ) and 62 cancers ( papillary thyroid cancer ( PTC ) 47 , follicular TC ( FTC ) 5 , medullary TC ( P04629 ) 5 and anaplastic TC ( ATC ) 5 ) . Q03405 expression was prospectively investigated with a labeled streptavidin - biotin method using an anti - Q03405 monoclonal antibody . Patients were classified into a low - and high - staining group according to the percentage of positive cells ( cut - off value = 10 % ) . RESULTS : Q03405 was more strongly expressed in thyroid cancers ( 35 . 5 % ) than benign tumors ( 7 . 5 % ) . FTC had a significantly higher Q03405 expression compared to follicular adenoma ( p < 0 . 01 ) . The positivity of Q03405 was as follows : PTC 36 . 2 % , FTC 60 % , P04629 0 % and ATC 40 % . In PTC , high Q03405 expression was associated with poorly - differentiated PTC ( p < 0 . 01 ) while had a trend to develop more distant metastases than those with low Q03405 expression ( p = 0 . 17 , by the Kaplan - Meier method ) . CONCLUSION : This study has shown that Q03405 expression might be useful for the discrimination between FTC and follicular adenoma and could possibly be used as a prognostic factor in PTC .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK89___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"P00749 is activated in stratum corneum after barrier disruption . The plasminogen / plasmin system in epidermis is thought to be the major protease involved in the delay of barrier recovery . However , little is known about the mechanism through which this system is activated . In order to clarify this mechanism , we first determined the distribution of proteolytic activity by using in situ zymography . As a result , plasminogen - activator activity was found to be present in the stratum corneum ( SC ) after barrier disruption . Next , SC subjected to repeated barrier disruption was collected to identify the protease . The protease was identified as urokinase - type plasminogen activator , because flybrinolytic activity of the collected SC was abolished by addition of anti - urokinase antibody . DB00013 activation in SC was confirmed by means of an in vitro assay , in which the precursor of urokinase ( pro - uPA ) became active after incubation with the insoluble component of SC homogenate . These findings indicated that urokinase - type plasminogen activator is activated in SC after barrier disruption and this activation might trigger the plasminogen / plasmin system in the epidermis .",
"Targeting uPA / Q03405 in prostate cancer . Prostate cancer ( CaP ) is one of the most common malignancies in men , with an increasing incidence . Despite significant advances in surgery , chemotherapy and radiotherapy to treat CaP , many patients unfortunately succumb to secondary disease ( metastases ) . The invasive ability of tumour cells plays a key role in CaP metastasis and is a major cause of treatment failure . DB00013 plasminogen activator ( uPA ) and its receptor ( Q03405 ) - mediated signalling have been implicated in tumour cell invasion , survival , and metastasis in a variety of cancers including CaP . Both uPA and Q03405 are expressed at much higher levels in CaP tissues than in benign and normal prostate tissues . They are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression . Current therapeutic options for patients with metastatic hormone - refractory CaP ( HRPC ) are very limited . Therefore , much effort is currently being directed toward targeting aberrant uPA or Q03405 activity in CaP . This review summarizes some important new findings supporting the role of uPA / Q03405 in CaP progression and establishing the potential therapeutic efficacy of uPA / Q03405 - targeted therapies in CaP .",
"DB00013 type plasminogen activator and its receptor regulate the invasive potential of gastric cancer cell lines . To assess the role of urokinase - type plasminogen activator ( uPA ) and uPA receptor ( Q03405 ) on the invasive potential of cancer cells , in vitro experiments were performed using two human gastric cancer cell lines , NUGC - 3 and MKN - 28 . NUGC - 3 cells secreted a higher level of uPA than MKN - 28 cells , while the Q03405 expression of NUGC - 3 cells was lower than that of MKN - 28 cells . Both cancer cell lines expressed DB00134 protein and did not express hepatocyte growth factor ( P14210 ) . In Matrigel invasion assay , MKN - 28 cells demonstrated significantly lower invasion index than NUGC - 3 cells . The addition of exogenous uPA significantly increased the invasive activity of MKN - 28 cells . The uPA expression in NUGC - 3 cells was enhanced by adding conditioned media of fibroblast cells or P14210 . These results suggest that uPA promotes the invasive capacity of the Q03405 - positive cancer cells , and that stromal cells may play an important role in cancer cell invasion by supplying uPA and / or promoting uPA production .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK78___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy ."
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"___MASK78___",
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___MASK78___
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MH_train_331
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interacts_with DB00998?
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[
"Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK9___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .",
"___MASK10___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK76___ ) in castrated male and female mice subjected to ___MASK76___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK76___ in mice CPs .",
"Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .",
"The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .",
"DB00998 , a P28222 / 1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half - life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half - life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and / or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double - blind , randomised , placebo - controlled trials . At 2h , headache response rates for frovatriptan 2 . 5 mg ranged from 38 to 40 % compared to 22 - 35 % for placebo . Headache recurrence for frovatriptan 2 . 5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine .",
"A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first - line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 / 1D receptors and long half - life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short - term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment - emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short - term prophylaxis of MM . Recent post - hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain - free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well - designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype .",
"' VASPFix ' for measurement of P50552 phosphorylation in platelets and for monitoring effects of Q9H244 antagonists . P50552 ( P50552 ) is phosphorylated and dephosphorylated consequent to increases and decreases in cyclic nucleotide levels . Monitoring changes in P50552 phosphorylation is an established method for indirect measurement of cyclic nucleotides . Here we describe the use of an innovative cocktail , VASPFix , which allows sensitive and reproducible measurement of phosphorylated P50552 ( P50552 - P ) in a simple , single - step procedure using cytometric bead technology . Frozen VASPFix - treated samples are stable for at least six months prior to analysis . We successfully used VASPFix to measure P50552 - P in platelets in both platelet - rich plasma and blood in response to compounds that increase ( dibutyryl DB02527 , adenosine , iloprost , PGE1 ) and decrease ( ADP , PGE1 ) DB02527 , and to determine the effects of certain receptor antagonists on the results obtained . The change in P50552 - P brought about by adding ADP to PGE1 - stimulated platelets is a combination of the effect of ADP at the Q9H244 receptor and of PGE1 at both IP and EP3 receptors . For iloprost - stimulated platelets EP3 receptors are not involved . A procedure in which iloprost , ADP and VASPFix were used to determine effectiveness of clopidogrel and prasugrel in patients was compared with an established commercial procedure that uses PGE1 and ADP ; the latter produced higher platelet reactivity values that were the result of PGE1 interacting with platelet EP3 receptors . We conclude that VASPFix can be used both as a research tool and for clinical investigations and provides better specificity for Q9H244 receptor inhibition . The latter confers a distinct advantage over existing methods used to monitor effects of Q9H244 antagonists on platelet function .",
"Activation of Akt1 by human 5 - hydroxytryptamine ( serotonin ) 1B receptors is sensitive to inhibitors of MEK . Akt1 / protein kinase B and the mitogen - activated protein ( Q96HU1 ) kinases extracellular signal - regulated kinase 1 ( P27361 ) and P28482 have been shown to promote cell survival in a cell - specific manner . Since many receptors activate both pathways , inhibitors are commonly used to study the relative role of each pathway . In the present study , we examined the effects of PD098059 and U0126 , two structurally dissimilar inhibitors of Q96HU1 kinase kinase ( Q02750 / 2 ) , on the activation of P29323 and Akt stimulated by human 5 - hydroxytryptamine ( 1B ) ( serotonin ) ( P28222 ) receptors . Surprisingly , pathways for activation of both P29323 and Akt were found to be sensitive to the two MEK inhibitors at concentrations commonly used to selectively inhibit the activation of P29323 . Both compounds caused complete inhibition of phosphorylation of P29323 and a maximal 60 % inhibition of P28222 receptor - mediated phosphorylation of Akt . Inhibition of Akt activation required almost complete inhibition of P29323 . Transfection with cDNA for activated forms of Q02750 / 2 caused increased phosphorylation of P29323 but not of Akt , demonstrating that independent activation of MEK / P29323 was insufficient for activation of Akt . Therefore , it is not clear whether inhibition of activation of Akt resulted from selective inhibition of MEK or from additional actions on other unidentified common pathways . Nevertheless , our findings that PD098059 and U0126 inhibit activation of Akt at commonly used concentrations demonstrate that in at least some systems , these compounds inhibit activation of both P29323 and Akt , and can not be used to discern the relative roles of each pathway in mediating cellular responses .",
"DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 / 1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK89___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"DB00998 : a selective type 1B / 1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long - standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 / 1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long - term , and overall a low - incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine .",
"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .",
"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .",
"DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries . black triangle A long terminal elimination half - life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function . black triangle A single oral dose of frovatriptan 2 . 5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials . black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24 - hour migraine recurrence was reduced . black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2 . 5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug - related adverse events .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK35___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Eugenosedin - A ameliorates hyperlipidemia - induced vascular endothelial dysfunction via inhibition of α1 - adrenoceptor / 5 - HT activity and NADPH oxidase expression . Eugenosedin - A ( Eu - A ) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated . Rats were randomly divided into four groups : two control groups and two treatment groups . The control rats received a regular diet or high fat diet ( HFD ) ; the treatment rats fed received an HFD with 5 mg / kg Eu - A or atorvastatin for 10 weeks . No changes in serotonin levels were observed in the four groups ; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu - A and atorvastatin . In the HFD group , the vascular reactivity was increased by vasoconstrictors ( 5 - nonyloxytryptamine , 5 - HT , and phenylephrine ) and decreased by an endothelium - dependent vasorelaxant , carbachol . Protein levels of α1 - adrenergic receptors ( not P28222 / 2A ) , reactive oxygen species ( ROS ) p47 ( phox ) , p67 ( phox ) , and gp91 ( phox ) , and oxidative damage markers 3 - nitrotyrosine ( 3 - NT ) and 4 - hydroxy - 2 - nonenal ( 4 - HNE ) were increased , but endothelial nitric oxide synthase ( P29474 ) , P - P29474 and vasodilator - stimulated phosphoprotein phosphorylation ( P - P50552 ) were decreased . P04040 and superoxide dismutase ( SOD - 1 and SOD - 2 ) proteins were increased , but glutathione peroxidase ( GPx ) was decreased in the aorta . Eu - A and atorvastatin reduced vasoconstrictor - induced aortic contractions that might be related to P28222 / 2A and α1 - adrenergic receptors inhibitory activities . Eu - A and atorvastatin improved P29474 / P - P29474 , P - P50552 , GPx , and malondialdehyde ( MDA ) levels , and decreased ROS and oxidative damage markers . Taken together , we suggest that Eu - A can ameliorate hyperlipidemia - induced vascular endothelial dysfunction and oxidative dysregulation .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK31___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Postnatal development of serotonin 1B , 2 A and 2C receptors in brainstem motoneurons . The effects of serotonin ( 5 - HT ) on motoneurons are mediated via multiple receptor subtypes . In hypoglossal ( XII ) motoneurons , the prototypic brainstem motoneurons whose functions change during the postnatal period , 5 - HT effects evolve from inhibitory to excitatory , probably in association with changes in receptor expression . We studied P28222 , 5 - Q13049 and P28335 receptor mRNA in 414 dissociated XII motoneurons and 5 - Q13049 protein in the XII , facial and spinal cervical ( P06681 - 3 ) motor nuclei . The percentage of motoneurons expressing distinct mRNAs varied with the postnatal age ( P09131 - 33 days ) and receptor subtype . Initially , P28222 mRNA was present in 50 - 85 % of cells , but on P14 its expression transiently decreased below 35 % . 5 - Q13049 mRNA was present in nearly all cells after P6 , but in less than 65 % on P09131 - 5 . Normal and / or short splice variants of the P28335 mRNA were expressed in less than 20 % of motoneurons on P09131 - 9 , and in approximately 35 % thereafter . P28222 and 5 - Q13049 mRNAs often were expressed in different cells during early and intermediate postnatal periods , whereas P28335 mRNA never occurred alone . The 5 - Q13049 receptor protein level gradually increased through P15 in the XII and facial nuclei , with dendritic labelling appearing in XII motoneurons only after P12 . In spinal motoneurons , both somatic and dendritic labelling was strongest on Q15084 and then decreased . The development of 5 - HT receptors in XII motoneurons may be related to changes in feeding behaviour , whereas different cues regulate 5 - HT receptor expression in upper spinal motoneurons .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK59___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK78___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK78___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .",
"Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \" pain - free \" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK34___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways ."
] |
[
"___MASK10___",
"___MASK31___",
"___MASK34___",
"___MASK35___",
"___MASK59___",
"___MASK76___",
"___MASK78___",
"___MASK89___",
"___MASK9___"
] |
___MASK59___
|
MH_train_332
|
interacts_with DB00126?
|
[
"Intraretinal lipid transport is dependent on high density lipoprotein - like particles and class B scavenger receptors . PURPOSE : In our companion paper we demonstrated that circulating lipoproteins enter the retina via the retinal pigment epithelium ( Q96AT9 ) and possibly Müller cells . In order to understand how these lipids are transported within the retina , expression and localization of the main proteins known to be involved in systemic lipid transport was determined . METHODS : Expression of O95477 , apoA1 ( the major HDL protein ) , Q8WTV0 , SR - Q15878 , P16671 , lecithin : cholesterol acyltransferase ( P04180 ) , and cholesteryl ester transfer protein ( P11597 ) was determined by reverse transcriptase polymerase chain reaction ( RT - PCR ) and immunoblots . Localization was determined by immunohistochemistry using fresh monkey vibrotome sections and imaged by confocal microscopy . RESULTS : O95477 and apoA1 were localized to the ganglion cell layer , retinal pigment epithelium ( Q96AT9 ) , and rod photoreceptor inner segments . ApoA1 was also observed associated with rod photoreceptor outer segments , presumably localized to the interphotoreceptor matrix ( IPM ) . The scavenger receptors Q8WTV0 and SR - Q15878 localized mainly to the ganglion cell layer and photoreceptor outer segments ; in the latter they appear to be associated with microtubules . P04180 and P11597 localized mainly to the IPM . CONCLUSIONS : The presence and specific localization of these well - known lipid transport proteins suggest that the retina employs an internal lipid transport mechanism that involves processing and maturation of HDL - like particles .",
"DB00126 is dispensable for oxygen sensing in vivo . Prolyl - 4 - hydroxylation is necessary for proper structural assembly of collagens and oxygen - dependent protein stability of hypoxia - inducible transcription factors ( HIFs ) . In vitro function of HIF prolyl - 4 - hydroxylase domain ( P20941 ) enzymes requires oxygen and 2 - oxoglutarate as cosubstrates with iron ( II ) and vitamin C serving as cofactors . Although vitamin C deficiency is known to cause the collagen - disassembly disease scurvy , it is unclear whether cellular oxygen sensing is similarly affected . Here , we report that vitamin C - deprived Gulo (-/-) knockout mice show normal HIF - dependent gene expression . The systemic response of Gulo (-/-) animals to inspiratory hypoxia , as measured by plasma erythropoietin levels , was similar to that of animals supplemented with vitamin C . Hypoxic HIF induction was also essentially normal under serum - and vitamin C - free cell - culture conditions , suggesting that vitamin C is not required for oxygen sensing in vivo . Glutathione was found to fully substitute for vitamin C requirement of all 3 P20941 isoforms in vitro . Consistently , glutathione also reduced HIF - 1α protein levels , transactivation activity , and endogenous target gene expression in cells exposed to CoCl ( 2 ) . A Cys201Ser mutation in Q9GZT9 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro , suggesting that this surface - accessible Q9GZT9 cysteine residue is a target of antioxidative protection by vitamin C and glutathione .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK23___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .",
"High - density lipoproteins augment hypoxia - induced angiogenesis via regulation of post - translational modulation of hypoxia - inducible factor 1α . Increasing evidence suggests that high - density lipoproteins ( HDLs ) promote hypoxia - induced angiogenesis . The hypoxia - inducible factor 1α ( HIF - 1α ) / vascular endothelial growth factor ( P15692 ) pathway is important in hypoxia and is modulated post - translationally by prolyl hydroxylases ( Q96KS0 - Q9H6Z9 ) and E3 ubiquitin ligases ( Siah1 and Siah2 ) . We aimed to elucidate the mechanisms by which HDLs augment hypoxia - induced angiogenesis . Preincubation ( 16 h ) of human coronary artery endothelial cells with reconstituted high - density lipoprotein ( rHDL ) containing apolipoprotein A - I ( apoA - I ) and phosphatidylcholine ( 20 μM , final apoA - I concentration ) , before hypoxia , increased Siah1 ( 58 % ) and Siah2 ( 88 % ) mRNA levels and suppressed Q9GZT9 ( 32 % ) and Q9H6Z9 ( 45 % ) protein levels compared with hypoxia - induced control levels . After Siah1 / 2 small interfering RNA knockdown , rHDL was unable to suppress Q9GZT9 / 3 and failed to induce HIF - 1α , P15692 , and tubulogenesis in hypoxia . Inhibition of the upstream phosphatidylinositol 3 - kinase ( PI3K ) / Akt signaling pathway also abrogated the effects of rHDL . Furthermore , knockdown of the scavenger receptor Q8WTV0 attenuated rHDL - induced elevations in Siah1 / 2 and tubulogenesis in hypoxia , indicating that Q8WTV0 plays a key role . Finally , the importance of P15692 in mediating the ability of rHDL to drive hypoxia - induced angiogenesis was confirmed using a P15692 - neutralizing antibody . In summary , rHDL augments the HIF - 1α / P15692 pathway via Q8WTV0 and modulation of the post - translational regulators of HIF - 1α ( PI3K / Siahs / PHDs ) . HDL - induced augmentation of angiogenesis in hypoxia may have implications for therapeutic modulation of ischemic injury .",
"___MASK56___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK56___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .",
"Inhibition of transforming growth factor β1 / P84022 signaling decreases hypoxia - inducible factor - 1α protein stability by inducing prolyl hydroxylase 2 expression in human periodontal ligament cells . BACKGROUND : Hypoxia - inducible factor - 1α ( HIF - 1α ) , the α subunit of the heterodimeric transcription factor Q9BYW2 , maintains oxygen homeostasis by regulating gene expression . Under normoxic conditions , HIF - 1α expression is maintained at low steady - state levels by the critical oxygen sensor prolyl hydroxylase 2 ( Q9GZT9 ) . Transforming growth factor β1 ( TGF - β1 ) activates P84022 signaling and contributes to HIF - 1α stabilization under normoxic conditions . In chronic periodontitis , HIF - 1α is expressed highly in gingival fibroblasts and upregulates inflammatory factor transcription , which promotes periodontal inflammation . Here , the authors investigated the effect of TGF - β1 / P84022 signaling and its blockade by the specific inhibitor of P84022 ( SIS3 ) on HIF - 1α expression and stability in human periodontal ligament cells . METHODS : The authors investigated the effect of TGF - β1 on HIF - 1α protein stability using cycloheximide . Furthermore , they analyzed HIF - 1α expression , Q9GZT9 expression , and P84022 phosphorylation following TGF - β1 stimulation in the presence or absence of SIS3 . RESULTS : The half - life of HIF - 1α was prolonged in TGF - β1 - treated cells . TGF - β1 treatment induced HIF - 1α gene expression and enhanced HIF - 1α protein stability while decreasing Q9GZT9 expression and activating P84022 phosphorylation . Notably , HIF - 1α protein expression was not detectable prior to TGF - β1 stimulation . Furthermore , SIS3 treatment abrogated P84022 phosphorylation , impaired TGF - β1 - induced HIF - 1α gene expression and protein stability , and stimulated TGF - β1 - mediated Q9GZT9 inhibition . CONCLUSION : These results demonstrate that HIF - 1α transcription and protein synthesis are controlled by TGF - β1 / P84022 signaling , whereas HIF - 1α protein stability is controlled by Q9GZT9 , which is regulated by TGF - β1 / P84022 signaling .",
"Deficiency of the oxygen sensor Q96KS0 augments liver regeneration after partial hepatectomy . PURPOSE : Liver regeneration after partial hepatectomy ( PH ) occurs in conditions of reduced oxygen supply . HIF prolyl hydroxylase enzymes ( Q96KS0 , Q9GZT9 , and Q9H6Z9 ) are oxygen sensors involved in adaptive response to hypoxia . Specific functions of these P20941 enzymes in liver regeneration have , however , remained enigmatic . Here , we investigated the significance of Q96KS0 in liver regeneration following hepatectomy . METHODS : Liver regeneration was studied in Q96KS0 - deficient ( Q96KS0 (-/-) ) and wild type ( WT ) mice subjected to 80 % hepatectomy . For in vitro analyses , hepatocytes were isolated from Q96KS0 (-/-) and WT livers . Cell cycle progression was studied via FACS - based analysis of nuclear DNA profile . Transcription factor binding assays , qRT - PCR , and immunoblotting were applied to study the relevance of Q96KS0 downstream effectors during liver regeneration . RESULTS : Liver regeneration was significantly enhanced in Q96KS0 (-/-) mice compared to WT littermates . This effect was due to enhanced proliferation rather than to hypertrophy of liver cells . Cell cycle progression was significantly enhanced , and transcriptional activity of the cell cycle regulator c - Myc was increased in Q96KS0 - deficient hepatocytes . These changes coincided with increased expression of cyclin D2 , a cell cycle - promoting c - Myc target , and decreased expression of the cell cycle - delaying c - Myc target P38936 . CONCLUSIONS : Loss of Q96KS0 enhances liver regeneration by boosting hepatocyte proliferation in a c - Myc - dependent fashion . Q96KS0 might , therefore , represent a potential target to facilitate liver regeneration after surgical resection .",
"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK34___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .",
"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .",
"DB00435 donor , (+/-)- S - nitroso - N - acetylpenicillamine , stabilizes transactive hypoxia - inducible factor - 1alpha by inhibiting von Hippel - Lindau recruitment and asparagine hydroxylation . We have confirmed that the NO donor (+/-)- S - nitroso - N - acetylpenicillamine ( P60880 ) stabilizes the transactive form of hypoxia - inducible factor - 1alpha ( HIF - 1alpha ) , leading to the induction of HIF - 1alpha target genes such as vascular endothelial growth factor and carbonic anhydrase 9 . Activation of HIF - 1alpha should require inhibition of the dual system that keeps it inactive . One is ubiquitination , which is triggered by hydroxylation of HIF - 1alpha - proline and the subsequent binding of E3 ubiquitin ligase , the von Hippel Lindau ( P40337 ) protein . The other is hydroxylation of HIF - 1alpha - asparagine , which reduces the affinity of HIF - 1alpha for its coactivator , DB02527 responsive element binding protein / p300 . We examined the effects of the NO donor P60880 on proline and asparagine hydroxylation of HIF - 1alpha peptides by measuring the activities of the corresponding enzymes , HIF - 1alpha - specific proline hydroxylase 2 ( Q9GZT9 ) and the HIF - 1alpha - specific asparagine hydroxylase , designated factor inhibiting HIF - 1alpha ( Q9NWT6 ) , respectively . We found that the P60880 did not prevent Q9GZT9 from hydroxylating the proline of HIF - 1alpha . Instead , it blocked the interaction between P40337 and the proline - hydroxylated HIF - 1alpha , but only when the reducing agents Fe ( II ) and vitamin C were limiting . The fact that the absence of cysteine 520 of HIF - 1alpha abolishes its responsiveness to P60880 suggests that this residue mediates the inhibition by P60880 of the interaction between P40337 and HIF - 1alpha , presumably by S - nitrosylation of HIF - 1alpha . Un - like Q9GZT9 , asparagine hydroxylation by Q9NWT6 was directly inhibited by P60880 , but again only when reducing agents were limiting . Substitution of cysteine 800 of HIF - 1alpha with alanine failed to reverse the inhibitory effects of P60880 on asparagine hydroxylation , implying that Q9NWT6 , not its substrate HIF - 1alpha , is inhibited by P60880 .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK86___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"A lactate - induced response to hypoxia . Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts . Regulation of hypoxic responses via the hypoxia - inducible factor ( HIF ) is well established , but evidence indicates that other , HIF - independent mechanisms are also involved . Here , we report a hypoxic response that depends on the accumulation of lactate , a metabolite whose production increases in hypoxic conditions . We find that the Q9UGV2 protein is degraded in a Q9GZT9 / P40337 - dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia . The stabilized Q9UGV2 protein binds c - Raf to mediate hypoxia - induced activation of Raf - P29323 pathway , promoting angiogenesis and cell growth . Inhibiting cellular lactate production abolishes the Q9UGV2 - mediated hypoxia responses . Our study , therefore , elucidates the molecular basis for lactate - induced hypoxia signaling , which can be exploited for the development of therapies targeting hypoxia - induced diseases .",
"Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia - inducible factor - 1 { alpha }- dependent mechanisms . Arterial O ( 2 ) levels are thought to modulate vascular smooth muscle cell ( VSMC ) proliferation and vascular remodeling , but the mechanisms involved are poorly understood . Here , we tested the hypothesis that Q9GZT9 , a prolyl hydroxylase domain ( P20941 ) - containing O ( 2 ) sensor , modulates growth factor - induced proliferative responses of human pulmonary artery SMC ( HPASMC ) . We found that both Q96KS0 and Q9GZT9 were robustly expressed by HPASMC , and inhibiting prolyl hydroxylase activity pharmacologically by using the nonselective dioxygenase inhibitor dimethyloxalylglycine ( DMOG ) inhibited proliferation and cyclin A expression induced by PDGF - AB or P09038 . Specific knockdown of Q9GZT9 using small interfering RNAs had similar effects . The inhibitory effects of DMOG and Q9GZT9 knockdown on proliferation and cyclin A expression were seen under both normoxic ( 20 % O ( 2 ) ) and moderately hypoxic ( 5 % O ( 2 ) ) conditions , and Q9GZT9 expression was not affected by O ( 2 ) level nor by stimulation with PDGF or P09038 , indicating that the proproliferative influence of Q9GZT9 does not involve alterations of its expression . Knockdown of Q9GZT9 increased hypoxia - inducible factor ( HIF ) - 1alpha expression , as expected , but we also found that HIF - 1alpha knockdown abolished the inhibitory effect of Q9GZT9 knockdown on PDGF - induced cyclin A expression . Therefore , we conclude that Q9GZT9 promotes growth factor - induced responses of human VSMC , acting by HIF - 1alpha - dependent mechanisms . Given the role of Q9GZT9 as an oxygen sensor in mammalian cells , these results raise the possibility that Q9GZT9 links VSMC proliferation to O ( 2 ) availability .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK85___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Prolyl - 4 - hydroxylase domain protein 2 controls NF - κB / p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus . Prolyl - 4 - hydroxylase ( P20941 ) proteins are key in sensing tissue hypoxia . In nucleus pulposus ( NP ) cells , our previous work demonstrated that P20941 isoforms have a differential contribution in controlling hypoxia - inducible factor ( HIF ) - α degradation and activity . Recently we have shown that a regulatory relationship exists between Q9H6Z9 and inflammatory cytokines in NP cells . With respect to Q9GZT9 , the most abundant P20941 isoform in NP cells , very little is known concerning its function and regulation under inflammatory conditions that characterize intervertebral disc degeneration . Here , we show that Q9GZT9 is a potent regulator of the catabolic activities of P01375 - α ; silencing of Q9GZT9 significantly decreased P01375 - α - induced expression of catabolic markers including P31431 , P08254 , P45452 , and Q9UNA0 , as well as several inflammatory cytokines and chemokines , while partially restoring aggrecan and collagen II expression . Use of NF - κB reporters with ShPHD2 , SiHIF - 1α , as well as p65 (-/-) , Q9GZT9 (-/-) , and Q9H6Z9 (-/-) cells , shows that Q9GZT9 serves as a co - activator of NF - κB / p65 signaling in Q9BYW2 - independent fashion . Immunoprecipitation of endogenous and exogenously expressed tagged proteins , as well as fluorescence microscopy , indicates that following P01375 - α treatment , Q9GZT9 interacts and co - localizes with p65 . Conversely , loss of function experiments using lentivirally delivered Sh - p65 , Sh - IKKβ , and NF - κB inhibitor confirmed that cytokine - dependent Q9GZT9 expression in NP cells requires NF - κB signaling . These findings clearly demonstrate that Q9GZT9 forms a regulatory circuit with P01375 - α via NF - κB and thereby plays an important role in enhancing activity of this cytokine . We propose that during disc degeneration Q9GZT9 may offer a therapeutic target to mitigate the deleterious actions of P01375 - α , a key proinflammatory cytokine .",
"___MASK15___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"___MASK71___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK71___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK71___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK71___ inhibits activated T cells . We show that in vitro , ___MASK71___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK71___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK71___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK71___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK71___ to treat chronic inflammatory disease .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK91___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK91___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK91___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK91___ among adults with ADHD .",
"Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist ___MASK2___ were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies ."
] |
[
"___MASK15___",
"___MASK23___",
"___MASK2___",
"___MASK34___",
"___MASK56___",
"___MASK71___",
"___MASK85___",
"___MASK86___",
"___MASK91___"
] |
___MASK85___
|
MH_train_333
|
interacts_with DB08860?
|
[
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK74___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK74___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK74___ .",
"Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .",
"Loss of Jak2 impairs endothelial function by attenuating P04049 / Q02750 / Sp - 1 signaling along with altered P29474 activities . A number of inhibitors have been used to dissect the functional relevance of Jak2 in endothelial homeostasis , with disparate results . Given that Jak2 deficiency leads to embryonic lethality , the exact role of Jak2 in the regulation of postnatal endothelial function is yet to be fully elucidated . We generated a model in which Jak2 deficiency can be induced by tamoxifen in adult mice . Loss of Jak2 significantly impaired endothelium - dependent response capacity for vasodilators . Matrigel plug assays indicated a notable decrease in endothelial angiogenic function in Jak2 - deficient mice . Studies in a hindlimb ischemic model indicated that Jak2 activity is likely to be a prerequisite for prompt perfusion recovery , based on the concordance of temporal changes in Jak2 expression during the course of ischemic injury and perfusion recovery . A remarkable delay in perfusion recovery , along with reduced capillary and arteriole formation , was observed in Jak2 - deficient mice . Antibody array studies indicated that loss of Jak2 led to repressed P29474 expression . In mechanistic studies , Jak2 deficiency attenuated P04049 / Q02750 signaling , which then reduced activity of Sp - 1 , an essential transcription factor responsible for P29474 expression . These data are important not only for understanding the exact role that Jak2 plays in endothelial homeostasis , but also for assessing Jak2 - based therapeutic strategies in a variety of clinical settings .",
"Inhibitory effects of 5 - S - Q99259 on phosphorylation of V - P12931 and P11274 - P00519 tyrosine kinase . We examined the inhibitory effects of N - beta - alanyl - 5 - S - glutathionyl - 3 , 4 - dihydroxyphenylalanine ( 5 - S - Q99259 ) , a novel antibacterial substance from the immunized adult Sarcophaga peregrina ( flesh fly ) , on protein phosphorylation using immune complexes of protein tyrosine kinases ( PTKs ) with anti - PTKs monoclonal antibody . We found that 5 - S - Q99259 directly inhibited not only tyrosine phosphorylation of PTK p60 ( v - src ) , but also tyrosine phosphorylation of PTK Q92817 ( P11274 - P00519 ) . The inhibitory potency of 5 - S - Q99259 was comparable to that of radicicol and herbimycin A of PTK inhibitor .",
"Increased plasma thyroid hormone concentrations in P01130 deficient mice may be explained by inhibition of aryl hydrocarbon receptor - dependent expression of hepatic UDP - glucuronosyltransferases . BACKGROUND : Overexpression of P36956 causes a repression of hepatic genes involved in phase II metabolism . In P01130 deficient ( P01130 (-/-) ) mice , active levels of P36956 in the liver are increased . We investigated the hypothesis that P01130 (-/-) mice have increased concentrations of thyroid hormones in plasma due to a reduced hepatic glucuronidation . METHODS : Female P01130 (-/-) and wild - type mice were used to study the effect of the P01130 (-/-) genotype on thyroid hormone metabolism . RESULTS : P01130 (-/-) mice had a higher concentration of nuclear P36956 , higher concentrations of thyroxine and triiodothyronine in plasma , a lower expression of relevant P22309 isoforms , reduced activities of pNP - P78381 , T ( 3 )- P78381 and T ( 4 )- P78381 and a lower mRNA and protein concentration of P35869 in the liver than wild - type mice ( P < 0 . 05 ) . Plasma concentration of DB00024 , mRNA concentrations of various genes involved in thyroid hormone synthesis in the thyroid , activity of deiodinase and mRNA concentrations of two thyroid hormone responsive genes , P22680 and Na (+)/ K (+)- ATPase , in the liver did not differ between both genotypes . CONCLUSIONS : This study shows that P01130 (-/-) mice have increased concentrations of thyroid hormones in plasma . This effect is probably due to an inhibition of thyroid hormone glucuronidation , which might be caused by down - regulation of P78381 genes due to a reduced expression of P35869 . However , with respect to plasma DB00024 concentration and expression of thyroid hormone responsive genes no overt hyperthyroidism was detected . GENERAL SIGNIFICANCE : P01130 deficiency leads to a reduced glucuronidation of thyroid hormones in the liver which causes a moderate increase of plasma thyroid hormone concentrations .",
"DB08860 , a potent hydroxymethylglutaryl coenzyme a reductase inhibitor , increases cholesterol 7 alpha - hydroxylase gene expression in HepG2 cells . BACKGROUND : The effect of pitavastatin on the mRNA levels of apolipoprotein ( apo ) A - I , peroxisome proliferator - activated receptor alpha ( PPARalpha ) , cholesterol 7alpha - hydroxylase ( P22680 ) , and farnesoid X receptor ( Q96RI1 ) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so , to determine a possible molecular mechanism . METHODS AND RESULTS : HepG2 cells were cultured in serum - free Dulbecco ' s modified Eagle medium for 18 h before drug treatment . Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription - real time polymerase chain reaction . DB08860 at 0 . 1 , 1 , 5 , and 10 micromol / L increased the mRNA levels of apo A - I , PPARalpha , P22680 , and Q96RI1 in a dose - dependent manner . The mRNA levels of apo A - I , Q07869 alpha , P22680 , and Q96RI1 similarly increased with increasing doses of pitavastatin . Coincubation of mevalonate ( 4 mmol / L ) with pitavastatin ( 5 micromol / L ) reversed the inductive effects of pitavastatin on the mRNA levels of these genes , indicating that the inductive effects of pitavastatin were related to its inhibition of P04035 . CONCLUSIONS : DB08860 increased the mRNA levels of P22680 in HepG2 cells , suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low - density lipoprotein cholesterol - lowering effects .",
"Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis - related genes peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) , CCAAT / enhancer binding protein - alpha ( C / EBP - α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis - related genes and P27361 / 2 activation in adipocytes .",
"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK13___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK13___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .",
"Anti - adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref - 1 expression . BACKGROUND AND PURPOSE : Adipocyte differentiation in vitro is coordinately activated by two transcription factors , peroxisome proliferator - activated receptor gamma ( PPARgamma ) and CCAAT enhancer binding protein alpha ( C / EBPalpha ) , but it is inhibited by preadipocyte factor - 1 ( pref - 1 ) . Statins , inhibitors of P04035 and de novo cholesterol synthesis , can have pleiotropic effects which influence adipocyte phenotype by ill - defined mechanisms . We investigated the effects of pitavastatin ( NK - 104 ) on adipocyte differentiation and the transcriptional pathways involved . EXPERIMENTAL APPROACH : The effects of pitavastatin on adipocyte differentiation were evaluated by the formation of oil droplets , content of cellular triglyceride and expression of adipocyte - specific genes . Regulatory mechanisms were assessed by analysis of PPARgamma , C / EBPalpha and pref - 1 expression . KEY RESULTS : DB08860 significantly inhibited adipocyte differentiation of 3T3 - Q9NUQ9 preadipocytes in response to adipogenic inducers . Evidence for inhibition included fewer Oil Red O positive droplets , less cellular triglyceride and decreased expression of adipocyte - specific genes , including fatty acid binding protein ( aP2 ) , P16671 , adipsin and glucose transporter 4 ( P14672 ) . The inhibitory effects of pitavastatin on adipocyte differentiation of 3T3 - Q9NUQ9 preadipocytes were time and concentration dependent . DB08860 significantly blocked induction of PPARgamma expression , but not C / EBPalpha expression or DNA binding activity of PPARgamma . Also , pitavastatin induced pref - 1 expression in preadipocytes and maintained expression of pref - 1 at high levels in differentiated cells . CONCLUSIONS AND IMPLICATIONS : Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARgamma expression and activating pref - 1 expression . These studies may have implications in the regulation of adipogenesis in response to statins .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK17___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK88___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK88___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK88___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK88___ - induced liver damage in the future .",
"Sinusoidal endothelial cells as an early target for hepatic toxicants . Recent studies demonstrate that the hepatic sinusoidal endothelial cells ( SEC ) are a sensitive direct target for early toxicity to acetaminophen ( paracetamol , ___MASK88___ ) and this toxicity is exacerbated following a single and multiple week - end type alcoholic binge ( s ) . SEC become swollen and begin to lose the ability to endocytose FITC - Q2LD37 , a ligand for the scavenger receptor , as early as 30 minutes after the administration of ___MASK88___ . Gaps through the SEC appear to be formed by the destruction and / or coalescence of fenestrae and are seen as early as 2 hrs after the administration of ___MASK88___ which is prior to any evidence of injury to parenchymal cells . The gaps permit red blood cells to penetrate into the Space of Disse . Subsequently , the sinusoid may collapse or disintegrate reducing blood flow . The gaps are larger and more frequent in ethanol binged animals subsequently treated with ___MASK88___ . Similar gaps are seen in the early stages of hepatic venoocclusive disease . Administration of a NO donor or a P08253 and P14780 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse . The injury is exacerbated when an inhibitor of P29474 is administered and minimized when P35228 is inhibited suggesting a protective role for constitutive NO derived from SEC . Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae .",
"DB08860 inactivates NF - kappaB and decreases P05231 production through Rho kinase pathway in MCF - 7 cells . The aim of the present study was to provide new mechanistic insight into the effect of pitavastatin at low dose on NF - kappaB activated by P01375 in the human breast cancer cell line ( MCF - 7 ) . We found that treatment of MCF - 7 with 1 microM pitavastatin inhibited the proliferation and suppressed the nuclear expression of NF - kappaB p65 induced by P01375 with Western blotting . Furthermore , EMSA showed that pitavastatin significantly reduced the DNA binding activity of NF - kappaB induced by P01375 . Subsequently , luciferase assay revealed that pitavastatin ( 1 microM ) inhibited the transcriptional activity of the NF - kappaB promoter , which was clearly related to the P04035 activity because addition of mevalonic acid ( MEV ) could elevate the NF - kappaB activity . Moreover , the Rho kinase inhibitor Y27632 abolished the effect of pitavastatin on NF - kappaB activity . Finally , the addition of P01375 significantly increased P05231 protein production , which was suppressed by the addition of pitavastatin . These results suggest that pitavastatin at low dose ( 1 microM ) inhibits NF - kappaB activation and decreases P05231 production induced by P01375 . It is dependent on Rho kinase pathway in human breast cancer cells .",
"DB08860 suppresses acute and chronic rejection in murine cardiac allografts . INTRODUCTION : P04035 inhibitors play several roles in the maintenance of organ transplants . We investigated the role of pitavastatin , a potent and newly developed P04035 inhibitor , in cardiac allograft rejection and mechanism of graft arterial disease ( Q99259 ) suppression . METHODS : Balb / c mice hearts were transplanted into C3H / He mice ( a full allomismatch combination ) to assess acute rejection or C57BL / 6 hearts into B6 . C - H2 ( < bm12 > ) KhEg ( a class II mismatch combination ) to examine the extent of Q99259 . DB08860 was administered orally to mice everyday ( 3 mg / kg / day ) . To assess the effect in acute rejection , mixed lymphocyte reaction was performed and cytokine mRNA expression was examined with ribonuclease protection assay . RESULTS : DB08860 significantly prolonged allograft survival . Lymphocyte proliferation was inhibited by pitavastatin , and RPA showed down - regulation of interleukin - 6 in pitavastatin - treated cardiac allografts . Allografts in the pitavastatin - treated group after 8 weeks showed less Q99259 compared with the control group . In vitro , pitavastatin suppressed the smooth muscle cell proliferation in response to activated T cells and inhibited extracellular signal - regulated kinase 1 / 2 activation . CONCLUSION : DB08860 could be effective in the suppression of acute rejection and Q99259 development in cardiac transplantation .",
"___MASK74___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK74___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK74___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK74___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"DB08860 attenuates the PDGF - induced Q92673 / uPA receptor - mediated migration of smooth muscle cells . Statins , inhibitors of P04035 , elicit various actions on vascular cells including the modulation of proliferation and migration of smooth muscle cells ( SMCs ) . Here , we have elucidated the mechanism by which statins , in particular pitavastatin , attenuate the migration activity of SMCs . The expression of Q92673 , a member of the P01130 family and an enhancer of cell surface localization of urokinase - type plasminogen activator receptor ( Q03405 ) , is increased in cultured SMCs by treatment with DB00102 . DB08860 attenuates the DB00102 - induced surface expression of Q92673 and Q03405 . The increased migration of SMCs observed both upon overexpression of Q92673 and via stimulation of secretion of soluble Q92673 is not reversed by pitavastatin . In vivo studies showed that the SMCs expressing Q92673 in plaques are almost congruent with intimal cells expressing nonmuscle myosin heavy chain ( SMemb ) . DB08860 reduced the expression of Q92673 and SMemb , and the levels of Q92673 , Q03405 , and SMemb in cultured intimal SMCs were reduced to those seen in medial SMCs . We propose that this statin reduces PDGF - induced migration through the attenuation of the Q92673 / Q03405 system in SMCs . Modulation of the Q92673 / Q03405 system with statins suggests a novel treatment strategy for atherogenesis based on suppression of intimal SMC migration .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK3___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"DB08860 up - regulates the induction of P35228 through enhanced stabilization of its mRNA in pro - inflammatory cytokine - stimulated hepatocytes . Studies have indicated that protective effects of statins ( P04035 inhibitor ) are associated with the regulation of endothelial nitric oxide synthase ( P29474 ) or inducible NOS ( P35228 ) in heart and liver diseases . Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis . However , it is unclear which NOS contributes to the increased NO production . We hypothesized that statins are involved in the up - regulation of P35228 in inflammatory liver , resulting in decreased hepatic resistance . Primary cultured rat hepatocytes were treated with pro - inflammatory cytokine interleukin ( IL ) - 1beta in the presence or absence of pitavastatin . Pretreatment of cells with pitavastatin resulted in up - regulation of P35228 induction by IL - 1beta , followed by increased NO production . DB08860 had no effects on the degradation of IkappaB or activation of NF - kappaB . However , pitavastatin super - induced the up - regulation of type I IL - 1 receptor ( IL - 1RI ) , which is essential for P35228 induction in addition to the IkappaB / NF - kappaB pathway . Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on P35228 and IL - 1RI induction . Transfection experiments revealed that pitavastatin increased the stability of P35228 mRNA rather than its promoter transactivation . In support of this observation , pitavastatin increased the antisense - transcript corresponding to the 3 '- UTR of P35228 mRNA , which stabilizes P35228 mRNA by interacting with the 3 '- UTR - and RNA - binding proteins . These findings demonstrate that pitavastatin up - regulates P35228 by the stabilization of its mRNA , presumably through the super - induction of IL - 1RI and antisense - transcript . This implies that statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis .",
"Novel function of histamine signaling in hyperlipidemia - induced atherosclerosis : DB11320 H1 receptors protect and H2 receptors accelerate atherosclerosis . DB11320 is not only essential for acute inflammatory reactions , but it also participates in a chronic inflammatory disorder . We generated apolipoprotein E ( apoE ) and histamine receptors ( HHRs ) , including the major H1 and H2 receptors ( P35367 , P25021 ) double knockout mice ( DKO ) to clarify the role of HHRs in hyperlipidemia - induced atherosclerosis , in which apoE - KO and DKO mice were fed a high cholesterol diet . We found that pronounced hyperlipidemia - induced atherosclerotic progression occurred in P35367 / apoE - DKO mice , but in P25021 / apoE - DKO mice less atherosclerosis , despite pro - atherogenic serum cholesterol levels compared with apoE - KO mice . Furthermore , the increased expressions of scavenger receptors ( SRs ) , such as SR - A , P16671 and lectin - like oxidized low - density lipoprotein receptor 1 ( P78380 ) , nuclear factor - kappa B ( NFκB ) , monocyte chemoattractant protein ( P13500 ) , matrix metalloproteinases ( MMPs ) or liver X receptor ( LXR ) - related inflammatory signaling factors , were consistent with the pro - atherogenic phenotype of P25021 / apoE - DKO mice . We hypothesize that histamine / P35367 and P25021 signaling has conflicting innate functions , inflammatory / atherogenic and anti - inflammatory / anti - atherogenic actions , and that there are innate links between histamine signaling and hyperlipidemia - induced atherosclerosis , independently of serum cholesterol metabolism . Specific histamine signaling blockers , in particular , P25021 blockers , are a possible novel therapeutic target for hyperlipidemia - induced atherosclerosis .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Role of erythropoietin receptor signaling in parvovirus P57058 replication in human erythroid progenitor cells . Parvovirus P57058 ( B19V ) infection is highly restricted to human erythroid progenitor cells . Although previous studies have led to the theory that the basis of this tropism is receptor expression , this has been questioned by more recent observation . In the study reported here , we have investigated the basis of this tropism , and a potential role of erythropoietin ( Epo ) signaling , in erythroid progenitor cells ( EPCs ) expanded ex vivo from P28906 (+) hematopoietic cells in the absence of Epo ( P16671 (+)/ Epo (-) EPCs ) . We show , first , that P16671 (+)/ Epo (-) EPCs do not support B19V replication , in spite of B19V entry , but Epo exposure either prior to infection or after virus entry enabled active B19V replication . Second , when O60674 ( Jak2 ) phosphorylation was inhibited using the inhibitor AG490 , phosphorylation of the Epo receptor ( EpoR ) was also inhibited , and B19V replication in ex vivo - expanded erythroid progenitor cells exposed to Epo ( P16671 (+)/ Epo (+) EPCs ) was abolished . Third , expression of constitutively active EpoR in P16671 (+)/ Epo (-) EPCs led to efficient B19V replication . Finally , B19V replication in P16671 (+)/ Epo (+) EPCs required Epo , and the replication response was dose dependent . Our findings demonstrate that EpoR signaling is absolutely required for B19V replication in ex vivo - expanded erythroid progenitor cells after initial virus entry and at least partly accounts for the remarkable tropism of B19V infection for human erythroid progenitors .",
"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .",
"___MASK88___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"The novel P04035 inhibitor , DB08860 , induces a protective action in vascular endothelial cells through the production of nitric oxide ( NO ) . This study sought to induce the effect of nitric oxide ( NO ) production in vascular endothelial cells by DB08860 , which is a novel P04035 inhibitor ( statin ) . The growth capacity of vascular endothelial cells significantly ( p < 0 . 01 ) declined when stimulated with P01375 ( 10 ng / ml ) . The growth capacity of the P01375 treated cells recovered , when the P01375 stimulation was performed after DB08860 ( 100 nM ) pretreatment . The recovery of the growth capacity of the cells was suppressed by the presence of the NO synthase inhibitor , L - NAME . DB08860 increased NO production by the vascular endothelial cells in a dose and time dependent manner . The NO production was suppressed by the presence of mevalonic acid and geranylgeranyl pyrophosphate . In addition , the expression of endothelial nitric oxide synthase was strongly induced by DB08860 , and was suppressed by mevalonic acid and geranylgeranyl pyrophosphate by Western blot analysis . Our results show that DB08860 induces NO production by vascular endothelial cells , and protects vascular endothelial cells from injury due to the inflammatory reaction induced by P01375 .",
"Angiogenic and inflammatory factor expressions in cutaneomeningospinal angiomatosis ( Cobb ' s syndrome ) : case report . We report on a case of cervical cutaneomeningospinal angiomatosis ( Cobb ' s syndrome ) , a rare somatic disorder , characterized by vascular abnormalities of the spinal cord , with a triad of associated vascular skin , muscle , bone , and dura involvement at the same somite . This case follows an 18 - year - old male patient presenting with left extremity weakness and back cervical pain . Magnetic resonance imaging ( Q9BWK5 ) revealed a spinal cord arteriovenous malformation ( AVM ) at the P01024 - P01031 level . Cobb ' s syndrome was diagnosed by coexistence of cutaneous naevi in a dermatomal pattern and neurological signs of a spinal cord lesion together with cervical Q9BWK5 and angiography . The patient underwent a combination of staged endovascular embolization and microsurgical resection . Multiple biopsies of the mass including the skin , muscle , dura , and spinal cord at the same somite revealed that the lesions had a similar pathology . Post - operative immunohistochemical characterizations on specimen included CD31 , smooth muscle actin ( SMA ) , vascular endothelial growth factor ( P15692 ) , and matrix metalloproteinase ( P14780 ) . The unique associations of somatic and spinal cord lesion as well as angiogenic and inflammatory factor expressions in all specimens are reported .",
"[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .",
"DB08860 prevents DB01221 - induced retinal ganglion cell death by suppressing leukocyte recruitment . Excitotoxicity is a major cause of retinal ganglion cell ( RGC ) death during ischemic diseases such as vessel occlusion and diabetic retinopathy . However , the underlying mechanisms are not well understood . Statins , inhibitors of the P04035 , have neuroprotective effects in addition to their original role in lowering cholesterol . We hypothesize that pitavastatin , a recently introduced potent statin , is protective against N - methyl - d - aspartic acid ( DB01221 ) - induced RGC death . DB08860 , administered by gavage , abolished DB01221 - induced loss of RGCs . To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin , we investigated its impact on inflammation . DB01221 increased the expression of interleukin - 1beta and P01375 , and endothelial adhesion molecules , including P05362 , and induced leukocyte accumulation in the retinal vessels . DB08860 significantly reduced DB01221 - induced leukocyte accumulation and up - regulation of endothelial adhesion molecules , whereas cytokine expression was unaffected . Systemic blockade of P05362 in wild - type mice or absence of P05107 in gene - deficient ( P05107 (-/-) ) mice significantly suppressed DB01221 - induced leukocyte accumulation and RGC death . These findings suggest a novel and causative role for inflammatory leukocyte recruitment in DB01221 - induced excitotoxicity . Furthermore , we show the novel neuroprotective effect of statins against excitotoxicity - induced RGC death . Statins or other anti - inflammatory agents may thus have therapeutic benefits in excitotoxicity - associated neuronal diseases through blockade of leukocyte recruitment .",
"A new P04035 inhibitor , pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits . BACKGROUND : The remarkable anti - atherosclerotic effects of 3 - hydroxy - 3 - methyl - glutaryl - DB01992 reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model . OBJECTIVE : We have investigated the effect of pitavastatin , a newly developed statin , on atherosclerosis in rabbits . METHODS AND RESULTS : Oophorectomized female NZW rabbits were fed 0 . 3 % cholesterol chow for 12 weeks with or without pitavastatin ( 0 . 1mg / kg per day ) ( Gp . NK and HCD ) . The level of serum cholesterol was decreased in Gp . NK compared with Gp . HCD ( 772 . 8 +/- 70 . 2 versus 1056 . 9 +/- 108 . 3 mg / d ) , whereas no significant alterations were observed in triglyceride and HDL - cholesterol . NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - l - arginine acetate were all improved by pitavastatin treatment . DB08860 treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits . In the aorta , the expression of P29474 mRNA was significantly up regulated and O ( 2 )(-) production was slightly reduced in Gp . NK animals . Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp . NK compared with those from Gp . HCD ( 15 . 1 +/- 5 . 3 versus 41 . 9 +/- 10 . 2 % , 3 . 1 +/- 1 . 1versus 7 . 9 +/- 1 . 2 % in Gp . NK and Gp . HCD aortic arch and thoracic aorta ) . Anti - macrophage staining area , the P03956 or 2 and the nitrotyrosine positive area were decreased in Gp . NK . CONCLUSION : DB08860 retards the progression of atherosclerosis formation and it improves NO bioavailability by P29474 up - regulation and decrease of O ( 2 )(-) .",
"Novel , small molecule induced GABA - hATSCs for targeting of neuropathic pain . Recent study showed that ROS has a crucial function during neuropathic pain development and maintenance . In this study , we suggest that a small , novel molecule , CMB - 1078 , can effectively induce GABAergic neuronal differentiation from human adipose tissue - derived stromal cells ( hATSCs ; GABA - hATSCs ) , which play a key role in ameliorating neuropathic pain caused by spinal cord injury . Compared to control hATSCs , the engraftment of GABA - hATSCs into animals with neuropathic pain significantly reduced secondary injury , including inflammation , GABAergic neuronal degeneration , and the circulation or propagation of proinflammatory factors cyclooxygenase2 ( P35354 ) , interlukin - 1 β ( IL - 1β ) , P04839 ( NOX 2 ) , Q9NPH5 ( NOX 4 ) and tumor necrosis factor α ( TNFα ) into the lesion . At the protein level , we also demonstrated that GABA - hATSCs engrafted into animals with neuropathic pain increased glutamic acid decarboxylase 65 ( Q05329 ) and glutamic acid decarboxylase 67 ( Q99259 ) expression levels . In addition , we evaluated functional pain behavior in the GABA - hATSCs - or control hATSCs - engrafted animal group , the pain in the PBS - infused animal group , and healthy animals by measuring mechanical and heat sensitivity . The pain plus GABA - hATSCs - engrafted animal groups showed paw withdrawal thresholds ( PWTs ) that gradually improved . In contrast , the mice with neuropathic pain did not show improved PWT . Further , the control hATSCs - engrafted animal showed attenuated PWTs . Finally , we suggest that the molecular function of GABA - hATSCs in neuropathic pain may provide potential therapeutic tools for the treatment of pain by controlling the pathology of neuropathic pain through neuroprotection and regeneration .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK33___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK33___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK33___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"DB11320 contributes to tissue remodeling via periostin expression . DB11320 is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases . Recent studies revealed that periostin , a matricelluar protein , contributed to tissue remodeling ; however , a link between periostin and histamine remains unproven . We investigated whether periostin was involved in histamine - induced collagen production . Cultured dermal fibroblasts derived from wild - type ( WT ) or periostin knockout ( PN (-/-) ) mice were stimulated with histamine , and then collagen and periostin production was evaluated . DB11320 induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase , whereas no effect on collagen expression was observed in histamine - stimulated PN (-/-) fibroblasts . In WT fibroblasts , histamine directly induced periostin expression in a dose - dependent manner , and an H1 receptor antagonist blocked both periostin and collagen expression . DB11320 activated extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) through the H1 receptor . Q15063 induction was inhibited by either H1 antagonist or P27361 / 2 inhibitor treatment in vitro and was attenuated in P35367 (-/-) mice . Elevated expression of periostin was found in lesional skin from atopic dermatitis patients . These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor - mediated P27361 / 2 pathway ; furthermore , histamine may accelerate the chronicity of atopic dermatitis .",
"GNAS mutation as an alternative mechanism of activation of the Wnt / β - catenin signaling pathway in gastric adenocarcinoma of the fundic gland type . Gastric adenocarcinoma of the fundic gland type ( GAFG ) is a rare variant of gastric tumor . We have recently reported the frequent accumulation of β - catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in P35222 / AXINs / P25054 , leading to the constitutive activation of the Wnt / β - catenin pathway . However , the mechanisms of Wnt signaling activation in the remaining cases are unknown . Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt / β - catenin pathway or the P27361 / 2 MAPK pathway . Therefore , we analyzed the mutations in GNAS ( exons 8 and 9 ) and in P01116 ( exon 2 ) in 26 GAFGs . Immunohistochemistry revealed nuclear β - catenin expression in 22 of 26 GAFGs , and 10 ( 38 . 5 % ) of 26 cases harbored at least 1 mutation in P35222 / AXINs / P25054 . Activating mutations in GNAS were found in 5 ( 19 . 2 % ) of 26 GAFGs , all of which harbored R201C mutations . Activating mutations in P01116 were found in 2 ( 7 . 7 % ) of 26 GAFGs , and both of these also contained GNAS activating mutations . Four of 5 cases with GNAS mutation showed nuclear β - catenin expression , and presence of GNAS mutation was associated with β - catenin nuclear expression ( P = . 01 ) . Furthermore , 3 of these 4 cases did not harbor mutations in P35222 , P25054 , or AXINs , suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively . These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt / β - catenin signaling pathway .",
"DB08860 , an P04035 inhibitor , exerts P29474 - independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency . Angiotensin II ( Ang II ) plays a pivotal role in cardiovascular remodeling leading to hypertension , myocardial infarction , and stroke . DB08860 , an P04035 inihibitor , is known to have pleiotropic actions against the development of cardiovascular remodeling . The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II - induced organ damage . C57BL6 / J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle . DB08860 treatment improved Ang II - induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis , cardiomyocyte hypertrophy , coronary perivascular fibrosis , and medial thickening . Ang II - induced oxidative stress , cardiac TGFbeta - 1 expression , and Smad 2 / 3 phosphorylation were all attenuated by pitavastatin treatment . DB08860 also reduced Ang II - induced cardiac remodeling and diastolic dysfunction in P29474 -/- mice as in wild - type mice . In P29474 -/- mice , the Ang II - induced cardiac oxidative stress and TGF - beta - Smad 2 / 3 signaling pathway were enhanced , and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway . Moreover , pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II - treated P29474 -/- mice , with suppression of glomerular oxidative stress and TGF - beta - Smad 2 / 3 signaling pathway . In conclusion , pitavastatin exerts P29474 - independent protective actions against Ang II - induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF - beta - Smad 2 / 3 signaling pathway by suppression of oxidative stress .",
"Selective inhibition of P23458 and O60674 is efficacious in rodent models of arthritis : preclinical characterization of INCB028050 . Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis . Kinase inhibitors have shown promising oral disease - modifying antirheumatic drug potential with efficacy similar to anti - P01375 biologics . Direct and indirect inhibition of the JAKs , with small molecule inhibitors like CP - 690 , 550 and ___MASK74___ or neutralizing Abs , such as the anti - P05231 receptor Ab tocilizumab , have demonstrated rapid and sustained improvement in clinical measures of disease , consistent with their respective preclinical experiments . Therefore , it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities . INCB028050 is a selective orally bioavailable P23458 / O60674 inhibitor with nanomolar potency against P23458 ( 5 . 9 nM ) and O60674 ( 5 . 7 nM ) . INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including P05231 and IL - 23 at concentrations < 50 nM . Significant efficacy , as assessed by improvements in clinical , histologic and radiographic signs of disease , was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and / or periodic inhibition of P23458 / O60674 and no inhibition of P52333 . Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats . INCB028050 was also effective in multiple murine models of arthritis , with no evidence of suppression of humoral immunity or adverse hematologic effects . These data suggest that fractional inhibition of P23458 and O60674 is sufficient for significant activity in autoimmune disease models . Clinical evaluation of INCB028050 in RA is ongoing .",
"Novel agents that potentially inhibit irinotecan - induced diarrhea . ___MASK33___ ( CPT - 11 , 7 - ethyl - 10 -[ 4 -( 1 - piperidino )- 1 - piperidino ] carbonyloxycamptothecin ) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting P11387 ( Topo I ) . However , severe and unpredictable dosing - limiting toxicities ( mainly myelosuppression and severe diarrhea ) hinder its clinical use . The latter consists of early and late - onset diarrhea , occurring within 24 hr or > or = 24 hr after CPT - 11 administration , respectively . This review highlights novel agents potentially inhibiting CPT - 11 - induced diarrhea , which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms . Early - onset diarrhea is observed immediately after CPT - 11 infusion and probably due to the inhibition of acetylcholinesterase activity , which can be eliminated by administration of atropine . Late - onset diarrhea appears to be associated with intestinal exposure to SN - 38 ( 7 - ethyl - 10 - hydroxycamptothecin ) , the major active metabolite of CPT - 11 , which may bind to Topo I and induce apoptosis of intestinal epithelia , leading to the disturbance in the absorptive and secretory functions of mucosa . CPT - 11 and SN - 38 may also stimulate the production of pro - inflammatory cytokines and prostaglandins ( PGs ) , thus inducing the secretion of Na (+) and Cl (-) . Early treatment of severe late - onset diarrhea with oral high - dose loperamide has decreased patient morbidity . Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models . These include intestinal alkalizing agents , oral antibiotics , enzyme inducers , P - glycoprotein ( PgP ) inhibitors , cyclooxygenase - 2 ( P35354 ) inhibitors , tumor necrosis factor - alpha ( P01375 ) inhibitors , or blockers of biliary excretion of SN - 38 . Further studies are needed to identify the molecular targets associated with CPT - 11 toxicity and safe and effective agents for alleviating CPT - 11 - induced diarrhea .",
"Synergism between bosutinib ( ___MASK13___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Novel future therapeutic options in myasthenia gravis . BACKGROUND : Myasthenia Gravis ( MG ) is an autoimmune disease caused by complement - fixing antibodies against the acetylcholine receptors ( AChR ) . Antigen - specific P01730 + T cells , Tregs and Th17 + are also necessary . Consequently , antibodies , B cells , molecules associated with signalling pathways on T helper cells , cytokines and complement are targets for more specific treatment options . OBJECTIVES : Because available immunosuppressive therapies cause unacceptable side effects after long - term use or are not always effective in inducing remission , novel biological agents directed against the following targets might be options for future therapies in MG : 1 ) T cell Intracellular Signaling Pathways associated with T cell activation , such as monoclonal antibodies against P31358 , Interleukin 2 - receptor ( P60568 R ) , co - stimulatory molecules or compounds inhibiting Janus tyrosine kinases P23458 , P52333 ; 2 ) B cells , against key B cell - surface molecules or trophic factors B cell activation factor ( Q9Y275 ) and a proliferating inducing ligand ( APRIL ) ; 3 ) Complement , against P01024 or P01031 that intercept membranolytic attack complex formation ; 4 ) Cytokines and cytokine receptors , including P05231 , Q16552 , the p40 subunit of IL12 / 1L - 23 , and GM - P04141 ; and 5 ) Lymphocyte migration molecules . Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies , can be a future molecular tool . CONCLUSION : New biological agents are in the offing for future therapies in MG . Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications .",
"The peroxisome proliferator - activated receptor interacts with the retinoid X receptor in vivo . The peroxisome proliferator - activated receptor ( Q07869 ) binds cooperatively to cognate peroxisome proliferator - responsive elements ( PPRE ) in vitro through heterodimerization with retinoid X receptors ( RXR ) . We used the yeast two - hybrid system to determine whether these two nuclear receptors physically interact in vivo . Mouse ( m ) Q07869 and human ( h ) RXR alpha were synthesized as fusion proteins to either the DNA - binding domain ( GBD ) or the transactivation domain ( Q99259 ) of the yeast GAL4 transcription - activator protein , and were tested for their ability to activate expression of a P22466 :: lacZ reporter gene . Strong activation was observed only in yeast transformed with combinations of GBD :: mPPAR and Q99259 :: hRXR alpha or with Q99259 :: mPPAR and GBD :: hRXR alpha . Homodimeric interaction by mPPAR was not detected . These results provide evidence for the interaction of Q07869 and RXR alpha in vivo in the absence of a PPRE target site or exogenously added ligands .",
"Transcriptome analysis of muscle in horses suffering from recurrent exertional rhabdomyolysis revealed energetic pathway alterations and disruption in the cytosolic calcium regulation . Recurrent exertional rhabdomyolysis ( Q13123 ) is frequently observed in race horses like trotters . Some predisposing genetic factors have been described in epidemiological studies . However , the exact aetiology is still unknown . A calcium homeostasis disruption was suspected in previous experimental studies , and we suggested that a transcriptome analysis of Q13123 muscles would be a possible way to investigate the pathway disorder . The purpose of this study was to compare the gene expression profile of Q13123 vs . control muscles in the French Trotter to determine any metabolic or structural disruption . Total RNA was extracted from the gluteal medius and longissimus lumborum muscles after biopsies in 15 French Trotter horses , including 10 controls and 5 Q13123 horses affected by ' tying - up ' with high plasmatic muscular enzyme activities . Gene expression analysis was performed on the muscle biopsies using a 25K oligonucleotide microarray , which consisted of 24 , 009 mouse and 384 horse probes . Transcriptome analysis revealed 191 genes significantly modulated in Q13123 vs . control muscles ( P < 0 . 05 ) . Many genes involved in fatty acid oxidation ( P16671 / FAT , O43808 ) , the Krebs cycle ( Q02978 , O75746 , P40926 ) and the mitochondrial respiratory chain were severely down - regulated ( tRNA , P03915 , P03923 , MT - P23219 ) . According to the down - regulation of P21817 , P32418 and P55851 and up - regulation of P05067 and P11021 , the muscle fibre calcium homeostasis seemed to be greatly affected by an increased cytosolic calcium and a depletion of the sarcoplasmic reticulum calcium . Gene expression analysis suggested an alteration of DB00171 synthesis , with severe mitochondrial dysfunction that could explain the disruption of cytosolic calcium homeostasis and inhibition of muscular relaxation .",
"Pharmacogenetics in chemotherapy of colorectal cancer . Although in recent years , chemotherapeutic options for colorectal carcinoma have expanded , overall response rates are still too low , with high rates of toxicity . Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients . This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer . P22309 * 28 leads to reduced conjugation of SN - 38 , the active metabolite of irinotecan , resulting in an increased rate of adverse effects , especially neutropenia . To a lesser extent , increased DB00544 toxicity is predicted by Q12882 * 2A . A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region , in combination with a single nucleotide polymorphism C > G , may predict poorer response to DB00544 . Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems , such as P07992 and P18887 . Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy . Furthermore , the antibody - depended cell - mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors . DB00112 efficacy is suspected to be influenced by polymorphisms in the P15692 gene and the hypoxia inducible factor 1alpha gene . Although the interpretation of pharmacogenetic studies is complicated , results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity .",
"DB11320 stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase . Oxidative stress has been implicated in the pathogenesis of bronchial asthma . Besides granulocytes , the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma - related oxidative stress . DB11320 is a major inflammatory mediator present in large quantities in asthmatic airways . Whether histamine triggers epithelium - derived oxidative stress is unknown . We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine . We found that air - liquid interface cultures of primary human bronchial epithelial cells ( BECs ) and an immortalized BEC model ( Cdk4 / hTERT HBEC ) produce H2O2 in response to histamine . The main source of airway epithelial H2O2 is an NADPH dual oxidase , Duox1 . Out of the four histamine receptors ( P35367 - Q9H3N8 ) , P35367 has the highest expression in BECs and mediates the H2O2 - producing effects of histamine . P05112 induces Duox1 gene and protein expression levels and enhances histamine - induced H2O2 production by epithelial cells . Using P29320 - 293 cells expressing Duox1 or Duox2 and endogenous P35367 , histamine triggers an immediate intracellular calcium signal and H2O2 release . Overexpression of P35367 further increases the oxidative output of Duox - expressing P29320 - 293 cells . Our observations show that BECs respond to histamine with Duox - mediated H2O2 production . These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways , suggesting novel therapeutic targets for treating asthmatic airway disease .",
"Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis . In order to know whether any protein tyrosine kinase ( PTK ) is involved in the over - proliferation and erosiveness of synovial fibroblasts ( SF ) of rheumatoid arthritis ( RA ) patients , RT - PCR and RNA dot blotting were done to analyse PTKs profile in RA SF . Platelet - derived growth factor receptor A ( P16234 ) , insulin - like growth factor 1 receptor ( IGF - 1R ) , P23458 ( P23458 ) , P29597 , discoidin domain receptor 2 ( Q16832 ) , and Lyn were expressed in SF , and the expression of P16234 , IGF - 1R , and Q16832 in SF of RA were higher than that of osteoarthritis ( OA , as control ) . Immunoblotting and gelatinase zymography showed that Q16832 in RA SF , which still secreted active matrix metalloproteinase 1 ( P03956 ) in vitro , were in active form . Stimulation of collagen II could make NIH - 3T3 cells ( as control ) produce P03956 , which could be inhibited by soluble extracellular part of Q16832 . These results indicated that the over - expression of P03956 in RA SF might be related to the activation of Q16832 , and collagen II , act as Q16832 ligand , might be one of the stimulators of the over - expression of P03956 of RA SF .",
"Possible involvement of Q07869 gamma in the regulation of basal channel opening of Q99572 receptor in cultured mouse astrocytes . AIMS : Recently , we demonstrated that cultured mouse astrocytes exhibited basal channel opening of Q99572 receptor ( P2X7R ) in the absence of any exogenous ligand , but the regulatory mechanism involved was not elucidated . Since our preliminary experiments suggested possible involvement of peroxisome proliferator - activated receptor ( Q07869 ) gamma in the regulation , we examined whether Q07869 gamma regulated P2X7R basal channel opening in mouse astrocytes . MAIN METHODS : P2X7R channel opening was assessed as to the uptake of a marker dye , YO - PRO - 1 ( YP ) , in the presence or absence of agonists and antagonists for Q07869 gamma under a fluorescence microscope . Expression of Q07869 gamma was evaluated by Western blotting and immunocytochemistry . KEY FINDINGS : NSAIDs such as flufenamic acid ( FFA ) and indomethacin , which are a cyclooxygenase inhibitor and a Q07869 gamma agonist , showed enhancing and inhibiting effects on YP uptake at low and high concentrations , respectively , and the enhanced uptake was abolished by periodate - oxidized DB00171 ( oxATP ) , a selective P2X7R antagonist . The Q07869 gamma agonists 15 - deoxy - Delta ( 12 , 14 )- prostaglandin J ( 2 ) and ciglitazone decreased the basal and FFA - enhanced YP uptake , while the antagonist GW9662 increased YP uptake , this effect being blocked by the agonists and also by oxATP . Q07869 gamma was distributed in the nucleus and cytosolic / membrane fraction of cultured mouse astrocytes . SIGNIFICANCE : These findings indicate that basal channel opening of P2X7R in mouse astrocytes is at least in part regulated by Q07869 gamma .",
"Peroxisome proliferator - activated receptor and age - related macular degeneration . Age - related macular degeneration ( AMD ) is the leading cause of new blindness in the western world and is becoming more of a socio - medical problem as the proportion of the aged population increases . There are multiple efforts underway to better understand this disease process . AMD involves the abnormal retinal pigment epithelium ( Q96AT9 ) , drusen formation , photoreceptor atrophy , and choroidal neovascularization . Peroxisome proliferator - activated receptors ( PPARs ) play an important role in lipid degeneration , immune regulation , regulation of reactive oxygen species ( ROSs ) , as well as regulation of vascular endothelial growth factor ( P15692 ) , matrix metalloproteinase - 9 ( P14780 ) , and docosahexaenoic acid ( DB01708 ) . These molecules have all been implicated in the pathogenesis of AMD . In addition , Q07869 gamma is expressed in Q96AT9 , an essential cell in photoreceptor regeneration and vision maintenance . This review summarizes the interactions between Q07869 , AMD - related molecules , and AMD - related disease processes .",
"Escherichia coli 23S ribosomal RNA truncated at its 5 ' terminus . In a strain of E . coli deficient in Q9NRR4 ( P00519 ) , 23S rRNA has been shown to be present in incompletely processed form with extra nucleotides at both the 5 ' and 3 ' ends ( King et al . , 1984 , Proc . Natl . Acad . Sci . U . S . 81 , 185 - 188 ) . RNA molecules with four different termini at the 5 ' end are observed in vivo , and are all found in polysomes . The shortest of these ( \" P01024 \" ) is four nucleotides shorter than the accepted mature terminus . In growing cells of both wild - type and mutant strains up to 10 % of the 23S rRNA chains contain the 5 ' P01024 terminus . In stationary phase cells , the proportion of P01024 termini remains the same in the wild - type cells ; but P01024 becomes the dominant terminus in the mutant . Species P01024 is also one of the 5 ' termini of 23S rRNA generated in vitro from larger precursors by the action of purified Q9NRR4 . We therefore suggest that some form of Q9NRR4 may still exist in the mutant ; and since no cleavage is detectable at any other Q9NRR4 - specific site , the remaining enzyme would have a particular affinity for the P01024 cleavage site , especially in stationary phase cells . We raise the question whether the P01024 terminus has a special role in cellular metabolism .",
"DB08860 , an P04035 inhibitor , ameliorates endothelial function in chronic smokers . BACKGROUND : Smoking is a major cardiovascular risk factor , leading to endothelial dysfunction . The present study investigated the hypothesis that pitavastatin , an P04035 inhibitor , may improve endothelial function in chronic smokers via its antioxidant properties . METHODS AND RESULTS : The 30 male chronic smokers who exhibited mild hypercholesterolemia at the time of physical check - up were enrolled and randomized to the pitavastatin group ( 2 mg / day , n = 15 ) or the untreated control group ( n = 15 ) . Before and after the 4 - week treatment period , endothelium - dependent flow - mediated dilation ( FMD ) and endothelium - independent dilation by glyceryl trinitrate ( GTD ) were examined , and the FMD / GTD ratio was calculated . The pitavastatin group showed a significant restoration of endothelial function ( percent change in FMD : + 49 . 6 % vs + 1 . 4 % ; percent change in FMD / GTD ratio : + 26 . 6 % vs 4 . 5 % , P < 0 . 05 respectively ) , and a significant reduction in oxidative stress levels ( malondialdehyde - low - density lipoprotein - cholesterol : 16 . 6 % vs + 7 . 5 % ; free radical activity : 1 . 8 % vs + 9 . 7 % , P < 0 . 05 respectively ) compared with the control group . DB08860 had no effect on the number of circulating P28906 (+) CD133 (+) progenitor cells , endothelial progenitor cells , or the P08253 , P14780 and P15692 levels . In vitro oxidative stress monitoring assay revealed that pitavastatin protected endothelial cells against oxidative stress . CONCLUSIONS : DB08860 restores endothelial function , even in chronic smokers , possibly through its antioxidative properties . ( Circ J 2010 ; 74 : 195 - 202 ) .",
"Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene . Hepatic hydroxymethyl glutary coenzyme A P04035 inhibitors ( statins ) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction . Human serum paraoxonase 1 ( P27169 ) is associated with high - density lipoprotein ( HDL ) and inhibits the oxidative modification of low - density lipoprotein ( LDL ) . We investigated the effects of statins on P27169 gene transcription using a reporter gene assay . Promoter activity of the P27169 gene was estimated by measuring luciferase activity of plasmids with a P27169 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney ( P29320 ) 293 cells . DB08860 , simvastatin , and atorvastatin each significantly increased P27169 promoter activity , and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate ( FPP ) , however , not by geranylgeranyl pyrophosphate . Further , P27169 promoter activity was enhanced by farnesyl transferase inhibitor ( FTI ) , but not by geranylgeranyl transferase inhibitor ( GGTI ) . P27169 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin , an inhibitor of Sp1 . Our results suggest that pitavastatin activates transcription of the P27169 gene through the FPP pathway , which may play an important role in the anti atherosclerotic effects of statins .",
"Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis . DB00435 ( NO ) plays a central role in the pathogenesis of bacterial meningitis . However , the role of NO produced by endothelial NO synthase ( P29474 ) in meningitis is still unclear . We investigated the influence of P29474 depletion on the inflammatory host response , intracranial complications , and outcome in experimental pneumococcal meningitis . Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected P29474 - deficient mice than in infected wild type mice . This effect could be attributed to an increased expression of P16109 , macrophage inflammatory protein - 2 , keratinocyte - derived cytokine , and interleukin ( IL ) - 1beta in the brain of infected P29474 - deficient mice . However , no differences in the cerebral expression of intercellular adhesion molecule - 1 , tumor necrosis factor - alpha , and P05231 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice . In addition to enhanced leukocyte infiltration into the P04141 , meningitis - associated intracranial complications including blood - brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected P29474 - deficient mice . The aggravation of intracranial complications was paralleled by a worsening of the disease , as evidenced by a more pronounced hypothermia , an enhanced weight reduction , and an increased death rate . The current data indicate that P29474 deficiency is detrimental in bacterial meningitis . This effect seems to be related to an increased expression of ( certain ) cytokines / chemokines and adhesion molecules ; thus leading to increased meningeal inflammation and , subsequently , to aggravated intracranial complications .",
"Protease - resistant human Q99259 - derived altered peptide ligands decrease P01375 and Q16552 production in peripheral blood cells from patients with type 1 diabetes mellitus . DB00142 decarboxylase 65 ( Q99259 ) and proinsulin are major diabetes - associated autoantigens that drive autoreactive T cells . Altered peptide ligands ( APL ) have been proposed as reagents for the modification of autoimmune reactions . Here , we have prepared Q99259 - derived protease - resistant APL ( prAPL ) by cleavage site - directed modification . The resulting prAPL are resistant to lysosomal and serum proteases , bind with high - affinity to HLA - Q8IUH3 (*) 0401 and have a prolonged half - life in the serum . Q99259 - derived prAPL significantly decreased the secretion of proinflammatory cytokines by a Q99259 - specific human T cell clone . Likewise , the production of Q16552 , P01375 , and secretion of P05231 by peripheral blood lymphocytes from patients with type 1 diabetes mellitus ( T1D ) was reduced , when stimulated with both Q99259 and Q99259 - derived prAPL . Thus , prAPL with high affinity for HLA - Q8IUH3 (*) 0401 mitigate the response of Q99259 - reactive human Th17 cells . The strategy of designing specific immunomodulatory protease - resistant altered peptide ligands provides the basis for novel avenues of therapeutic intervention .",
"DB08860 inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal - regulated kinases 1 / 2 . We recently reported that lysophosphatidylcholine ( lysoPC ) acts on vascular smooth muscle cells ( VSMCs ) to produce a mitogenic response through the activation of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) . In this study , we examined the role of P04035 inhibitors on lysoPC - induced VSMC proliferation . DB08860 , a new P04035 inhibitor , suppressed lysoPC - induced DNA synthesis in primary cultured rat VSMCs . Since lysoPC - induced P27361 / 2 activation contributes to smooth muscle cell proliferation , we explored the effect of pitavastatin on P27361 / 2 activation . DB08860 inhibited lysoPC - induced P27361 / 2 phosphorylation and P27361 / 2 activation . The other P04035 inhibitors , atrovastatin and fluvastatin , also inhibited lysoPC - induced P27361 / 2 phosphorylation . DB08860 also inhibited lysoPC - induced c - fos mRNA expression . To gain insight into the mechanism of the inhibitory effect of pitavastatin on P27361 / 2 activation by lysoPC , we examined the role of the mevalonate pathways . Mevalonate and farnesylpyrophosphate reduced the inhibition of P27361 / 2 phosphorylation by pitavastatin . These studies demonstrate that pitavastatin may inhibit lysoPC - induced VSMC proliferation , at least in part , by inactivating P27361 / 2 , which is linked to mevalonate metabolism .",
"DB08860 , a P04035 inhibitor , blocks vascular smooth muscle cell populated - collagen lattice contraction . Constrictive arterial remodeling plays a major role in lumen narrowing following angioplasty . We investigated the effect of pitavastatin , a 3 - hydroxy - 3 - methylglutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor , on vascular smooth muscle cell ( SMC ) - populated collagen lattice contraction , an in vitro model of vascular contraction . Type I collagen gel contraction by SMCs , which are cultured in collagen gel , was used as a model of vascular remodeling . DB08860 pretreatment inhibited 10 % serum - or platelet - derived growth factor - BB ( PDGF ) - induced SMC - mediated collagen lattice contraction in a concentration - dependent manner . The effect of pitavastatin was prevented by mevalonate or geranylgeranyl pyrophosphate , but not by squalene , a precursor of cholesterol , or farnesyl pyrophosphate . The serum - or PDGF - induced SMC - mediated collagen gel contraction was inhibited by GGTI - 298 , a geranylgeranyltransferase inhibitor , P01024 exoenzyme , an inhibitor of Rho , or Y27634 , a Rho kinase inhibitor , but not by FTI - 277 , a farnesyltransferase inhibitor . Serum or PDGF treatment increased the stress fiber organization in SMCs , which was blocked by the pitavastatin pretreatment . DB08860 had no effect on the serum - and PDGF - induced lamelliopodia extension of SMC . These results may suggest that pitavastatin attenuates SMC - mediated collagen gel contraction probably via an inhibition of geranylgeranylated Rho protein and a disruption of actin cytoskeletal reorganization .",
"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK80___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"___MASK49___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"Lack of the adhesion molecules P16109 and intercellular adhesion molecule - 1 accelerate the development of P11274 / P00519 - induced chronic myeloid leukemia - like myeloproliferative disease in mice . In vitro studies show that P11274 / P00519 - expressing hematopoietic cells exhibit altered adhesion properties . No in vivo studies show whether the altered adhesion properties affect P11274 / P00519 leukemogenesis . Using mice with homozygous inactivation of genes encoding the 2 adhesion molecules P16109 and intercellular adhesion molecule - 1 ( P05362 ) , we show that the mutant mice develop P11274 / P00519 - induced chronic myeloid leukemia ( CML ) - like leukemia at a significantly faster rate than do wild - type ( WT ) mice . Lack of P16109 and P05362 did not have a significant effect on the development of B - cell acute lymphoblastic leukemia ( BALL ) induced by P11274 / P00519 . Using mice deficient for P16109 or P05362 alone , we show that P16109 plays a major role in the acceleration of CML - like leukemia . Lack of P16109 resulted in early release of P11274 / P00519 - expressing myeloid progenitors from bone marrow , appearing to alter the biologic properties of leukemic cells rather than their growth rate by increasing their homing to the lungs , causing fatal lung hemorrhages . These results indicate that adhesion of P11274 / P00519 - expressing myeloid progenitors to marrow stroma through P16109 and P05362 play an inhibitory role in the development of CML - like disease , suggesting that improvement of adhesion between P11274 / P00519 - expressing myeloid progenitor cells and bone marrow stroma may be of therapeutic value for human CML .",
"Rosiglitazone affects nitric oxide synthases and improves renal outcome in a rat model of severe ischemia / reperfusion injury . Background . DB00435 ( NO ) - signal transduction plays an important role in renal ischemia / reperfusion ( I / R ) injury . NO produced by endothelial NO - synthase ( P29474 ) has protective functions whereas NO from inducible NO - synthase ( P35228 ) induces impairment . Rosiglitazone ( RGZ ) , a peroxisome proliferator - activated receptor ( Q07869 ) - γ agonist exerted beneficial effects after renal I / R injury , so we investigated whether this might be causally linked with NOS imbalance . Methods . RGZ ( 5 mg / kg ) was administered i . p . to SD - rats ( f ) subjected to bilateral renal ischemia ( 60 min ) . Following 24 h of reperfusion , inulin - and PAH - clearance as well as PAH - net secretion were determined . Morphological alterations were graded by histopathological scoring . Plasma NO ( x )- production was measured . P29474 and P35228 expression was analyzed by qPCR . Cleaved caspase 3 ( Q9BUP3 ) was determined as an apoptosis indicator and Q92838 as a marker of macrophage infiltration in renal tissue . Results . RGZ improves renal function after renal I / R injury ( PAH -/ inulin - clearance , PAH - net secretion ) and reduces histomorphological injury . Additionally , RGZ reduces NO ( x ) plasma levels , ED - 1 positive cell infiltration and Q9BUP3 expression . P35228 - mRNA is reduced whereas P29474 - mRNA is increased by RGZ . Conclusion . RGZ has protective properties after severe renal I / R injury . Alterations of the NO pathway regarding P29474 and P35228 could be an explanation of the underlying mechanism of RGZ protection in renal I / R injury .",
"Atrial natriuretic peptides inhibit conductive sodium uptake by rabbit inner medullary collecting duct cells . The inner medullary collecting duct ( IMCD ) effects net sodium reabsorption under the control of volume regulatory hormones , including atrial natriuretic peptides ( P01160 ) . These studies examined the mechanisms of sodium transport and its regulation by P01160 in fresh suspensions of IMCD cells . Sodium uptake was inhibited by amiloride but insensitive to furosemide , bu - metanide , and hydrochlorthiazide . These results are consistent with uptake mediated by a sodium channel or Na +/ H + exchange . To determine the role of sodium channels , cells were hyperpolarized by preincubation in high potassium medium followed by dilution into potassium - free medium . Membrane potential measurements using the cyanine dye , Di ( S )- P01024 - 5 verified a striking hyperpolarization of IMCD cells using this protocol . Hyperpolarization increased the apparent initial rate of sodium uptake fourfold . DB00594 and P01160 inhibited potential - stimulated sodium uptake 73 % and 65 % , respectively ; the two agents together were not additive . Addition of 5 mM sodium to hyperpolarized cells resulted in a significant amiloride - sensitive depolarization . Half - maximal inhibition of potential - driven sodium uptake occurred at 3 X 10 (- 7 ) M amiloride , and 5 X 10 (- 11 ) M P01160 . We conclude that sodium enters IMCD cells via a conductive , amiloride - sensitive sodium channel , which is regulated by P01160 . P01160 inhibition of luminal sodium entry in the IMCD appears to contribute to the marked natriuretic effect of this hormone in vivo .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Immune functions of serum amyloid A . Serum amyloid A ( P0DJI8 ) is a highly conserved , acute - phase protein synthesized predominantly by the liver . After secretion into the circulation , it associates with high - density lipoprotein ( HDL ) particles . During acute inflammation , serum P0DJI8 levels may rise up to 1000 - fold , and under these conditions , P0DJI8 displaces apolipoprotein A - I from HDL , thus becoming the major apolipoprotein of circulating HDL3 . P0DJI8 exhibits significant immunological activity by , for example , inducing the synthesis of several cytokines and by being chemotactic for neutrophils and mast cells . It exerts many of its immunological activities by binding and activating cell - surface receptors , including Toll - like receptor ( TLR ) 2 and O00206 , formyl peptide receptor - like 1 ( P25090 ) , class B scavenger receptor P16671 , and the DB00171 receptor Q99572 . P0DJI8 also recently has been shown to activate the inflammasome cascade , which has a key role in immune activation , thus further stressing the unique role of P0DJI8 in immunomodulation . Traditionally , P0DJI8 has been considered to have a key role in the pathogenesis of amyloid A - type amyloidosis , but we now understand that it may also participate in the pathogenesis of chronic inflammatory diseases , such as rheumatoid arthritis and atherosclerosis . Thus , P0DJI8 is one potential target in the treatment of diseases associated with chronic inflammation . The purpose of this review is to shed light on P0DJI8 as an immunologically active protein . We also focus on the recent findings implicating P0DJI8 in the regulation of the inflammasome cascade .",
"P16671 or alphavbeta3 and alphavbeta5 integrins are not essential for MHC class I cross - presentation of cell - associated antigen by CD8 alpha + murine dendritic cells . Cross - presentation of cell - associated Ag is thought to involve receptor - mediated uptake of apoptotic cells by dendritic cells ( DC ) , and studies with human DC strongly implicate the endocytic receptor P16671 and the integrins alpha ( v ) beta ( 3 ) and / or alpha ( v ) beta ( 5 ) in this process . In the mouse , cross - presentation was recently shown to be a function of CD8alpha (+) DC . Here we report that P16671 is expressed on CD8alpha (+) , but not on CD8alpha (-) , DC . To address the role of P16671 in cross - presentation we compared P16671 (-/-) and P16671 (+/+) H - 2 ( b ) DC for their ability to stimulate naive OT - 1 T cells specific for OVA plus H - 2K ( b ) in the presence of OVA - loaded MHC - mismatched splenocytes as a source of cell - associated Ag for cross - presentation . Surprisingly , no difference was seen between P16671 (-/-) and P16671 (+/+) CD8alpha (+) DC in their ability to cross - present cell - associated OVA or to capture OVA - bearing cells . Furthermore , the proliferation of CFSE - labeled OT - 1 cells in response to OVA cross - presentation in vivo was normal in P16671 (-/-) bone marrow chimeras , also arguing against a necessary role for P16671 in cross - presentation by DC or other P25054 . DC doubly deficient for beta ( 3 ) and beta ( 5 ) integrins were similarly unimpaired in their ability to cross - present OVA - bearing cells in vitro . These data demonstrate that in the mouse , receptors other than P16671 or beta ( 3 ) and beta ( 5 ) integrins can support the specialized cross - presenting function of CD8alpha (+) DC .",
"___MASK41___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"[ Effect of pitavastatin on macrophage cholesterol metabolism ] . OBJECTIVES : DB08860 is the first totally synthetic HMG - Co A reductase inhibitor in Japan that significantly reduces LDL cholesterol while raising HDL cholesterol . Clinical trial showed that pitavastatin has potent effects for LDL cholesterol lowering and is expected effectively to prevent atherosclerosis . To clarify the mechanism of reduction of atherosclerosis by pitavastatin , we examined the effect of pitavastatin on foam cell formation of RAW264 . 7 macrophages . METHODS & RESULTS : Macrophages were cultured with pitavastatin for 24 h and exposed to oxidized LDL with pitavastatin for 3 days . DB08860 decreased the cellular cholesteryl ester content in a dose - dependent manner , and this effect was not via inhibition of P04035 because the 3 - 30 nM pitavastatin did not inhibit [ 14C ] cholesterol synthesis from [ 14C ] acetic acid and the effect was not influenced by addition of mevalonic acid . DB08860 increased neutral cholesterol esterase ( NCEase ) activity and did not affect ACAT activity , and decreased the expression of P16671 and O95477 mRNA . The mechanism of the increase of NCEase activity was that pitavastatin directly modified the substrate state , which was cholesterol oleate emulsified with lecithin . CONCLUSION : Clinical blood concentrations of pitavastatin prevent foam cell formation of RAW macrophages by oxidized LDL , and this was not via inhibition of P04035 , and modify substrate condition ."
] |
[
"___MASK13___",
"___MASK17___",
"___MASK33___",
"___MASK3___",
"___MASK41___",
"___MASK49___",
"___MASK74___",
"___MASK80___",
"___MASK88___"
] |
___MASK80___
|
MH_train_334
|
interacts_with DB00277?
|
[
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK53___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti - inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor - kappaB and activator protein - 1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase - 2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti - inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative / nitrative stress so that inflammation becomes resistant to the anti - inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti - inflammatory approaches to manage severe inflammatory diseases .",
"The potential role of PD0332991 ( ___MASK78___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK78___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"___MASK63___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Can we delay the accelerated lung aging in P48444 ? Anti - aging molecules and interventions . Chronic obstructive pulmonary disease ( P48444 ) has been recently characterized as a disease of accelerated lung aging . The prevalence of P48444 is age - dependent suggesting an intimate relationship between the pathogenesis of P48444 and aging . Lung function decline , the hallmark feature of P48444 evolution , is more prominent with increasing age and this decline is greater in smoking individuals . One of the major goals of P48444 pharmacotherapy is the development of drugs that would be able to result in a decrease of the decline in lung function over years . However , till nowadays smoking cessation is the only known intervention which is able to decelerate lung function decline . Several mechanisms of aging , including oxidative stress , inflammation and telomere shortening have been shown to be implicated in P48444 . Furthermore , numerous anti - aging molecules , including sirtuins and Nrf - 2 are reduced , and pathways such as P42345 and genes such as Q9UEF7 have also been shown to be abnormal in the lungs of P48444 patients . The above mechanisms have been associated with the accelerated lung aging in P48444 patients . Numerous therapeutic interventions have been studied in an attempt to reverse accelerated lung aging , and some of them have already been tested in clinical trials . The aim of the present review is to summarize the mechanisms associated with the accelerated lung aging in P48444 and to provide information about the possible therapeutic implications targeting those mechanisms .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK71___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK71___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK34___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Decreased exercise - induced expression of nuclear factor - κB - regulated genes in muscle of patients with P48444 . BACKGROUND : Nuclear factor ( NF ) - κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with P48444 . Therefore , we investigated NF - κB activity and expression of NF - κB - regulated genes in muscle of patients with P48444 and control subjects before and after exercise . METHODS : Quadriceps specimens were obtained before , immediately after , and 2 h after a submaximal cycle ergometry test from seven patients with P48444 ( 50 . 6 ± 5 . 7 SEM Q99581 ( 1 ) of patients with P48444 ) and seven age - matched control subjects . NF - κB DNA - binding activity in muscle and peripheral blood mononuclear cells ( PBMCs ) was determined using electrophoretic mobility shift assay and enzyme - linked immunosorbent assay , respectively . mRNA expression and protein carbonylation were measured by real - time polymerase chain reaction and Western blot , respectively . RESULTS : In control subjects , P05231 , IκBα , tumor necrosis factor - α , IL - 1β , superoxide dismutase , thioredoxin , heme oxygenase 1 , and heat shock protein - 70 were upregulated in muscle after exercise , whereas in patients with P48444 only P05231 mRNA was increased . Exercise - induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with P48444 compared with control subjects . Basal muscle protein oxidation was higher in patients with P48444 than in control subjects , but attenuated in response to exercise . No exercise - induced changes in NF - κB DNA - binding activity in muscle and PBMCs of either group were detected . CONCLUSIONS : Skeletal muscle of patients with P48444 is characterized by an impaired response to exercise of NF - κB - regulated genes encoding inflammatory cytokines , antioxidants , stress proteins , and survival factors .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK33___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"[ ___MASK87___ sodium ( Photofrin - II ) ] . ___MASK87___ sodium ( ___MASK87___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK87___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"[ Transport of mucoid mucus in healthy individuals and patients with chronic obstructive pulmonary disease and bronchiectasis ] . OBJECTIVE : To characterise and compare the in vitro transport properties of respiratory mucoid secretion in individuals with no lung disease and in stable patients with chronic obstructive pulmonary disease ( P48444 ) and bronchiectasis . METHODOLOGY : Samples of mucus were collected , from 21 volunteers presenting no lung disease who had undergone surgery , from 10 patients presenting chronic P48444 , and from 16 patients with bronchiectasis . Mucociliary transport ( Q8IVS2 ) , transport by cough ( DB00919 ) , and contact angle ( P62158 ) were evaluated . RESULTS : Q8IVS2 was found to be greater in healthy individuals ( 1 . 0 ± 0 . 19 ) than in P48444 ( 0 . 91 ± 0 . 17 ) and bronchiectasis ( 0 . 76 ± 0 . 23 ) patients ( p < 0 . 05 ) , whereas DB00919 was greater in P48444 patients ( 16 . 31 ± 7 . 35 cm ) than in patients with bronchiectasis ( 12 . 16 ± 6 . 64 cm ) and healthy individuals ( 10 . 50 ± 25 . 8 cm ) ( p < 0 . 05 ) . No significant differences were observed between the groups regarding P62158 . CONCLUSION : Mucus from healthy individuals allows better mucociliary transport compared to that from patients with lung diseases . However , the mucus from P48444 patients allows a better transport by coughing , demonstrating that these individuals have adapted to a defence mechanism compared to patients with bronchiectasis , who have impairment in their ciliary and cough transport mechanisms .",
"c - Jun N - terminal kinase and Akt signalling pathways regulating tumour necrosis factor - α - induced interleukin - 32 expression in human lung fibroblasts : implications in airway inflammation . Airway inflammatory diseases such as chronic obstructive pulmonary disease ( P48444 ) and asthma are associated with elevated expression of interleukin - 32 ( P24001 ) , a recently described cytokine that appears to play a critical role in inflammation . However , so far , the regulation of pulmonary P24001 production has not been fully established . We examined the expression of P24001 by tumour necrosis factor - α ( P01375 - α ) in primary human lung fibroblasts . Human lung fibroblasts were cultured in the presence or absence of P01375 - α and / or other cytokines / Toll - like receptor ( TLR ) ligands or various signalling molecule inhibitors to analyse the expression of P24001 by quantitative RT - PCR and ELISA . Next , activation of Akt and c - Jun N - terminal kinase ( JNK ) signalling pathways was investigated by Western blot . P24001 mRNA of four spliced isoforms ( α , β , γ and δ ) was up - regulated upon P01375 - α stimulation , which was associated with a significant P24001 protein release from P01375 - α - activated human lung fibroblasts . The combination of interferon - γ and P01375 - α induced enhanced P24001 release in human lung fibroblasts , whereas P05112 , Q16552 , Q8TAD2 and TLR ligands did not alter P24001 release in human lung fibroblasts either alone , or in combination with P01375 - α . Furthermore , the activation of Akt and JNK pathways regulated P01375 - α - induced P24001 expression in human lung fibroblasts , and inhibition of the Akt and JNK pathways was able to suppress the increased release of P24001 to nearly the basal level . These data suggest that P01375 - α may be involved in airway inflammation via the induction of P24001 by activating Akt and JNK signalling pathways . Therefore , the P01375 - α / P24001 axis may be a potential therapeutic target for airway inflammatory diseases .",
"Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post - translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase - 2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide - 3 - kinase - delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant - activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid - resistant inflammation .",
"P00747 activator inhibitor - 1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells . P00747 activator inhibitor - 1 ( P05121 ) plays a role in regulating levels of some cytokines and cell migration in addition to its classic role in inhibiting fibrinolysis . P05121 levels in induced - sputum of chronic obstructive pulmonary disease ( P48444 ) patients were elevated significantly and correlated negatively with pulmonary function . To study the role of P05121 in inflammatory process in P48444 , the authors transfected alveolar epithelial cells ( AECs ) with siRNA - targeted P05121 and stimulated the cells by cigarette smoke extraction ( CSE ) or lipopolysaccharides ( LPS ) . The expression of inflammatory factors , interleukin - 8 ( P10145 ) and leukotriene B4 ( LTB4 ) , and the monocyte migration were detected . The exposure to CSE or LPS induced the expression of P05121 , P10145 , and LTB4 in AECs and monocyte migration to AECs . However , they were attenuated after transfection with siRNA - targeted P05121 . In conclusion , P05121 stimulates inflammation induced by CSE or LPS in AECs through up - regulation of inflammatory factors and promoting inflammatory cell migration . P05121 may play a proinflammatory role in the pathogenesis of P48444 .",
"Statins control oxidized LDL - mediated histone modifications and gene expression in cultured human endothelial cells . OBJECTIVE : Activation of the endothelium by oxidized low - density lipoprotein ( oxLDL ) has been implicated in the development of atherosclerosis . Histone modifications impact on the transcriptional activity state of genes . We tested the hypothesis that oxLDL - induced inflammatory gene expression is regulated by histone modifications and experienced the effect of statins on these alterations . METHODS AND RESULTS : OxLDL - related interleukin - 8 ( P10145 ) and monocyte - chemoattractant protein - 1 ( P13500 ) secretion in endothelial cells was reduced by statins but enhanced by histone deacetylase inhibitors . OxLDL induced lectin - like oxidized P01130 - 1 ( P78380 ) and extracellular regulated kinases ( P27361 / 2 ) - dependent acetylation of histone H3 and H4 as well as phosphorylation of histone H3 , both globally and on the promoters of il8 and mcp1 . Pretreatment of oxLDL - exposed cells with statins reduced the above mentioned histone modification , as well as recruitment of CREB binding protein ( CBP ) 300 , NF - kappaB , and of RNA polymerase II but prevented loss of binding of histone deacetylase ( HDAC ) - 1 and - 2 at the il8 and mcp1 gene promoters . OxLDL reduced Q13547 and 2 expression , and statins partly restored global HDAC - activity . Statin - related effects were reverted with mevalonate . In situ experiments indicated decreased expression of Q92769 in endothelial cells in atherosclerotic plaques of human coronary arteries . CONCLUSIONS : Histone modifications seem to play an important role in atherosclerosis .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Histone deacetylase - 2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase - 2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor - kappaB - activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant - activated phosphoinositide - 3 - kinase - delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid - resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK29___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Targeted inactivation of Q92769 restores p16INK4a activity and exerts antitumor effects on human gastric cancer . Aberrant regulation of histone deacetylase 2 ( Q92769 ) was reported for gastric cancers . However , responsive cancer genes in disease onset and progression are less understood . Q92769 expression was studied by quantitative RT - PCR and Western blotting . The functional consequences of Q92769 knockdown on cell - cycle regulation , programmed cell death , and gene target identification was investigated by flow cytometry , Western blotting , electron microscopy , anchorage - independent colony formation , and cell migration assay and by whole - genome microarray . Therapeutic efficacy of Q92769 knockdown was determined in nude mice with small hairpin expressing human gastric cancer cells . Epigenetic regulation of p16 ( INK4a ) was studied by methylation - specific PCR and chromatin - IP to evidence Q92769 or acetylated - histone - H4 binding at gene specific promoter sequences . Q92769 gene and protein expression was significantly upregulated in different histopathologic grades of human gastric cancers and cancer cell lines . Q92769 inactivation significantly reduced cell motility , cell invasion , clonal expansion , and tumor growth . Q92769 knockdown - induced G ( 1 )- S cell cycle arrest and restored activity of p16 ( INK4a ) and the proapoptotic factors . This treatment caused PARP cleavage and hypophosphorylation of the Rb - protein , repressed cyclinD1 , P11802 , and Bcl - 2 expression and induced autophagic phenotype , that is , LC3B - II conversion . Some gastric tumors and cancer cells displayed p16 ( INK4a ) promoter hypermethylation but treatment with 5 - aza - deoxycitidine restored activity . With others the methylation status was unchanged . Here , chromatin - IP evidenced Q92769 binding . Nonetheless , expression of p16 ( INK4a ) was restored by Q92769 knockdown with notable histone - H4 - acetylation , as determined by chromatin - IP . Thus , p16 ( INK4a ) is regulated by Q92769 . Q92769 is a bona fide target for novel molecular therapies in gastric cancers .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK3___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK3___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK3___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK3___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK3___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK3___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK3___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK3___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK3___ in the treatment of changes in hypervigilance following severe stress ."
] |
[
"___MASK29___",
"___MASK33___",
"___MASK34___",
"___MASK3___",
"___MASK53___",
"___MASK63___",
"___MASK71___",
"___MASK78___",
"___MASK87___"
] |
___MASK78___
|
MH_train_335
|
interacts_with DB00887?
|
[
"Enhanced IgE allergic response to Aspergillus fumigatus in P13569 -/- mice . To gain insight into aberrant cytokine regulation in cystic fibrosis ( CF ) , we compared the phenotypic manifestations of allergen challenge in gut - corrected P13569 - deficient mice with background - matched C57Bl6 ( B6 ) mice . Aspergillus fumigatus ( Af ) antigen was used to mimic allergic bronchopulmonary aspergillosis , a peculiar hyper - IgE syndrome with a high prevalence in CF patients . P13569 -/- , C57BL / 6 and FVB / NJ mice were sensitized with Af antigen by serial intraperitoneal injections . Control mice were mock sensitized with PBS . Challenges were performed by inhalation of Af antigen aerosol . After Af antigen challenge , histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains . However , total serum IgE levels were markedly elevated in CF mice . Sensitized CF mice showed a five - fold greater IgE response to sensitization as compared with B6 - and FVB - sensitized controls . Additional littermate controls to fully normalize for B6 - FVB admixture in the strain background confirmed the role of P13569 mutation in the hyper - IgE syndrome . Cytokine mRNA levels of P05113 and GM - P04141 in the bronchoalveolar lavage ( BAL ) fluid , and BAL cell differentials indicated that P13569 mutation caused a shift from an P05113 - predominant to an P05112 - predominant cytokine profile . This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease .",
"DB00887 blocks P13569 GCl in the native sweat duct . DB00887 is well known for its ability to inhibit the nonconductive Na +- K +- 2Cl - cotransporter . We were surprised in preliminary studies to find that bumetanide in the contraluminal bath also inhibited NaCl absorption in the human sweat duct , which is apparently poor in cotransporter activity . Inhibition was accompanied by a marked decrease in the transepithelial electrical conductance . Because the cystic fibrosis transmembrane conductance regulator ( P13569 ) Cl - channel is richly expressed in the sweat duct , we asked whether bumetanide acts by blocking this anion channel . We found that bumetanide 1 ) significantly increased whole cell input impedance , 2 ) hyperpolarized transepithelial and basolateral membrane potentials , 3 ) depolarized apical membrane potential , 4 ) increased the ratio of apical - to - basolateral membrane resistance , and 5 ) decreased transepithelial Cl - conductance ( GCl ) . These results indicate that bumetanide inhibits P13569 GCl in both cell membranes of this epithelium . We excluded bumetanide interference with the protein kinase A phosphorylation activation process by \" irreversibly \" phosphorylating P13569 [ by using adenosine 5 '- O -( 3 - thiotriphosphate ) in the presence of a phosphatase inhibition cocktail ] before bumetanide application . We then activated P13569 GCl by adding 5 mM DB00171 . DB00887 in the cytoplasmic bath ( 10 (- 3 ) M ) inhibited approximately 71 % of this DB00171 - activated P13569 GCl , indicating possible direct inhibition of P13569 GCl . We conclude that bumetanide inhibits P13569 GCl in apical and basolateral membranes independent of phosphorylation . The results also suggest that > 10 (- 5 ) M bumetanide can not be used to specifically block the Na +- K +- 2Cl - cotransporter .",
"Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells . P13569 ( P13569 ) is a P13569 in epithelial cells ; recently , we identified it in mast cells . Previous work that we confirmed showed that interferon gamma ( IFNgamma ) down - regulated P13569 expression in epithelial cells ( T84 ) , but by contrast , we found that IFNgamma up - regulated P13569 mRNA and protein expression in rat and human mast cells . IFNgamma up - regulation of P13569 in mast cells was inhibited by p38 and extracellular signal - regulated kinase ( P29323 ) kinase inhibitors but not a Janus tyrosine kinase ( JAK ) 2 inhibitor , whereas in T84 cells IFNgamma - mediated down - regulation of P13569 was O60674 - dependent and P29323 - and p38 - independent . Furthermore , IFNgamma down - regulation of P13569 in T84 epithelial cells was P42224 - dependent , but up - regulation of P13569 in mast cells was P42224 - independent . Thus , differential regulatory pathways of P13569 expression in mast cells and epithelial cells exist that depend upon either p38 / P29323 or JAK / P35610 pathways , respectively . Surprisingly , IFNgamma treatment of mast cells inhibited Cl (-) efflux , in contrast to up - regulation of P13569 / mRNA and protein expression . However , down - regulation of Cl (-) flux correlated with IFNgamma - mediated inhibition of mediator secretion . This and other work suggests that the effect of IFNgamma on P13569 expression in mast cells is important for their function .",
"Parthenolide inhibits O15111 , NF - kappaB activation , and inflammatory response in cystic fibrosis cells and mice . Cystic fibrosis ( CF ) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF - kappaB . Parthenolide is a sesquiterpene lactone derived from the plant feverfew , which has been used in folk medicine for anti - inflammatory activity . Several studies suggest that this compound inhibits the NF - kappaB pathway , but the exact site is controversial . We hypothesized that parthenolide might ameliorate the excessive inflammatory response in CF models by inhibiting activation of NF - kappaB . This was tested in vitro , using two pairs of cell lines with defective versus normal CF transmembrane conductance regulator ( P13569 ) ( antisense / sense transfected 16 P02100 and IB - 3 / S9 ) , and in vivo , using P13569 - knockout ( KO ) mice . All cell lines were pretreated with parthenolide and then stimulated with IL - 1beta and / or P01375 . Parthenolide significantly inhibited P10145 secretion induced by these cytokines and prevented NF - kappaB activation , P25963 degradation , and IkappaB Kinase complex activity . P13569 - KO and wild - type mice were pretreated with parthenolide or vehicle alone then challenged intratracheally with LPS . Bronchoalveolar lavage was performed 3 , 6 , and 8 h later . Parthenolide pretreatment inhibited PMN influx as well as cytokine and chemokine production . This was also associated with inhibition of P25963 degradation and NF - kappaB activation . We thus conclude that parthenolide inhibits O15111 , resulting in stabilization of cytoplasmic P25963 , which in turn leads to inhibition of NF - kappaB translocation and attenuation of subsequent inflammatory responses . O15111 may be a good target , and parthenolide and / or feverfew might be promising treatments for the excessive inflammation in CF .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK6___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK76___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Effect of allergy and inflammation on eicosanoid gene expression in P13569 deficiency . BACKGROUND : Allergic bronchopulmonary aspergillosis ( ABPA ) is a complicating factor in cystic fibrosis ( CF ) , affecting 2 - 15 % of patients . We hypothesized that sensitization / challenge of P13569 (-/-) mice with an Aspergillus fumigatus ( Af ) extract will affect eicosanoid pathway gene expression , impacting ABPA and CF . METHODS : FABP - hCFTR (+/-)- P13569 (-/-) mice were sensitized / challenged with an Af extract and gene expression of lung mRNA was evaluated for > 40 genes , with correlative data in human CF ( IB3 . 1 ) and P13569 - corrected ( S9 ) bronchoepithelial cell lines . RESULTS : Pla2g4c , Pla2g2c , Pla2g2d and Pla2g5 were induced in response to Af in P13569 (-/-) mice . Interestingly , Q9UNK4 was induced by LPS , P60568 , P05231 , P35225 , and Af only in P13569 - deficient human IB3 . 1 cells . Prostanoid gene expression was relatively constant , however , several P16050 genes were induced in response to Af . Numerous cytokines also caused differential expression of P16050 only in IB3 . 1 cells . CONCLUSIONS : The distinct regulation of Q9UP65 , Q9UNK4 and P16050 genes in Aspergillus sensitization and / or cystic fibrosis could provide new insights into diagnosis and treatment of ABPA and CF .",
"Microelectrode measurements of the effects of basolateral adenosine in polarized human intestinal epithelial cells in culture . Activation of the basolateral receptor for adenosine in HT - 29cl . 19A cells , by 100 microM adenosine , increased the equivalent short - circuit current ( DeltaIsc = 24 +/- 2 microA / cm2 ) , depolarized the intracellular potential ( DeltaVa = 26 +/- 2 mV ) and decreased the fractional apical membrane resistance ( DeltafRa =- 0 . 48 ) . The changes in all parameters reached their peak values simultaneously . This suggests that the primary action of the adenosine - activated pathway is on only one membrane . DB00887 inhibited the transepithelial response and repolarized the cell potential . After preincubation with 100 microM forskolin , application of 300 microM adenosine caused a significant further change in Va , Isc , the transepithelial potential ( Vt ) and fRa . Together with the results from ion - replacement studies , the observations indicate that adenosine activates channels other than the cystic fibrosis transmembrane conductance regulator ( P13569 ) . The rank order of potencies of adenosine and adenosine analogues implies that the receptor is of the A2 subtype . Preincubation with 4 - bromophenacyl bromide ( 4 - BPB ) inhibited the effect of an adenosine analogue by 50 % , indicating that activation of phospholipase A2 may be involved in the adenosine - induced response .",
"P13569 mediated chloride secretion in the avian renal proximal tubule . In primary cell cultures of the avian ( Gallus gallus ) renal proximal tubule parathyroid hormone and DB02527 activation generate a Cl (-)- dependent short circuit current ( I ( SC ) ) response , consistent with net transepithelial Cl (-) secretion . In this study we investigated the expression and physiological function of the Na - K - 2Cl ( NKCC ) transporter and P13569 chloride channel , both associated with Cl (-) secretion in a variety of tissues , in these proximal tubule cells . Using both RT - PCR and immunoblotting approaches , we showed that NKCC and P13569 are expressed , both in proximal tubule primary cultures and in a proximal tubule fraction of non - cultured ( native tissue ) fragments . We also used electrophysiological methods to assess the functional contribution of NKCC and P13569 to forskolin - activated I ( SC ) responses in filter grown cultured monolayers . DB00887 ( 10 μM ) , a specific blocker of NKCC , inhibited forskolin activated I ( SC ) by about 40 % , suggesting that basolateral uptake of Cl (-) is partially mediated by NKCC transport . In monolayers permeabilized on the basolateral side with nystatin , forskolin activated an apical Cl (-) conductance , manifested as bidirectional diffusion currents in the presence of oppositely directed Cl (-) gradients . Under these conditions the apical conductance appeared to show some bias towards apical - to - basolateral Cl (-) current . Two selective P13569 blockers , P13569 Inhibitor 172 and GlyH - 101 ( both at 20 μM ) inhibited the forskolin activated diffusion currents by 38 - 68 % , with GlyH - 101 having a greater effect . These data support the conclusion that avian renal proximal tubules utilize an apical P13569 Cl (-) channel to mediate DB02527 - activated Cl (-) secretion .",
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK42___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK42___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .",
"___MASK49___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .",
"DCEBIO stimulates Cl - secretion in the mouse jejunum . We investigated the effects of 5 , 6 - dichloro - 1 - ethyl - 1 , 3 - dihydro - 2H - benzimidazol - 2 - one ( DCEBIO ) on the Cl - secretory response of the mouse jejunum using the Ussing short - circuit current ( Isc ) technique . DCEBIO stimulated a concentration - dependent , sustained increase in Isc ( EC50 41 +/- 1 microM ) . Pretreating tissues with 0 . 25 microM forskolin reduced the concentration - dependent increase in Isc by DCEBIO and increased the EC50 ( 53 +/- 5 microM ) . DB00887 blocked ( 82 +/- 5 % ) the DCEBIO - stimulated Isc consistent with Cl - secretion . DCEBIO was a more potent stimulator of Cl - secretion than its parent molecule , 1 - ethyl - 2 - benzimidazolinone . DB01016 or P16860 reduced the DCEBIO - stimulated Isc by > 80 % indicating the participation of P13569 in the DCEBIO - stimulated Isc response . Clotrimazole reduced DCEBIO - stimulated Isc by 67 +/- 15 % , suggesting the participation of the intermediate conductance Ca2 +- activated K + channel ( IKCa ) in the DCEBIO - activated Isc response . In the presence of maximum forskolin ( 10 microM ) , the DCEBIO response was reduced and biphasic , reaching a peak response of the change in Isc of 43 +/- 5 microA / cm2 and then falling to a steady - state response of 17 +/- 10 microA / cm2 compared with DCEBIO control tissues ( 61 +/- 6 microA / cm2 ) . The forskolin - stimulated Isc in the presence of DCEBIO was reduced compared with forskolin control tissues . Similar results were observed with DCEBIO and 8 - BrcAMP where adenylate cyclase was bypassed . H89 , a PKA inhibitor , reduced the DCEBIO - activated Isc , providing evidence that DCEBIO increased Cl - secretion via a DB02527 / PKA - dependent manner . These data suggest that DCEBIO stimulates Cl - secretion of the mouse jejunum and that DCEBIO targets components of the Cl - secretory mechanism .",
"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK83___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK83___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK83___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .",
"___MASK60___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK60___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK60___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK60___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"___MASK96___ and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . ___MASK96___ and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : ___MASK96___ and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"Rescuing Trafficking Mutants of the DB00171 - binding Cassette Protein , P78363 , with Small Molecule Correctors as a Treatment for Stargardt Eye Disease . Stargardt disease is the most common form of early onset macular degeneration . Mutations in P78363 , a member of the DB00171 - binding cassette ( DB01048 ) family , are associated with Stargardt disease . Here , we have examined two disease - causing mutations in the NBD1 region of P78363 , R1108C , and R1129C , which occur within regions of high similarity with P13569 , another ABC transporter gene , which is associated with cystic fibrosis . We show that R1108C and R1129C are both temperature - sensitive processing mutants that engage the cellular quality control mechanism and show a strong interaction with the chaperone Hsp 27 . Both mutant proteins also interact with HDCAC6 and are degraded in the aggresome . We also demonstrate that novel corrector compounds that are being tested as treatment for cystic fibrosis , such as VX - 809 , can rescue the processing of the P78363 mutants , particularly their expression at the cell surface , and can reduce their binding to Q9UBN7 . Thus , our data suggest that VX - 809 can potentially be developed as a new therapy for Stargardt disease , for which there is currently no treatment .",
"Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens . OBJECTIVE : To investigate whether genetic modifiers of cystic fibrosis ( CF ) lung disease also predispose to congenital bilateral absence of the vas deferens ( CBAVD ) in association with cystic fibrosis transmembrane conductance regulator ( P13569 ) mutations . We tested the hypothesis that polymorphisms of transforming growth factor ( TGF ) - β1 ( rs 1982073 , rs 1800471 ) and endothelin receptor type A ( P25101 ) ( rs 5335 , rs 1801708 ) are associated with the CBAVD phenotype . DESIGN : Genotyping of subjects with clinical CBAVD . SETTING : Outpatient and hospital - based clinical evaluation . PATIENT ( S ) : DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe . This is one of the largest genetic studies of this disease to date . INTERVENTION ( S ) : None . MAIN OUTCOME MEASURE ( S ) : Genotype analysis . RESULT ( S ) : For single nucleotide polymorphism ( SNP ) rs 5335 , we found increased frequency of the CC genotype among subjects with CBAVD . The difference was significant among Turkish patients versus controls ( 45 . 2 % vs . 19 . 4 % ) , and between all cases versus controls ( 36 % vs . 15 . 7 % ) . No associations between CBAVD penetrance and polymorphisms rs 1982073 , rs 1800471 , or rs 1801708 were observed . CONCLUSION ( S ) : Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance . To our knowledge , this is the first study to investigate genetic modifiers relevant to CBAVD .",
"Prolonged interferon - gamma exposure decreases ion transport , P55011 , and Na +- K +- ATPase expression in human intestinal xenografts in vivo . P01579 is elevated in intestinal inflammation and alters barrier and transport functions in human colonic epithelial cell lines , but its effects on normal human small intestinal epithelium in vivo are poorly defined . We investigated effects of prolonged P01579 exposure on ion transport and expression of transporters by using human fetal small intestinal xenografts . Xenograft - bearing mice were injected with P01579 , and 24 h later xenografts were harvested and mounted in Ussing chambers . Baseline potential difference ( PD ) was not affected by P01579 treatment . However , conductance was enhanced and agonist - stimulated ion transport was decreased . P01579 also decreased expression of the Na +- K +- 2Cl - cotransporter and the alpha - subunit of Na +- K +- ATPase compared with controls , whereas levels of the calcium - activated Cl - channel and P13569 were unaltered . Thus prolonged exposure to P01579 leads to decreased ion secretion due , in part , to decreased ion transporter levels . These findings demonstrate the implications of elevated P01579 levels in human small intestine and validate the human intestinal xenograft as a model to study chronic effects of physiologically relevant stimuli .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK29___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK29___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"P16455 hypermethylation and MDR system in glioblastoma cancer stem cells . BACKGROUND : Cancer stem cells ( CSCs ) in gliomas are associated with resistance to radio - and chemotherapy , based on O ( 6 )- methylguanine - DNA methyltransferase ( P16455 ) hypermethylation and the Multidrug resistance ( MDR ) system activation . MATERIALS AND METHODS : Samples from 21 glioblastomas ( GBMs ) were put in culture with growth factors or serum in order to obtain neurospheres or adherent cells . Both were genetically and immunohistochemically characterized for DB00171 - binding cassette , sub - family B ( MDR / TAP ) , member 1 ( P08183 ) , DB00171 - binding cassette , sub - family C ( P13569 / MRP ) , member 1 ( P33527 ) and P16455 expression together with primary tumors . RESULTS : P08183 expression was positive in endothelial cells of primary tumors . P33527 expression was variably positive in tumor cells and positive in neurospheres , and less expressed in adherent cells . P16455 was methylated and unmethylated in primary tumors and in neurospheres , respectively , and unmethylated in adherent cells . CONCLUSION : Methylation is an epigenetic event affecting progenitors before the separation of the two glia lineages and maximally the future initiating cells . P08183 expression is limited to endothelial cells , whereas P33527 expression could mark a minority of tumor cells approaching a stem - like status .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK16___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"DB01645 stimulates electrogenic Cl (-) secretion in mouse jejunum . We used the short - circuit current ( I ( sc ) ) technique to investigate the effects of the isoflavone genistein on the electrogenic Cl (-) secretion of the mouse jejunum . DB01645 stimulated a sustained increase in I ( sc ) that was dose dependent . DB00887 inhibited 76 +/- 5 % of the genistein - stimulated I ( sc ) consistent with activation of Cl (-) secretion . DB01645 failed to stimulate I ( sc ) following maximal activation of the DB02527 pathway by forskolin . In addition , forskolin had a reduced effect on I ( sc ) of the mouse jejunum in the presence of genistein . DB01016 , a blocker of P13569 , eliminated the genistein - stimulated increase of I ( sc ) and reduced the forskolin - activated I ( sc ) . Clotrimazole , a Ca ( 2 +)- activated K (+) channel blocker , failed to reduce the genistein - stimulated I ( sc ) . Vanadate , a blocker of tyrosine - dependent phosphatases , reduced the genistein - activated I ( sc ) . Tyrphostin A23 , a tyrosine kinase inhibitor , reduced basal I ( sc ) , after which genistein failed to stimulate I ( sc ) . These data suggest that genistein activated a sustained Cl (-) secretory response of the mouse jejunum and that the effect of genistein was via a tyrosine - dependent phosphorylation pathway .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK96___ ( ___MASK96___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK96___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK96___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Methoxsalen stimulates electrogenic Cl - secretion in the mouse jejunum . We used the short - circuit current ( I ( sc ) ) and patch - clamp techniques to investigate the effects of methoxsalen ( MTX ) on the electrogenic Cl - secretion of the mouse jejunum . MTX stimulated a sustained increase in Isc that was dose dependent . DB00887 inhibited MTX - stimulated Isc in a dose - dependent manner consistent with activation of Cl - secretion . MTX failed to stimulate I ( sc ) following maximal activation of the DB02527 pathway by forskolin , but did increase Isc after a submaximal dose of forskolin . DB01016 , a blocker of the cystic fibrosis transmembrane conductance regulator ( P13569 ) , reduced the MTX - stimulated increase of Isc by 59 +/- 6 % . The DB02527 - dependent K + channel blocker 293B did not alter the MTX - activated I ( sc ) ; however , clotrimazole , an intermediate Ca2 (+)- activated K + channel ( IK ( Ca ) ) blocker , reduced the MTX - stimulated I ( sc ) . MTX did not alter Na (+)- glucose cotransport across the mouse jejunum . In cell - attached membrane patches , MTX increased the open probability of the basolateral IK ( Ca ) channel of isolated crypts . These data suggest that the P13569 and IK ( Ca ) channels participate in the MTX - activated , sustained Cl - secretory response of the mouse jejunum .",
"Role of chloride transport proteins in the vasorelaxant action of nitroprusside in isolated rat aorta . Chloride ions play a key role in smooth muscle contraction , but little is known concerning their role in smooth muscle relaxation . Here we investigated the effect of chloride transport inhibitors on the vasorelaxant responses to nitroprusside in isolated and endothelium - denuded rat aorta , precontracted with phenylephrine 1 muM . Incubation of aortic rings in NO ( 3 )(-) media strongly potentiated the vasorelaxant responses to nitroprusside . DB00887 , DIDS ( 4 , 4 '- diisothiocyanatostilbene - 2 , 2 '- disulfonic acid ) and acetazolamide strongly potentiated the vasorelaxant responses to nitroprusside ( by 70 - 100 % ) . EC ( 50 ) were 2 . 3 +/- 0 . 5 microM for bumetanide , 26 +/- 15 microM for DIDS and 510 +/- 118 microM for acetazolamide ( n = 6 for condition ) . Niflumic acid , a selective inhibitor of ClCa ( calcium - activated chloride channels ) , potentiated nitroprusside relaxation to a similar extent as chloride transport inhibitors , in a non - additive manner . Zinc and nickel ions , both modestly potentiated nitroprusside vasorelaxation ( by 20 - 30 % ) . Cobaltum had negligible effect on nitroprusside vasorelaxation . P15085 ( p - chlorophenoxy - acetic acid ) , an inhibitor of volume - sensitive chloride channels ( ClC ) , slightly potentiated nitroprusside vasorelaxation ( by 15 % ) , and the cystic fibrosis transmembrane conductance regulator ( P13569 ) chloride channel inhibitors P13569 ( inh ) 172 ( 5 -[( 4 - Carboxyphenyl ) methylene ]- 2 - thioxo - 3 - [ ( 3 - trifluoromethyl ) phenyl - 4 - thiazolidinone ) , DPC ( diphenylamine - 2 , 2 '- dicarboxylic acid ) and glibenclamide were without significant effect . In conclusion , inhibition of chloride transport proteins strongly potentiates the vasorelaxant responses to nitroprusside in isolated rat aorta . This effect seems mediated by chloride depletion and inhibition of a chloride channel activated by both , calcium and cyclic GMP ( cGMP ) .",
"DB02527 inhibition of murine intestinal Na / H exchange requires P13569 - mediated cell shrinkage of villus epithelium . BACKGROUND AND AIMS : Unlike the intestine of normal subjects , small - intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein - null ( P13569 (-) ) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption . Because P13569 - mediated anion secretion has been associated with changes in crypt cell volume , we hypothesized that P13569 - mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na (+)/ H (+) exchanger ( primarily P48764 ) activity in the proximal small intestine . METHODS : Transepithelial ( 22 ) Na flux across the jejuna of P13569 (+) , P13569 (-) , the basolateral membrane Na (+)/ K (+)/ 2Cl (-) co - transporter protein P55011 (+) , and P55011 (-) mice were correlated with changes in epithelial cell volume of the midvillus region . RESULTS : Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na (+)/ H (+) exchanger - mediated Na (+) absorption ( J ( ms )( NHE ) ) in P13569 (+) jejunum but had no effect on J ( ms )( NHE ) across P13569 (-) jejunum . Cell volume indices indicated an approximately 30 % volume reduction of villus epithelial cells in P13569 (+) jejunum but no changes in P13569 (-) epithelium after intracellular cyclic adenosine monophosphate stimulation . In contrast , cell shrinkage induced by hypertonic medium inhibited J ( ms )( NHE ) in both P13569 (+) and P13569 (-) mice . DB00887 treatment to inhibit Cl (-) secretion by blockade of the Na (+)/ K (+)/ 2Cl (-) co - transporter , P55011 , of stimulated P13569 (+) jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40 % of J ( ms )( NHE ) . Likewise , J ( ms )( NHE ) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in P55011 (-) jejuna . CONCLUSIONS : These findings show a previously unrecognized role of functional P13569 expressed in villus epithelium : regulation of P48764 - mediated Na (+) absorption by alteration of epithelial cell volume .",
"Telomere shortening is associated with reduced duodenal HCOFormula secretory but normal gastric acid secretory capacity in aging mice . The incidence of duodenal ulcer , especially Helicobacter pylori - negative duodenal ulcer , strongly increases with age . In humans , telomere length shortening is considered to be one critical factor in cellular senescence and organ survival . In this study , we compared basal and stimulated gastric acid and duodenal HCO ( 3 )(-) secretory rates in aged late - generation ( G ( 3 ) ) telomerase - deficient ( mTERC (-/-) ) mice , which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division . We found that basal and forskolin - stimulated HCO ( 3 )(-) secretion and short - circuit current ( I ( sc ) ) in isolated duodenal mucosa of G ( 3 ) mTERC (-/-) mice were markedly reduced compared with age - matched wild - type mice . In contrast , basal and forskolin - stimulated acid secretory rates in isolated G ( 3 ) mTERC (-/-) gastric mucosa were not significantly altered . Correspondingly , duodenal mucosa of G ( 3 ) mTERC (-/-) mice showed slimming and shortening of villi , whereas gastric mucosal histology was not significantly altered . However , the ratios of cystic fibrosis transmembrane conductance regulator ( P13569 ) and solute - linked carrier 26 gene family ( Slc26a6 ) mRNA expression in relation to cytokeratin - 18 were not altered in duodenal mucosa . The further knockout of P38936 , which is a downstream effector of telomere shortening - induced senescence , rescued villus atrophy of duodenal mucosa , and basal and forskolin - stimulated duodenal HCO ( 3 )(-) secretion and I ( sc ) in mTERC (-/-) P38936 (-/-) double - knockout mice were not different from wild - type controls . In conclusion , genetic ablation of telomerase resulted in P38936 - dependent duodenal mucosal atrophy and reduced duodenal HCO ( 3 )(-) secretory capacity , whereas gastric morphology and acid secretory function were preserved . This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation ."
] |
[
"___MASK16___",
"___MASK29___",
"___MASK42___",
"___MASK49___",
"___MASK60___",
"___MASK6___",
"___MASK76___",
"___MASK83___",
"___MASK96___"
] |
___MASK49___
|
MH_train_336
|
interacts_with DB00428?
|
[
"___MASK83___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK83___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Involvement of phosphatidylinositol 3 - kinase - mediated up - regulation of I kappa B alpha in anti - inflammatory effect of gemfibrozil in microglia . The present study underlines the importance of PI3K in mediating the anti - inflammatory effect of gemfibrozil , a prescribed lipid - lowering drug for humans , in mouse microglia . Gemfibrozil inhibited LPS - induced expression of inducible NO synthase ( P35228 ) and proinflammatory cytokines in mouse BV - 2 microglial cells and primary microglia . By overexpressing wild - type and dominant - negative constructs of peroxisome proliferator - activated receptor - alpha ( Q07869 ) in microglial cells and isolating primary microglia from Q07869 -/- mice , we have demonstrated that gemfibrozil inhibits the activation of microglia independent of Q07869 . Interestingly , gemfibrozil induced the activation of p85alpha - associated PI3K ( P42338 but not P42336 ) and inhibition of that PI3K by either chemical inhibitors or dominant - negative mutants abrogated the inhibitory effect of gemfibrozil . Conversely , overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS - induced expression of proinflammatory molecules . Similarly , gemfibrozil also inhibited fibrillar amyloid beta ( Abeta ) - , prion peptide ( P04156 ) - , dsRNA ( poly IC ) - , HIV - 1 Tat - , and 1 - methyl - 4 - phenylpyridinium ( P25189 + ) - , but not P01579 - , induced microglial expression of P35228 . Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on Abeta - , P04156 - , poly IC - , Tat - , and P25189 +- induced microglial expression of P35228 . Involvement of NF - kappaB activation in LPS - , Abeta - , P04156 - , poly IC - , Tat - , and P25189 +- , but not P01579 - , induced microglial expression of P35228 and stimulation of P25963 expression and inhibition of NF - kappaB activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF - kappaB and the expression of proinflammatory molecules in microglia via PI3K - mediated up - regulation of P25963 .",
"Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .",
"Atheroprotective effect of oleoylethanolamide ( OEA ) targeting oxidized LDL . Dietary fat - derived lipid oleoylethanolamide ( OEA ) has shown to modulate lipid metabolism through a peroxisome proliferator - activated receptor - alpha ( Q07869 - α ) - mediated mechanism . In our study , we further demonstrated that OEA , as an atheroprotective agent , modulated the atherosclerotic plaques development . In vitro studies showed that OEA antagonized oxidized LDL ( ox - LDL ) - induced vascular endothelial cell proliferation and vascular smooth muscle cell migration , and suppressed lipopolysaccharide ( LPS ) - induced LDL modification and inflammation . In vivo studies , atherosclerosis animals were established using balloon - aortic denudation ( Q92934 ) rats and ApoE (-/-) mice fed with high - caloric diet ( HCD ) for 17 or 14 weeks respectively , and atherosclerotic plaques were evaluated by oil red staining . The administration of OEA ( 5 mg / kg / day , intraperitoneal injection , i . p . ) prevented or attenuated the formation of atherosclerotic plaques in HCD - Q92934 rats or HCD - ApoE (-/-) mice . Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of Q07869 - α and downregulated the expression of M - CFS , an atherosclerotic marker , and genes involved in oxidation and inflammation , including P35228 , P35354 , P01375 - α and P05231 . Collectively , our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti - atherosclerosis drug .",
"P01308 resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients . OBJECTIVE : Metabolic syndrome ( MetS ) is associated with insulin resistance and increases the cardiovascular risk . Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease . The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance , and the effect of this interaction on the cardiovascular risk in MetS patients . METHODS : NADPH oxidase - dependent superoxide production and expression was evaluated by luminescence and western blot , respectively , in peripheral blood mononuclear cells obtained from 125 patients with MetS . P01308 resistance was defined by the homeostasis model assessment index . P14780 was quantified by enzyme - linked immunosorbent assay in plasma samples . To ascertain the mechanisms involved in vivo , we performed in - vitro experiments in cultured macrophages . RESULTS : Fifty - six percent of patients with MetS showed insulin resistance . Plasma matrix metalloproteinase - 9 levels were higher ( P < 0 . 05 ) in insulin - resistant patients than in patients with insulin sensitivity . NADPH oxidase - dependent superoxide production was augmented ( P < 0 . 05 ) in insulin - resistant patients with respect to insulin - sensitive patients . The interaction between insulin resistance and abnormally high NADPH oxidase - mediated superoxide production was associated with the highest matrix metalloproteinase - 9 values . Increased NADPH oxidase - dependent superoxide production was significantly associated with higher NADPH oxidase P13498 expression in insulin - resistant than in insulin - sensitive patients . Interestingly , insulin upregulated P13498 in peripheral blood mononuclear cells and in murine macrophages . CONCLUSION : P01308 resistance is associated with phagocytic NADPH oxidase activation . This association results in the highest cardiovascular risk in MetS patients .",
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .",
"DB00428 diabetes and the expression of P11166 at the brush border and basolateral membranes of intestinal enterocytes . Changes in membrane expression of sodium - dependent glucose transporter ( P13866 ) and glucose transporter isoform ( P11168 ) protein have been implicated in the increased intestinal glucose transport in streptozotocin - diabetes . The possible involvement of P11166 in the transport response , however , has not previously been studied . Using confocal microscopy on tissue sections and Western blotting of purified brush border membrane ( BBM ) and basolateral membrane ( BLM ) , we have examined enterocyte expression of P11166 in untreated and in 1 and 21 day streptozotocin diabetic rats . In control enterocytes , P11166 was absent at the BBM and detected at low levels at the BLM . Diabetes resulted in a 4 - to 5 - fold increased expression of P11166 at the BLM and the protein could also be readily detected at the BBM . P01308 treatment of diabetic rats increased P11166 level at the BBM but was without effect on expression of the protein at the BLM .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? ___MASK40___ - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 ) - positive breast cancer . In pre - clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non - HER ) tyrosine kinase receptors , and resistance to antibody - dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 - positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3 - kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods .",
"Exposure to an organophosphate ( ___MASK75___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK75___ ( ___MASK75___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK75___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK75___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK75___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"Dynamic regulation of platelet - derived growth factor receptor α expression in alveolar fibroblasts during realveolarization . Although the importance of platelet - derived growth factor receptor ( P09619 ) - α signaling during normal alveogenesis is known , it is unclear whether this signaling pathway can regulate realveolarization in the adult lung . During alveolar development , P09619 - α - expressing cells induce α smooth muscle actin ( α - SMA ) and differentiate to interstitial myofibroblasts . Fibroblast growth factor ( FGF ) signaling regulates myofibroblast differentiation during alveolarization , whereas peroxisome proliferator - activated receptor ( Q07869 ) - γ activation antagonizes myofibroblast differentiation in lung fibrosis . Using left lung pneumonectomy , the roles of FGF and Q07869 - γ signaling in differentiation of myofibroblasts from P09619 - α - positive precursors during compensatory lung growth were assessed . FGF receptor ( FGFR ) signaling was inhibited by conditionally activating a soluble dominant - negative P21802 transgene . Q07869 - γ signaling was activated by administration of rosiglitazone . Changes in α - SMA and P09619 - α protein expression were assessed in P09619 - α - green fluorescent protein ( GFP ) reporter mice using immunohistochemistry , flow cytometry , and real - time PCR . Immunohistochemistry and flow cytometry demonstrated that the cell ratio and expression levels of P09619 - α - GFP changed dynamically during alveolar regeneration and that α - SMA expression was induced in a subset of P09619 - α - GFP cells . Expression of a dominant - negative P21802 and administration of rosiglitazone inhibited induction of α - SMA in P09619 - α - positive fibroblasts and formation of new septae . Changes in gene expression of epithelial and mesenchymal signaling molecules were assessed after left lobe pneumonectomy , and results demonstrated that inhibition of P21802 signaling and increase in Q07869 - γ signaling altered the expression of Shh , FGF , Wnt , and Bmp4 , genes that are also important for epithelial - mesenchymal crosstalk during early lung development . Our data demonstrate for the first time that a comparable epithelial - mesenchymal crosstalk regulates fibroblast phenotypes during alveolar septation .",
"Attenuation of the progression of adjuvant - induced arthritis by 3 - aminobenzamide treatment . Rheumatoid arthritis ( RA ) is a disease that is still insufficiently controlled by current treatments . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors ameliorate immune - mediated diseases in several experimental models , including RA , colitis , experimental autoimmune encephalomyelitis and allergy . Together these findings showed that ADP - ribosylating enzymes , in particular P09874 , play a pivotal role in the regulation of immune responses and may represent a noble target for new therapeutic approaches in immune - mediated diseases . The effect of 3 - aminobenzamide ( 3 - AB ) , an inhibitor of poly ( ADP - ribose ) synthetase activity , was evaluated in a mouse model of adjuvant - induced arthritis ( AIA ) on pro - inflammatory cytokines , adhesion molecules , inflammatory mediators and chemokine production / expression in serum and knee joint . Histopathological examination was also done on joint section . Our data demonstrates that 3 - AB , 10mg / kg , intraperitoneally ( i . p . ) significantly reduces pro - inflammatory cytokine ( Q16552 , P01375 - α and P60568 ) and chemokine ( P13500 and MIP - 2 ) production / expression , accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores and was associated with a significant reduction of P19320 and P05362 expression in the knee joint . Moreover , the expression of inflammatory mediators ( P35228 , P35354 , P08253 , P14780 ) and joint histological inflammatory damage was also markedly decreased . The results of this study suggest that P09874 inhibitor may play a role in the inflammatory arthritic process after administration of 3 - AB may be a beneficial therapeutic approach .",
"[ Moclobemide ( ___MASK85___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 - mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator - activated receptor - gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) - induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 - induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro - angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0 . 001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0 . 001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti - angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients .",
"Antihyperglycemic Activity of Houttuynia cordata Thunb . in DB00428 - Induced Diabetic Rats . Present study is an attempt to investigate plausible mechanism involved behind antidiabetic activity of standardized Houttuynia cordata Thunb . extract in streptozotocin - induced diabetic rats . The plant is used as a medicinal salad for lowering blood sugar level in North - Eastern parts of India . Oral administration of extract at 200 and 400 mg / kg dose level daily for 21 days showed a significant ( P < 0 . 05 ) decrease in fasting plasma glucose and also elevated insulin level in streptozotocin - induced diabetic rats . It also significantly reversed all the alterations in biochemical parameters , that is , total lipid profile , blood urea , creatinine , protein , and antioxidant enzymes in liver , pancreas , and adipose tissue of diabetic rats . Furthermore , we have demonstrated that the extract significantly reversed the expression patterns of various glucose homeostatic enzyme genes like P11168 , P14672 , and caspase - 3 levels but did not show any significant effect on Q07869 - γ protein expressions . Additionally , the extract positively regulated mitochondrial membrane potential and succinate dehydrogenase ( SDH ) activity in diabetic rats . The findings justified the antidiabetic effect of H . cordata which is attributed to an upregulation of P14672 and potential antioxidant activity , which may play beneficial role in resolving complication associated with diabetes .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK52___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .",
"Dietary soy protein isolate attenuates metabolic syndrome in rats via effects on Q07869 , LXR , and SREBP signaling . To determine the effects of feeding soy or isoflavones on lipid homeostasis in early development , weanling rats were fed AIN - 93G diets made with casein , soy protein isolate ( SPI + ) , isoflavone - reduced SPI + ( SPI - ) , or casein supplemented with genistein or daidzein for 14 d . PPARalpha - regulated genes and proteins involved in fatty acid degradation were upregulated by SPI + ( P < 0 . 05 ) accompanied by increased promoter binding and expression of PPARalpha mRNA ( P < 0 . 05 ) . Feeding SPI - or pure isoflavones did not alter PPARalpha - regulated pathways . SPI + feeding had similar effects on PPARgamma signaling . SPI + , SPI - , and casein plus isoflavones all increased liver Q9UBH6 ( LXR ) alpha - regulated genes and enzymes involved in cholesterol homeostasis . Feeding SPI + increased promoter binding of LXRalpha , expression of the transcription factor mRNA , and protein ( P < 0 . 05 ) . In a second experiment , male Sprague - Dawley rats were fed casein diets from postnatal d ( P01160 ) 24 to PND64 or were fed high - fat Western diets containing 5 g x kg (- 1 ) cholesterol made with either casein or SPI + . P01308 resistance , steatosis , and hypercholesterolemia in the Western diet - fed rats were partially prevented by SPI + ( P < 0 . 05 ) . Nuclear sterol receptor element binding protein ( SREBP ) - 1c protein and mRNA and protein expression of enzymes involved in fatty acid synthesis were increased by feeding Western diets containing casein but not SPI + ( P < 0 . 05 ) . These data suggest that activation of Q07869 and LXR signaling and inhibition of SREBP - 1c signaling may contribute to insulin sensitization and improved lipid homeostasis in SPI +- fed rats after consumption of diets high in fat and cholesterol .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK40___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK40___ is also being investigated as part of triplet drug regimens . ___MASK40___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"G protein - coupled receptor kinase 2 mediates endothelin - 1 - induced insulin resistance via the inhibition of both Galphaq / 11 and insulin receptor substrate - 1 pathways in 3T3 - Q9NUQ9 adipocytes . G protein - coupled receptor kinases ( GRKs ) regulate seven - transmembrane receptors ( 7TMRs ) by phosphorylating agonist - activated 7TMRs . Recently , we have reported that P25098 can function as a negative regulator of insulin action by interfering with G protein - q / 11 alpha - subunit ( Galphaq / 11 ) signaling , causing decreased glucose transporter 4 ( P14672 ) translocation . We have also reported that chronic endothelin - 1 ( ET - 1 ) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate ( P41252 ) - 1 and Galphaq / 11 , and decreased insulin - stimulated glucose transport in 3T3 - Q9NUQ9 adipocytes . In the current study , we have investigated the role of P25098 in chronic ET - 1 - induced insulin resistance . P01308 - induced P14672 translocation was inhibited by pretreatment with ET - 1 for 24 h , and we found that this inhibitory effect was rescued by microinjection of anti - P25098 antibody or P25098 short interfering RNA . We further found that P25098 mediates the inhibitory effects of ET - 1 by two distinct mechanisms . Firstly , adenovirus - mediated overexpression of either wild - type ( WT ) - or kinase - deficient ( KD ) - P25098 inhibited Galphaq / 11 signaling , including tyrosine phosphorylation of Galphaq / 11 and cdc42 - associated phosphatidylinositol 3 - kinase activity . Secondly , ET - 1 treatment caused DB00133 / DB00156 phosphorylation of P35568 and P35568 protein degradation . Overexpression of KD - P25098 , but not WT - P25098 , inhibited ET - 1 - induced serine 612 phosphorylation of P35568 and restored activation of this pathway . Taken together , these results suggest that P25098 mediates ET - 1 - induced insulin resistance by 1 ) inhibition of Galphaq / 11 activation , and this effect is independent of P25098 kinase activity , and 2 ) P25098 kinase activity - mediated P35568 serine phosphorylation and degradation .",
"___MASK25___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .",
"Obesity and breast cancer : the roles of peroxisome proliferator - activated receptor - γ and plasminogen activator inhibitor - 1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high - fat diet and obesity . P00747 activator inhibitor - 1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 - γ and P05121 expression to high - fat diet and obesity in the risk of breast cancer .",
"[ Hyperlipidemia and peroxisome proliferator - activated receptor ( Q07869 ) -- regulation of the PPARalpha gene by O15516 : O00327 ] . The main pathological findings in atherosclerosis include abnormal reactions of neutrophils , lymphocytes and monocytes / macrophages , vascular smooth muscle cells and vascular endothelial cells , and the accumulation of cholesterol ester in the arterial wall . Therefore , investigating the effects of these abnormal reactions on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis . Three types of peroxisome proliferator - activated receptors ( PPARs ) : PPARalpha , PPARbeta / delta , and PPARgamma are expressed in endothelial cells . In endothelial cells , the ligands / activators for PPARalpha and PPARgamma increase Cu2 + , DB01593 - superoxide dismutase . In addition , the phorbol myristate acetate ( PMA ) - stimulated 22 kDa - subunit ( P13498 ) protein levels and 47 kDa - subunit ( p47phox ) protein levels in NADPH ( superoxide generating enzyme nicotinamide adenine dinucleotide phosphate ( reduced form ) ) oxidase were decreased by treatment with PPARalpha and PPARgamma ligands / activators . Recently , we showed that the O15516 : O00327 heterodimer regulates the PPARalpha gene via promoter of PPARalpha . Moreover , we report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia , in which the former may have caused the latter two conditions . This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function . Here , based on recent studies including our own , we describe the relationships between risk factors for atherosclerosis , especially hyperlipidemia and PPARs and the molecular mechanisms that govern lipid metabolism in the arteries .",
"Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .",
"___MASK33___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK33___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Involvement of protein kinase Cdelta / extracellular signal - regulated kinase / poly ( ADP - ribose ) polymerase - 1 ( P09874 ) signaling pathway in histamine - induced up - regulation of histamine H1 receptor gene expression in HeLa cells . The histamine H ( 1 ) receptor ( P35367 ) gene is up - regulated in patients with allergic rhinitis . However , the mechanism and reason underlying this up - regulation are still unknown . Recently , we reported that the P35367 expression level is strongly correlated with the severity of allergic symptoms . Therefore , understanding the mechanism of this up - regulation will help to develop new anti - allergic drugs targeted for P35367 gene expression . Here we studied the molecular mechanism of P35367 up - regulation in HeLa cells that express P35367 endogenously in response to histamine and phorbol 12 - myristate 13 - acetate ( PMA ) . In HeLa cells , histamine stimulation caused up - regulation of P35367 gene expression . Rottlerin , a PKCδ - selective inhibitor , inhibited up - regulation of P35367 gene expression , but Go6976 , an inhibitor of Ca ( 2 +)- dependent PKCs , did not . DB11320 or PMA stimulation resulted in PKCδ phosphorylation at DB00135 ( 311 ) and DB00156 ( 505 ) . Activation of PKCδ by H ( 2 ) O ( 2 ) resulted in P35367 mRNA up - regulation . Overexpression of PKCδ enhanced up - regulation of P35367 gene expression , and knockdown of the PKCδ gene suppressed this up - regulation . DB11320 or PMA caused translocation PKCδ from the cytosol to the Golgi . U0126 , an MEK inhibitor , and DPQ , a poly ( ADP - ribose ) polymerase - 1 inhibitor , suppressed PMA - induced up - regulation of P35367 gene expression . These results were confirmed by a luciferase assay using the P35367 promoter . Phosphorylation of P29323 and P04049 in response to PMA was also observed . However , real - time PCR analysis showed no inhibition of P35367 mRNA up - regulation by a P04049 inhibitor . These results suggest the involvement of the PKCδ / P29323 / poly ( ADP - ribose ) polymerase - 1 signaling pathway in histamine - or PMA - induced up - regulation of P35367 gene expression in HeLa cells .",
"[ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non - insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F - VII , F - X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non - diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F - VII , F - X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance .",
"P01308 - like growth factor - I receptor signaling and resistance to trastuzumab ( Herceptin ) . BACKGROUND : ___MASK40___ ( Herceptin ) , an anti - P04626 / neu receptor monoclonal antibody that inhibits growth of ErbB2 - overexpressing breast cancer , is used to treat such cancers . Development of resistance to trastuzumab , however , is common . We investigated whether insulin - like growth factor - I ( P05019 ) , which activates cell survival signals , interferes with the growth - inhibitory action of trastuzumab . METHODS : MCF - 7 / P04626 - 18 and SKBR3 human breast cancer models were used to assess cell proliferation , colony formation in soft agar , and cell cycle parameters . Throughout , we used trastuzumab at a dose of 10 microg / mL and P05019 at a dose of 40 ng / mL . All statistical tests were two - sided . RESULTS : ___MASK40___ inhibited the growth of MCF - 7 / P04626 - 18 cells , which overexpress P04626 / neu receptors and express P05019 receptors ( IGF - IRs ) , only when IGF - IR signaling was minimized . For example , in 1 % fetal bovine serum ( FBS ) , trastuzumab reduced cell proliferation by 42 % ( P =. 002 ) ; however , in 10 % FBS or P05019 , trastuzumab had no effect on proliferation . In SKBR3 cells , which overexpress P04626 / neu receptor but express few IGF - IRs , trastuzumab reduced proliferation by 42 % ( P =. 008 ) regardless of P05019 concentration . When SKBR3 cells were genetically altered to overexpress IGF - IRs and cultured with P05019 , trastuzumab had no effect on proliferation . However , the addition of IGF - binding protein - 3 , which decreased IGF - IR signaling , restored trastuzumab - induced growth inhibition . CONCLUSIONS : In breast cancer cell models that overexpress P04626 / neu , an increased level of IGF - IR signaling appears to interfere with the action of trastuzumab . Thus , strategies that target IGF - IR signaling may prevent or delay development of resistance to trastuzumab .",
"Triple negative breast cancer : therapeutic and prognostic implications . Triple negative breast cancers ( TNBC ) lack oestrogen receptor ( ER ) , progesterone receptor ( PR ) , nor over - express human epidermal growth factor receptor 2 ( P04626 ) . Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinic - pathologic features and risk factors when compared to women with other subtypes of breast cancer . They are associated with poor prognosis , as defined by low five - year survival . To date many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings . Targeted therapy options involving P09874 and P00533 inhibition , are currently in different phases of development and will hopefully change the paradigm of how patients with TNBC are treated . The present commentary aims to summarize the latest findings on chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents .",
"P26718 receptor regulates human effector T - cell cytokine production . Although innate immune signals shape the activation of naive T cells , it is unclear how innate signals influence effector T - cell function . This study determined the effects of stimulating the P26718 receptor in conjunction with the TCR on human effector CD8 (+) T cells . Stimulation of CD8 (+) T cells through CD3 and P26718 simultaneously or through a chimeric P26718 receptor , which consists of P26718 fused to the intracellular region of CD3ζ , activated β - catenin and increased expression of β - catenin - induced genes , whereas T cells stimulated through the TCR or a combination of the TCR and P10747 did not . Activation by TCR and P26718 prevented expression and production of anti - inflammatory cytokines P22301 , P15248 , P35225 , and P15692 - α in a β - catenin - and Q07869 γ - dependent manner . P26718 stimulation also modulated the cytokine secretion of T cells activated simultaneously through CD3 and P10747 . These data indicate that activating CD8 (+) T cells through the P26718 receptor along with the TCR modulates signal transduction and the production of anti - inflammatory cytokines . Thus , human effector T cells alter their function depending on which innate receptors are engaged in conjunction with the TCR complex .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .",
"DB09341 transporter - 2 ( P11168 ) promoter mediated transgenic insulin production reduces hyperglycemia in diabetic mice . P01308 production afforded by hepatic gene therapy ( HGT ) retains promise as a potential treatment for type 1 diabetes , but successful approaches have been limited . We employed a novel and previously untested promoter for this purpose , glucose transporter - 2 ( P11168 ) to drive insulin production via delivery by recombinant adeno - associated virus ( rAAV ) . In vitro , the P11168 promoter was capable of robust glucose - responsive expression in transduced HepG2 human hepatoma cells . Therefore , rAAV constructs were designed to express the furin - cleavable human preproinsulin B10 gene , under the control of the murine P11168 promoter and packaged for delivery with rAAV expressing the type 5 capsid . DB00428 - induced diabetic mice were subjected to hepatic portal vein injection immediately followed by implantation of a sustained - release insulin pellet to allow time for transgenic expression . All mice injected with the rAAV5 - P11168 - fHPIB10 virus remained euglycemic for up to 35 days post - injection , with 50 % euglycemic after 77 days post - injection . In contrast , mock - injected mice became hyperglycemic within 15 days post - injection following dissolution of the insulin pellet . Serum levels of both human insulin and C - peptide further confirmed successful transgenic delivery by the rAAV5 - P11168 - fHPIB10 virus . These findings indicate that the P11168 promoter may be a potential candidate for regulating transgenic insulin production for hepatic insulin gene therapy in the treatment of type I diabetes .",
"DB00428 - nicotinamide - induced diabetes in the rat . Characteristics of the experimental model . Administration of both streptozotocin ( Q11206 ) and nicotinamide ( NA ) has been proposed to induce experimental diabetes in the rat . Q11206 is well known to cause pancreatic B - cell damage , whereas NA is administered to rats to partially protect insulin - secreting cells against Q11206 . Q11206 is transported into B - cells via the glucose transporter P11168 and causes DNA damage leading to increased activity of poly ( ADP - ribose ) polymerase ( P09874 ) to repair DNA . However , exaggerated activity of this enzyme results in depletion of intracellular NAD (+) and DB00171 , and the insulin - secreting cells undergo necrosis . The protective action of NA is due to the inhibition of P09874 activity . NA inhibits this enzyme , preventing depletion of NAD (+) and DB00171 in cells exposed to Q11206 . Moreover , NA serves as a precursor of NAD (+) and thereby additionally increases intracellular NAD (+) levels . The severity of diabetes in experimental rats strongly depends on the doses of Q11206 and NA given to these animals . Therefore , in diabetic rats , blood glucose may be changed in a broad range -- from slight hyperglycemia to substantial hyperglycemia compared with control animals . Similarly , blood insulin may be only slightly decreased or substantial hypoinsulinemia may be induced . In vitro studies demonstrated that the insulin - secretory response to glucose is attenuated in Q11206 - NA - induced diabetic rats compared with control animals . This is due to reduced B - cell mass as well as metabolic defects in the insulin - secreting cells . Results of numerous experiments have demonstrated that this model of diabetes is useful in studies of different aspects of diabetes .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK26___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK26___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK79___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"P01308 - like growth factor - 1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2 - overexpressing breast cancer cells via Src - focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 ) - targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 - positive metastatic breast cancer . Increased expression or signaling from the insulin - like growth factor - 1 receptor ( IGF - 1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF - 1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF - 1R was invasion , which was mediated by both Src - focal adhesion kinase ( Q05397 ) signaling and Q08050 ( FoxM1 ) . Cotargeting IGF - 1R and P04626 using either IGF - 1R antibodies or IGF - 1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF - 1R and P04626 in trastuzumab - resistant cells . Constitutively active Src blocked the anti - invasive effect of IGF - 1R / P04626 cotargeted therapy . Furthermore , knockdown of FoxM1 blocked DB01277 - mediated invasion , and dual targeting of IGF - 1R and P04626 reduced expression of FoxM1 . Re - expression of FoxM1 restored the invasive potential of IGF - 1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF - 1R and P04626 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1 .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Whole - exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment . Whole - exome sequencing of individuals with mild cognitive impairment , combined with genotype imputation , was used to identify coding variants other than the apolipoprotein E ( P02649 ) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design . Matched unrelated P02649 ε3 homozygous male Caucasian participants from the Alzheimer ' s Disease Neuroimaging Initiative ( ADNI ) were selected at the extremes of the 2 - year longitudinal change distribution of hippocampal volume ( eight subjects with rapid rates of atrophy and eight with slow / stable rates of atrophy ) . We identified 57 non - synonymous single nucleotide variants ( SNVs ) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group , but not in any of the 8 subjects in the slow atrophy group . Among these SNVs , the variants that accounted for the greatest group difference and were predicted in silico as ' probably damaging ' missense variants were rs9610775 ( Q9BWT7 ) and rs1136410 ( P09874 ) . To further investigate and extend the exome findings in a larger sample , we conducted quantitative trait analysis including whole - brain search in the remaining ADNI P02649 ε3 / ε3 group ( N = 315 ) . Genetic variation within P09874 and Q9BWT7 was associated with rate of hippocampal neurodegeneration in P02649 ε3 / ε3 . Meta - analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in P02649 ε3 / ε3 individuals ( N = 923 ) . Larger sequencing studies and longitudinal follow - up are needed for confirmation . The combination of next - generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration .",
"Relationship between NADPH oxidase P13498 C242T , P09874 Val762Ala polymorphisms , angiographically verified coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus . INTRODUCTION : There has been compelling evidence for the role of oxidative stress in the pathogenesis of cardiovascular complications in type 2 diabetes mellitus ( T2DM ) . We analyzed the association of C242T and Val762Ala polymorphisms of NADPH oxidase P13498 and poly ( ADP - ribose ) polymerase - 1 ( P09874 ) genes respectively with coronary artery disease ( CAD ) and its severity , myocardial infarction ( MI ) and cardiovascular risk factors in T2DM patients . MATERIALS AND METHODS : We screened 283 T2DM patients , inclusive of 160 with angiographically defined CAD , 73 with and 89 without MI and 121 T2DM individuals with no evidence of CAD for the two gene polymorphisms . RESULTS : The 242T and 762Ala alleles were significantly more frequent in T2DM subjects without CAD than those with CAD , thereby associating them with a significant protective effect against development of CAD [ p = 0 . 002 ( C242T ) ; 0 . 02 ( Val762Ala ) ] . The association was further characterized by a relatively lower frequency of 242T and 762Ala alleles in T2DM patients with multi ( P53602 ) / triple vessel disease respectively [ p = 0 . 003 ( C242T ) ; 0 . 02 ( Val762Ala ) ] . Conversely , the genotype and allele frequencies of these polymorphisms were not significantly different in T2DM + CAD patients with or without MI . Stratification of risk by putative risk factors for CAD revealed a significant interaction with these polymorphisms . Multiple logistic regression analysis revealed a significant and independent association of C242T and Val762Ala polymorphisms and other putative risk factors with CAD / P53602 in T2DM individuals . CONCLUSIONS : Our observations indicate a significant relationship between P13498 C242T and P09874 Val762Ala polymorphisms , CAD and its severity , but not with occurrence of MI in T2DM individuals with significant coronary stenoses .",
"7 , 12 - Dimethylbenz [ a ] anthracene exposure induces the DNA repair response in neonatal rat ovaries . 7 , 12 - Dimethylbenz [ a ] anthracene ( DMBA ) destroys ovarian follicles at all stages of development . This study investigated DMBA - induced DNA double strand break ( DSB ) formation with subsequent activation of the ovarian DNA repair response in models of pre - antral or pre - ovulatory follicle loss . Postnatal day ( P01160 ) 4 Fisher 344 ( F344 ) rat ovaries were cultured for 4 days followed by single exposures of vehicle control ( 1 % DB01093 ) or DMBA ( 12 . 5 nM or 75 nM ) and maintained in culture for 4 or 8 days . Alternately , PND4 F344 rat ovaries were exposed to 1 μM DMBA at the start of culture for 2 days . Total RNA or protein was isolated , followed by qPCR or Western blotting to quantify mRNA or protein level , respectively . γ P16104 and phosphorylated Q13315 were localized and quantified using immunofluorescence staining . DMBA exposure increased caspase 3 and γ P16104 protein . Additionally , DMBA ( 12 . 5 nM and 1 μM ) increased levels of mRNA encoding Atm , Xrcc6 , Brca1 and Rad51 . In contrast , Parp1 mRNA was decreased on d4 and increased on d8 of DMBA exposure , while P09874 protein increased after 8 days of DMBA exposure . Total Q13315 increased in a concentration - dependent temporal pattern ( 75 nM d4 ; 12 . 5 nM d8 ) , while pATM was localized in large primary and secondary follicles and increased after 8 days of 75 nM DMBA exposure compared to both control and 12 . 5 nM DMBA . These findings support that , despite some concentration effects , DMBA induces ovarian DNA damage and that DNA repair mechanisms are induced as a potential mechanism to prevent follicle loss .",
"Poly ( ADP - ribose ) polymerase - 1 mediates angiotensin II - induced expression of plasminogen activator inhibitor - 1 and fibronectin in rat mesangial cells . OBJECTIVE : To investigate the effects of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) on angiotensin II ( Ang II ) - induced plasminogen activator inhibitor - 1 ( P05121 ) and fibronectin ( FN ) in rat mesangial cells ( RMCs ) . METHODS : Followed by serum starvation for 16 h , RMCs were exposed to Ang II for an indicated time to examine the protein expression of P09874 . The cells were treated with or without Ang II for 12 - 24 h in the presence or absence of an inhibitor of PARP , N -( 6 - oxo - 5 , 6 - dihydrophenanthridin - 2 - yl )- N , N - dimethylacetamide hydrochloride ( PJ34 ) or small interfering RNA ( siRNA ) duplexes targeting P09874 . The mRNA and protein expressions of P09874 , P05121 and FN were determined by real - time RT - PCR and Western blot , respectively . The activity of P09874 was examined by colorimetric assay . RESULTS : Ang II did not only significantly induce P09874 expression and activity , but also increased P05121 and FN expression in RMCs . All these responses induced by Ang II were significantly inhibited by both the PARP inhibitor PJ34 and downregulating P09874 with the siRNA technique . CONCLUSIONS : Our data suggest that P09874 mediates Ang II - induced P05121 and FN in RMCs and may thus represent a potential therapeutic target in the treatment of glomerular disease ."
] |
[
"___MASK25___",
"___MASK26___",
"___MASK33___",
"___MASK40___",
"___MASK52___",
"___MASK75___",
"___MASK79___",
"___MASK83___",
"___MASK85___"
] |
___MASK40___
|
MH_train_337
|
interacts_with DB08864?
|
[
"Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK91___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK91___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK91___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK85___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"___MASK62___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK62___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Selective immunomodulation by the antineoplastic agent mitoxantrone . I . Suppression of B lymphocyte function . Novantrone mitoxantrone , an antineoplastic agent with antiproliferative properties , is under investigation as an immunomodulating agent . The impact of mitoxantrone treatment on B lymphocyte reactivity is presented here . Administered i . p . in H2O at a dose of 0 . 5 mg / kg , daily for 14 days , mitoxantrone abrogated both the in vivo antibody response ( to ovalbumin ) and the in vitro plaque - forming cell ( P27918 ) response ( to P12931 ) . In addition to the effects on thymus - dependent reactivity , P27918 responses to the thymus - independent antigens TNP - LPS and TNP - Ficoll were also inhibited when tested in vivo or in vitro . B cells were identified as a target for the suppressive activity of mitoxantrone by using T cell - replacing factor to reconstitute the in vitro anti - P12931 P27918 response of a T lymphocyte - depleted spleen cell preparation . LPS - induced B cell mitogenesis was largely inhibited by mitoxantrone treatment . However , depletion of Sephadex G - 10 - adherent cells significantly restored the proliferative response . Flow cytometric analysis revealed a dramatic decrease in splenic B lymphocyte content . Therefore , mitoxantrone exerted a potent suppressive influence on the humoral immune system through a direct reduction in B cell number augmented by macrophage - mediated inhibition of B cell proliferation .",
"A novel 5 - HT1 - like receptor subtype mediates DB02527 synthesis in porcine pial vein . The 5 - hydroxytryptamine ( 5 - HT ) receptor subtype mediating 5 - HT inhibition of spontaneous rhythmic contractions ( P12931 ) in the porcine pial vein was characterized . Results from pharmacological studies using in vitro tissue bath techniques indicated that the inhibitory effects of 5 - HT on P12931 were qualitatively and quantitatively mimicked by 5 - HT1 - like agonists 5 - methoxytryptamine ( 5 - MT ) and 5 - carboxamidotryptamine ( 5 - CT ) . 5 - HT - , 5 - MT - , and 5 - CT - induced inhibitions of P12931 were attenuated in a concentration - dependent manner by methysergide , which yielded similar pA2 values against these three agonists , suggesting that 5 - HT , 5 - MT , and 5 - CT act on the same 5 - HT1 - like receptors . 5 - MT inhibition of P12931 was not affected by blocking 5 - HT2 ( with ketanserin and spiperone ) , 5 - Q9H205 ( with MDL - 72222 and ICS - 205 - 930 ) , or Q13639 ( with ICS - 205 - 930 ) receptors . Neither was 5 - MT inhibition of P12931 affected by blocking P08908 ( with propranolol and spiperone ) , P28222 ( with propranolol ) , or P28335 ( with ketanserin ) receptors . Furthermore , 5 - HT and 5 - MT inhibitions of P12931 were enhanced by cilostazol [ a selective adenosine 3 ', 5 '- cyclic monophosphate ( DB02527 ) phosphodiesterase inhibitor ] and were diminished by KT - 5720 ( a DB02527 - dependent protein kinase inhibitor ) but were not affected by M & B - 22948 [ a selective guanosine 3 ', 5 '- cyclic monophosphate ( cGMP ) phosphodiesterase inhibitor ] or KT - 5823 ( a cGMP - dependent protein kinase inhibitor ) . Biochemical studies further demonstrated that 5 - HT inhibition of P12931 in porcine pial veins was accompanied by an increase in DB02527 , but not cGMP , synthesis . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Ontogeny of steroid receptor coactivators in the hippocampus and their role in regulating postnatal Q9Y251 axis function . The function and regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis during ontogeny differs markedly from the situation in adult animals . Postnatally mice undergo a so - called stress hypo - responsive period , which is characterized by a relative inability of mild stressors to induce a marked corticosterone response . Steroid receptor coactivators ( SRCs ) have been shown to influence the function of the Q9Y251 axis in adult animals by interacting with steroid receptors as the mineralocorticoid and the glucocorticoid receptor . Here we test the hypothesis that expression changes of the three identified P12931 genes ( SRC1 , SRC2 and SRC3 ) correlate with differences in Q9Y251 axis activity during postnatal development . First , we mapped the ontogeny of the three SRCs during postnatal development in the hippocampus . We found a time - and region - specific regulation of gene expression , which was specific for each P12931 . However , there was no relation between the age - dependent stress system activity and the expression levels of the SRCs . Further , we studied the acute regulation of the three SRCs following maternal deprivation in 9 - day - old wild - type or P06850 receptor type 1 ( CRHr1 ) knockout mice . Under these conditions , no differential expression of any of the tested SRCs could be detected . Thus , while it seems likely that their varying abundance throughout postnatal life affects steroid receptor function in the different hippocampal subregions , acute changes of Q9Y251 axis activity or reactivity are not mediated by hippocampal changes in expression of this coactivator family .",
"Dietary omega - 3 deficiency reduces P23560 content and activation DB01221 receptor and Fyn in dorsal hippocampus : implications on persistence of long - term memory in rats . Omega - 3 ( n - 3 ) fatty acids are important for adequate brain function and cognition . The aim of the present study was to evaluate how n - 3 fatty acids influence the persistence of long - term memory ( LTM ) in an aversive memory task and to explore the putative mechanism involved . Female rats received isocaloric diets that included n - 3 ( n - 3 group ) or not ( D group ) . The adult litters were subjected to an inhibitory avoidance task ( 0 . 7 mA , 1 . 0 seconds foot shock ) to elicit persistent LTM . Twelve hours after the training session , the fatty acid profile and the brain derived neurotrophic factor ( P23560 ) content of the dorsal hippocampus were assessed . In addition , we measured the activation of the Q13224 subunit of the N - methyl - d - aspartate ( DB01221 ) receptor and the P12931 family protein Fyn . Despite pronounced learning in both groups , the persistence of LTM was abolished in the D group 7 days after the training session . We also observed that the D group presented reductions in hippocampal DB01708 ( 22 : 6 n - 3 ) and P23560 content . Twelve hours after the training session , the D group showed decreased Q13224 and Fyn phosphorylation in the dorsal hippocampus , with no change in the total content of these proteins . Further , there was a decrease in the interaction of Fyn with Q13224 in the D group , as observed by co - immunoprecipitation . Taken together , these data suggest that n - 3 fatty acids influence the persistence of LTM by maintaining adequate levels of DB01708 and P23560 as well as by influencing the activation of Q13224 and Fyn during the period of memory formation .",
"Association between Q5S007 and Q13541 protein levels in normal and malignant cells . Translational control is a crucial component of cancer development and progression . Eukaryotic initiation factor ( eIF ) 4E mediates eIF4F association with the mRNA 5 ' cap structure to stimulate cap - dependent translation initiation . The P06730 - binding protein , Q13541 , regulates cap - dependent translation through its phosphorylation at multiple sites . It has been described that some human carcinomas present a high level of p - Q13541 , not always associated with high levels of p - P42345 . These previous observations suggest that other kinases could be involved in Q13541 phosporylation . Investigation in new kinases that could be implicated in Q13541 phosphorylation and mechanisms that affect Q13541 stability is important to understand the role of P06730 in cell transformation . In this study , we examined 48 kinases that could be involved in Q13541 phosphorylation and stability . The screening study was based on analysis of Q13541 status after inhibition of these kinases in a breast carcinoma cell line . Several kinases affecting Q13541 stability ( Q5S007 , RAF - 1 , p38γ , GSK3β , AMPKα , PRKACA and P22694 ) and Q13541 phosphorylation ( P06493 , PDK1 , P12931 , P05771 , Q13177 , p38β , P17252 and CaMKKB ) were identified . These findings provide evidence that Q13541 can be regulated and stabilized by multiple kinases implicated in several cell signaling pathways . We focus on the finding that Q5S007 down - regulation was associated with a clearly decreased Q13541 protein ( and not with mRNA down - regulation ) . Importantly , knockdown of Q5S007 associated with high proliferative rate in normal cells and treatment with rapamycin and / or proteosome inhibition suppressed Q13541 protein degradation . These results offer new insights into the regulation of total and phosphorylated Q13541 .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not DB00834 , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to DB00834 . Unlike DB00834 , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to DB00834 or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK18___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Agonism of human pregnane X receptor by rilpivirine and etravirine : comparison with first generation non - nucleoside reverse transcriptase inhibitors . DB08864 and etravirine are second generation non - nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus - 1 infection . O75469 ( O75469 ) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions . The present study investigated the effects of rilpivirine and etravirine on the activity of human O75469 ( hPXR ) , including the mode of activation , and compared them to those of efavirenz , nevirapine , and delavirdine , which are first generation non - nucleoside reverse transcriptase inhibitors . In transiently transfected HepG2 cells , rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , activated human , mouse , and rat O75469 . Results from mechanistic studies indicated that rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , bound to the ligand - binding domain of hPXR , as assessed by a transactivation assay and by a competitive ligand - binding assay using time - resolved fluorescence resonance energy transfer ; triggered nuclear translocation of a green fluorescence protein - tagged hPXR , as visualized by confocal imaging ; and recruited steroid receptor coactivator - 1 ( Q15788 ) , P12931 - 2 , and Q9Y6Q9 to hPXR , as demonstrated by mammalian two - hybrid assays . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , increased hPXR target gene ( P08684 ) expression in primary cultures of human hepatocytes . In summary , select non - nucleoside reverse transcriptase inhibitors activated human and rodent O75469 . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , were identified as agonists of hPXR , as assessed in mechanistic experiments , and inducers of P08684 , as determined in primary cultures of human hepatocytes .",
"P00747 activator inhibitor - 1 is increased in colonic epithelial cells from patients with colitis - associated cancer . BACKGROUND : Patients with long - term ulcerative colitis are at risk for developing colorectal cancer . METHODS : Archival formalin - fixed paraffin - embedded tissue from ulcerative colitis patients who underwent a colectomy for high - grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor - 1 ( P05121 ) as well as other mediators of inflammation - associated cancer . Epithelia from areas of colons that showed histologic evidence of carcinoma , high - grade dysplasia , and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation ( quiescent colitis ) was microdissected using laser capture microscopy . mRNA was extracted from the microdissected tissue and PCR array analysis was performed . To extend our findings , P05121 protein levels were determined using immunohistochemistry . RESULTS : The mRNA expression of P05121 is increased 6 - fold ( p = 0 . 02 ) when comparing the carcinoma group to the quiescent colitis group ; increases were also observed in Q00653 , Q04864 , P12931 , and P15692 . The protein levels of P05121 are increased by 50 % ( p < 0 . 001 ) in high - grade dysplasia and by 60 % ( p < 0 . 001 ) in carcinoma when compared to the quiescent colitis group . CONCLUSIONS : The increase in P05121 in high - grade dysplasia and carcinoma suggests a functional role for P05121 in malignant transformation in colitis - associated cancer . P05121 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis - associated cancer .",
"Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK52___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .",
"___MASK94___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK94___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Two - dimensional liquid crystalline growth within a phase - field - crystal model . By using a two - dimensional phase - field - crystal ( P27918 ) model , the liquid crystalline growth of the plastic triangular phase is simulated with emphasis on crystal shape and topological defect formation . The equilibrium shape of a plastic triangular crystal ( PTC ) grown from an isotropic phase is compared with that grown from a columnar or smectic - A ( Q13216 ) phase . While the shape of a PTC nucleus in the isotropic phase is almost identical to that of the classical P27918 model , the shape of a PTC nucleus in Q13216 is affected by the orientation of stripes in the Q13216 phase , and irregular hexagonal , elliptical , octagonal , and rectangular shapes are obtained . Concerning the dynamics of the growth process , we analyze the topological structure of the nematic order , which starts from nucleation of + 1 / 2 and - 1 / 2 disclination pairs at the PTC growth front and evolves into hexagonal cells consisting of + 1 vortices surrounded by six satellite - 1 / 2 disclinations . It is found that the orientational and the positional order do not evolve simultaneously ; the orientational order evolves behind the positional order , leading to a large transition zone , which can span over several lattice spacings .",
"Effects of P28335 - receptor expression on cell proliferation control in hamster fibroblasts : serotonin fails to induce a transformed phenotype . 5 - HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells , inducing ligand - dependent focus formation . In order to assess their mitogenic and oncogenic potential in a different cell system , we transfected these receptors into CCL39 hamster fibroblasts , a well - characterized growth factor - dependent cell line . Cell clones expressing functional receptors were isolated and tested for ( a ) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum , ( b ) the response to serotonin alone or in combination with other growth factors , and ( c ) the capacity for anchorage - independent proliferation . In the absence or presence of serotonin , the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar . None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments , but synergy was observed between serotonin and the tyrosine kinase activating growth factors P01133 and FGF . However , the major part of this effect could be abolished by an antagonist of 5 - HT1b receptors , which are endogenous in CCL39 cells . The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha - ras - transfected cells . The fact that 5 - HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like DB01367 , P12931 , or P07333 .",
"Temporal / spatial expression of nuclear receptor coactivators in the mouse lung . Our laboratory has previously demonstrated that retinoic acid nuclear receptor , thyroid transcription factor - 1 ( Q15669 - 1 ) , and nuclear receptor coactivators such as DB02527 response element binding protein ( CREB ) binding protein ( CBP ) / p300 and steroid receptor coactivator - 1 ( Q15788 ) form an enhanceosome on the 5 '- enhancer region of the human surfactant protein B gene . Immunohistochemistry was used to identify cells that coexpressed CBP / p300 , Q15788 , retinoid X receptor , and Q15669 - 1 in the developing and mature lung . CBP / p300 and Q15788 were expressed in the adult mouse lung , CBP and p300 being present in both alveolar type I and type II epithelial cells and Q15788 and Q15669 - 1 being restricted to type II epithelial cells . CBP / p300 , Q15788 , and Q15669 - 1 were readily detected in the nuclei of developing respiratory epithelial tubules in fetal mice from embryonic days 10 to 18 . CBP / p300 and Q15788 were also detected in developing mesenchymal cells . These coactivators were coexpressed with Q15669 - 1 and P07988 in human pulmonary adenocarcinoma cells ( H441 cells ) in vitro . Interaction assays with a two - hybrid reporter analysis demonstrated direct interactions among Q15669 - 1 , Q15788 , and CBP / p300 in H441 cells . These findings support a role for retinoic acid receptor and nuclear receptor coactivators in the regulation of P07988 gene expression in the respiratory epithelium .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK22___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK2___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK81___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together ."
] |
[
"___MASK18___",
"___MASK22___",
"___MASK2___",
"___MASK52___",
"___MASK62___",
"___MASK81___",
"___MASK85___",
"___MASK91___",
"___MASK94___"
] |
___MASK81___
|
MH_train_338
|
interacts_with DB08904?
|
[
"P01375 as a therapeutic target in inflammatory diseases , ischemia - reperfusion injury and trauma . P01375 - alpha ( P01375 ) is a central regulator of inflammation , and P01375 antagonists may be effective in treating inflammatory disorders in which P01375 plays an important pathogenetic role . Recombinant or modified proteins are an emerging class of therapeutic agents . To date , several recombinant or modified proteins which acts as P01375 antagonists have been disclosed . In particular , antibodies that bind to and neutralise P01375 have been sought as a means to inhibit P01375 activity . Inhibition of P01375 has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis , psoriatic arthritis , and ankylosing spondylitis , inflammatory bowel disease . Additionally , the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research . The currently available therapies include a soluble p75 P01375 receptor : Fc construct , etanercept , a chimeric monoclonal antibody , infliximab , and a fully human monoclonal antibody , adalimumab . DB08904 is a novel P01375 inhibitor which is an antigen - binding domain of a humanized P01375 antibody coupled to polyethylene glycol ( PEG ) to increase half - life , and thus is Fc - domain - free . In this review , we discuss briefly the present understanding of P01375 - mediated biology and the current therapies in clinical use , and focus on some of the new therapeutic approaches with small - molecule inhibitors . Moreover , we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs , as P01375 activity inhibitories , especially in therapies of several inflammatory diseases within the nervous system .",
"DB08904 for the treatment of Crohn ' s disease . DB08904 is a polyethylene glycolated FAb ' fragment of a humanized anti - P01375 monoclonal antibody . This pegylated molecule binds with circulating P01375 and forms an inactive complex that is then eliminated from the body . The drug has been shown to be better than placebo in the treatment of Crohn ' s disease and maintaining a clinical response in adult patients with moderate - to - severe active disease who have had an inadequate response to conventional therapy , and the treatment of adults with moderately to severely active rheumatoid arthritis . Comparative trials with an active control group are lacking . The most common adverse reactions include abdominal pain , diarrhea , injection site reactions and infection . All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy , patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy , and the initiation of therapy should be avoided if the patient has an active infection . Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia . Therapy should be discontinued if the patient develops a serious infection during therapy .",
"The clinical efficacy and safety of certolizumab pegol in rheumatoid arthritis . IMPORTANCE OF THE FIELD : The treatment of rheumatoid arthritis has changed dramatically over the past 25 years , first with the introduction of methotrexate and then the introduction of biologic therapy . These agents have provided patients with multiple treatment options to try to achieve disease remission . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies , even those with the same mechanism of action , in different ways . Another medication , such as certolizumab pegol , is a welcome addition to our treatment armamentarium of rheumatoid arthritis . AREAS COVERED IN THIS REVIEW : The basis of this review is all the peer - reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years . WHAT THE READER WILL GAIN : This review should enable the reader to fully understand the benefit : risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis . TAKE HOME MESSAGE : DB08904 is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved P01375 inhibitors .",
"Profile of certolizumab and its potential in the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory arthropathy associated with psoriasis ( PsO ) . PsA could be considered an enthesal disease because of the link between mechanical stress ( entheses ) and immunologically active tissue ( synovium ) . Evidence of efficacy of anti - tumor necrosis factor alpha ( P01375 - α ) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment . DB08904 ( CZP ) is a polyethylene glycolylated ( PEGylated ) Fab ' fragment of a humanized monoclonal antibody that binds and neutralizes human P01375 - α . The PEG moiety of the Fab fragment , markedly increases the half - life of CZP and confers to the drug a unique structure that differs from the other anti - P01375 - α agents tested for the treatment of Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , axial spondyloarthritis , nonradiographic spondyloarthritis , PsO , and PsA . In contrast to other anti - P01375 - α agents , CZP did not mediate increased levels of apoptosis , suggesting that these mechanisms are not essential for the anti - P01375 - α efficacy in Crohn ' s disease . As CZP , infliximab , and adalimumab , but not etanercept , almost completely inhibited lipopolysaccharide - induced interleukin - 1 beta release from monocytes , this cytokine - production inhibition may be relevant for drug efficacy . Due to these characteristics , it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO , with a safety profile similar to rheumatoid arthritis . This drug can be considered as a valid treatment in patients affected by PsA . The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA .",
"___MASK35___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK35___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"Pulmonary infectious complications of tumor necrosis factor blockade . The understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs first were introduced . Recent prospective studies have confirmed the risk of tuberculosis ( TB ) reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment , appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 or activate complement . Two - step ( boosted ) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of P01375 - dependent inflammation . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases .",
"Prefilled certolizumab pegol ( Cimzia (®) ) syringes for self - use in the treatment of rheumatoid arthritis . A new anti - tumor necrosis factor alpha ( P01375 - α ) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis ( RA ) . DB08904 ( Cimzia (®) ) is a humanized Fab ' antibody fragment against P01375 - α with a polyethylene glycol tail that prevents complement - dependent and antibody - dependent cell - mediated cytotoxicity or apoptosis . Four randomized clinical trials have been published so far . Reported results are similar to those published in previous studies with other P01375 - α inhibitors , with ACR20 , ACR50 , and ACR70 responses of around 60 % , 40 % , and 20 % , respectively , when combined with methotrexate and slightly lower when used as monotherapy . Safety was shown to be similar to that seen with P01375 - α blockers and some cases of tuberculosis were seen in the trials , stressing the importance of a complete screening in these patients . Although we still need effectiveness and safety data in larger numbers of patients and longer follow - up , this new P01375 inhibitor is a welcome addition to our current armamentarium for the treatment of RA .",
"The efficacy and safety of certolizumab pegol ( CZP ) in the treatment of active rheumatoid arthritis ( RA ) : a meta - analysis from nine randomized controlled trials . OBJECTIVE : DB08904 ( CZP ) is a novel anti - P01375 agent that is used for patients with moderate to severe active rheumatoid arthritis ( RA ) . However , the efficacy of CZP in RA remains controversial . Thus , we performed this meta - analysis to assess the efficacy and safety of CZP in the treatment of RA patients . METHODS : Eligible studies were randomized controlled trials ( RCTs ) that evaluated the efficacy and safe of CZP in the patients with active RA . The primary outcome was American College of Rheumatology 20 % ( ACR20 ) , and secondary outcome were ACR50 , ACR70 , disease activity , patient - reported outcomes ( PROs ) , and adverse events . A fixed - effect model or random - effect model was used to pool the estimates , depending on the absence or presence of heterogeneity among the included studies . RESULTS : Nine RCTs with a total of 5228 patients were included in this meta - analysis , and all of the patients were administered CZP or placebo . The pooled results showed that CZP significantly improved the ACR20 , ACR50 , ACR70 response rates , and physical function . CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints - Erythrocyte sedimentation rate , arthritis pain , and fatigue . Patients who received CZP treatment did not have a higher incidence of treatment - related adverse events , no matter in any intensity . CONCLUSIONS : CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms , and improved physical function as compared with the placebo . More large - scale RCTs are needed to evaluate the long - term efficacy and safety of CZP in the treatment of active RA .",
"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK63___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .",
"Treatment of Crohn ' s disease with certolizumab pegol . Biologic therapies have revolutionized the treatment of Crohn ' s disease ( CD ) . Targeting P01375 with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD . Intravenous use of infliximab , a chimeric monoclonal antibody to P01375 is , however , limited by the occurrence of adverse events , infusion reactions , infectious complications , aggravation of heart failure , the occurrence of neurological demyelinating conditions and induction of rare malignancies . The incremental development of next - generation P01375 antibodies and binding proteins through antibody - engineering techniques has followed , with the aim of producing efficacious drugs that are less expensive to produce , have a convenient route of administration and have fewer side effects . DB08904 ( DB08904 , Cimzia ) is an engineered humanized anti - P01375 antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol . Clinical studies have demonstrated efficacy in the treatment of moderate - to - severe active CD . Reported adverse events in the clinical trial program have been largely of mild - to - moderate severity , and occurred at similar frequencies in the active - treatment and placebo groups . DB08904 will be a useful addition to the armamentarium of biologic agents that can be used for the long - term treatment of CD .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK71___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Autosomal - dominant hypophosphatemic rickets ( P30518 ) mutations stabilize Q9GZV9 . BACKGROUND : The gene for the renal phosphate wasting disorder autosomal - dominant hypophosphatemic rickets ( P30518 ) is Q9GZV9 , which encodes a secreted protein related to the fibroblast growth factors ( FGFs ) . We previously detected missense mutations R176Q , R179W , and R179Q in Q9GZV9 from P30518 kindreds . The mutations replace R residues within a subtilisin - like proprotein convertase ( Q969E3 ) cleavage site 176RHTR - 179 ( RXXR motif ) . The goal of these studies was to determine if the P30518 mutations lead to protease resistance of Q9GZV9 . METHODS : The P30518 mutations were introduced into human Q9GZV9 cDNA clones with or without an N - terminal FLAG tag by site - directed mutagenesis and were transiently transfected into HEK293 cells . Protein expression was determined by Western analyses . RESULTS : Antibodies directed toward the C - terminal portion of Q9GZV9 revealed that the native Q9GZV9 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media ; however , the three mutated proteins were detected only as the 32 kD band . An N - terminal FLAG - tagged native Q9GZV9 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody , whereas the R176Q mutant resolved primarily as the 36 kD protein species . Cleavage of Q9GZV9 was not enhanced by extracellular incubation of Q9GZV9 with HEK293 cells . Native and mutant FGF - 23s bound heparin . CONCLUSIONS : Q9GZV9 proteins containing the P30518 mutations are secreted , and produce polypeptides less sensitive to protease cleavage than wild - type Q9GZV9 . Therefore , the P30518 mutations may protect Q9GZV9 from proteolysis , thereby potentially elevating circulating concentrations of Q9GZV9 and leading to phosphate wasting in P30518 patients .",
"The use of P01375 blocking agents in rheumatoid arthritis : an update . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are , at present , three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate : 2 monoclonal antibodies , infliximab and adalimumab , and a fusion protein with p75 receptors , etanercept . These three agents have proved to be effective and safe in large placebo - controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease , improving quality of life and in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs were described serious adverse events , particularly infections such as tuberculosis , especially with infliximab . The risk for malignancies under P01375 antagonists , especially lymphoma , remains controversial . Specific recommendations are given by international experts for selecting and monitoring RA patients with P01375 antagonists . Other drugs targeting P01375 such as PEGylated molecules ( DB08904 or certolizumab ) are in development . These new biological therapies blocking P01375 undoubtedly constitute a considerable advancement in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK13___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Strategies for targeting tumour necrosis factor in Q9UKU7 . Tumour necrosis factor ( P01375 ) plays an important role in mediating the inflammation of inflammatory bowel disease , in particular , Crohn ' s disease . Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse / human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP571 , the human soluble P01375 p55 receptor onercept , the human monoclonal antibody D2E7 ( adalimumab ) , the anti - P01375 human antibody Fab ' fragment - polyethelene glycol ( PEG ) conjugate DB08904 , and the small molecules thalidomide and CNI - 1493 ( Q96HU1 - kinase inhibitor ) . DB00065 is effective for treating active Crohn ' s disease , maintaining remission , closing fistulas , maintaining fistula closure , and treating ankylosing spondylitis . DB00065 is also being investigated for the treatment of ulcerative colitis . Side - effects occurring in patients treated with infliximab include human anti - chimeric antibodies , infusion reactions , delayed hypersensitivity reactions , formation of autoantibodies , and , in rare circumstances , drug - induced lupus and serious infections , including tuberculosis . CDP571 is effective for treating active Crohn ' s disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side - effects occurring in patients treated with CDP571 include anti - idiotype antibodies , infusion reactions and the formation of autoantibodies . A controlled trial of etanercept in patients with Crohn ' s disease was negative . Pilot studies with onercept , thalidomide , and CNI - 1493 have suggested benefit for Crohn ' s disease . There are no published data on the efficacy of adalimumab ( D2E7 ) or DB08904 for either Crohn ' s disease or ulcerative colitis . Anti - tumour necrosis factor therapies are effective for the treatment of Crohn ' s disease and are being investigated for ulcerative colitis .",
"Optimizing anti - tumor necrosis factor strategies in inflammatory bowel disease . The introduction of infliximab , a mouse / human chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , is an important advance in the treatment of Crohn ' s disease . DB00065 is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease . The development of human antichimeric antibodies ( HACAs ) has led to infusion reactions and loss of efficacy in patients treated with infliximab . Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three - dose regimen at 0 , 2 , and 6 weeks followed by systematic maintenance dosing every 8 weeks ; concomitant immunosuppressive therapy with azathioprine , 6 - mercaptopurine , or methotrexate ; and premedication with intravenous corticosteroids . Humanized or fully human anti - P01375 biotechnologic agents , including CDP571 , DB08904 , etanercept , adalimumab , and onercept , are theoretically less immunogenic than the chimeric antibody infliximab . DB00005 is not effective for Crohn ' s disease . CDP571 is not effective in unselected patients with active Crohn ' s disease , but it may be effective in patients with elevated P02741 . The efficacy of DB08904 , adalimumab , and onercept is under investigation . The different mechanisms of action of these anti - P01375 agents may account for their variable efficacy . Their benefits , however , must be considered in the context of their risks , including infusion reaction ; delayed hypersensitivity - like reaction ; new onset of autoimmunity , with rare cases of drug - induced lupus and new - onset demyelination ; and the potential for rare but serious infections .",
"Efficacy and safety of certolizumab pegol in rheumatoid arthritis : meeting rheumatologists ' requirements in routine clinical practice . DB08904 , a pegylated Fab ' anti - tumour necrosis factor ( P01375 ) - α agent , has shown efficacy in patients with rheumatoid arthritis ( RA ) unresponsive to previous treatment . In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease - modifying antirheumatic drug ( DMARD ) , the efficacy of certolizumab pegol , as monotherapy or with methotrexate , was similar to that reported in other anti - P01375 clinical studies , with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA . Rapid clinical response was also seen , with significant differences evident at week 1 , and efficacy maintained at study end and in open - label extensions . Adding certolizumab pegol to non - biological DMARDs is efficacious in other RA populations . In the CERTAIN study , certolizumab increased remission rates , prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA . In the REALISTIC study , rapid and consistent clinical responses were observed in a diverse group of anti - P01375 - eligible RA patients representing those seen in clinical practice . In the RAPID studies , rapid and sustained reduction in RA signs and symptoms , inhibition of structural joint damage progression , and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate . DB08904 was generally well - tolerated in clinical trials , although long - term observational data are not yet available . Current data suggest that certolizumab pegol suits a ' treat to target ' approach , providing rapid and sustained improvements in RA signs and symptoms , and beneficial effects on workplace and home productivity in patients with RA .",
"DB08904 -- what role does this new P01375 inhibitor have in the treatment of RA ? The efficacy and safety of a new tumor necrosis factor inhibitor , certolizumab pegol , in active rheumatoid arthritis has now been assessed in three phase III , multicenter , randomized , double - blind , placebo - controlled clinical trials . This commentary focuses on the paper by Keystone et al . , in which patients were followed for the longest duration . This study , which compared two doses of subcutaneous certolizumab pegol with placebo in patients with active RA receiving methotrexate , showed no advantage of 400 mg over 200 mg certolizumab pegol over 52 weeks , after induction with 400 mg . The nature of the patients enrolled in this study , trial design and possible safety issues are discussed , as is whether this trial can teach us anything about tumor necrosis factor inhibitors in general . On the basis of the results from this study , certolizumab pegol does not represent a major addition to our armamentarium , but because of the slightly different mechanism of action and structure of this drug , and the apparently acceptable therapeutic effects over one year , it is , nevertheless , welcome .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK9___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn ' s disease . INTRODUCTION : P01375 - α antagonists have transformed the treatment of patients with Crohn ' s disease ( CD ) . DB08904 ( CZP ) is the third P01375 - α antagonist to be approved for use in the United States but is not currently approved in Europe . AREAS COVERED : This review evaluates the pharmacokinetics , pharmacodynamics and efficacy of CZP in CD . Safety , immunogenicity and its use in pregnancy have also been assessed . A literature search was conducted using Pub Med ( 2004 - 2014 ) for the terms ' Crohn ' s disease ' and ' certolizumab pegol ' or ' certolizumab ' or ' cimzia ' . Additional studies were identified from other sources including citation . EXPERT OPINION : As a Fab ' fragment , CZP is effective in binding P01375 - α , but does not cause Fc - mediated effects . PEGylation has improved its pharmacokinetic profile and allowed for an increased half - life of 2 weeks . Benefit for inducing response ( an improvement in symptoms ) and maintenance of remission has been shown . However , the benefit is less clear for the more stringent end - points of inducing remission and mucosal healing . There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection - site reactions , reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab .",
"DB08904 for the treatment of Crohn ' s disease . In this article we provide a contemporary overview of available clinical data on certolizumab pegol , a pegylated anti - tumor necrosis factor ( P01375 ) alpha agent that comprises a uniquely small protein , and its emerging role as a therapy for Crohn ' s disease ( CD ) . The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD . DB08904 is an effective and well - tolerated therapy both in patients who have already received biologics and in patients who are anti - P01375 naïve . Benefits of therapy include a stable dosing regimen , which allows for rapid induction of a clinical response followed by long - term maintenance of response and remission under one fixed dose . Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD , and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression . Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients .",
"The attenuation of experimental lung metastasis by a bile acid acylated - heparin derivative . The inhibitory efficacies of new bile acid acylated - heparin derivative ( heparin - DOCA ) were evaluated on experimental lung metastasis . We evaluated the effect of heparin - DOCA on intercellular interactions including those between B16F10 and thrombin - activated platelets and P01375 - activated HUVECs , and between B16F10 and immobilized mouse P16109 . In addition , the inhibitory effects of heparin - DOCA on adhesion and invasion of B16F10 to Matrigel were studied . In an animal mouse study , the blood clot formation and the retention of red fluorescence protein ( RFP ) - B16F10 in lungs were assessed after heparin - DOCA and RFP - B16F10 intravenous administration . Furthermore , we investigated the anti - metastatic effect of heparin - DOCA against lung metastasis induced by B16F10 and SCC7 . ___MASK41___ - DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P - and P16581 - mediated interactions . Moreover , it reduced adhesion and invasion of B16F10 to Q13201 , thereby affecting the reduction of early retention of B16F10 in the lung . ___MASK41___ - DOCA attenuated lung colony formation on the surfaces and in interior of the lung , and attenuated metastasis by B16F10 and SCC7 . These results suggest that heparin - DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression .",
"DB08904 in the treatment of Crohn ' s disease . INTRODUCTION : The introduction of antibodies directed against tumour necrosis factor ( anti - P01375 ) has dramatically changed the concept of treating patients with Crohn ' s disease ( CD ) . Unfortunately , the long - term efficacy of anti - P01375 agents may be hampered by immunogenicity . The availability of more anti - P01375 agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti - P01375 . In this review , the authors will focus on the efficacy of certolizumab pegol ( CZP ) . AREAS COVERED : A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD . The authors first focused on the mechanism of action of CZP . Second , they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure . Next , they explored the influence of previous anti - P01375 exposure and baseline P02741 levels . Finally , they analysed the safety data on CZP , including the development of antibodies against CZP and the use of CZP during pregnancy . EXPERT OPINION : Based on the provided literature , CZP could be a good alternative in patients with moderate - to - severe CD failing another anti - P01375 agent . More data are required to conclude on its impact on the long - term outcome of CD .",
"Pegylation of biological molecules and potential benefits : pharmacological properties of certolizumab pegol . PEGylation of biological proteins , defined as the covalent conjugation of proteins with polyethylene glycol ( PEG ) , leads to a number of biopharmaceutical improvements , including increased half - life , increased solubility and reduced aggregation , and reduced immunogenicity . Since their introduction in 1990 , PEGylated proteins have significantly improved the management of various chronic diseases , including rheumatoid arthritis ( RA ) and Crohn ' s disease . DB08904 is the only PEGylated anti - tumour necrosis factor ( P01375 ) - α agent . It is a PEGylated , humanised , antigen - binding fragment of an anti - P01375 monoclonal antibody . Unlike other anti - P01375 agents , it has no crystallisable fragment ( Fc ) domain . Because of its novel structure , certolizumab pegol may have a different mechanism of action to the other anti - P01375 agents , and also has different pharmacodynamic properties , which could possibly translate to a different safety profile . Pharmacodynamic studies have shown that certolizumab pegol binds to P01375 with a higher affinity than adalimumab and infliximab . DB08904 is also more potent at neutralising soluble P01375 - mediated signalling than adalimumab and infliximab , and has similar or lesser potency to etanercept . DB08904 does not cause detrimental in vitro effects such as degranulation , loss of cell integrity , apoptosis , complement - dependent cytotoxicity and antibody - dependent cell - mediated cytotoxicity . DB08904 may also penetrate more effectively into inflamed arthritic tissue than other anti - P01375 agents , and is not actively transported across the placenta during pregnancy . Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics . The pharmacokinetics of certolizumab pegol in patients with RA and Crohn ' s disease were consistent with pharmacokinetics in healthy volunteers .",
"DB08904 compared to natalizumab in patients with moderate to severe Crohn ' s disease : results of a decision analysis . INTRODUCTION : A significant proportion of patients with Crohn ' s disease ( CD ) lose response to antibodies directed against tumor necrosis factor α ( P01375 ) . Prior P01375 - antagonist failure is associated with lower rates of response to subsequent P01375 - antagonist therapy . In patients failing two anti - P01375 agents , a choice exists between using a third - anti - P01375 therapy or natalizumab ( NAT ) , an α - 4 integrin inhibitor . A cost - effectiveness analysis comparing these competing strategies has not been performed . METHODS : A decision analytic model was constructed to compare the performance of certolizumab pegol ( CZP ) versus NAT in patients with moderate to severe CD . Previously published estimates of efficacy of third - line anti - P01375 therapy and NAT were used to inform the model . Costs were expressed in 2010 US dollars . A 1 - year time frame was used for the analysis . RESULTS : In the base case estimate , use of NAT was only marginally more effective [ 0 . 71 vs . 0 . 70 quality adjusted life - years ( QALYs ) ] than CZP but was expensive with an incremental cost - effectiveness ratio ( Q03060 ) of $ 381 , 678 per QALY gained . For CZP 2 months response rate of at least 24 % , NAT had an Q03060 above the willingness - to - pay ( WTP ) threshold . The model was sensitive to the costs of both therapies ; for all CZP costs below $ 2 , 300 per dose , NAT had higher Q03060 than the WTP threshold . Substituting adalimumab for CZP resulted in similar Q03060 estimates and thresholds for NAT use . CONCLUSIONS : In patients with moderate to severe CD failing two P01375 - antagonists , using a third P01375 - antagonist therapy appears to be a cost - effective strategy without significantly compromising treatment efficacy .",
"DB08904 : an evidence - based review of its place in the treatment of Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing / remitting course with transmural inflammation of potentially any section of the digestive tract . DB08904 ( CZP ) is a pegylated Fc - free Fab ' fragment of a humanized anti - P01375 - alfa monoclonal antibody that is in development for clinical use in CD . AIMS : To review the available data with CZP in CD , to investigate its possible place in therapy . EVIDENCE REVIEW : Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD , and to improve quality of life compared with placebo . Further studies with CZP are also ongoing . PLACE IN THERAPY : Although only suggested by currently available studies , successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti - P01375 treatment in CD . The impact on clinical management or on resources can not be estimated until the results from all phase III clinical trials are available and the price is determined .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK47___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK47___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Randomised clinical trial : improvement in health outcomes with certolizumab pegol in patients with active Crohn ' s disease with prior loss of response to infliximab . BACKGROUND : Crohn ' s disease ( CD ) is associated with impaired health - related quality of life ( HRQoL ) . DB08904 , administered either every 2 weeks ( q2w ) or q4w , maintains efficacy in patients previously failing on the anti - P01375 agent infliximab ( WELCOME study ) . AIM : To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study . METHODS : Patients with loss of response to infliximab received open - label certolizumab pegol induction and were randomised to receive double - blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24 , with a final evaluation at week 26 . Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment : CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively . RESULTS : Baseline HRQoL burden was representative of moderately to severely active CD . HRQoL , daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26 . Treatment benefits to HRQoL , daily activity and work productivity were similar between the certolizumab pegol q2w vs . q4w groups . CONCLUSIONS : DB08904 therapy results in meaningful improvements in work productivity , daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab ( ClinicalTrials . gov number : NCT00308581 ) .",
"Anti - P01375 therapy in Crohn ' s disease . Anti - tumour necrosis factor ( P01375 ) strategies , the most studied of biological therapies , include chimeric monoclonal ( infliximab ) , humanized monoclonal ( CDP571 and the PEGylated DB08904 ) and fully human monoclonal ( adalimumab ) antibodies , p75 fusion protein ( etanercept ) , p55 soluble receptor ( onercept ) and small molecules such as MAPkinase inhibitors . The principal use of infliximab is in treating active Crohn ' s disease patients not responding to or intolerant of conventional therapies . DB00065 is steroid sparing . The development of antibodies against infliximab is associated with an increased risk of infusion reactions , and a reduced duration of response to treatment , and concomitant immunosuppressive therapy reduces the immunogenic response . The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised , controlled , ACCENT I trial opened up the strategy for regular maintenance . In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates , and patients with fistulizing disease , where infliximab therapy is chosen , regular maintenance therapy with infliximab is likely to be required . On the other hand , patients with severely active , steroid - refractory disease in whom immunosuppressive therapy and infliximab are initiated together , may respond adequately and be continued on long - term immunosuppressive therapy alone . In ulcerative colitis the role of infliximab remains uncertain .",
"Targeting nanomedicines in the treatment of Crohn ' s disease : focus on certolizumab pegol ( DB08904 ) . A variety of targets for therapeutic intervention are based upon advances in understanding of the immunopathogenesis of Crohn ' s disease . Crohn ' s disease is initiated by an innate immune response , which eventuates in a T - cell driven process , characterized by a T - helper cell 1 type cytokine profile . Several new treatments now focus on suppressing T - cell differentiation or T - cell inflammation . Since inflammatory bowel disease ( Q9UKU7 ) represents a state of dysregulated inflammation , drugs that augment the anti - inflammatory response have the potential to downregulate inflammation and thereby hopefully modify the disease . Tumour necrosis factor ( P01375 ) is a major target of research and clinical investigation . P01375 has proinflammatory effects in the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade . DB08904 ( DB08904 ) is a PEGylated , Fab ' fragment of a humanized anti - P01375 monoclonal antibody . PEGylation increases the half - life , reduces the requirement for frequent dosing , and possibly reduces antigenicity as well . Certolizumab has been shown in Phase III trials to achieve and maintain clinical response and remission in Crohn ' s disease patients . It improves the quality of life . DB08904 will be indicated for moderately to severely active Crohn ' s disease , but it is not yet licensed in Europe or the US . It is not possible to construct an algorithm for treatment , but when compared with infliximab the two principal advantages are likely to be lower immunogenicity ( as shown by anti - drug antibodies , absence of infusion reactions , and low rate of antinuclear antibodies ) , and a subcutaneous route of administration . These two factors may be sufficient to promote it up the pecking order of anti - P01375 agents .",
"DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"DB08904 : a review of its use in the management of rheumatoid arthritis . DB08904 ( Cimzia (®) ) is a recombinant , polyethylene glycolylated , antigen - binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor ( P01375 ) - α . The drug is indicated for subcutaneous use every 2 or 4 weeks ( q2w or q4w ) for the treatment of adults with moderate to severe active rheumatoid arthritis ( RA ) . The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed , placebo - controlled trials . In four pivotal studies of ≤ 52 weeks duration , patients with moderate to severe disease receiving recommended dosages of certolizumab pegol ( 200 mg q2w or 400 mg q4w ) , either as monotherapy ( after failing prior disease - modifying anti - rheumatic drug [ DMARD ] therapy ) or in combination with methotrexate ( after responding inadequately to methotrexate alone ) , experienced rapid clinical improvement , with some combination trials also demonstrating inhibition of radiographic progression . The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈ 5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w . Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity , as well as more clinically representative patient populations . The tolerability profile of certolizumab pegol was acceptable , with infections / infestations the most common adverse events . Thus , certolizumab pegol is an effective option for the management of active RA in adults , although additional long - term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs , particularly other anti - P01375 agents .",
"DB08904 : a new biologic targeting rheumatoid arthritis . The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis . This is mostly due to targeted biologic agents that have changed the outcome of this disease . DB08904 ( Cimzia (®) , UCB Inc . , GA , USA ) , which targets P01375 - α with a different mechanism of action than widely used biologics , was initially investigated for Crohn ' s disease but has now been shown to be effective for rheumatoid arthritis . There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis ; two with combination methotrexate and one with monotherapy . This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease - modifying antirheumatic drugs and other biologic agents . Treatment recommendations are beyond the scope of this review ; however , with many options available , there will be annotations on current trends in the care of this chronic disease .",
"Current directions of biologic therapies in inflammatory bowel disease . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . A greater understanding of their pathophysiology has led to new therapies that target specific molecules of the inflammatory cascade . Three anti - tumor necrosis factor ( P01375 ) monoclonal antibodies have been developed . DB00065 and adalimumab can induce clinical response and sustained remission in CD . DB00065 is also effective in UC . DB08904 gives good short - term results but long - term efficacy has yet to be determined in other clinical trials . Therapies that target leucocyte trafficking ( anti - integrins ) have also been developed and are associated with good clinical response in CD . DB00108 ( anti - α4 integrin antibody ) is associated with important side effects and is not used anymore in gastroenterology in Europe but is still used in the USA . DB09033 ( MLN0002 ) , an anti - α4β7 integrin antibody , has a good efficacy and safety profile . Monoclonal antibodies targeting other cytokines are also under development . For example , ustekinumab ( CNTO 1275 ) inhibits interleukins 12 and 23 . It is associated with a good clinical response in CD .",
"P01375 and its inhibitors in cancer . P01375 ( P01375 ) - alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro - inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti - tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long - term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use .",
"The cytotoxic effects of certolizumab pegol and DB06674 mediated by transmembrane tumor necrosis factor α . BACKGROUND : Anti - tumor necrosis factor α ( anti - P01375 - α ) agents have been successfully applied for the treatment of rheumatoid arthritis , Crohn ' s disease , and other chronic inflammatory diseases . Not only the neutralization of soluble P01375 - α but also the effect on transmembrane P01375 - α is important mechanisms of action of anti - P01375 - α agents . This study investigated the cytotoxic effects of new anti - P01375 - α agents , certolizumab pegol and DB06674 , which are mediated by transmembrane P01375 - α . METHODS : Transmembrane P01375 - α - expressing Jurkat T cells that did not express P01375 receptors were used . The binding ability of each anti - P01375 - α agent to transmembrane P01375 - α , antibody - dependent cell - mediated cytotoxicity , complement - dependent cytotoxicity , and the apoptotic effect were examined . RESULTS : DB08904 and DB06674 bound to transmembrane P01375 - α . Golimumab induced antibody - dependent cell - mediated cytotoxicity and complement - dependent cytotoxicity , which was comparable to infliximab and adalimumab . However , certolizumab pegol did not induce antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity . DB08904 directly induced nonapoptotic cell death in transmembrane P01375 - α - expressing cells . Golimumab induced a weaker apoptotic effect than infliximab and adalimumab . CONCLUSIONS : The cytotoxic effects of anti - P01375 - α agents on P01375 - α - expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases . The direct cytotoxic effect of certolizumab pegol on P01375 - α - producing cells may contribute to its clinical efficacy in Crohn ' s disease . Golimumab may be less effective for granulomatous diseases .",
"Infectious complications of tumor necrosis factor blockade . PURPOSE OF REVIEW : Our understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs were first introduced . This review summarizes recent data regarding infection risk , examines potential structure - function relationships that may account for the differences , and discusses their implications with regard to tuberculosis prevention and management . RECENT FINDINGS : Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 . Screening and initiation of treatment for latent tuberculosis ( TB ) infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . However , alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of P01375 - dependent inflammation . Recent case reports suggest reinstitution of P01375 blockade may be safe and effective adjunctive treatment in such cases , but prospective studies are needed to confirm these observations . SUMMARY : P01375 blockers have transformed treatment of several chronic inflammatory conditions . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases .",
"Q9GZV9 contributes to diminished bone mineral density in childhood inflammatory bowel disease . BACKGROUND : Diminished bone mineral density ( BMD ) is of significant concern in pediatric inflammatory bowel disease ( Q9UKU7 ) . Exact etiology is debatable . The recognition of fibroblast growth factor 23 ( Q9GZV9 ) , a phosphaturic hormone related to tumor necrosis factor alpha ( P01375 - α ) makes it plausible to hypothesize its possible relation to this pathology . METHODS : In this follow up case control study , BMD as well as serum levels of Q9GZV9 , calcium , phosphorus , alkaline phosphatase , creatinine , parathyroid hormone , 25 hydroxy vitamin D3 and 1 , 25 dihydroxy vitamin D3 were measured in 47 children with Q9UKU7 during flare and reassessed in the next remission . RESULTS : Low BMD was frequent during Q9UKU7 flare ( 87 . 2 % ) with significant improvement after remission ( 44 . 7 % ) . During disease flare , only 21 . 3 % of patients had vitamin D deficiency , which was severe in 12 . 8 % . During remission , all patients had normal vitamin D except for two patients with Crohn ' s disease ( CD ) who remained vitamin D deficient . Mean value of serum Q9GZV9 was significantly higher among patients with Q9UKU7 during flare compared to controls . It showed significant improvement during remission but not to the control values . 1 , 25 dihydroxy vitamin D3 , Q9GZV9 , serum calcium and urinary phosphorus were significant determinants of BMD in Q9UKU7 patients . CONCLUSIONS : We can conclude that diminished BMD in childhood Q9UKU7 is a common multifactorial problem . Elevated Q9GZV9 would be a novel addition to the list of factors affecting bone mineral density in this context . Further molecular studies are warranted to display the exact interplay of these factors .",
"[ Biologic therapies in chronic inflammatory bowel diseases ] . Crohn ' s disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . Thanks to a better knowledge of their physiopathology , new therapies aimed at specific targets of the inflammatory cascade were developed . Three monoclonal anti - P01375 antibodies were produced . DB00065 and adalimumab , currently widely used , can induce sustained remission in Crohn ' s disease . DB00065 is also efficacious in UC . DB08904 provides good short term results ; its long term efficacy , however , remains to be assessed by further clinical trials . Therapies targeting leucocyte trafficking ( anti - integrine ) have also been provided and are associated with good clinical responses in Crohn ' s disease . DB00108 ( anti - alpha4 ) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 ( anti - alpha417 ) has a good profile in terms of efficacy and safety . Monoclonal anti bodies targeting other cytokines are under development , mainly ustekinumab which inhibits IL12 and IL23 . Ustekinumab generates favourable clinical responses in Crohn ' s disease . The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders .",
"The use of P01375 blocking agents in rheumatoid arthritis : an overview . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . The overexpression of P01375 in RA synovium , the data from in vitro synovial cell cultures with the use of anti - P01375 antibody and the results from P01375 blockade in animal models of arthritis argued for the importance of this cytokine in RA . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are currently three drugs available in the treatment of RA patients with active disease , which was refractory to conventional treatments including methotrexate , infliximab ( a chimeric mouse / human monoclonal antibody ) , etanercept ( a fusion protein combining 2 p75 P01375 receptors with a Fc fragment of human IgG ( 1 ) ) and adalimumab ( a fully human monoclonal antibody ) . These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs serious adverse events were described , particularly intracellular organism infections such as tuberculosis . Other drugs targeting P01375 are in development and include monoclonal antibody ( CDP571 ) , pegylated molecules ( DB08904 and PEG - r - Hu - sTNF - RI ) or soluble p55 P01375 receptor construct ( lenercept ) . These new biological therapies blocking P01375 undoubtedly constitute a considerable advance in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"[ Treatment of patients with destructive arthritis with certolizumab pegol ] . DB08904 is a new anti - P01375 inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009 . Due to the modification of the antibody fragment by the adherence of polyethylene glycol ( PEG ) a sufficient distribution in inflammatory tissue was found in animal experiments . In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol .",
"DB08904 for the treatment of rheumatoid arthritis . INTRODUCTION : Improved understanding of the pathogenesis of rheumatoid arthritis ( RA ) , and subsequent development of targeted therapies , have greatly advanced the management of this chronic inflammatory disease . The aim of treatment is a state of clinical remission . DB08904 ( CZP ) is a novel pegylated P01375 alpha inhibitor ( TNFi ) therapy and is the focus of this review . AREAS COVERED : CZP is different from other TNFi as it contains a polyethylene glycol ( PEG ) moiety , and lacks the constant fragment ( Fc ) of immunoglobulin ; therefore it does not activate complement . In this review in addition to clinical efficacy of CZP , effects on radiographic and patient - reported outcomes , are discussed . Adverse event data from clinical trials and extension studies are also reviewed . EXPERT OPINION : The addition of novel TNFi therapies to treat RA is welcomed . As well as displaying clinical efficacy , there is evidence to suggest that CZP has unique characteristics , including reduced transfer across the placenta and reduced frequency of injection site reactions . Furthermore , randomised controlled trials ( RCTs ) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA .",
"A review and expert opinion of the use of certolizumab for Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the last decade , one of the most significant developments in therapy has been a class of biological agents that neutralize TNFa . DB08904 ( CZP ) is the most recently FDA approved anti - P01375 agent for the induction and maintenance of moderate to severely active Crohn ' s disease . AREAS COVERED : The currently available evidence regarding the use of CZP in CD , the expected efficacy and possible adverse events associated with this population . EXPERT OPINION : CZP is a TNFa inhibitor that is a safe and effective agent for treatment of CD . It has several unique features which make it useful in patients with moderate to severe disease .",
"New concepts in anti - tumor necrosis factor therapy for inflammatory bowel disease . Crohn ' s disease is a T helper type 1 response immune disease characterized by increased production of interleukin - 12 tumor necrosis factor - a ( P01375 ) , and interferon - g . Clinical trials have demonstrated that inhibition of P01375 is effective for the treatment of Crohn ' s disease . Adverse events reported in patients treated with anti - P01375 agents include immunogenicity , acute infusion reactions , delayed hypersensitivity - type reactions , autoimmune diseases including drug - induced lupus and demyelination , and infection . This article reviews new concepts in the treatment of Crohn ' s disease and ulcerative colitis with a variety of anti - P01375 biologic therapies : infliximab , adalimumab , DB08904 , CDP571 , etanercept , and onercept .",
"Recommendations for the treatment of Crohn ' s disease with tumor necrosis factor antagonists : an expert consensus report . BACKGROUND : Symptom relief is the traditional treatment goal in Crohn ' s disease ( CD ) . New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor ( P01375 ) antagonists . DB00065 and adalimumab are approved as second - line treatments for severe , active CD . DB08904 is approved only in the U . S . and Switzerland as second - line treatment for moderate - to - severe , active CD . Data from trials of infliximab suggest that high - risk patients and patients with active inflammation ( CRP elevation and / or ileocolonic ulcers ) may benefit from earlier use of this drug . METHODS : A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of P01375 antagonists . At the time of this survey , infliximab was the only P01375 antagonist approved for the treatment of CD in Europe , Canada , and Australia . An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated . RESULTS : The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals , and form a rationale for using P01375 antagonists in CD patients . Control of inflammation and induction of mucosal healing were considered essential for bowel preservation . Consensus areas : 1 ) mucosal healing is predictive of improved long - term disease course and increases the likelihood of steroid - free remission ; 2 ) infliximab induces sustained mucosal healing , promotes bowel preservation , and reduces hospitalizations and surgeries ; 3 ) benefits of infliximab in relation to mucosal healing , bowel preservation , and clinical remission increase when therapy is initiated earlier . CONCLUSIONS : Treatment with P01375 antagonists helps preserve the bowel in CD patients .",
"Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK87___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK87___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK87___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK87___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .",
"DB08904 attenuates the pro - inflammatory state in endothelial cells in a manner that is atheroprotective . OBJECTIVES : Rheumatoid arthritis ( RA ) is associated with accelerated atherosclerosis and premature cardiovascular death . Anti - P01375 therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients . However , the specific effects of P01375 inhibitors on endothelial cell function are largely unknown . Our aim was to explore the effects of certolizumab pegol ( CZP ) on P01375 - activated human aortic endothelial cells ( HAoECs ) . METHODS : HAoECs were cultured in vitro and exposed to i ) P01375 alone , ii ) P01375 plus CZP , or iii ) neither agent . Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression . Activation of NF - κB was investigated using immunocytochemistry , high content analysis and western blotting . Flow cytometry was performed to detect microparticle release from HAoECs . RESULTS : P01375 alone had strong effects on endothelial gene expression , while P01375 and CZP together produced a global gene expression pattern similar to untreated controls . In particular , genes for P16581 , P19320 and P05362 were significantly up - regulated by P01375 treatment . Notably , the P01375 / CZP cocktail prevented the up - regulation of these genes . P01375 - induced nuclear translocation of NF - κB was abolished by treatment with CZP . In addition the increased production of endothelial microparticles in P01375 - activated HAoECs was prevented by treatment with CZP . CONCLUSIONS : We have found at cellular level , that a clinically available P01375 inhibitor , CZP i ) reduces adhesion molecule expression ; ii ) prevents P01375 - induced activation of the NF - κB pathway and iii ) prevents the production of microparticles by activated endothelial cells . This could be central to the prevention of inflammatory environments underlying these conditions .",
"DB08904 and rheumatoid arthritis . Just another P01375 alpha antagonist , no therapeutic advantage . No comparison with other P01375 alpha antagonists ; possible bleeding risk .",
"[ DB08904 ] . DB08904 is a new anti - P01375 drug formed by the Fab ' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol . DB08904 recognizes and binds to human P01375 - α , both in its soluble and membrane bound form , and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns ' disease . In this review we summarize the structural characteristics and clinical efficacy data , as well as safety data of this anti - P01375 agent in patients with RA .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"DB08904 for the treatment of psoriatic arthritis . DB08904 ( CZP ) is a P01375 - α inhibitor approved for the treatment of psoriatic arthritis in 38 countries , including many European countries and the USA . It is a pegylated humanized anti - P01375 - α antigen - binding fragment , administered subcutaneously . As other P01375 - α antibodies , CZP binds to and neutralizes both soluble and membrane P01375 - α . In contrast to whole antibodies and etanercept , CZP does not activate antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity , as it does not have an Fc piece . CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate - to - severe plaque psoriasis . In a Phase III study of CZP in 409 psoriatic arthritis patients , CZP treatment resulted in improvements in peripheral arthritis , as well as dactylitis , enthesitis , nail disease and quality of life . The safety profile of CZP appears to be similar to that of other P01375 - α inhibitor .",
"___MASK36___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK36___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK36___ is a promising pharmacological tool in the treatment of renal edema .",
"DB08904 in Crohn ' s disease . DB08904 is a humanized Fab ' fragment monoclonal antibody to tumor necrosis factor alpha ( P01375 ) . PEGylation increases its half - life , and it is administered subcutaneously to treat immune - mediated inflammatory diseases such as Crohn ' s disease and rheumatoid arthritis . DB08904 improves quality of life and reduces clinical disease activity . Inflammatory markers such as P02741 ( CRP ) also decrease after administration of certolizumab pegol . The dose for induction of remission is 400 mg subcutaneously at weeks 0 , 2 and 4 . The dose for maintenance of remission is 400 mg sc given every four weeks . The safety profile is comparable with other anti - P01375 agents , and the major adverse events are related to infections . This article reviews the published data regarding the efficacy and safety of certolizumab pegol .",
"How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn ' s disease . The chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , infliximab , is an effective therapy for Crohn ' s disease . However , the formation of human anti - chimeric antibodies to infliximab ( immunogenicity ) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions . The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment DB08904 are biologic therapies against P01375 that might be effective for Crohn ' s disease and less immunogenic than infliximab . Other potential alternatives to infliximab for Crohn ' s disease include the humanized anti - adhesion molecule antibodies natalizumab and DB05802 , the humanized anti - interleukin 12 antibody ABT - 874 , the humanized anti - interferon g antibody fontolizumab , the humanized anti - interleukin 6 receptor antibody DB06273 , and human recombinant granulocyte macrophage colony stimulating factor ( sargramostim ) . Some , or all , of these therapies will likely represent important treatments for Crohn ' s disease in the future .",
"Meta - analysis : the efficacy and safety of certolizumab pegol in Crohn ' s disease . BACKGROUND : DB08904 is the third anti - P01375 agent approved by the Food and Drug Administration of the United States . AIM : To provide a comprehensive up - to - date review of the efficacy and safety of certolizumab in Crohn ' s disease ( CD ) . METHODS : Electronic databases , including PubMed , EMBASE , the Cochrane library and the Science Citation Index , were searched to retrieve relevant trials . In addition , meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies . RESULTS : Three trials , enrolling a total of 1040 patients , are included in the meta - analysis to evaluate the short - term efficacy of certolizumab , which is effective for rapid induction and long - term maintenance of clinical response or remission and can improve quality of life in patients with Crohn ' s disease . Certolizumab is also effective for patients who have lost response to infliximab . However , its efficacy in infliximab - exposed patients is probably less than in infliximab - naive patients . Re - induction with certolizumab in patients who have flared on maintenance therapy can rescue a significant proportion of patients . There is no significant association between the efficacy of certolizumab and the baseline P02741 level . In comparison with placebo , certolizumab does not increase the risk of serious adverse events . CONCLUSIONS : Certolizumab is effective and safe in treating Crohn ' s disease . Further studies are still required to assess its full safety profile .",
"The PRECiSE 2 trial of certolizumab pegol , a new PEGylated anti - P01375 agent , in the treatment of Crohn ' s disease : An interview with David A Schwartz , 13 June 2007 . DB08904 ( CDP 870 ) is a new anti - tumor necrosis factor ( P01375 ) therapy currently in development for the treatment of Crohn ' s disease , rheumatoid arthritis , and psoriasis . DB08904 is the first PEGylated biologic anti - P01375 agent and has a high binding affinity for P01375 . Dr . Schwartz was an investigator of the PRECiSE ( PEGylated Antibody Fragment Evaluation in Crohn ' s Disease Safety and Efficacy ) 2 trial of certolizumab pegol in patients with Crohn ' s disease .",
"DB08904 in rheumatoid arthritis : current update . INTRODUCTION : The development of P01375 - α inhibitors ( P01375 - is ) represents a major advancement in the treatment of rheumatoid arthritis ( RA ) . Currently , there are five agents licensed for moderate - to - severely active RA . DB08904 ( CZP ) is a novel PEGylated , constant fragment - free P01375 - i therapy , which is the focus of this review . AREAS COVERED : Data from Phase III randomised controlled trials in terms of clinical efficacy , radiographic progression , patient - reported outcomes and safety profile are reviewed . These include long - term data from open - label extension studies . EXPERT OPINION : The advantages of CZP include rapid reduction of disease activity , low rates of injection - site reaction and may be safe for use in pregnancy . The long - term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti - rheumatic drugs ( DMARDs ) , in moderate - to - severely active RA , comparable to other P01375 - is . Notably , prolonged CZP exposure is not associated with increased risk of severe infection compared to general population , contrasting with preliminary analysis of short - term data . Over the next few years , evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD - naïve patients , biomarkers and the development and licensing of P01375 - i biosimilars .",
"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization ."
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___MASK87___
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MH_train_339
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interacts_with DB00700?
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"P01308 and P05019 phosphorylate P29474 in HUVECs by a caveolin - 1 dependent mechanism . Caveolae are plasmamembrane regions which take part in the regulation of intracellular trafficking and signaling of tyrosine kinase receptors . P01308 and P05019 receptors and their intracellular substrates localize in caveolae . Also P29474 is targeted to caveolae and caveolin - 1 , the major caveolar protein , acts as a regulator of P29474 activity . Since P01308 and P05019 phosphorylate and activate P29474 , we investigated the role of caveolin - 1 in P01308 and P05019 stimulated P29474 activity . Here we show that : ( 1 ) in human endothelial cells , P01308 and P05019 stimulate P29474 phosphorylation in a different manner both qualitatively and quantitatively ; ( 2 ) caveolin - 1 down regulation abolishes P01308 and P05019 stimulated P29474 phosphorylation . These results suggest that caveolae could represent an intracellular site that contributes to differentiate IR and IGF - IR activity , and demonstrate the role of caveolin - 1 in the P29474 activation by P01308 and P05019 .",
"DB00644 1 directly affects corpora lutea lifespan in Mediterranean buffalo ( Bubalus bubalis ) during diestrus : presence and in vitro effects on enzymatic and hormonal activities . The expression of gonadotropin - releasing hormone ( P01148 ) receptor ( P30968 ) and the direct role of P01148 on corpora lutea function were studied in Mediterranean buffalo during diestrus . Immunohistochemistry evidenced at early , mid , and late luteal stages the presence of P30968 only in large luteal cells and P01148 in both small and large luteal cells . Real - time PCR revealed P30968 and P01148 mRNA at the three luteal stages , with lowest values in late corpora lutea . In vitro corpora lutea progesterone production was greater in mid stages and lesser in late luteal phases , whereas prostaglandin F2 alpha ( PGF2alpha ) increased from early to late stages , and DB00917 was greater in the earlier - luteal phase . Cyclooxygenase 1 ( prostaglandin - endoperoxide synthase 1 ; P23219 ) activity did not change during diestrus , whereas P35354 increased from early to late stages , and DB00917 - 9 - ketoreductase ( DB00917 - 9 - K ) was greater in late corpora lutea . P23219 activity was greater than P35354 in early corpora lutea and lesser in late luteal phase . In corpora lutea cultured in vitro , the P01148 analog ( buserelin ) reduced progesterone secretion and increased PGF2alpha secretion as well as P35354 and DB00917 - 9 - K activities at mid and late stages . DB00917 release and P23219 activity were increased by buserelin only in late corpora lutea . These results suggest that P01148 is expressed in all luteal cells of buffalo , whereas P30968 is only expressed in large luteal phase . Additionally , P01148 directly down - regulates corpora lutea progesterone release , with the concomitant increases of PGF2alpha production and P35354 and DB00917 - 9 - K enzymatic activities .",
"Endothelial Q09428 - 8 acts in an P29323 - independent pathway during atrioventricular cushion development . Q09428 - 8 , a conserved leucine - rich repeats protein , was first identified as a positive regulator of Ras pathway in Caenorhabditis elegans . Biochemical studies indicated that Q09428 - 8 interacts with Ras and Raf , leading to the elevated P29323 activity . However , the physiological role of Q09428 - 8 during mammalian development remains unclear . Here we found that germline deletion of Q09428 - 8 in mice resulted in early embryonic lethality . Inactivated Q09428 - 8 specifically in mouse endothelial cells ( ECs ) revealed that Q09428 - 8 is essential for embryonic heart development . Q09428 - 8 deficiency in ECs resulted in late embryonic lethality , and the mutant mice displayed multiple cardiac defects . The reduced endothelial - mesenchymal transformation ( EMT ) and the reduced mesenchyme proliferation phase were observed in the atrioventricular canal ( AVC ) within the mutant hearts , leading to the formation of hypoplastic endocardial cushions . However , P29323 activation did not appear to be affected in mutant ECs , suggesting that Q09428 - 8 may act in an P29323 - independent pathway to regulate AVC development .",
"Uptake of DB06704 and catecholamines in noradrenaline - and organic cation transporter - expressing cells : potential use of corticosterone for a preferred uptake in neuroblastoma - and pheochromocytoma cells . For imaging of neuroblastoma and phaeochromocytoma , [( 123 ) I ] meta - iodobenzylguanidine ( [( 123 ) I ] DB06704 ) is routinely used , whereas [( 18 ) F ] 6 - fluorodopamine ( [( 18 ) F ] 6 - FDA ) is sporadically applied for positron emission tomography in pheochromocytoma . Both substances are taken up by catecholamine transporters ( CATs ) . In competition , some other cell types are able to take up catecholamines and related compounds probably by organic cation ( O75051 ) [ extraneuronal monoamine ( EMT ) ] transporters ( OCT1 , OCT2 , OCT3 = EMT ) . In this study , we investigated the uptake of radioiodine - labeled meta - iodobenzylguanidine ( DB06704 ) as well as [( 3 ) H ] dopamine ( mimicring 6 - fluorodopamine ) and [( 3 ) H ] noradrenaline . SK - N - SH ( neuroblastoma ) and PC - 12 ( phaeochromocytoma ) cells were used and compared with P29320 - 293 cells transfected with OCT1 , OCT2 and OCT3 , respectively . In order to gain a more selective uptake in CAT expressing tumor cells , different specific inhibitors were measured . Uptake of DB06704 into O75051 - expressing cells was similar or even better as into both CAT - expressing cell lines , whereas dopamine and noradrenaline uptake was much lower in O75051 - expressing cells . In presence of corticosterone ( f . c . 10 (- 4 ) M ] , catecholamine and DB06704 uptake into SK - N - SH and PC - 12 cells was only slightly reduced . In contrast , this process was significantly inhibited in OCT2 and OCT3 transfected P29320 - 293 as well as in Caki - 1 cells , which naturally express OCT3 . We conclude that the well - known corticosteroid corticosterone might be used in combination with [( 18 ) F ] 6 - FDA or [( 123 ) I ] DB06704 to improve specific imaging of neuroblastoma and pheochromocytoma and to reduce irradiation dose to nontarget organs in [( 131 ) I ] DB06704 treatment .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK78___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"P40763 - dependent enhanceosome assembly and disassembly : synergy with GR for full transcriptional increase of the alpha 2 - macroglobulin gene . We describe a detailed time course of the assembly and disassembly of a P40763 - dependent , glucocorticoid - supplemented enhanceosome for the alpha2 - macroglobulin ( alpha2 - M ) gene and compare this with a detailed time course of transcription of the gene by run - on analysis . The glucocorticoid receptor ( GR ) can associate with the enhanceosome without P40763 . Furthermore , the enhanceosome contains c - Jun / c - Fos and O75051 - 1 constitutively . All of these factors ( GR , c - Jun , O75051 - 1 ) have transcription activation domains , but P40763 is required for the observed transcriptional increase . The time course of enhanceosome occupation by GR and tyrosine - phosphorylated P40763 shows that these transcription factors precede by approximately 5 - 10 min the arrival of RNA polymerase II ( Pol II ) . The enhanceosome remains assembled for approximately 90 min in the continued presence of both inducers . When P05231 and DB00514 are removed ( after 30 min of treatment ) , the disappearance within an additional 30 min of the established enhanceosome indicates that renewal of P40763 and GR binding must occur in the continued presence of P05231 + DB00514 . Compared with the total nuclear tyrosine - phosphorylated P40763 capable of binding DNA , the chromatin - associated P40763 resists dephosphorylation and appears to recycle to maintain the enhanceosome . Run - on transcription shows a lag after full enhanceosome occupation that can be largely but not completely explained by the approximately 30 min transit time of Pol II across the alpha2 - Mlocus .",
"Role of cardiovascular aldosterone in hypertension . DB04630 plays an important role in the pathogenesis of cardiovascular disease . We have reported that aldosterone is synthesized in cardiovascular tissues and local aldosterone synthesis plays important roles for hypertension and cardiac hypertrophy . High sodium intake develops and accelerates vascular injury and cardiac hypertrophy in SHRSP . Plasma aldosterone concentrations and P06703 were decreased by high salt intake in SHRSP . DB04630 production , the expression of P19099 mRNA and angiotensin II receptor AT1R mRNA in blood vessels were significantly increased by high salt intake . These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the vascular tissue in SHRSP , which may contribute to the development of malignant hypertension in salt - loaded SHRSP . However , there are several reports of conflicting data . P08235 ( MR ) binding is tightly regulated by the enzyme 11beta - hydroxysteroid dehydrogenase type 2 ( 11beta - HSD2 ) which selectively metabolizes glucocorticoids to inactive metabolites , thus allowing for MR activation by aldosterone . We have reported that decreased 11beta - HSD2 in blood vessels in Dahl salt - sensitive ( DS ) rats , a model for salt - sensitive hypertension . Local aldosterone excess may play a significant role in the salt sensitivity and development of hypertension . High sodium intake decreased circulating rennin - angiotensin - aldosterone system and increased blood pressure and cardiac hypertrophy in DS rats , which were prevented by the treatment with a selective MR antagonist , eplerenone . DB00700 also improved endothelial nitric oxide synthase ( P29474 ) activity and P29474 mRNA expression in blood vessels in DS rats . These results further suggest that not only circulating aldosterone but also local aldosterone is of critical importance in the pathophysiology of cardiovascular disorders .",
"DB03404 upregulates Egr - 1 expression in vascular smooth muscle cells via reactive oxygen species P27361 / 2 - Elk - 1 and NF - kappaB . Reactive oxygen species ( ROS ) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis . One source of ROS in the vasculature is free heme released from hemoglobin . Because Egr - 1 , the regulator of cell proliferation and apoptosis , is also induced by oxidant stress and is likewise implicated in atherosclerosis , we examined the regulation of Egr - 1 by heme in vascular smooth muscle cells ( SMCs ) . DB03404 increased Egr - 1 expression ( mRNA , protein ) within 30 minutes and P27361 / 2 phosphorylation and nuclear translocation within 5 minutes . Inhibiting hemin - induced P27361 / 2 activation by U0126 ( MAPK - inhibitor ) , the antioxidant N - acetyl cysteine , the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride , the superoxide scavenger tiron , or tricarbonyldichlororuthenium ( II )- dimer ( carbon - monoxide donor ; CORM - 2 ) blocked hemin - induced Egr - 1 expression . DB03404 activated Elk - 1 , P11831 , and NF - kappaB and promoted their interaction with the Egr - 1 promoter . Downregulating Elk - 1 ( via siRNA ) or blocking NF - kappaB activation ( via BAY - 11 - 7082 ) abolished hemin induction of Egr - 1 . Finally , hemin - induced Egr - 1 bound the promoters of tissue factor ( TF ) , P00747 Activator Inhibitor ( P05121 ) - 1 , and P01138 - 1A Binding ( NAB ) - 2 , upregulating their expression , and increased the biochemical activity of TF and P05121 . Upregulation of Egr - 1 and its target genes by heme - induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis .",
"AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 / MAPK , the PI3K / AKT / P42345 and the JAK / P40763 pathways . Here , we tested the efficacy of a P23458 / 2 - inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC - 1 ) , P07949 M918T ( MZ - CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC - 1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and / or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC - 1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC - 1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho - Y1062 P07949 levels , and P42345 effector phospho - S6 , while P23458 / 2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e . g . via JAK / phospho - P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers .",
"Pixelation effect removal from fiber bundle probe based optical coherence tomography imaging . A method of eliminating pixelization effect from en face optical coherence tomography ( O75051 ) image when a fiber bundle is used as an O75051 imaging probe is presented . We have demonstrated that applying a histogram equalization process before performing a weighted - averaged Gaussian smoothing filter to the original lower gray level intensity based image not only removes the structural artifact of the bundle but also enhances the image quality with minimum blurring of object ' s image features . The measured contrast - to - noise ratio ( P21554 ) for an image of the US DB09337 Force test target was 14 . 7dB ( 4 . 9dB ) , after ( before ) image processing . In addition , by performing the spatial frequency analysis based on two - dimensional discrete Fourier transform ( 2 - D DFT ) , we were able to observe that the periodic intensity peaks induced by the regularly arrayed structure of the fiber bundle can be efficiently suppressed by 41 . 0dB for the first nearby side lobe as well as to obtain the precise physical spacing information of the fiber grid . The proposed combined method can also be used as a straight forward image processing tool for any imaging system utilizing fiber bundle as a high - resolution imager .",
"Opposite effect of Hsp90α and Hsp90β on P29474 ability to produce nitric oxide or superoxide anion in human embryonic kidney cells . Heat shock protein 90 subfamily is composed by two cytosolic isoforms known as Hsp90α and Hsp90β . Endothelial nitric oxide synthase ( P29474 ) is regulated by Hsp90 , however the specific role of each Hsp90 isoform on NO production has not been established . This study was designed to evaluate the effect of Hsp90α and Hsp90β over - expression on P29474 / NO pathway . Rat Hsp90α and Hsp90β were cloned into pcDNA3 . 1 (+) and transfected in human embryonic kidney cells ( P29320 - 293 ) . Hsp90α and Hsp90β transfection was corroborated by Western blot analysis and their effect on NO production ( NO ( 2 )/ NO ( 3 ) ) , P29474 protein and its phosphorylation at Ser1177 and Thr495 , as well as Akt / P31749 Ser473 phosphorylation was determined . The interaction of Hsp90α and Hsp90β with P29474 and the dimer / monomer ratio of Hsp90 , as well as O ( 2 )(-) generation were also assessed . After transfection , Hsp90α and Hsp90β levels were significantly increased in P29320 - 293 cells . The Hsp90α over - expression induced a significant increase in NO ( 2 )/ NO ( 3 ) levels , an effect that was associated with increased phosphorylation of P29474 DB00133 1177 and Akt / P31749 Ser473 , as well as with a greater Hsp90α dimerization . Noteworthy , pcHsp90β transfection reduced significantly NO ( 2 )/ NO ( 3 ) and increased O ( 2 )(-) generation . These effects were associated with a reduction of P29474 dimeric conformation , increased P29474 Thr495 phosphorylation , reduced Akt / P31749 phosphorylation , and by a greater amount of monomeric Hsp90β conformation . These data show for first time that Hsp90α and Hsp90β differentially modulate NO and O ( 2 )(-) generation by P29474 through promoting changes in P29474 conformation and phosphorylation state .",
"Platelet - endothelial cell adhesion molecule - 1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3 - dependent Q8IVI9 expression . BACKGROUND : NO produced by the endothelial NO synthase ( P29474 ) is an important regulator of cardiovascular physiological and pathological features . P29474 is activated by numerous stimuli , and its activity is tightly regulated . Platelet - endothelial cell adhesion molecule - 1 ( P16284 ) has been implicated in regulating P29474 activity in response to shear stress . The current study was conducted to determine the role of P16284 in the regulation of basal P29474 activity . METHODS AND RESULTS : We demonstrate that P16284 - knockout ECs have increased basal P29474 activity and NO production . Mechanistically , increased P29474 activity is associated with a decrease in the inhibitory interaction of P29474 with caveolin - 1 , impaired subcellular localization of P29474 , and decreased P29474 traffic inducer ( Q8IVI9 ) expression in the absence of P16284 . Furthermore , we demonstrate that activation of blunted signal transducers and activators of transcription 3 ( P40763 ) in the absence of P16284 results in decreased Q8IVI9 expression via direct binding of the signal transducers and activators of transcription 3 to the Q8IVI9 promoter . CONCLUSIONS : Our results reveal an elegant mechanism of P29474 regulation by P16284 through signal transducers and activators of transcription 3 - mediated transcriptional control of Q8IVI9 .",
"P08235 antagonism in the treatment of chronic central serous chorioretinopathy : a pilot study . PURPOSE : Based on experimental data showing that central serous chorioretinopathy could result from overactivation of mineralocorticoid receptor pathway in choroid vessels , the authors studied eplerenone , a mineralocorticoid receptor antagonist , as a potential treatment for chronic central serous chorioretinopathy . METHODS : This nonrandomized pilot study included 13 patients with central serous chorioretinopathy of at least 4 - month duration , treated with 25 mg / day of oral eplerenone for a week followed by 50 mg / day for 1 or 3 months . The primary outcome measure was the changes in central macular thickness recorded by optical coherence tomography , and the secondary outcomes included changes in foveal subretinal fluid ( P11831 ) measured by O75051 , in best - corrected visual acuity ( BCVA ) and the percentage of eyes achieving complete resolution of subretinal fluid during the treatment period . RESULTS : Central macular thickness decreased significantly from 352 ± 139 μm at baseline to 246 ± 113 μm and 189 ± 99 μm at 1 and 3 months under eplerenone treatment ( P < 0 . 05 and P < 0 . 01 , respectively ) . At 3 months , the subretinal fluid significantly decreased compared with baseline subretinal fluid ( P < 0 . 01 ) and best - corrected visual acuity significantly improved compared with baseline best - corrected visual acuity ( P < 0 . 001 ) . CONCLUSION : DB00700 treatment was associated with a significant reduction in central macular thickness , subretinal fluid level , and an improvement in visual acuity . Randomized controlled trials are needed to confirm these encouraging results .",
"DB04540 attenuates linoleic acid - induced endothelial cell activation . Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis . Even though very low or high levels of cholesterol can compromise cellular functions , cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid - mediated inflammatory responses . We have previously shown that the parent omega - 6 fatty acid linoleic acid can markedly activate vascular endothelial cells . We now propose that membrane cholesterol can modify and inhibit linoleic acid - mediated endothelial cell dysfunction . To test this hypothesis , pulmonary artery endothelial cells were incubated with cholesterol ( 0 to 100 micromol / L ) for 24 hours and then treated with 90 micromol / L of linoleic acid ( 18 : 2n - 6 ) for 6 to 24 hours . In control cells , treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor - kappaB ( NF - kappaB ) leading to the upregulation of interleukin - 6 ( P05231 ) . In addition , the expression of endothelial nitric oxide synthase ( P29474 ) was altered , with linoleic acid increasing P29474 activity . In contrast , enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid - induced activation of NF - kappaBand the production of P05231 . Prior exposure to 50 micromol / L cholesterol also prevented the fatty acid - induced increase in P29474 activation . DB04540 loading activated peroxisome proliferator - activated receptor - gamma ( P37231 ) , a nuclear receptor that can decrease inflammatory responses . Furthermore , the P37231 agonist thiazolidinedione markedly downregulated the NF - kappaB activation mediated by linoleic acid . Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK32___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats . AIMS : P08235 ( MR ) blockade is an effective treatment for hypertension and diabetic nephropathy . There are no data on the effects of MR blockade on diabetic peripheral neuropathy ( DPN ) . The aim of this study was to determine whether MRs are present in the peripheral nerves and to investigate the effectiveness of MR blockade on DPN in streptozotocin ( Q11206 ) - induced diabetic rats . METHODS : Expression of MR protein and messenger RNA ( mRNA ) was examined in the peripheral nerves using Western blot analysis and RT - PCR . We next studied the effects of the selective MR antagonist eplerenone and the angiotensin II receptor blocker candesartan on motor and sensory nerve conduction velocity ( NCV ) , morphometric changes and cyclooxygenase - 2 ( P35354 ) gene and NF - κB protein expression in the peripheral nerves of Q11206 - induced diabetic rats . RESULTS : Expression of MR protein and mRNA in peripheral nerves was equal to that in the kidney . Motor NCV was significantly improved by 8 weeks of treatment with either eplerenone ( Q04695 ± 1 . 2 m / s ) or candesartan ( 46 . 4 ± 6 . 8 m / s ) compared with control diabetic rats ( 33 . 7 ± 2 . 0 m / s ) ( p < 0 . 05 ) . Sensory NCV was also improved by treatment with candesartan or eplerenone in diabetic rats . DB00700 and candesartan caused significant improvement in mean myelin fibre area and mean myelin area compared with control diabetic rats ( p < 0 . 05 ) . P35354 mRNA and NF - κB protein were significantly elevated in the peripheral nerves of diabetic rats compared with control rats , and treatment with eplerenone or candesartan reduced these changes in gene expression ( p < 0 . 05 ) . CONCLUSION : MR blockade may have neuroprotective effects on DPN .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK79___ and Tissue P00747 Activator in Occluded Arteries .",
"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .",
"Examination of ceramic restorative material interfacial debonding using acoustic emission and optical coherence tomography . OBJECTIVE : CAD / P62158 ceramic restorative material is routinely bonded to tooth substrates using adhesive cement . This study investigates micro - crack growth and damage in the ceramic / dentin adhesive interface under fatigue shear testing monitored using the acoustic emission ( AE ) technique with optical coherence tomography ( O75051 ) . METHODS : Ceramic / dentin adhesive samples were prepared to measure the shear bond strength ( SBS ) under static load . Fatigue shear testing was performed using a modified ISO14801 method . Loads in the fatigue tests were applied at 80 % , 70 % , and 60 % of the SBS to monitor interface debonding . The AE technique was used to detect micro - crack signals in static and fatigue shear bond tests . RESULTS : The results showed that the average SBS value in the static tests was 10 . 61 ± 2 . 23MPa ( mean ± standard deviation ) . The average number of fatigue cycles in which ceramic / dentin interface damage was detected in 80 % , 70 % and 60 % of the SBS were 152 , 1962 and 9646 , respectively . The acoustic behavior varied according to the applied load level . Events were emitted during 60 % and 70 % fatigue tests . A good correlation was observed between crack location in O75051 images and the number of AE signal hits . SIGNIFICANCE : The AE technique and O75051 images employed in this study could potentially be used as a pre - clinical assessment tool to determine the integrity of cemented load bearing restored ceramic material . Sustainable cyclic load stresses in ceramic / dentin - bonded specimens were substantially lower than the measured SBS . Predicted S - N curve showed that the maximum endured load was 4 . 18MPa passing 10 ( 6 ) fatigue cyclic .",
"DB00082 increases intra - abdominal fat in patients with acromegaly : a pilot study . OBJECTIVE : Acromegalic patients have increased lipolysis and decreased fat mass as well as reduced insulin sensitivity and glucose intolerance . During somatostatin analog therapy , these changes persist despite GH suppression , but they are now due to drug - induced suppression of insulin secretion . By contrast , during pegvisomant ( PEG ) therapy , GH no longer stimulates lipolysis due to the blockade of its receptor , while insulin action is unabated . Hence , both insulin sensitivity and fat mass , including intra - abdominal fat , should increase . We therefore studied intra - abdominal fat and insulin resistance in acromegalic patients after a 3 - month octreotide - washout period , i . e . , during untreated acromegaly , and during PEG treatment . METHODS : Five acromegalic patients , not controlled on octreotide ( O75051 ) therapy , were studied after 3 - month O75051 washout and 6 - month PEG therapy . P01308 sensitivity was determined by homeostatic model assessment value and hyperinsulinemic , normoglycemic clamp . Subcutaneous and intra - abdominal fat were measured by electron beam computed tomography . RESULTS : During PEG therapy , all the patients had normal , age - adjusted P05019 concentrations . Compared with washout , insulin sensitivity ( HOMA and M value ) was not significantly different . However , intra - abdominal fat mass increased significantly during therapy ( median ( range ) cm ( 2 ) : 112 ( 84 - 480 ) and 172 ( 112 - 524 ) respectively , P < 0 . 05 ) , while subcutaneous fat was not significantly different . Low - density lipoprotein cholesterol , high - density lipoprotein cholesterol , and triglycerides remained unchanged . CONCLUSIONS : During PEG therapy of acromegalic patients , intra - abdominal fat increases . Visceral obesity is a risk factor for cardiovascular disease . Hence , confirmation and further studies in a larger cohort of acromegalic patients on PEG treatment are warranted .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK4___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"DB04630 stimulates vascular smooth muscle cell proliferation via big mitogen - activated protein kinase 1 activation . The nongenomic effects of aldosterone have been implicated in the pathogenesis of various cardiovascular diseases . DB04630 - induced nongenomic effects are attributable in part to the activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) , a classical mitogen - activated protein ( Q96HU1 ) kinase . Q13164 ( Q13164 ) , a newly identified Q96HU1 kinase , has been shown to be involved in cell proliferation , differentiation , and survival . We examined whether aldosterone stimulates Q13164 - mediated proliferation of cultured rat aortic smooth muscle cells ( RASMCs ) . P08235 ( MR ) expression and localization were evaluated by Western blotting analysis and fluorolabeling methods . P27361 / 2 and Q13164 activities were measured by Western blotting analysis with the respective phosphospecific antibodies . Cell proliferation was determined by Alamar Blue colorimetric assay . DB04630 ( 0 . 1 to 100 nmol / L ) dose - dependently activated Q13164 in RASMCs , with a peak at 30 minutes . To clarify whether aldosterone - induced Q13164 activation is an MR - mediated phenomenon , we examined the effect of eplerenone , a selective MR antagonist , on aldosterone - induced Q13164 activation . DB00700 ( 0 . 1 to 10 micromol / L ) dose - dependently inhibited aldosterone - induced Q13164 activation in RASMCs . DB04630 also stimulated RASMC proliferation , which was inhibited by eplerenone . DB04630 - mediated phenomena were concluded to be attributable to a nongenomic effect because cycloheximide failed to inhibit aldosterone - induced Q13164 activation . Transfection of dominant - negative Q96HU1 kinase / P29323 kinase 5 ( Q13163 ) , which is an upstream regulator of Q13164 , partially inhibited aldosterone - induced RASMC proliferation , which was almost completely inhibited by MEK inhibitor PD98059 . In addition to the classical steroid activity , rapid nongenomic effects induced by aldosterone may represent an alternative etiology for vascular diseases such as hypertension .",
"Clathrin - dependent internalization of the angiotensin II AT₁A receptor links receptor internalization to P35354 protein expression in rat aortic vascular smooth muscle cells . The major effects of Angiotensin II ( AngII ) in vascular tissue are mediated by AngII AT1A receptor activation . Certain effects initiated by AT1A receptor activation require receptor internalization . In rat aortic vascular smooth muscle cells ( RASMC ) , AngII stimulates cyclooxygenase 2 protein expression . We have previously shown this is mediated by β - arrestin - dependent receptor internalization and NF - κB activation . In this study , a specific inhibitor of clathrin - mediated endocytosis ( CME ) , pitstop - 2 , was used to test the hypothesis that clathrin - dependent internalization of activated AT1A receptor mediates NF - κB activation and subsequent cyclooxygenase 2 expression . Radioligand binding assays , real time qt - PCR and immunoblotting were used to document the effects of pitstop - 2 on AngII binding and signaling in RASMC . Laser scanning confocal microscopy ( LSCM ) was used to image pitstop - 2 ׳ s effects on AT1 receptor / GFP internalization in P29320 - 293 cells and p65 NF - κB nuclear localization in RASMC . Pitstop - 2 significantly inhibited internalization of AT1A receptor ( 44 . 7 % ± 3 . 1 % Control vs . 13 . 2 % ± 8 . 3 % Pitstop - 2 ; n = 3 ) as determined by radioligand binding studies in RASMC . Studies utilizing AT1A receptor / GFP expressed in P29320 293 cells and LSCM confirmed these findings . Pitstop - 2 significantly inhibited AngII - induced p65 NF - κB phosphorylation and nuclear localization , P35354 message and protein expression in RASMC without altering activation of Q8NFH3 / 44 P29323 or TNFα signaling . Pitstop - 2 , a specific inhibitor of clathrin - mediated endocytosis , confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC . These data provide support for additional intracellular signaling pathways activated through β - arrestin mediated internalization of G protein - coupled receptors , such as AT1A receptors .",
"Inhibition of suicidal erythrocyte death by nitric oxide . DB00435 ( NO ) is known to counteract apoptosis by S - nitrosylation of protein thiol groups . NO is generated and stored in erythrocytes , which may undergo eryptosis , a suicidal cell death similar to apoptosis of nucleated cells . Eryptosis is triggered by increased cytosolic Ca2 + activity and / or ceramide and characterized by cell shrinkage and phosphatidylserine exposure at the cell surface . The present study explored whether nitric oxide could interfere with the machinery underlying eryptosis . To this end , erythrocyte phosphatidylserine exposure ( annexin V - binding ) and cell volume ( forward scatter ) were determined by flow cytometry . The Ca2 + ionophore ionomycin ( 0 . 1 microM ) increased cytosolic Ca2 + activity , triggered annexin binding , and decreased forward scatter . The annexin binding and decrease of forward scatter but not the increase of cytosolic Ca2 + activity were reversed by the NO - donor nitroprusside ( 1 microM ) and papanonoate ( 100 microM ) . Higher concentrations of nitroprusside ( 0 . 1 and 1 mM ) stimulated eryptosis . DB09341 depletion , exposure to P13671 - ceramide ( 3 microM ) , hypertonic ( addition of 550 mM sucrose ) , and isotonic ( replacement of Cl - with gluconate ) cell shrinkage all triggered annexin V binding , effects all reversed by nitroprusside ( 1 microM ) . Dibutyryl - cGMP ( 1 mM ) blunted the ionomycin - but not the ceramide - induced annexin V binding . Ionomycin decreased protein nitrosylation and thioredoxin activity , effects reversed by the NO - donor papanonoate . Clearance of erythrocytes from circulating blood was significantly faster in P29474 knockout mice than in their wild - type littermates . In conclusion , nitric oxide participates in the regulation of erythrocyte survival , an effect partially mimicked by cGMP and paralleled by alterations of protein nitrosylation and thioredoxin activity .",
"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .",
"Inhibition of cyclooxygenase - 2 elicits a P21554 - mediated decrease of excitatory transmission in rat P00915 hippocampus . Cannabinoid receptor ( P21554 ) ligands decrease excitatory and inhibitory transmission in the hippocampus , but the influence of endogenously formed cannabinoids ( eCBs ) on basal excitatory transmission remains uncertain . Here , we investigated the influence of eCBs on synaptic transmission in P00915 hippocampus using the slice preparation . Blockade of P21554 with the selective receptor antagonists SR141716 ( rimonabant ) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals . This effect persisted in the presence of bicuculline or CGP55845 to block GABA ( A ) or GABA ( B ) receptors , revealing a tonic eCB influence on excitatory transmission . Selective inhibition of cyclooxygenase - 2 ( P35354 ) with meloxicam or NS - 398 decreased excitatory responses partly in a P21554 - dependent manner , independently of GABA ( A ) transmission . Paired - pulse paradigms suggested a presynaptic P21554 mechanism to decrease glutamate release . Inhibition of P23219 or other routes of eCB degradation did not affect synaptic transmission . We conclude that P35354 regulates the formation of P21554 ligands that decrease hippocampal excitatory transmission .",
"Proinflammatory cytokines downregulate gene expression and activity of constitutive nitric oxide synthase in porcine pulmonary artery endothelial cells . We evaluated the effects of cytokines on the catalytic activity and expression of porcine pulmonary artery endothelial cell ( PAEC ) constitutive ( P29474 ) and inducible ( P35228 ) isoforms of nitric oxide synthase ( NOS ) . Exposure of PAEC to the combination of P01579 , P01375 , and P01584 did not alter P35228 activity in cytosolic and membrane fractions but significantly ( p < 0 . 01 ) reduced P29474 activity in the membrane fraction , but not in the cytosolic fraction , after a 24 - h exposure . The cytokine - induced loss of membrane fraction P29474 activity was associated with significant reductions of P29474 mRNA and protein content ( p < 0 . 01 for both ) . Treatment with the protein synthesis inhibitor , cycloheximide , but not the transcriptional inhibitor actinomycin D prevented cytokine - induced reduction of P29474 mRNA expression . These results suggest that cytokine - induced loss of catalytic activity of P29474 is associated with a reduction in P29474 mRNA and protein mass and that cytokines alter P29474 mRNA stability . Inhibition of protein synthesis prevented reduction of P29474 mRNA by cytokines , suggesting that the mechanism by which cytokines alter P29474 mRNA stability involves protein synthesis .",
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK79___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"X - irradiation - induced cell cycle delay and DNA double - strand breaks in the murine osteoblastic cell line O75051 - 1 . Radiation response of bone cells , especially the bone - forming osteoblasts , is an important issue for radiotherapy in young age . A radiation - induced cell cycle arrest may enhance or accelerate osteoblastic differentiation . To analyze radiation response of osteoblastic cells , the correlation between DNA double - strand break induction ( DSB ) , cell cycle alterations and gene expression modifications after X - irradiation was investigated in the osteoblast - like cell line O75051 - 1 . As marker of the cellular response to DSB , the temporal appearance of gamma - P16104 foci after X - irradiation was visualized . Gene expression profiles of the key cell cycle regulatory protein P38936 ( P38936 ) , and the most abundant growth factor in human bone , transforming growth factor beta 1 ( TGF - beta1 ) were recorded using quantitative real - time reverse transcription PCR ( qRT - PCR ) . The distribution of cells in the cell cycle phases P55008 , S and G2 was determined by propidium iodide ( PI ) staining and flow cytometry . Initial studies show a strong dose dependency in the number of gamma - P16104 foci shortly after X - irradiation . Exposure to 1 Gy yields approximately 36 small foci in O75051 - 1 cells after 30 min that became larger after 1 h of incubation ; after 24 h most of the foci had disappeared . X - rays provoked a dose - dependent arrest in G2 phase of the cell cycle , accompanied by a dose - dependent gene expression regulation for P38936 and TGF - beta1 . As TGF - beta1 is known to affect osteoblast differentiation , matrix formation and mineralization , modulation of its expression could influence the expression of the main osteogenic transcription factor Runx2 ( Cbfa1 ) and other osteoblast differentiation markers .",
"Neutrophil apoptosis : selective regulation by different ligands of integrin alphaMbeta2 . Neutrophils undergo spontaneous apoptosis , but their survival can be extended during inflammatory responses . alpha ( M ) beta ( 2 ) is reported either to delay or accelerate neutrophil apoptosis , but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood . The abilities of closely related alpha ( M ) beta ( 2 ) ligands , plasminogen and angiostatin , derived from plasminogen , as well as fibrinogen and its two derivative alpha ( M ) beta ( 2 ) recognition peptides , P1 and P2 - C , differed markedly in their effects on neutrophil apoptosis . P00747 , fibrinogen , and P2 - C suppressed apoptosis via activation of Akt and P27361 / 2 kinases , while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis . Using cells transfected with alpha ( M ) beta ( 2 ) or its individual alpha ( M ) or beta ( 2 ) subunits , and purified receptors and its constituent chains , we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response . Hence , engagement of a single integrin by closely related ligands can induce distinct signaling pathways , which can elicit distinct cellular responses .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK17___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"2 , 3 , 5 , 4 '- tetrahydroxystilbene - 2 - O - β - d - glucoside ameliorates vascular senescence and improves blood flow involving a mechanism of p53 deacetylation . BACKGROUND AND AIMS : 2 , 3 , 5 , 4 '- tetrahydroxystilbene - 2 - O - β - d - glucoside ( THSG ) , a resveratrol analog with glucoside , has been shown in various studies to inhibit proliferation of vascular smooth muscle cells , attenuate inflammation , and prevent vascular endothelial dysfunction . In the study , we examined the effects of THSG on vascular senescence and blood flow . METHODS AND RESULTS : Oral administration of THSG for 14 weeks , resulted in notable increases in blood flow in spontaneously hypertensive rats ( SHRs ) ; and effective inhibition of vascular senescence as indicated by senescence - associated β - galactosidase ( SA - β - gal ) staining , phosphorylation of γ P16104 observed by stain analysis of immunofluorescence , and K373 acetylation of p53 in the aortic arches of SHRs . Oral administration of THSG also induced P29474 expression and urinary NOx production . THSG weekly activated Q96EB6 activity , stimulated P29474 promoter reporter gene activity , and ameliorated H ( 2 ) O ( 2 )- induced cellular senescence and K373 acetylation of p53 in cultured human umbilical vein endothelial cells ( HUVECs ) . CONCLUSIONS : THSG improves blood flow and ameliorates vascular senescence by increasing P29474 expression and Sirt1 activity and decreasing acetylation of p53 at K373 site , at least in part , both in vitro and in vivo .",
"P19957 - kinase and Q96HU1 - kinase signaling cascades in Q9Y6W8 / Q9Y6W8 - and P10747 - costimulated T - cells have distinct functions between cell proliferation and P22301 production . Both Q9Y6W8 / Q9Y6W8 and P10747 provide positive costimulatory signals for T - cell activation , resulting in proliferation and cytokine production . In this study , we attempted to clarify the key signaling molecules in T - cell proliferation , and also P60568 and P22301 production , during T - cell activation by CD3 induced by costimulation with either Q9Y6W8 / Q9Y6W8 or P10747 . We examined the role of both the P19957 - kinase / Akt pathway and Q96HU1 kinase family members such as P27361 / 2 , JNK , and p38 kinase in this process . P19957 - kinase and Erk1 / 2 were shown to potentially regulate primary T - cell activation and subsequent proliferation via both Q9Y6W8 / Q9Y6W8 - or P10747 - mediated costimulation and the Erk signaling cascade was essential for this proliferation induction and also for P60568 production . The JAK inhibitor , AG490 , inhibited this induction . Our studies indicate that P60568 is necessary for induction of T - cell proliferation and that the quantities of P60568 produced by Q9Y6W8 / Q9Y6W8 ligation are also sufficient for T - cells to proliferate . In contrast , inhibition of Akt and p38 , that are phosphorylated by both Q9Y6W8 / Q9Y6W8 and P10747 - ligation , could downregulate P22301 production but not T - cell proliferation . These data raise the interesting possibility that the signaling cascades between T - cell proliferation and P22301 production are regulated by different molecules in Q9Y6W8 / Q9Y6W8 - and P10747 - costimulated T - cells .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK20___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK20___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"___MASK80___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK80___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK80___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK80___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK80___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"___MASK35___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK35___ , in the USA in 2003 .",
"Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK35___ , and 86 % ± 8 % in Q8NE62 - ___MASK35___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK35___ , and 86 % ± 8 % in Q8NE62 - ___MASK35___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .",
"Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism ( s ) by which chronic inflammation drives cancer initiation and promotion include increased production of pro - inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo - oxygenase - 2 ) , 5 - P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro - inflammatory transcription factors such as NF - κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP - 1 ( activator protein 1 ) and HIF - 1α ( hypoxia - inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation - associated molecules are activated by a number of environmental and lifestyle - related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .",
"Phosphorylation of Grainy head by P29323 is essential for wound - dependent regeneration but not for development of an epidermal barrier . Grainy head ( P01148 ) is a key transcription factor responsible for epidermal barrier formation and repair , whose function is highly conserved across diverse animal species . However , it is not known how P01148 function is reactivated to repair differentiated epidermal barriers after wounding . Here , we show that P01148 is directly regulated by extracellular signal - regulated kinase ( P29323 ) phosphorylation , which is required for wound - dependent expression of P01148 target genes in epidermal cells . DB00133 91 is the principal residue in P01148 that is phosphorylated by P29323 . Although mutations of the P29323 phosphorylation sites in P01148 do not impair its DNA binding function , the P29323 sites in P01148 are required to activate Dopa decarboxylase ( Ddc ) and misshapen ( msn ) epidermal wound enhancers as well as functional regeneration of an epidermal barrier upon wounding . This result indicates that the phosphorylation sites are essential for damaged epidermal barrier repair . However , P01148 with mutant P29323 phosphorylation sites can still promote barrier formation during embryonic epidermal development , suggesting that P29323 sites are dispensable for the P01148 function in establishing epidermal barrier integrity . These results provide mechanistic insight into how tissue repair can be initiated by posttranslational modification of a key transcription factor that normally mediates the developmental generation of that tissue .",
"The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice . P00747 activation to plasmin protects from lung fibrosis , but the mechanism underlying this antifibrotic effect remains unclear . We found that mice lacking plasminogen activation inhibitor - 1 ( P05121 ) , which are protected from bleomycin - induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 activation upregulated DB00917 synthesis in alveolar epithelial cells , lung fibroblasts , and lung fibrocytes from saline - and bleomycin - treated mice , as well as in normal fetal and adult primary human lung fibroblasts . This response was exaggerated in cells from Pai1 -/- mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase - activated receptor 1 ( P25116 ) and instead reflected proteolytic activation and release of P14210 with subsequent induction of P35354 . That the P14210 / P35354 / DB00917 axis mediates in vivo protection from fibrosis in Pai1 -/- mice was demonstrated by experiments showing that a selective inhibitor of the P08581 c - DB00134 increased lung collagen to WT levels while reducing P35354 protein and DB00917 levels . Of clinical interest , fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce P35354 and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 . These studies demonstrate crosstalk between plasminogen activation and DB00917 generation in the lung and provide a mechanism for the well - known antifibrotic actions of the fibrinolytic pathway .",
"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK4___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK4___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .",
"P35354 regulates the proliferation of glioma stem like cells . Cancer stem - like cells ( CSCs ) possessing features of neural precursor cells ( NPC ) influence initiation , recurrence and chemoresistance of glioblastoma multiforme ( GBM ) . As inflammation is crucial for glioblastoma progression we investigated the effect of chronic IL - 1β treatment on CSCs derived from glioblastoma cell line U87MG . Exposure to IL - 1β for 10 days increased ( i ) accumulation of 8 - OHdG - a key biomarker of oxidative DNA damage ; ( ii ) DNA damage response ( DDR ) indicators γ P16104 , Q13315 and DNA - PK ; ( iii ) nuclear and cytoplasmic p53 and P35354 levels and ( iv ) interaction between P35354 and p53 . Despite upregulating p53 expression IL - 1β had no effect on cell cycle progression , apoptosis or self renewal capacity of CSCs . P35354 inhibitor Celecoxib reduced self renewal capacity and increased apoptosis of both control and IL - 1β treated CSCs . Therefore the ability of P35354 to regulate proliferation of CSCs irrespective of exposure to IL - 1β , warrants further investigation of P35354 as a potential anti - glioma target .",
"___MASK13___ block of cloned human T - type voltage - gated calcium channels . ___MASK13___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK35___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK35___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .",
"Differential role for phospholipase D1 and phospholipase D2 in 12 - O - tetradecanoyl - 13 - phorbol acetate - stimulated MAPK activation , Cox - 2 and P10145 expression . Phospholipase D ( PLD ) is expressed in many tissues and stimulated by growth factors and cytokines . However , the role of PLD in signal transduction is still not well - understood . Human embryonic kidney ( P29320 - 293 ) cells exhibit low levels of both Q13393 and O14939 mRNA , however , only Q13393 protein was detected by Western blot . When either isoform of PLD was stably expressed in P29320 - 293 cells , we observed an increased PLD activity in a cell - free system and a 12 - O - tetradecanoyl - 13 - phorbol acetate ( TPA ) - stimulated increase in PLD activity in intact cells . This system was then used to elucidate the effects of PLD activity on TPA - stimulated signaling pathways . Two such pathways , the mitogen - activated protein kinases ( MAPK ) , extracellular regulated protein kinase ( P29323 ) and p38 are activated by growth factors and cellular stress , respectively . We found that TPA stimulated P29323 phosphorylation regardless of the expression status of PLD . In contrast to P29323 kinase , P29320 - 293 cells were unable to induce p38 phosphorylation by TPA stimulation . When P29320 - 293 cells expressed either Q13393 or O14939 , we observed elevated p38 phosphorylation in response to TPA stimulation . The P29323 and p38 MAPKs can also stimulate the expression of both cyclooxygenase - 2 ( Cox - 2 ) and interleukin - 8 ( P10145 ) . We used this system to differentiate the effect of Q13393 or O14939 activity on the expression of Cox - 2 and P10145 . Increased Cox - 2 and P10145 expression was found only in P29320 - 293 cells expressing Q13393 . These data identify a novel role for the Q13393 isoform in the induction of gene expression and provide new insight into the differential role of Q13393 and O14939 in cells .",
"Pharmacogenetics and future strategies in treating hyperglycaemia in diabetes . This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes : metformin , sulphonylureas and thiazolidinediones . Currently , metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in O75051 transporters might affect metformin response . An aetiological approach has identified monogenic patients with diabetes due to TCF1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas , and Q14654 or Q09428 mutations in which sulphonylureas can be used in place of insulin treatment . In Type 2 diabetes sulphonylurea response has been shown to be associated with variants Q9NQB0 associated with type 2 diabetes risk . For thiazolidinediones , focus has been on PPARgamma variants although with no consistent result . Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies . Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required . Establishing such cohorts is a priority in diabetes pharmacogenetics research ."
] |
[
"___MASK13___",
"___MASK17___",
"___MASK20___",
"___MASK32___",
"___MASK35___",
"___MASK4___",
"___MASK78___",
"___MASK79___",
"___MASK80___"
] |
___MASK35___
|
MH_train_340
|
interacts_with DB01064?
|
[
"Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .",
"Neurotrophic factors increase tyrosine hydroxylase immunoreactive cell density of fetal mesencephalic cells . OBJECTIVE : To hibernate fetal ventral mesencephalic tegmental ( VMT ) cells from Spraque - Dawley rats E - 15 for 5 days at 4 degrees C in either hibernation media ( HM ) or in conditioned hibernation media ( P24386 ) supplemented with trophic factors such as epidermal growth factor ( P01133 200 ng / ml ) , basic fibroblast growth factor ( P09038 100 ng / ml ) , recombinant human brain derived neurotrophic factor ( rhBDNF 20 micrograms / ml ) , recombinant human glial cell - derived neurotrophic factor ( rhGDNF 20 micrograms / ml ) , fetal calf serum ( FCS 9 % ) , or human placental cord serum ( HPCS 10 % ) . METHODS : The percent of cell viability and the density of tyrosine hydroxylase immunoreactive ( THir ) cells in fetal striatal - VMT co - culture were determined . RESULTS : The viability of fetal striatal cells ( 0 . 8 +/- 0 . 104 ) was slightly higher than that of fetal VMT cells ( 0 . 7 +/- 0 . 072 ) at 0 - time point ( F17 , 1 = 4 . 677 ; P = 0 . 045 ) . After 5 days of hibernation , the viability of fetal VMT cells reduced by 30 % ( P08709 , 1 = 88 . 493 ; P < 0 . 001 ) in HM . However , THir - cell density reduced by more than 90 % as compared to the freshly harvested VMT cells ( P08709 , 1 = 179 . 944 ; P < 0 . 001 ) . P24386 with HPCS , P09038 , P01133 , P23560 , and P39905 showed higher THir - cell density than that of HM or P24386 supplemented with FCS ( P < 0 . 001 ) . CONCLUSION : Supplementation of appropriate trophic factors for hibernated fetal VMT cells promotes cell viability and the subsequent expression of THir - cell density .",
"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .",
"Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration . AflatoxinB1 ( AFB1 ) is well known as a potent carcinogen . Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans . AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1 - 8 , 9 - exo - epoxide , which acts as a mutagen to react with DNA . In addition , recent study demonstrates AFB1 positively regulates type I insulin - like growth factor receptor ( IGF - IR ) signaling in hepatoma cells . The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate ( P41252 ) in lung cancer cells and the effects of AFB1 on lung cancer cell migration . To this end , the effects of AFB1 on P41252 expression , Src , Akt , and P29323 phosphorylation were measured by Western blot analysis . The migration of lung cancer cells was detected by wound - healing assay . AFB1 downregulates P35568 but paradoxically upregulates Q9Y4H2 through positive regulation of the stability of Q9Y4H2 and the proteasomal degradation of P35568 in lung cancer cell lines A549 and P08709 - 1 . In addition , AFB1 induces Src , Akt , and P27361 / 2 phosphorylation . Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1 - induced Q9Y4H2 accumulation . Moreover , AFB1 stimulates lung cancer cell migration , which can be inhibited by saracatinib . We conclude that AFB1 may upregulate Q9Y4H2 and stimulate lung cancer cell migration through Src .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK51___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .",
"Down - regulation of Aquaporin1 ( P29972 ) by peptidoglycan via p38 MAPK pathways in primary rat pleural mesothelial cells . BACKGROUND AND OBJECTIVE : This study was designed to investigate the p38 mitogen - activated protein kinase ( MAPK ) signaling pathway involved in Aquaporin1 ( P29972 ) expression caused by staphylococcal peptidoglycan ( Q9UQ90 ) in cultured rat pleural mesothelial cells ( rPMCs ) in vitro . METHODS : RT - PCR and immunoblot analysis were used to determine the relative mRNA and protein levels of P29972 by Q9UQ90 in rPMCs . O75791 kinase inhibitor SB203580 , JNK inhibitor SP600125 , and P27361 / 2 inhibitor PD98059 were used to determine the effects of Q9UQ90 - induced P29972 expression by immunoblot . Activation of p38 by Q9UQ90 was reflected by detecting the phosphorylation constituent of p38 , using immunoblot . The shift of localization after activation of p38 by Q9UQ90 was investigated by immunofluorescence assay . RESULTS : P29972 transcription and protein expression were decreased by Q9UQ90 in dose - dependent and time - dependent manners in rPMCs . Down - regulation of P29972 by Q9UQ90 was blocked only by SB203580 , neither by SP600125 nor by PD98059 . Furthermore , rPMCs exposed to Q9UQ90 showed activation of p38 MAPK . Phospho - p38 protein production was increased by Q9UQ90 stimulation in rPMCs . The localization of phospho - p38 was both in the cytosol and nuclei after Q9UQ90 treatment , while its normal distribution is mainly in the cytosol in rPMCs . CONCLUSION : P29972 expression was decreased by Q9UQ90 in both dose - dependent and time - dependent manners in rPMCs . This down - regulation by Q9UQ90 - induced P29972 in rPMCs may be mediated by the activation of p38 Q9P0L2 pathway .",
"The protein kinases TPL2 and P00533 contribute to P27361 / P28482 hyperactivation in CFTRΔF508 - expressing airway epithelial cells exposed to Pseudomonas aeruginosa . Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cysticfibrosis ( CF ) lung disease . In this manuscript , we describe a novel mechanism of P27361 / P28482 activationand P10145 expression in airway epithelial cells ( AECs ) lacking functional P13569 . In both non - CF and CFAECs , the protein kinase TPL2 is required for P27361 / P28482 MAPK activation . However , we have found that P00533 is strongly phosphorylated in the airway epithelium of CF lung and contributes to P27361 / P28482 MAPK activation in CF AECs exposed to P . aeruginosa diffusible material ( PsaDM ) . Moreover , PsaDM stimulates the expression of the P00533 pro - ligand HB - P01133 more strongly , and in a sustained manner , in CF AECs compared to non - CF cells . Finally , although both non - CF and CF AECs expresses P10145 in response to PsaDM , the levels of P10145 are higher and P00533 plays a more important role in regulating P10145 synthesis in CF AECs . Together , our finding shows that in addition to the TLR - mediated TPL2 activation of P27361 / P28482 , an additional pathway contributing to P27361 / P28482 activation is triggered by infection of CF AECs : the P00533 signaling pathway . This second pathway may contribute to excessive inflammation observed in CF .",
"17 ___MASK47___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen - activated protein kinases ( MAPK ) [ extracellular signal - regulated kinase - 2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng / mL ) induced a significant 4 - fold increase in P28482 activity and [ 3H ] - thymidine incorporation ( 6 - fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10 (- 6 ) M ) induced a more modest increase in P28482 activity ( 2 - fold ) and [ 3H ] - thymidine incorporation ( 35 +/- 4 % ) . The mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 - induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . DB01064 inhibited the basal and P09038 - induced proliferation of HFMc through a MEK - 1 / 2 - independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK - 1 / 2 - dependent and independent signaling pathways . Activation of MEK - 1 / 2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK - 1 / 2 - independent pathway .",
"Q9H4A3 activates large - conductance Ca2 +- activated K + channels through modulation of P27361 / 2 signaling . With no lysine ( WNK ) kinases are members of the serine / threonine kinase family . We previously showed that Q96J92 inhibits renal large - conductance Ca ( 2 +)- activated K (+) ( BK ) channel activity by enhancing its degradation through a lysosomal pathway . In this study , we investigated the effect of Q9H4A3 on Q12791 activity . In HEK293 cells stably expressing the α subunit of BK ( P29320 - BKα cells ) , siRNA - mediated knockdown of Q9H4A3 expression significantly inhibited both BKα channel activity and open probability . Knockdown of Q9H4A3 expression also significantly inhibited BKα protein expression and increased P27361 / 2 phosphorylation , whereas overexpression of Q9H4A3 significantly enhanced BKα expression and decreased P27361 / 2 phosphorylation in a dose - dependent manner in HEK293 cells . Knockdown of P27361 / 2 prevented Q9H4A3 siRNA - mediated inhibition of BKα expression . Similarly , pretreatment of P29320 - BKα cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of Q9H4A3 siRNA on BKα expression in a dose - dependent manner . Knockdown of Q9H4A3 expression also increased the ubiquitination of BKα channels . Notably , mice fed a high - K (+) diet for 10 days had significantly higher renal protein expression levels of BKα and Q9H4A3 and lower levels of P27361 / 2 phosphorylation compared with mice fed a normal - K (+) diet . These data suggest that Q9H4A3 enhances Q12791 function by reducing P27361 / 2 signaling - mediated lysosomal degradation of the channel .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK90___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"___MASK38___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK38___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Involvement of histone deacetylation in ras - induced down - regulation of the metastasis suppressor O95980 . O95980 is a membrane - anchored glycoprotein that may negatively regulate matrix metalloproteinase ( MMP ) activity and inhibit tumor metastasis . Previous study demonstrated that oncogenic ras inhibited O95980 expression via an Sp1 binding site in the O95980 promoter . In this study , we investigated the molecular mechanism by which ras inhibited O95980 expression . Co - transfection assay showed that Sp1 and Sp3 are transactivators , rather than repressors , for O95980 gene . So , we tested whether ras activation induced the binding of histone deacetylases ( HDACs ) to Sp1 to repress O95980 expression . Our data showed Sp1 - associated Q13547 in cells was increased after ras induction . By using DNA affinity precipitation assay , we found that induction of oncogenic ras enhanced the binding of Q13547 to the DNA probe corresponding to the Sp1 site in the O95980 promoter . Additionally , a HDAC inhibitor trichostatin A ( P32119 ) potently antagonized the inhibitory action of ras on O95980 . The signaling pathway by which ras suppresses O95980 was also addressed . Induction of oncogenic ras activated extracellular signal - regulated kinase ( P29323 ) , but not c - Jun N - terminal kinase ( JNK ) and p38 ( HOG ) kinase in 2 - 12 cells . Addition of PD98059 or overexpression of dominant - negative mutant of P28482 indeed reversed ras - mediated inhibition of O95980 promoter activity . Taken together , our results suggest that oncogenic ras represses O95980 expression via a histone deacetylation mechanism .",
"Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6 . 1 - composed K - DB00171 channels expressed in neural stem cells . BACKGROUND AND PURPOSE : Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases . Iptakalim ( Ipt ) , a novel DB00171 - sensitive potassium ( K - DB00171 ) channel opener , has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro . However , it remains unknown whether Ipt could regulate the adult neurogenesis . METHODS AND RESULTS : Based on the finding that adult neural stem cells ( ANSCs ) in hippocampus expressed Kir6 . 1 / Q09428 - composed K - DB00171 channel , Kir6 . 1 heterozygotic ( Kir6 . 1 (+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis . We showed that administration of Ipt ( 10 mg / kg ) or fluoxetine ( Flx , 10 mg / kg ) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ ) of Kir6 . 1 (+/+) mice but failed to affect those of Kir6 . 1 (+/-) mice . Meanwhile , ANSCs in Kir6 . 1 (+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes . We further found that Kir6 . 1 (+/-) mice showed lower level of brain - derived neurotrophic factor ( P23560 ) in hippocampus compared with Kir6 . 1 (+/+) mice . Furthermore , Ipt increased the levels of P23560 and basic fibroblast growth factor ( P09038 ) throughout the hippocampus in Kir6 . 1 (+/+) mice but not in Kir6 . 1 (+/-) mice . Moreover , Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6 . 1 (+/+) mice . Notably , these effects were completely abolished in Kir6 . 1 (+/-) mice . CONCLUSIONS : Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6 . 1 - composed K - DB00171 channels , which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency , such as major depression .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Oxidative stress induces extracellular signal - regulated kinase 1 / 2 mitogen - activated protein kinase in cystic fibrosis lung epithelial cells : Potential mechanism for excessive P10145 expression . Cystic fibrosis ( CF ) is a lethal disease caused by defective function of the cftr gene product , the CF transmembrane conductance regulator ( P13569 ) that leads to oxidative damage and excessive inflammatory response in lungs of CF patients . We here report the effects of oxidative stress ( hyperoxia , 95 % O ( 2 ) ) on the expression of pro - inflammatory interleukin ( IL ) - 8 and P25024 / 2 receptors in two human CF lung epithelial cell lines ( IB3 - 1 , with the heterozygous F508del / W1282X mutation and CFBE41o - with the homozygous F508del / F508del mutation ) and two control non - CF lung epithelial cell lines ( S9 cell line derived from IB3 - 1 after correction with wtCFTR and the normal bronchial cell line 16HBE14o - ) . Under oxidative stress , the expression of P10145 and P25024 / 2 receptors was increased in CF , corrected and normal lung cell lines . The effects of oxidative stress were also investigated by measuring the transcription nuclear factor kappaB ( NF - kappaB ) and activator protein - 1 ( AP - 1 ) activities . Under oxidative stress , no increase of NF - kappaB activation was observed in CF lung cells in contrast to that observed in normal and corrected CF lung cells . The signalling of mitogen - activated protein ( Q96HU1 ) kinases was further studied . We demonstrated that extracellular signal - regulated kinase ( P27361 / 2 ) and AP - 1 activity was markedly enhanced in CF but not non - CF lung cells under oxidative stress . Consistently , inhibition of P27361 / 2 in oxidative stress - exposed CF lung cells strongly decreased both the P10145 production and P25024 / 2 expression . Therefore , targeting of P27361 / 2 Q96HU1 kinase may be critical to reduce oxidative stress - mediated inflammation in lungs of CF patients .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK8___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK8___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK8___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK8___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK8___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"DB01064 inhibits fibroblast growth factor - 2 - induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen - activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8 - bromo - DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin - Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8 - bromo - DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8 - bromo - DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 / 2 ) , blocked the P09038 mitogenic effects , but did not affect the 8 - bromo - DB02527 - induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth - promoting effects of P09038 in RTEc via MEK - dependent and - independent pathways .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK30___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Phosphorylation of the ARE - binding protein Q96EP5 by P28482 induces its dissociation from Q9NQZ3 . A protein in RAW 264 . 7 macrophages , which became phosphorylated in response to LPS ( lipopolysaccharide ) , was identified as the RNA - binding protein called Q96EP5 [ Q9NQZ3 ( deleted in azoospermia ) - associated protein 1 ] . The phosphorylation of this protein was prevented by specific inhibition of Q02750 [ MAPK ( mitogen - activated protein kinase ) kinase 1 ] , indicating that it was phosphorylated via the classical MAPK cascade . Further experiments showed that Q96EP5 was phosphorylated stoichiometrically in vitro by P28482 ( extracellular - signal - regulated protein kinase 2 ) at two DB00156 - Pro sequences ( Thr269 and Thr315 ) , and that both sites became phosphorylated in P29320 - 293 ( human embryonic kidney 293 ) cells in response to PMA or P01133 ( epidermal growth factor ) , or RAW 264 . 7 macrophages in response to LPS . Phosphorylation induced by each stimulus was prevented by two structurally distinct inhibitors of Q02750 ( PD184352 and U0126 ) , demonstrating that Q96EP5 is a physiological substrate for P27361 / P28482 . The mutation of Thr269 and Thr315 to aspartate or the phosphorylation of these residues caused Q96EP5 to dissociate from its binding partner Q9NQZ3 . Q9NQZ3 interacts with PABP [ poly ( A )- binding protein ] and thereby stimulates the translation of mRNAs containing short poly ( A ) tails [ Collier , Gorgoni , Loveridge , Cooke and Gray ( 2005 ) EMBO J . 24 , 2656 - 2666 ] . In the present study we have shown that Q9NQZ3 can not bind simultaneously to Q96EP5 and PABP , and suggest that the phosphorylation - induced dissociation of Q9NQZ3 and Q96EP5 may allow the former to stimulate translation by interacting with PABP .",
"DB09280 - ___MASK81___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Epigenetic mechanisms in the dopamine D2 receptor - dependent inhibition of the prolactin gene . Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region . Based on the inducibility of prolactin gene expression by inhibitors of histone deacetylases ( HDACs ) , we examined the role of histone acetylation at the genomic prolactin promoter as a late step in transcriptional regulation . Chromatin immunoprecipitation analysis of GH4 cells revealed elevated levels of acetylated histones in the promoter and enhancer regions of the gene , compared with downstream intron sequences . 17beta - Estradiol stimulated histone H4 acetylation in the promoter region by 2 - to 3 - fold within 30 min . Dopamine inhibited histone H4 acetylation by 2 - fold in 30 min , an effect mimicked by the MAPK kinase ( Q02750 ) inhibitor U0126 . In contrast , the synthetic glucocorticoid dexamethasone , which inhibits prolactin transcription , failed to alter histone acetylation over the same time frame . Association of transcription activator Pit - 1 with the prolactin promoter was unchanged by hormone treatment . However , in response to dopamine , histone deacetylase Q92769 and corepressor mSin3A were rapidly recruited to the prolactin promoter , and association was sustained above basal levels over a 1 - h period . Consistent with this corepressor function , depletion of endogenous mSin3A by small interfering RNA was sufficient to enhance prolactin gene expression by 70 % , comparable to the induction by the HDAC inhibitor , trichostatin A . These studies demonstrate that dopamine D2 receptor activation and inhibition of MAPK ( P27361 / 2 ) signaling lead to rapid deacetylation of histones at the genomic prolactin promoter . Recruitment of specific HDAC / corepressor complexes may be an important mechanism for repression of target gene transcription by Gi / o - coupled receptors .",
"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK93___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"PKC putative phosphorylation site Ser235 is required for MIP / P30301 translocation to the plasma membrane . PURPOSE : To investigate the functional significance of MIP / P30301 phosphorylation at serine ( 235 ) . METHODS : MIP / P30301 expression and cellular localization was studied in rat lens epithelia explants induced to differentiate by P09038 . MIP wild type ( WT ) and MIP ( S235A ) mutant expression plasmids were constructed and transiently expressed in RK13 cells . Subcellular localization of endogenous MIP in differentiating lens epithelia explants or of transfected MIP expression vectors in RK13 cells was analyzed by immunofluorescence confocal microscopy . RESULTS : MIP / P30301 expressed in lens epithelia explants induced to differentiate by P09038 localizes to the plasma membrane of elongating cells . However , MIP / P30301 translocation to the plasma membrane was prevented by inhibiting PKC activity with Go6976 , resulting in retention in the cytoplasmic compartment . This effect was specific to MIP / P30301 ; localization of P29972 to the cell membrane was not affected by Go6976 . When the consensus PKC phosphorylation site at MIP DB00133 ( 235 ) was mutated to alanine and transiently expressed in transfected RK13 cells , the mutant MIP was retained in the cytoplasmic compartment in contrast to WT MIP that localized to the plasma membrane of the transfected RK13 cells . Colocalization studies indicated that the mutant MIP was retained in the trans - Golgi network . CONCLUSIONS : Our results indicate that serine ( 235 ) is required for proper intracellular transport of MIP / P30301 from the trans - Golgi network to the plasma membrane . A PKC dependent phosphorylation event involving MIP at serine ( 235 ) is most likely involved in this process .",
"Phosphorylation of beta - arrestin2 regulates its function in internalization of beta ( 2 )- adrenergic receptors . Beta - arrestins mediate agonist - dependent desensitization and internalization of G protein - coupled receptors . Previously , we have shown that phosphorylation of beta - arrestin1 by ERKs at DB00133 - 412 regulates its association with clathrin and its function in promoting clathrin - mediated internalization of the receptor . In this paper we report that beta - arrestin2 is also phosphorylated , predominantly at residues DB00156 - 383 and DB00133 - 361 . DB01064 stimulation of the beta ( 2 )- adrenergic receptor promotes dephosphorylation of beta - arrestin2 . Mutation of beta - arrestin2 phosphorylation sites to aspartic acid decreases the association of beta - arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta ( 2 )- adrenergic receptor . Its ability to bind and desensitize the beta ( 2 )- adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta - arrestin1 , phosphorylation / dephosphorylation of beta - arrestin2 regulates clathrin - mediated internalization of the beta ( 2 )- adrenergic receptor . In contrast to beta - arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta - arrestin2 at DB00156 - 383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 - 366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein - coupled receptors is regulated by distinct phosphorylation / dephosphorylation mechanisms .",
"Noncatalytic function of P27361 / 2 can promote Raf / MEK / P29323 - mediated growth arrest signaling . Kinase activity is known as the key biochemical property of MAPKs . Here , we report that P27361 / 2 also utilizes its noncatalytic function to mediate certain signal transductions . Sustained activation of the Raf / MEK / P29323 pathway induces growth arrest , accompanied by changes in cell cycle regulators ( decreased retinoblastoma phosphorylation , Q01094 down - regulation , and / or P38936 ( CIP1 ) up - regulation ) and cell type - specific changes in morphology and expression of c - Myc or P07949 in the human tumor lines LNCaP , U251 , and TT . Ablation of P27361 / 2 by RNA interference abrogated all these effects . However , active site - disabled P29323 mutants ( P27361 - K71R , P28482 - K52R , and P28482 - D147A ) , which competitively inhibit activation of endogenous P27361 / 2 , could not block Raf / MEK - induced growth arrest as well as changes in the cell cycle regulators , although they effectively blocked phosphorylation of the P27361 / 2 catalytic activity readouts , p90 ( RSK ) and ELK1 , as well as the cell type - specific changes . Because this indicated a potential noncatalytic P27361 / 2 function , we generated stable lines of the tumor cells in which both P27361 and P28482 were significantly knocked down , and we further investigated the possibility using rat - derived kinase - deficient P29323 mutants ( P28482 - K52R and P28482 - T183A / Y185F ) that were not targeted by human small hairpin RNA . Indeed , P28482 - K52R selectively restored Raf - induced growth inhibitory signaling in P27361 / 2 - depleted cells , as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c - Myc and morphology . However , P28482 - T183A / Y185F was less effective , indicating the requirement of TEY site phosphorylation . Our study suggests that functions of P27361 / 2 other than its \" canonical \" kinase activity are also involved in the pathway - mediated growth arrest signaling .",
"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK78___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided ."
] |
[
"___MASK30___",
"___MASK38___",
"___MASK47___",
"___MASK51___",
"___MASK78___",
"___MASK81___",
"___MASK8___",
"___MASK90___",
"___MASK93___"
] |
___MASK30___
|
MH_train_341
|
interacts_with DB01083?
|
[
"Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase . Dietary intake of soy protein decreases tumor incidence in rat models of chemically induced colon cancer . We hypothesized that decreased expression of fatty acid synthase ( P49327 ) underlies , in part , the tumor - preventive effects of soy protein , since P49327 overexpression characterizes early tumorigenesis . Here , we show that colonic P49327 levels are reduced with dietary intake of soy protein isolate ( SPI ) , compared with a control casein diet , in male Sprague - Dawley rats administered the colon carcinogen azoxymethane . SPI consumption resulted in decreased serum insulin levels and decreased azoxymethane - induced tumor suppressor p53 phosphorylation in colon crypt epithelium . To evaluate potential links between insulin and P49327 leading to DNA damage , P06681 ( BBe ) 1 colon epithelial cells , treated with insulin and / or the carcinogen N - nitroso - N - methylurea ( P48645 ) , were evaluated for DNA damage and apoptosis after transfection with control or P49327 small interfering RNAs ( siRNAs ) . While the numbers of DNA apurinic / apyrimidinic sites ( biomarker of DNA damage ) induced by P48645 were unaffected by transfection of P49327 siRNA , insulin induction of these sites was decreased with P49327 knockdown . By contrast , P48645 - induced apoptosis of P06681 ( BBe ) 1 , as well as intestinal epithelial cell ( IEC ) - 6 , was enhanced by transfected P49327 siRNA . Increased P49327 expression in IEC - 6 cells by addition of liver X receptor agonist T0901317 did not affect apurinic / apyrimidinic site number , but enhanced cell killing by cerulenin , a P49327 inhibitor . Moreover , insulin rescued P48645 - treated cells from apoptosis in an P49327 - dependent manner . Results suggest that dietary SPI , by decreasing circulating insulin levels and colon P49327 expression , attenuates insulin - induced DNA damage and P49327 - mediated anti - apoptosis during carcinogenesis , resulting in an overall reduced tumorigenic state .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK83___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK39___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Targeting androgen receptor in estrogen receptor - negative breast cancer . Endocrine therapies for breast cancer that target the estrogen receptor ( ER ) are ineffective in the 25 % - 30 % of cases that are ER negative ( ER - ) . P10275 ( AR ) is expressed in 60 % - 70 % of breast tumors , independent of ER status . How androgens and AR regulate breast cancer growth remains largely unknown . We find that AR is enriched in ER - breast tumors that overexpress P04626 . Through analysis of the AR cistrome and androgen - regulated gene expression in ER -/ P04626 + breast cancers we find that AR mediates ligand - dependent activation of Wnt and P04626 signaling pathways through direct transcriptional induction of P56706 and P21860 . Specific targeting of AR , Wnt or P04626 signaling impairs androgen - stimulated tumor cell growth suggesting potential therapeutic approaches for ER -/ P04626 + breast cancers .",
"Immunoreactive parathyroid hormone - related protein : its association with preterm labor . OBJECTIVE : P12272 ( P12272 ) is a 141 amino acid protein which contains a 1 - 36 N - terminal domain resembling parathyroid hormone which has smooth muscle relaxant activity and a mid ( 67 - 86 ) domain which reportedly alters placental calcium transport . Using specific antibodies to these regions of P12272 , the objective of this study was to determine changes in the levels and localization of the peptides in placenta and membranes that might be indicative of their biological activity and role during term and preterm labor . STUDY DESIGN : Placenta and fetal membranes were collected from patients with preterm delivery ( P16233 ) ( n = 16 ) , term cesarean section in the absence of labor ( n = 10 ) and term vaginal delivery ( n = 5 ) . Immunohistochemistry was performed with specific antisera visualized by the avidin - biotin peroxidase method and the staining intensity was quantified with an image analysis system MCID . RESULTS : Immunoreactive ( ir )- P12272 ( 1 - 34 ) and ir - P12272 ( 67 - 86 ) were localized to the amnionic epithelium chorionic trophoblasts , decidual cells and placental syncytiotrophoblast . Intense immunostaining was observed for ir - P12272 ( 67 - 86 ) but not for ir - P12272 ( 1 - 34 ) in the endothelial lining of the villous capillaries . Ir - P12272 ( 1 - 34 ) staining was lower in placenta and fetal membranes of P16233 patients compared with term cesarean section in the absence of labor ( P < 0 . 05 Mann - Whitney test ) . In contrast , there was no difference in ir - P12272 [ 67 - 86 ] staining intensity between delivery categories . CONCLUSION : These results showing differential localization of P12272 ( 1 - 34 ) and P12272 ( 67 - 86 ) suggest cell specific processing of P12272 precursor in the human placenta . Moreover , the changes in ir - P12272 ( 1 - 34 ) but not ir - PTHr ( 67 - 86 ) with labor are indicative of a particular role for this peptide in the delivery process .",
"Haplotype analysis improved evidence for candidate genes for intramuscular fat percentage from a genome wide association study of cattle . In genome wide association studies ( GWAS ) , haplotype analyses of SNP data are neglected in favour of single point analysis of associations . In a recent GWAS , we found that none of the known candidate genes for intramuscular fat ( IMF ) had been identified . In this study , data from the GWAS for these candidate genes were re - analysed as haplotypes . First , we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain - calpastatin complex and musculus longissimus lumborum peak force ( LLPF ) , because these genes had been confirmed through single point analysis in the GWAS . Then , for intramuscular fat percent ( IMF ) , we found significant partial haplotype substitution effects for the genes Q15848 and P61073 , as well as suggestive associations to the genes P49715 , P49327 , and P07384 . Haplotypes for these genes explained 80 % more of the phenotypic variance compared to the best single SNP . For some genes the analyses suggested that there was more than one causative mutation in some genes , or confirmed that some causative mutations are limited to particular subgroups of a species . Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses . Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data , would be a useful method to extract more information from these data sets , and may contribute to reducing the missing heritability problem .",
"Regulation of heparanase expression in coronary artery disease in diabetic , hyperlipidemic swine . OBJECTIVE : Enzymatic degradation of the extracellular matrix is known to be powerful regulator of atherosclerosis . However , little is known about the enzymatic regulation of heparan sulfate proteoglycans ( HSPGs ) during the formation and progression of atherosclerotic plaques . METHODS AND RESULTS : Swine were rendered diabetic through streptozotocin injection and hyperlipidemic through a high fat diet . Arterial remodeling and local endothelial shear stress ( ESS ) were assessed using intravascular ultrasound , coronary angiography and computational fluid dynamics at weeks 23 and 30 . Coronary arteries were harvested and 142 arterial subsegments were analyzed using histomorphologic staining , immunostaining and real time PCR . Q9Y251 staining and activity was increased in arterial segments with low ESS , in lesions with thin cap fibroatheroma ( TCFA ) morphology and in lesions with severely degraded internal elastic laminae . In addition , heparanase staining co - localized with staining for P08575 and P08253 within atherosclerotic plaques . Dual staining with gelatinase zymography and heparanase immunohistochemical staining demonstrated co - localization of matrix metalloprotease activity with heparanase staining . A heparanase enzymatic activity assay demonstrated increased activity in TCFA lesions , subsegments with low ESS and in macrophages treated with oxidized LDL or angiotensin II . CONCLUSIONS : Taken together , our results support a critical role for heparanase in the development of vulnerable plaques and suggest a novel therapeutic target for the treatment of atherosclerosis .",
"P49327 inhibitor orlistat induces apoptosis in T cell lymphoma : role of cell survival regulatory molecules . BACKGROUND : De novo fatty acid synthesis catalyzed by fatty acid synthase ( P49327 ) is crucial for tumor cell survival . Thus therapeutic targeting of P49327 is considered as a novel antineoplastic strategy . However , little is understood in this respect regarding malignancies of hematological origin . The present investigation was therefore , undertaken to study the molecular mechanisms of the antitumor action of P49327 inhibitor orlistat ( tetrahydrolipstatin ) using a murine model of a T cell lymphoma . METHODS : The antitumor efficacy of orlistat was investigated in vitro by estimating cell survival by MTT assay and apoptosis by Wright Giemsa , TUNEL , Annexin - V / PI staining and % DNA fragmentation . Generation of reactive oxygen species ( ROS ) in tumor cells was studied using fluorescence microscopy . Expression of genes and proteins was carried out by RT - PCR and western blot analyses respectively . P49327 and CPT - 1 activity was estimated by spectrophotometer . Cytokines expression was analyzed by ELISA . RESULTS : We report that inhibition of P49327 with its specific inhibitor orlistat manifests tumor - specific inhibition of cell survival , accompanied by induction of apoptosis . DB01083 - treated tumor cells showed an altered ROS generation , shift in cytokine balance and modulated expression of cell survival regulatory molecules like HSP70 , Bcl2 , p53 , PUMA , P42574 and CAD . It was observed that IFN - γ mediates orlistat - dependent modulation of P49327 expression . CONCLUSION AND GENERAL SIGNIFICANCE : In this study , we report some of the so far unexplored novel aspects underlying the molecular mechanisms associated with orlistat - dependent modulation of tumor cell survival . These observations will help in designing antineoplastic therapeutic protocols using orlistat against malignancies of hematological origin .",
"P03372 profiles : changes in mouse and rat mammary tumors by treatment with selective estrogen receptor modifiers . OBJECTIVE : The aim of this work was to analyze the effect of estradiol ( E ( 2 ) ) , medroxyprogesterone and the two selective estrogen receptor modulators ( SERMs ) ( tamoxifen ( Tam ) and raloxifene ( Ral ) ) on the estrogen receptor ( ER ) conformers profile performed by size exclusion HPLC in relation to hormone dependence of mammary tumors . MATERIALS AND METHODS : Two types of mammary tumors were studied : tumors transplanted in BALB / c mice that are medroxyprogesterone acetate ( ___MASK36___ ) - dependent for growth , and tumors induced in Sprague - Dawley rats by intraperitoneal injection of N - nitroso - N - methylurea ( P48645 ) . Tumors from mice treated with ___MASK36___ , E ( 2 ) , Tam or Ral and P48645 - treated rats were analyzed and compared to that of control . RESULTS : The tumor conformer profiles were as follows : control and ___MASK36___ - treated mice showed only one peak ( oligomeric form ) ; E ( 2 )- treated mice also showed only one peak ( dimer ) ; Tam - treated mice showed one peak corresponding to a possible proteolytic fragment , and Ral - treated mice showed two peaks ( oligomeric and a possible proteolytic fragment ) . On the other hand , P48645 - induced mammary tumors from rats showed three peaks ( oligomeric , monomeric and proteolytic ) . CONCLUSION : Our findings may indicate that SERMs affect the aggregation state of ER and thereby its ability to modulate genomic transcription mechanisms related to growth rate .",
"Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with DB01083 reduces cell viability and triggers apoptosis . P49327 ( P49327 ) , catalyzing the de novo synthesis of fatty acids , is known to be deregulated in several cancers . Inhibition of this enzyme reduces tumor cell proliferation . Unfortunately , adverse effects and chemical instability prevent the in vivo use of the best - known inhibitors , Cerulenin and C75 . DB01083 , a drug used for obesity treatment , is also considered as a potential P49327 inhibitor , but its impact on glioma cell biology has not yet been described . In this study , we analyzed P49327 expression in human glioma samples and primary glioblastoma cell cultures and the effects of P49327 inhibition with DB01083 , Cerulenin and C75 . Immunohistochemistry followed by densitometric analysis of 20 glioma samples revealed overexpression of P49327 that correlated with the WHO tumor grade . Treatment of glioblastoma cells with these inhibitors resulted in a significant , dose - dependent reduction in tumor cell viability and fatty acid synthesis . Compared to Cerulenin and C75 , DB01083 was a more potent inhibitor in cell cultures and cell lines . In LN229 , cell - growth was reduced by 63 . 9 ± 8 . 7 % after 48 h and 200 µM DB01083 compared to controls ; in LT68 , the reduction in cell growth was 76 . 3 ± 23 . 7 % . Nuclear fragmentation assay and Western blotting analysis after targeting P49327 with DB01083 demonstrated autophagy and apoptosis . Organotypic slice cultures treated with DB01083 showed reduced proliferation after Ki67 staining and increased caspase - 3 cleavage . Our results suggest that P49327 may be a therapeutic target in malignant gliomas and identify DB01083 as a possible anti - tumor drug in this setting .",
"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .",
"Altered distribution of keratinization markers in epidermolytic hyperkeratosis . Epidermolytic hyperkeratosis ( EH ) is a genetic disorder of keratins associated with epidermal differentiation . Affected individuals carry gene mutations for conserved sequences of keratins P04264 or P13645 . The structural alterations of tonofilaments in EH seem to be a direct consequence of the keratin gene mutations . EH epidermis , however , shows many other unexplained abnormalities including acanthosis , hypergranulosis , and hyperkeratosis . To further elucidate the pathogenetic mechanism of EH , we studied distribution patterns of other keratinization - associated molecules including involucrin , small proline - rich protein ( SPRR ) 1 , loricrin and trichohyalin in the skin of four patients by light and electron microscopic immunohistochemistry in conjunction with conventional transmission electron microscopy . The middle to upper epidermal cells showed moderate to strong immunoreactivities to involucrin , SPRR1 and loricrin antibodies . Both intracellular staining and cell peripheral staining was seen for involucrin and SPRR1 antibodies . P23490 labelling was prematurely associated with the plasma membrane of granular cells , possibly relating to abnormal keratin filament aggregation and cellular vacuolization . Some loricrin labelling was localized on the keratin aggregates , suggesting intermolecular associations between keratin and loricrin . Q07283 , hardly detectable in normal epidermis , was present in some granular and cornified cells in EH in association with keratin filaments , suggesting that it may function as an intermediate filament - associated protein . While cornified cell envelopes were intensely labelled only with loricrin antibodies in normal skin , they were immunoreactive to involucrin , SPRR1 and loricrin antibodies in EH . Sequential change in electron density of the cornified cell envelopes , a constant feature in normal skin , was often absent in EH . These results suggest an altered assembly process of cornified cell envelopes in EH .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"Regulation of the SREBP transcription factors by mTORC1 . In recent years several reports have linked mTORC1 ( mammalian target of rapamycin complex 1 ) to lipogenesis via the SREBPs ( sterol - regulatory - element - binding proteins ) . SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis . Lipid metabolism is perturbed in some diseases and SREBP target genes , such as P49327 ( fatty acid synthase ) , have been shown to be up - regulated in some cancers . We have previously shown that mTORC1 plays a role in SREBP activation and Akt / P31749 ( protein kinase B ) - dependent de novo lipogenesis . Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co - ordinates protein and lipid biosynthesis during cell growth . In the present paper , we discuss the increasing amount of data supporting the potential mechanisms of mTORC1 - dependent activation of SREBP as well as the implications of this signalling pathway in cancer .",
"Wnt - 11 signalling controls ventricular myocardium development by patterning P19022 and beta - catenin expression . AIMS : The stage - dependent organization of the cardiomyocytes during formation of the different layers of the developing ventricular wall is critical for the establishment of a functional heart , but the instructive signals involved are still poorly known . We have addressed the potential role of Wnt - 11 in the control of early ventricular myocardium assembly . METHODS AND RESULTS : We demonstrate by means of expression analysis and a mouse model in which Wnt - 11 function has been inactivated that Wnt - 11 is expressed by the embryonic ventricular cardiomyocytes and serves as one important signal for ventricular wall development . In the absence of Wnt - 11 , the coordinated organization , intercellular contacts , co - localized expression of the cell adhesion components P19022 and beta - catenin , and the cytoskeleton of the differentiating ventricular cardiomyocytes are all disturbed . Moreover , the ventricular wall lacking Wnt - 11 signalling is thinner and the expression of the Gata - 4 , Nkx2 . 5 , Mef2c , P01160 , and DB04899 genes is down - regulated relative to controls . These defects lie behind disturbed embryonic cardiac functional development , marked by an increase in the ventricular relaxation time during the early diastole . CONCLUSION : We conclude that Wnt - 11 signalling serves as a critical cell adhesion cue for the organization of the cardiomyocytes in the developing ventricular wall , which is essential for the establishment of a functional heart .",
"Stretch and inflammatory cytokines drive myometrial chemokine expression via NF - κB activation . Both human preterm labor ( P16233 ) and term labor are consistently associated with a chemokine - induced inflammatory infiltration of the myometrium . However , what regulates myometrial chemokine expression and whether the increase in expression precedes the onset of labor , and so may have a role in its causation , or occurs after , and is simply a consequence of labor , is uncertain . Therefore , we assessed 1 ) chemokine expression in nonlaboring and laboring myometrial samples obtained at and before term and 2 ) the factors that regulate myometrial chemokine expression . We found that term labor was characterized by an increase in P10145 and P13500 in both upper and lower segments , whereas P16233 was associated with a distinct pattern of chemokine expression , with increases in P13501 , P42830 , and P78556 in the lower segment myometrium only . Further , we found that chemokine expression in myometrial cell cultures was increased by stretch and inflammatory cytokines and reduced by prostglandins and oxytocin and that the primary mediator of stretch and cytokine effects was nuclear factor κB ( NF - κB ) and to a lesser extent MAPK . These data show that P16233 appears to be associated with a distinct pattern of chemokine expression , that stretch and cytokines both drive myometrial chemokine expression primarily via activation of NF - κB . These data suggest that the modulation of NF - κB activity may be of potential benefit in the management of P16233 .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK30___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK36___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK36___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK36___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK36___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .",
"The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .",
"A role of DNA - PK for the metabolic gene regulation in response to insulin . P49327 ( FAS ) is a central enzyme in lipogenesis and transcriptionally activated in response to feeding and insulin signaling . The transcription factor P22415 is required for the activation of FAS transcription , and we show here that P22415 phosphorylation by DNA - PK , which is dephosphorylated by P50391 in response to feeding , triggers a switch - like mechanism . Under fasting conditions , P22415 - 1 is deacetylated by Q9UKV0 , causing promoter inactivation . In contrast , feeding induces the recruitment of DNA - PK to P22415 - 1 and its phosphorylation , which then allows recruitment of Q92831 , resulting in P22415 - 1 acetylation and FAS promoter activation . DNA break / repair components associated with P22415 induce transient DNA breaks during FAS activation . In DNA - PK - deficient SCID mice , feeding - induced P22415 - 1 phosphorylation / acetylation , DNA breaks , and FAS activation leading to lipogenesis are impaired , resulting in decreased triglyceride levels . Our study demonstrates that a kinase central to the DNA damage response mediates metabolic gene activation .",
"Lectin array analysis for wild - type and α - Gal - knockout pig islets versus healthy human islets . PURPOSE : We performed lectin microarray analyses of islets from wild - type ( WT ) pigs and α1 - 3galactosyltransferase gene knockout ( GKO ) pigs and compared the results with the corresponding values for islets from healthy humans . METHODS : Islets were isolated from the pancreas . After sonication and centrifugation , the proteins in the supernatant from each islet were labeled with Cy3 and applied to a lectin array . RESULTS : Despite negligible expression of the Gal antigen on the adult pig islets ( APIs ) , GKO - islets showed weaker signals , not only for GS - I - B4 but also for PNA , WFA , P16233 - I , and GS - I - A4 , than the WT islets , indicating reduced contents of α - linked GalNAc and Galβ1 - 3GalNAc . In comparing the islets of pigs vs . humans , human islets showed stronger signals for UEA - I , AAL , TJA - II , EEL , WFA , Q9Y251 , DBA , SBA and P16233 - I , indicating that besides P16442 blood type antigens , high levels of fucose and α - linked GalNAc are present . On the other hand , the high mannose form was very rich in the APIs . CONCLUSION : GKO reduced alpha - linked GalNAc , despite negligible expression of the Gal antigen on WT - DB00058 . On the other hand , the high - mannose form was richer in both APIs than in healthy human islets . These results provide useful information for future studies .",
"Signaling cascade that mediates endothelial nitric oxide synthase activation induced by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 ) induces activation of nitric oxide - synthase ( NOS ) . AIMS : to identify the isoform of NOS involved in P01160 effects , to study whether P01160 modifies NOS expression and to investigate the signaling pathways and receptors involved in NOS stimulation . NOS activation induced by P01160 would be mediated by endothelial NOS ( P29474 ) since neuronal or inducible NOS inhibition did not alter P01160 effect . The peptide induced no changes in P29474 protein expression . NOS activity stimulated by P01160 , in the kidney , aorta and left ventricle , was partially abolished by the P16066 / B antagonist , as well as PKG inhibition , but no difference in atria was observed . 8 - Br - cGMP partially mimicked the effect of P01160 on NOS in all tissues . NOS stimulation by P01160 in atria disappeared when G protein was inhibited , but this effect was partial in the other tissues . P62158 antagonist abolished NOS stimulation via P01160 . Inhibition of the P98160 , PKC or P19957 kinase / Akt pathway failed to alter NOS activation induced by P01160 . P01160 would activate P29474 in the aorta , heart and kidney without modifying the expression of the enzyme . P01160 would interact with P17342 coupled via G proteins leading to the activation of Ca ( 2 +)- calmodulin - dependent NOS in atria ; while in ventricle , aorta and kidney , P01160 could also interact with P16066 / B , increasing cGMP , which in turns activates PKG to stimulate P29474 .",
"P49327 inhibition results in a magnetic resonance - detectable drop in phosphocholine . Expression of fatty acid synthase ( P49327 ) , the key enzyme in de novo synthesis of long - chain fatty acids , is normally low but increases in cancer . Consequently , P49327 is a novel target for cancer therapy . However , because P49327 inhibitors can lead to tumor stasis rather than shrinkage , noninvasive methods for assessing P49327 inhibition are needed . To this end , we combined ( 1 ) H , ( 31 ) P , and ( 13 ) C magnetic resonance spectroscopy ( P59665 ) ( a ) to monitor the metabolic consequences of P49327 inhibition and ( b ) to identify P59665 - detectable metabolic biomarkers of response . Treatment of PC - 3 cells with the P49327 inhibitor DB01083 for up to 48 h resulted in inhibition of P49327 activity by 70 % , correlating with 74 % inhibition of fatty acid synthesis . Furthermore , we have determined that P49327 inhibition results not only in lower phosphatidylcholine levels but also in a 59 % drop in the phospholipid precursor phosphocholine ( PCho ) . This drop resulted from inhibition in PCho synthesis as a result of a reduction in the cellular activity of its synthetic enzyme choline kinase . The drop in PCho levels following P49327 inhibition was confirmed in SKOV - 3 ovarian cancer cells treated with DB01083 and in MCF - 7 breast cancer cells treated with DB01083 as well as cerulenin . Combining data from all treated cells , the drop in PCho significantly correlated with the drop in de novo synthesized fatty acid levels , identifying PCho as a potential noninvasive P59665 - detectable biomarker of P49327 inhibition in vivo .",
"DB09372 is an inhibitor of P48061 ( SDF - 1alpha ) / P61073 with antiangiogenic activity . PURPOSE : Increasing evidence suggests that interaction between the chemoattractant P48061 / stromal cell - derived factor - 1alpha and its receptor P61073 plays a pivotal role in the metastasis of various tumors . Our previous studies showed that multi - component Chinese herbal medicines inhibited the effects of P48061 / P61073 . As a result of sequential chromatographic fractionation of one herbal medicine ingredient , Lianqiao ( fruit of Forsythia suspensa ) , we observed that tannins were , at least in part , responsible for this activity . The aim of this study was to assess the anti - P48061 / P61073 activity of a commercial tannic acid and evaluate its potential to inhibit tumor cell migration and angiogenesis in vitro . EXPERIMENTAL DESIGN : The inhibitory effect of tannic acid on P48061 / P61073 was measured by chemotaxis assay , ligand binding assay , and fluorescence - activated cell sorter analysis . The antiangiogenic effect of tannic acid was assessed by in vitro endothelial cell tube formation . RESULTS : DB09372 , at nontoxic concentrations , specifically inhibited P48061 - induced human monocyte migration ( IC ( 50 ) , 7 . 5 micro g / ml ) but did not inhibit P13500 - , P10147 - , P13501 - , formylmethionylleucylphenylalanine ( fMLP ) - , or C5a - induced migration . The compound markedly blocked P48061 binding to THP - 1 cells ( IC ( 50 ) , 0 . 36 micro g / ml ) . DB09372 also inhibited P48061 - induced , but not epidermal growth factor - induced , migration of MDA 231 breast tumor cells . Additionally , 0 . 5 micro g / ml of tannic acid selectively inhibited P48061 - mediated , but not basic fibroblast growth factor - or endothelial cell growth supplement - mediated , bovine aorta endothelial cell capillary tube formation . CONCLUSION : These studies indicate that tannic acid is a novel selective P48061 / P61073 antagonist and consequently may provide a mechanistic basis for the reported antitumor and anti - inflammatory properties of tannic acid .",
"Cancer cell - associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer . Upregulation of fatty acid synthase ( P49327 ) , a key enzyme of de novo lipogenesis , is associated with metastasis in colorectal cancer ( CRC ) . However , the mechanisms of regulation are unknown . Since angiogenesis is crucial for metastasis , we investigated the role of P49327 in the neovascularization of CRC . The effect of P49327 on tumor vasculature was studied in orthotopic CRCs , the chick embryo chorioallantoic membrane ( P62158 ) and Matrigel plug models using immunohistochemistry , immunofluorescent staining and confocal microscopy . Cell secretion was evaluated by ELISA and antibody arrays . Proliferation , migration and tubulogenesis of endothelial cells ( ECs ) were assessed in CRC - EC coculture models . In this study , we found that stable knockdown of P49327 decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in ' normalization ' of tumor vasculature in both orthotopic and P62158 models . Furthermore , P49327 regulated secretion of pro - and antiangiogenic factors , including vascular endothelial growth factor - A ( P15692 ) . Mechanisms associated with the antiangiogenic activity noted with knockdown of P49327 included : downregulation of P15692 ( 189 ) , upregulation of antiangiogenic isoform P15692 ( 165b ) and a decrease in expression and activity of matrix metalloproteinase - 9 . Furthermore , conditioned medium from P49327 knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor - 2 and its downstream signaling and decreased proliferation , migration and tubulogenesis of ECs as compared with control medium . Together , these results suggest that cancer cell - associated P49327 regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability . Inhibition of P49327 upstream of P15692 and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC .",
"Chemical genomic screening reveals synergism between parthenolide and inhibitors of the P19957 kinase and P42345 pathways . We have previously shown that the plant - derived compound parthenolide ( P16233 ) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia ( AML ) stem cells . However , despite the activity of this agent , P16233 also induces cellular protective responses that likely function to reduce its overall cytotoxicity . Thus , we sought to identify pharmacologic agents that enhance the antileukemic potential of P16233 . Toward this goal , we used the gene expression signature of P16233 to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database . This screen identified compounds acting along the phosphatidylinositol 3 - kinase and mammalian target of rapamycin pathways . Compared with single agent treatment , exposure of AML cells to the combination of P16233 and phosphatidylinositol 3 - kinase / mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models . Taken together , our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells .",
"Potential pancreatic lipase inhibitory activity of an endophytic Penicillium species . P16233 ( PL ) is considered as one of the safest target for diet - induced anti - obesity drug development . DB01083 is the only PL inhibitor approved for anti - obesity treatment till date . In the process of exploration of new PL inhibitors , we have screened culture filtrates of 70 endophytic fungi of medicinal plants using qualitative as well as quantitative in - vitro PL assays . The qualitative assays indicated potential PL inhibition in only three isolates , namely # 57 TBBALM , # 33 TBBALM and # 1 CSSTOT . Only ethyl acetate extracts of the culture filtrates of these isolates exhibited the PL inhibition . # 57 TBBLAM ethyl acetate extract of culture filtrate exhibited potential PL inhibition with an IC50 of 3 . 69 µg / ml which was comparable to the positive control , i . e . DB01083 exhibiting IC50 value of 2 . 73 µg / ml . Further molecular phylogenetic tools and morphological studies were used to identify the isolate # 57 TBBALM as Penicillium species .",
"P05067 staining in nonhomicidal pediatric medicolegal autopsies . Immunohistochemical staining for beta - amyloid precursor protein ( betaAPP ) has been validated as a marker for axonal injury in adults surviving > or = 2 hours after white matter damage . The significance of betaAPP staining in pediatric brains and spinal cords is not as well established . We evaluated the white matter immunoreactivity for betaAPP from a variety of pediatric medicolegal autopsies : natural disease ( non - Sudden Infant Death Syndrome [ P22304 ] ) , P22304 , motor vehicle accidents , drowning , near - drowning , overlay , carbon monoxide toxicity , miscellaneous trauma , and mechanical asphyxia . The cases of carbon monoxide toxicity , motor vehicle accidents ( death at scene ) , drowning ( with resuscitation ) , and a natural ( non - P22304 ) death had no significant white matter staining . The traumatic deaths with a significant survival interval , a variety of natural deaths , the near - drowning case , and surprisingly , all P22304 had detectable betaAPP white matter immunostaining . These results demonstrate that features other than traumatic axonal injury , such as metabolic insults and hypoxic - ischemic injury secondary to vascular compromise , must contribute to betaAPP immunostaining . In addition , we describe a variety of betaAPP - immunoreactive structures not previously reported in the pediatric population . This study illustrates that betaAPP immunostaining enhances detection of a variety of white matter changes , and provides a basis for interpretation of these results .",
"Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication . The hepatitis C virus ( HCV ) induces alterations of host cells to facilitate its life cycle . P49327 ( P49327 ) is a multidomain enzyme that plays a key role in the biosynthesis of fatty acids and is upregulated during HCV infection . Herein , we applied activity - based protein profiling ( P05067 ) that allows for the identification of differentially active enzymes in complex proteomic samples , to study the changes in activity of P49327 during HCV replication . For this purpose , we used an activity - based probe based on the P49327 inhibitor DB01083 , and observed an increase in the activity of P49327 in the presence of a subgenomic and a genomic HCV replicon as well as in chimeric SCID / Alb - uPA mice infected with HCV genotype 1a . To study the molecular basis for this increase in P49327 activity , we overexpressed individual HCV proteins in Huh7 cells and observed increased expression and activity of P49327 in the presence of core and NS4B , as measured by western blots and P05067 , respectively . Triglyceride levels were also elevated in accordance with P49327 expression and activity . Lastly , immunofluorescence and P05067 imaging analyses demonstrated that while the abundance and activity of P49327 increases significantly in the presence of HCV , its localization does not change . Together these data suggest that the HCV - induced production of fatty acids and neutral lipids is provided by an increase in P49327 abundance and activity that is sufficient to allow HCV propagation without transporting P49327 to the replication complexes .",
"The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas . P49327 ( P49327 ) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids . It is downregulated in most normal cells , except in lipogenic tissues such as liver , lactating breast , fetal lung , and adipose tissue . Conversely , several human cancers , including head and neck squamous cell carcinomas ( HNSCC ) , overexpress P49327 , which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein . DB01083 is an irreversible inhibitor of P49327 activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas , respectively . To explore whether the inhibition of P49327 could impact oral tongue squamous cell carcinoma ( OTSCC ) metastatic spread , an orthotopic model was developed by the implantation of SCC - 9 ZsGreen LN - 1 cells into the tongue of BALB / c nude mice . These cells were isolated through in vivo selection , show a more invasive behavior in vitro than the parental cells , and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only . SCC - 9 ZsGreen LN - 1 cells also exhibit enhanced production of P08253 , P04626 , and P19022 . The treatment with orlistat reduced proliferation and migration , promoted apoptosis , and stimulated the secretion of VEGFA165b by SCC - 9 ZsGreen LN - 1 cells . In vivo , the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and , importantly , reduced the number of metastatic cervical lymph nodes by 43 % . These results suggest that P49327 is a potential molecular target for the chemotherapy of patients with OTSCC .",
"P05067 - dependent alteration of GSK3β activity impairs neurogenesis in the Ts65Dn mouse model of Down syndrome . Intellectual disability in Down syndrome ( DS ) appears to be related to severe neurogenesis impairment during brain development . The molecular mechanisms underlying this defect are still largely unknown . Accumulating evidence has highlighted the importance of GSK3β signaling for neuronal precursor proliferation / differentiation . In neural precursor cells ( NPCs ) from Ts65Dn mice and human fetuses with DS , we found reduced GSK3β phosphorylation and , hence , increased GSK3β activity . In cultures of trisomic subventricular - zone - derived adult NPCs ( aNPCs ) we found that deregulation of GSK3β activity was due to higher levels of the AICD fragment of the trisomic gene P05067 that directly bound to GSK3β . We restored GSK3β phosphorylation in trisomic aNPCs using either lithium , a well - known GSK3β inhibitor , or using a 5 - HT receptor agonist or fluoxetine , which activated the serotonin receptor P08908 . Importantly , this effect was accompanied by restoration of proliferation , cell fate specification and neuronal maturation . In agreement with results obtained in vitro , we found that early treatment with fluoxetine , which was previously shown to rescue neurogenesis and behavior in Ts65Dn mice , restored GSK3β phosphorylation . These results provide a link between GSK3β activity alteration , P05067 triplication and the defective neuronal production that characterizes the DS brain . Knowledge of the molecular mechanisms underlying neurogenesis alterations in DS may help to devise therapeutic strategies , potentially usable in humans . Results suggest that drugs that increase GSK3β phosphorylation , such as lithium or fluoxetine , may represent useful tools for the improvement of neurogenesis in DS .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK83___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"[ Complex characteristics of the alterations of oncogenes HER - 2 / P00533 - 2 , HER - 1 / P00533 - 1 , P01112 - 1 , C - MYC and antioncogenes p53 , P06400 , as well as deletions of loci of chromosome 17 in colon carcinoma ] . Abnormalities of some oncogenes , antioncogenes and losses of heterozygosity ( LOH ) of chromosome 11p , 17p , and 17q in colorectal carcinomas ( CC ) was studied . Amplification of P00533 - 1 / HER - 1 oncogene was detected in 2 of 56 cases ; P00533 - 2 / HER - 2 - in 4 of 62 . There was a lack of evidence for C - MYC oncogene amplification ( 67 cases ) . LOH of chromosome 11p ( P01112 - 1 probe ) was found in 2 of 37 informative ( heterozygous ) cases ; such events were not accompanied by point mutations in \" hot \" codons ( 12th or 61st ) in the remaining allele . Prevalence of A3 and A4 alleles of P01112 - 1 oncogene ( 68 cases ) as compared to healthy donors was noted . Q8IUH3 ( 41 cases ) and p53 ( 62 cases ) suppressor genes did not show any alterations in Southern - blot analysis . LOH of chromosome 17p ( YNZ - 22 probe ) was found in 15 of 26 heterozygous CC ; 17q ( Q07283 - 59 probe ) -- in 4 of 16 . Analysis of 175th codon of p53 gene revealed only one case of mutation in 35 CC studied . Finally , we were able to detect genetic alterations in 23 of 40 ( 58 % ) CC , that were studied on each parameter using Southern - blot . We failed to find any correlation between various molecular abnormalities or clinical characteristics . The data obtained are in disagreement with the view concerning frequent involvement of p53 antioncogene in chromosome 17p deletions .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer . P10275 ( AR ) signaling is critical for the tumorigenesis and development of prostate cancer , as well as the progression to castration - resistant prostate cancer . We previously showed that the heterochromatin protein 1 ( P59665 ) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation . However , the roles of other P59665 isoforms , HP1α and HP1γ , in AR expression and prostate cancer remain unclear . Here , we found that knockdown of HP1γ , but not HP1α , reduced AR expression and cell proliferation by inducing cell cycle arrest at P55008 phase in LNCaP cells . Conversely , overexpression of full - length HP1α and its C - terminal deletion mutant increased AR expression and cell growth , whereas overexpression of HP1γ had no effect . Similarly , HP1α overexpression promoted 22Rv1 cell growth , whereas HP1γ knockdown reduced the proliferation of CxR cells , a castration - resistant LNCaP derivative . Taken together , P59665 isoforms distinctly augment AR signaling and cell growth in prostate cancer . Therefore , silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer .",
"The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase . DB01083 ( Q07283 ) is a selective inhibitor of fat absorption . In animal models , it has anti - obesity and anti - hypercholesterolemic activity and is presently in clinical trials for these indications . Q07283 binds covalently to pancreatic lipase . Complete inhibition of lipolytic activity is obtained concomitant with the incorporation of 1 mol of Q07283 / mol of enzyme . P16233 is the best studied lipase , but published results concerning its catalytic mechanism are still controversial . In order to learn more about the inhibitory mechanism of Q07283 , a selective lipase inhibitor interacting at or near the catalytic site , and therefore , to obtain more information on the catalytic mechanism of lipase , we have determined the amino acid residue to which Q07283 is bound . After proteolytic degradation of porcine pancreatic lipase inhibited with radioactively labeled Q07283 , the labeled peptides were isolated and analyzed by quantitative amino acid analysis , N - terminal sequencing , and by mass spectrometry with fast atom bombardment ionization . The data clearly show that Q07283 is bound as an ester to the serine 152 of the lipase .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK30___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"___MASK51___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"P49327 inhibition with DB01083 promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model . P49327 ( P49327 ) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate . In contrast to most normal cells , malignant cells depend on P49327 activity for growth and survival . In fact , P49327 is overexpressed in a variety of human cancers including cutaneous melanoma , in which its levels of expression are associated with a poor prognosis and depth of invasion . Here , we show that the specific inhibition of P49327 activity by the antiobesity drug DB01083 or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16 - F10 . These results prompted us to verify the effect of P49327 inhibition on the metastatic process in a model of spontaneous melanoma metastasis , in which B16 - F10 cells injected in the peritoneal cavity of C57BL / 6 mice metastasize to the mediastinal lymph nodes . We observed that mice treated with DB01083 48 hr after the inoculation of B16 - F10 cells exhibited a 52 % reduction in the number of mediastinal lymph node metastases , in comparison with the control animals . These results suggest that P49327 activity is essential for B16 - F10 melanoma cell proliferation and survival while its inactivation by DB01083 significantly reduces their metastatic spread . The chemical inhibition of P49327 activity could have a potential benefit in association with the current chemotherapy for melanoma .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK46___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"miR - 17 - 5p targets the p300 / CBP - associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells . BACKGROUND : P10275 ( AR ) signalling is critical to the initiation and progression of prostate cancer ( PCa ) . Transcriptional activity of AR involves chromatin recruitment of co - activators , including the p300 / CBP - associated factor ( Q92831 ) . Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease . Whether miRNAs regulate Q92831 expression in PCa cells to regulate AR transcriptional activity is still unclear . METHODS : Expression of Q92831 was investigated in several PCa cell lines by qRT - PCR , Western blot , and immunocytochemistry . The effects of Q92831 expression on AR - regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation , reporter gene construct analysis , and MTS assay . Targeting of Q92831 by miR - 17 - 5p was evaluated using the luciferase reporter assay . RESULTS : Q92831 was upregulated in several PCa cell lines . Upregulation of Q92831 promoted AR transcriptional activation and cell growth in cultured PCa cells . Expression of Q92831 in PCa cells was associated with the downregulation of miR - 17 - 5p . Targeting of the 3 '- untranslated region of Q92831 mRNA by miR - 17 - 5p caused translational suppression and RNA degradation , and , consequently , modulation of AR transcriptional activity in PCa cells . CONCLUSIONS : Q92831 is upregulated in cultured PCa cells , and upregulation of Q92831 is associated with the downregulation of miR - 17 - 5p . Targeting of Q92831 by miR - 17 - 5p modulates AR transcriptional activity and cell growth in cultured PCa cells .",
"Myelopoietic efficacy of orlistat in murine hosts bearing T cell lymphoma : implication in macrophage differentiation and activation . DB01083 , an inhibitor of fatty acid synthase ( P49327 ) , acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells . Although , myelopoiesis also depends on de novo fatty acid synthesis , the effect of orlistat on differentiation of macrophages , which play a central role in host ' s antitumor defence , remains unexplored in a tumor - bearing host . Therefore , the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host . Administration of orlistat ( 240 mg / kg / day / mice ) to tumor - bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells ( BMC ) . The expression of apoptosis regulatory caspase - 3 , Bax and Bcl2 was modulated in the BMC of orlistat - administered tumor - bearing mice . DB01083 administration also resulted in an increase in serum level of IFN - γ along with decreased TGF - β and P22301 . BMC of orlistat - administered tumor - bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor ( P09603 ) and its receptor ( M - CSFR ) . The macrophages differentiated from BMC of orlistat - administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c , TLR - 2 , generation of reactive oxygen species , phagocytosis , tumor cell cytotoxicity , production of IL - 1 , P01375 - α and nitric oxide . These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor - bearing host .",
"Suppression of parathyroid hormone - related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues . The level of parathyroid hormone - related protein ( P12272 ) expressed in breast cancer tissue is closely related to the incidence of bone metastasis . We examined the P12272 mRNA expression in breast cancer tissues by coamplification polymerase chain reaction ( PCR ) in mole ratio to internal standard beta - actin mRNA . The P12272 expression was higher in premenopausal patients than in postmenopausal patients ( P < 0 . 05 ) . More pronounced difference by menopause found in estrogen receptor ( ER ) positive groups ( P < 0 . 001 ) indicated that the P12272 expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents . To clarify the changes of P12272 expression by endocrine therapy of breast cancer , we measured P12272 expression in the breast cancer tissue incubated for 24 h with 1 x 10 (- 8 ) M of estradiol ( E2 ) , 1 x 10 (- 6 ) M of tamoxifen ( TAM ) and 1 x 10 (- 5 ) M of medroxyprogesterone acetate ( ___MASK36___ ) . The P12272 expression was decreased significantly by ___MASK36___ ( P < 0 . 005 ) , while E2 and TAM did not change the P12272 expression . P06401 ( PgR ) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM . The results were well compatible with the better therapeutic effect of ___MASK36___ reported for the treatment of breast cancer with bone metastases . As a potential candidate for the receptor that mediates the suppressive effect of ___MASK36___ , androgen receptor ( AR ) is suggested most probable . Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen .",
"Pro - labour myometrial gene expression : are preterm labour and term labour the same ? Preterm labour ( P16233 ) is the most important cause of neonatal morbidity and mortality . While some causes have been identified , the mechanisms involved remain elusive . This study investigates whether term labour ( TL ) is an appropriate model for P16233 by examining pro - labour gene expression , using quantitative rtPCR , and protein synthesis , using Western analysis , in preterm and term myometrial samples obtained from the upper and lower uterine segments before and after the onset of labour . In the lower segment , the levels of prostaglandin H synthase type - 2 ( P35354 ) , interleukin - 1beta ( IL - 1beta ) , P05231 and P10145 mRNA expression were significantly higher in TL compared with P16233 samples . Compared with non - labour controls , the expression of IL - 1beta and P10145 mRNA was increased in both P16233 and TL samples and the expression of P35354 and P05231 mRNA was increased in TL samples only . In the upper segment , there were no differences between P16233 and TL samples and the mRNA expression of P35354 and IL - 1beta was increased in TL compared with term no labour samples . No effect of P16233 or TL was seen on either oxytocin receptor or connexin - 43 mRNA expression or protein levels . The multiple regression analysis and studies in primary cultures of uterine myocytes suggest that the inflammatory cytokines , IL - 1beta and tumour necrosis factor - alpha , are the most important regulators of P35354 and P10145 . Our data show that preterm and term labouring myometrium are significantly different and that the most marked labour - induced changes in gene expression are in the lower segment . These changes may occur in response to the release of inflammatory cytokines by the labour - associated inflammatory infiltration .",
"Peptides from purified soybean beta - conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain . P49327 ( FAS ) is uniquely expressed at high levels in cancer cells and adipose tissue . The objectives of this study were to identify , purify and validate soy FAS inhibitory peptides and to predict their binding modes . Soy peptides were isolated from hydrolysates of purified beta - conglycinin by co - immunoprecipitation and identified using LC - MS / MS . Three peptides , KNPQLR , EITPEKNPQLR and RKQEEDEDEEQQRE , inhibited FAS . The biological activity of these peptides was confirmed by their inhibitory activity against purified chicken FAS ( IC ( 50 ) = 79 , 27 and 16 mum , respectively ) and a high correlation ( r = - 0 . 7 ) with lipid accumulation in 3T3 - Q9NUQ9 adipocytes . The FAS inhibitory potency of soy peptides also correlated with their molecular mass , pI value and the number of negatively charged and hydrophilic residues . Molecular modeling predicted that the large FAS inhibitory peptides ( EITPEKNPQLR and RKQEEDEDEEQQRE ) bond to the thioesterase domain of human FAS with lower interaction energies ( - 442 and - 353 kcal . mol (- 1 ) , respectively ) than classical thioesterase inhibitors ( DB01083 , - 91 kcal . mol (- 1 ) and C75 , - 51 kcal . mol (- 1 ) ) . Docking studies suggested that soy peptides blocked the active site through interactions within the catalytic triad , the interface cavity and the hydrophobic groove in the human FAS thioesterase domain . FAS thioesterase inhibitory activities displayed by the synthetic soy peptides EITPEKNPQLR and RKQEEDEDEEQQRE ( IC ( 50 ) = 10 . 1 +/- 1 . 6 and 10 . 7 +/- 4 . 4 mum , respectively ) were higher than C75 ( 58 . 7 mum ) but lower than DB01083 ( 0 . 9 mum ) . This is the first study to identify FAS inhibitory peptides from purified beta - conglycinin hydrolysates and predict their binding modes at the molecular level , leading to their possible use as nutraceuticals .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK59___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"P05067 is a primary androgen target gene that promotes prostate cancer growth . P10275 ( AR ) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently . Here , we identify amyloid precursor protein ( P05067 ) as a primary androgen target through chromatin immunoprecipitation ( ChIP ) combined with genome tiling array analysis ( ChIP - chip ) . ChIP - treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies . Ligand - dependent AR binding was further enriched by PCR subtraction . Using chromosome 21 / 22 arrays , we identified P05067 as one of the androgen - regulated genes with adjacent functional AR binding sites . P05067 expression is androgen - inducible in LNCaP cells and P05067 immunoreactivity was correlated with poor prognosis in patients with prostate cancer . Gain - of - function and loss - of - function studies revealed that P05067 promotes the tumor growth of prostate cancer . The present study reveals a novel P05067 - mediated pathway responsible for the androgen - dependent growth of prostate cancer . Our findings will indicate that P05067 could be a potential molecular target for the diagnosis and treatment of prostate cancer .",
"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK83___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .",
"A new mechanism of drug resistance in breast cancer cells : fatty acid synthase overexpression - mediated palmitate overproduction . Multidrug resistance is a major problem in successful cancer chemotherapy . Various mechanisms of resistance , such as ABC transporter - mediated drug efflux , have been discovered using established model cancer cell lines . While characterizing a drug - resistant breast cancer cell line , MCF7 / AdVp3000 , we found that fatty acid synthase ( P49327 ) is overexpressed . In this study , we showed that ectopic overexpression of P49327 indeed causes drug resistance and that reducing the P49327 expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA - MB - 468 but not in the normal mammary epithelial cell line MCF10A1 . Use of P49327 inhibitor , DB01083 , at low concentrations also sensitized cells with P49327 overexpression to anticancer drugs . The P49327 - mediated drug resistance appears to be due to a decrease in drug - induced apoptosis from an overproduction of palmitic acid by P49327 . Together with previous findings of P49327 as a poor prognosis marker for breast cancer patients , our results suggest that P49327 overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy .",
"Inhibition of the phosphatidylinositol 3 - kinase / mammalian target of rapamycin pathway in hematologic malignancies . The phosphatidylinositol 3 - kinase ( P19957 - K ) / mammalian target of rapamycin ( P42345 ) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival . Key components of the pathway are the lipid kinase P19957 - K , the small guanosine triphosphate - binding protein Rheb , and the protein kinases Akt and P42345 . Important natural inhibitors of the pathway include the lipid phosphatase P60484 and the tuberous sclerosis complex . Several components of this pathway are targeted by investigational antineoplastic agents . DB00877 ( sirolimus ) , the prototypic P42345 inhibitor , exhibits activity in acute myeloid leukemia . Three rapamycin analogs , temsirolimus , everolimus , and AP23573 , are in clinical trials for various hematologic malignancies . ___MASK2___ has produced a 38 % overall response rate in relapsed mantle cell lymphoma , and AP23573 has demonstrated activity in acute leukemia . DB01590 is undergoing clinical testing in lymphoma ( Hodgkin and non - Hodgkin ) and multiple myeloma . In addition , perifosine , an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models , is being examined in relapsed multiple myeloma . Based on results obtained to date , it appears that inhibitors of the P19957 - K / P42345 pathway hold promise as single agents and in combination for hematologic malignancies .",
"Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L / P50591 ( dulanermin ) , a dual proapoptotic receptor ( DR4 / DR5 ) agonist . Recombinant human Apo2L / P50591 ( dulanermin ) is based on the ligand for death receptors ( DR4 and DR5 ) , which promotes apoptosis . We report a patient with refractory chondrosarcoma who showed a prolonged response to dulanermin and explore mechanisms of response and resistance . This heavily pretreated patient had progressive metastatic chondrosarcoma to the lung . On dulanermin ( 8 mg / kg i . v . on days 1 - 5 in a 21 - day cycle ) , the patient achieved a sustained partial response with only subcentimeter nodules remaining . After 62 months of dulanermin treatment , progressive disease in the lungs was noted , and the patient underwent a resection that confirmed chondrosarcoma . DR4 was detected ( immunohistochemistry ) in the patient ' s tumor , which may have enabled the response . However , upregulation of prosurvival proteins , namely , phosphorylated ( p )- NF - κBp65 ( DB00133 536 ) , p - P40763 ( DB00135 705 ) , p - P29323 1 / 2 ( DB00156 202 / DB00135 204 ) , p - P42345 ( DB00133 2448 ) , P49327 , and Bcl - 2 , were also detected , which may have provided the underlying mechanisms for acquired dulanermin resistance . The patient was restarted on dulanermin and has continued on this treatment for an additional 16 months since surgery ( 78 months since initiation of treatment ) , with his most recent computed tomography ( CT ) scans showing no evidence of disease .",
"Visualizing inhibition of fatty acid synthase through mass spectrometric analysis of mitochondria from melanoma cells . P49327 ( P49327 ) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long - chain fatty acid palmitate . In contrast to most normal cells , P49327 is overexpressed in a variety of human cancers including cutaneous melanoma , in which its levels of expression are associated with a poor prognosis and depth of invasion . Recently , we have demonstrated the mitochondrial involvement in P49327 inhibition - induced apoptosis in melanoma cells . Herein we compare , via electrospray ionization mass spectrometry ( P19957 - MS ) , free fatty acids ( FFA ) composition of mitochondria isolated from control ( EtOH - treated cells ) and DB01083 - treated B16 - F10 mouse melanoma cells . Principal component analysis ( DB11245 ) was applied to the P19957 - MS data and found to separate the two groups of samples . Mitochondria from control cells showed predominance of six ions , that is , those of m / z 157 ( Pelargonic , 9 : 0 ) , 255 ( Palmitic , 16 : 0 ) , 281 ( Oleic , 18 : 1 ) , 311 ( Arachidic , 20 : 0 ) , 327 ( Docosahexaenoic , 22 : 6 ) and 339 ( Behenic , 22 : 0 ) . In contrast , P49327 inhibition with DB01083 changes significantly mitochondrial FFA composition by reducing synthesis of palmitic acid , and its elongation and unsaturation products , such as arachidic and behenic acids , and oleic acid , respectively . P19957 - MS of mitochondria isolated from DB01083 - treated cells presented therefore three major ions of m / z 157 ( Pelargonic , 9 : 0 ) , 193 ( unknown ) and 199 ( Lauric , 12 : 0 ) . These findings demonstrate therefore that P49327 inhibition by DB01083 induces significant changes in the FFA composition of mitochondria .",
"___MASK2___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK2___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK2___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK2___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Increased constitutive activity of P31749 / Akt in tamoxifen resistant breast cancer MCF - 7 cells . The tamoxifen - resistant ( TAM - R ) MCF - 7 breast cancer cell line has been used as a model to identify the signalling pathways that enable resistant cancer cells to grow independently of steroid hormones . In TAM - R cells , peptide growth factor signalling pathways appear to be important in modified cell behaviour , growth and survival . The P19957 kinase signalling components Akt1 and Akt2 are expressed at similar levels by both parental wild - type MCF - 7 and TAM - R cells , but Akt1 phosphorylation is significantly increased in TAM - R cells grown under basal conditions . High levels of basal Akt , GSK3 alpha / beta and p70S6 kinase phosphorylation are all inhibited by the P19957 kinase inhibitor , LY 294002 . The ligands for the P00533 / erbB1 receptor , P01133 ( epidermal growth factor ) and TGF alpha ( transforming growth factor - alpha ) demonstrate an increased ability to activate Akt in TAM - R compared with parental MCF - 7 cells and it is proposed that the preferred autocrine or paracrine activation of Akt occurs via the erbB heterodimer P00533 / erbB2 in TAM - R cells . Akt phosphorylation is reduced by gefitinib ( \" ___MASK55___ \" / ZD1839 ) . The results suggest that the P19957 kinase pathway plays a role in proliferation of TAM - R cells and is important in the increased P01133 induced membrane ruffling detected in the resistant cells . Increased Akt1 activation may contribute to the aggressive phenotype of tamoxifen resistant ER ( oestrogen receptor ) positive breast cancers .",
"Simultaneous inhibition of epidermal growth factor receptor ( P00533 ) signaling and enhanced activation of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) receptor - mediated apoptosis induction by an scFv : sTRAIL fusion protein with specificity for human P00533 . P00533 ( P00533 ) signaling inhibition by monoclonal antibodies and P00533 - specific tyrosine kinase inhibitors has shown clinical efficacy in cancer by restoring susceptibility of tumor cells to therapeutic apoptosis induction . P01375 - related apoptosis - inducing ligand ( P50591 ) is a promising anti - cancer agent with tumor - selective apoptotic activity . Here we present a novel approach that combines P00533 - signaling inhibition with target cell - restricted apoptosis induction using a P50591 fusion protein with engineered specificity for P00533 . This fusion protein , scFv425 : sTRAIL , comprises the P00533 - blocking antibody fragment scFv425 genetically fused to soluble P50591 ( sTRAIL ) . Treatment with scFv425 : sTRAIL resulted in the specific accretion to the cell surface of P00533 - positive cells only . P00533 - specific binding rapidly induced a dephosphorylation of P00533 and down - stream mitogenic signaling , which was accompanied by cFLIP ( L ) down - regulation and Bad dephosphorylation . P00533 - specific binding converted soluble scFv425 : sTRAIL into a membrane - bound form of P50591 that cross - linked agonistic P50591 receptors in a paracrine manner , resulting in potent apoptosis induction in a series of P00533 - positive tumor cell lines . Co - treatment of P00533 - positive tumor cells with the P00533 - tyrosine kinase inhibitor ___MASK55___ resulted in a potent synergistic pro - apoptotic effect , caused by the specific down - regulation of O15519 . Furthermore , in mixed culture experiments binding ( L ) of scFv425 : sTRAIL to P00533 - positive target cells conveyed a potent apoptotic effect toward P00533 - negative bystander tumor cells . The favorable characteristics of scFv425 : sTRAIL , alone and in combination with ___MASK55___ , as well as its potent anti - tumor bystander activity indicate its potential value for treatment of P00533 - expressing cancers .",
"Dual inhibition of P00533 at protein and activity level via combinatorial blocking of PI4KIIα as anti - tumor strategy . Our previous studies indicate that phosphatidylinositol 4 - kinase IIα can promote the growth of multi - malignant tumors via HER - 2 / PI3K and MAPK pathways . However , the molecular mechanisms of this pathway and its potential for clinical application remain unknown . In this study , we found that PI4KIIα could be an ideal combinatorial target for P00533 treatment via regulating P00533 degradation . Results showed that PI4KIIα knockdown reduced P00533 protein level , and the expression of PI4KIIα shows a strong correlation with P00533 in human breast cancer tissues ( r = 0 . 77 , P < 0 . 01 ) . PI4KIIα knockdown greatly prolonged the effects and decreased the effective dosage of AG - 1478 , a specific inhibitor of P00533 . In addition , it significantly enhanced AG1478 - induced inhibition of tumor cell survival and strengthened the effect of the P00533 - targeting anti - cancer drug ___MASK55___ in xenograft tumor models . Mechanistically , we found that PI4KIIα suppression increased P00533 ligand - independent degradation . Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture ( SILAC ) and LC - MS / MS suggested that HSP90 mediated the effect of PI4KIIα on P00533 . Furthermore , we found that combined inhibition of PI4KIIα and P00533 suppressed both PI3K / AKT and MAPK / P29323 pathways , and resulted in downregulation of multiple oncogenes like P32119 , P49327 , O94776 , ultimately leading to suppression of tumor growth . Therefore , we conclude that combined inhibition of PI4KIIα and P00533 exerts a multiple anti - tumor effect . Dual inhibition of P00533 at protein and activity level via combinatorial blocking of PI4KIIα presents a novel strategy to combat P00533 - dependent tumors .",
"Neuropathogenesis of central nervous system HIV - 1 infection . Neuronal damage and death are consistent pathologic findings in the brains of patients with ADC , and multiple cell model systems have demonstrated neurotoxicity through the effects of HIV - 1 infection in macrophages and microglia . Brain Q9BWK5 studies ( 1H - P59665 ) indicate that reversible neuronal cell dysfunction occurs early during the course of HIV - 1 infection , long before overt symptoms of ADC appear . Epidemiologic studies suggest that a high viral load in the CNS is a major risk factor for ADC and that HAART may significantly reduce , but not eliminate , the risk of developing ADC . Targeted adjunctive therapies administered early are likely necessary to maximize CNS protection against HIV , and rational approaches to such therapy are rapidly evolving through in vitro analysis of the mechanisms of HIV - associated neurotoxicity . Soluble factors released by infected cells may directly or indirectly damage neurons and induce apoptosis at the level of DB01221 subtype of glutamate receptors , and DB01221 receptor antagonists represent a major therapeutic option currently under intense clinical investigation . Likewise , drugs with antioxidant or free radical scavenging effects offer another rational approach to adjunctive therapy and are also under intense clinical scrutiny . Finally , agents that inhibit neuronal death - signaling pathways ( e . g . , p38 MAPK inhibitors ) and that stimulate cell survival pathways ( e . g . , Akt / P31749 ) may represent the next investigational step in designing anti - ADC therapies .",
"A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .",
"P49327 - associated protein with death domain : a prognostic factor for survival in patients with nasopharyngeal carcinoma . P49327 - associated protein with death domain ( Q13158 ) is a key adaptor protein that bridges a death receptor ( eg , death receptor 5 ) to caspase 8 to form the death - inducing signaling complex during apoptosis . The expression and prognostic impact of Q13158 in nasopharyngeal carcinoma ( NPC ) have not been well studied . This study focused on detecting Q13158 expression and analyzing its prognostic impact on NPC . Q13158 expression was assessed on pretreatment tumor tissues of 248 cases of NPC patients and 76 cases of noncancerous nasopharyngeal control tissue . The results showed that the positive percentage of Q13158 expression in NPC ( 63 . 7 % , 158 / 248 ) was significantly higher than that in the noncancerous nasopharyngeal control tissues ( 28 . 9 % , 22 / 76 ) ( P < . 0001 ) . The positive expression of Q13158 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis ( P = . 009 ) . Furthermore , Q13158 expression was more pronouncedly increased in metastatic NPC than the matched primary NPC tissues ( P = . 017 ) . Both univariate and multivariate survival analysis indicated that increased Q13158 expression was significantly correlated inversely with overall survival in NPC patients ( P = . 003 and P = . 007 , respectively ) . Taken together , high expression of Q13158 may be an independent biomarker for poor prognosis in NPC .",
"In silico identification of potent pancreatic triacylglycerol lipase inhibitors from traditional Chinese medicine . P16233 ( P16233 ) are primary lipases that are critical for triacylglyceride digestion in human . Since reduced metabolism of triacylglyceride might be a plausible concept for weight loss , we screened for potential P16233 inhibitors from traditional Chinese medicine ( TCM ) with the aim to identify weight loss candidate compounds . TCM candidates Aurantiamide , Cnidiadin , and 2 - hexadecenoic acid exhibited higher Dock Scores than the commercial drug DB01083 , and were also predicted to have inhibitory characteristics against P16233 using constructed P08235 ( R ( 2 ) = 0 . 8664 ) and SVM ( R ( 2 ) = 0 . 9030 ) models . Molecular dynamics indicated that the TCM - P16233 complexes formed were stable . We identified that the P16233 binding site has several residues that can serve as anchors , and a hydrophobic corridor that provides additional stability to the complex . Aurantiamide , Cnidiadin , and 2 - hexadecenoic acid all have features that correspond to these binding site features , indicating their potential as candidates for P16233 inhibitors . The information presented in this study may provide helpful insights to designing novel weight - control drugs ."
] |
[
"___MASK2___",
"___MASK30___",
"___MASK36___",
"___MASK39___",
"___MASK46___",
"___MASK51___",
"___MASK55___",
"___MASK59___",
"___MASK83___"
] |
___MASK59___
|
MH_train_342
|
interacts_with DB02701?
|
[
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"Redox regulation of Q96EB6 in inflammation and cellular senescence . Sirtuin 1 ( Q96EB6 ) regulates inflammation , aging ( life span and health span ) , calorie restriction / energetics , mitochondrial biogenesis , stress resistance , cellular senescence , endothelial functions , apoptosis / autophagy , and circadian rhythms through deacetylation of transcription factors and histones . Q96EB6 level and activity are decreased in chronic inflammatory conditions and aging , in which oxidative stress occurs . Q96EB6 is regulated by a NAD (+)- dependent DNA repair enzyme , poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , and subsequent NAD (+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence . Q96EB6 has been shown to undergo covalent oxidative modifications by cigarette smoke - derived oxidants / aldehydes , leading to posttranslational modifications , inactivation , and protein degradation . Furthermore , oxidant / carbonyl stress - mediated reduction of Q96EB6 leads to the loss of its control on acetylation of target proteins including p53 , RelA / p65 , and O43524 , thereby enhancing the inflammatory , prosenescent , and apoptotic responses , as well as endothelial dysfunction . In this review , the mechanisms of cigarette smoke / oxidant - mediated redox posttranslational modifications of Q96EB6 and its roles in P09874 and NF - κB activation , and O43524 and P29474 regulation , as well as chromatin remodeling / histone modifications during inflammaging , are discussed . Furthermore , we have also discussed various novel ways to activate Q96EB6 either directly or indirectly , which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Pleiotropic mechanisms facilitated by resveratrol and its metabolites . DB02709 has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway . In addition , resveratrol was shown to promote cell survival , increase lifespan and mimic caloric restriction , thereby improving health and survival of mice on high - calorie diet . All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including P23219 ( cyclo - oxygenase - 1 ) and P35354 , NAD +- dependent histone deacetylase Q96EB6 ( sirtuin 1 ) and P16083 ( quinone reductase 2 ) . Nonetheless , the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned , since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates , resulting in low plasma concentrations . To help resolve these issues , we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro . In the present study , we have shown that P23219 , P35354 and P16083 are potently inhibited by resveratrol , and that P23219 and P35354 are also inhibited by the resveratrol 4 '- O - sulfate metabolite . We determined the X - ray structure of resveratrol bound to P23219 and demonstrate that it occupies the P36551 active site similar to other NSAIDs ( non - steroidal anti - inflammatory drugs ) . Finally , we have observed that resveratrol 3 - and 4 '- O - sulfate metabolites activate Q96EB6 equipotently to resveratrol , but that activation is probably a substrate - dependent phenomenon with little in vivo relevance . Overall , the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK24___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK24___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"P62158 interacts with the cytoplasmic tails of the parathyroid hormone 1 receptor and a sub - set of class b G - protein coupled receptors . Parathyroid hormone ( PTH ) binds to its receptor ( PTH 1 receptor , Q03431 ) and activates multiple pathways . The Q03431 , a class b GPCR , contains consensus calmodulin - binding motifs . The Q03431 cytoplasmic tail interacts with calmodulin in a calcium - dependent manner via the basic 1 - 5 - 8 - 14 motif . DB01373 - dependent calmodulin interactions with the cytoplasmic tails of receptors for Q9Y3E5 , vasoactive intestinal peptide , pituitary adenylate cyclase activating peptide , corticotropin releasing hormone , calcitonin , and the glucagon - like peptides 1 and 2 are demonstrated . The cytoplasmic tails of the secretin receptor and the growth hormone releasing hormone receptor either interact poorly or not at all with calmodulin , respectively . ___MASK70___ , a calmodulin antagonist , enhances PTH - mediated accumulation of total inositol phosphates , suggesting that calmodulin regulates signaling via phospholipase C .",
"DB02701 rescues human embryonic stem cell - derived neuroectoderm from parthanatic cell death . Abundant cell death is observed when human embryonic stem cells ( hESCs ) undergo neuralization , a critical first step for future cell - based therapies addressing neurodegeneration . Using hESC neuralization as an in vitro model of human development , we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death . We found that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) / apoptosis - inducing factor ( O95831 ) - mediated cell death ( parthanatos ) is a dominant mechanism responsible for cell loss during hESC neuralization . The demise of neural progenitor cells , at least in part , is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions . Under such conditions , P09874 overactivation triggered cell death through the mitochondrial - nuclear translocation of O95831 . Blocking P09874 activity with small hairpin RNA interference or nicotinamide dramatically enhanced hESC neuralization , providing optimal survival of the developing neuroepithelium . Because nicotinamide is a physiological metabolite , our results raise the possibility that neural stem / progenitor cell survival in vivo requires a metabolic niche . We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine .",
"___MASK39___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK39___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .",
"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .",
"O75791 plays an important role in glucolipotoxicity - induced apoptosis in P01308 - 1 cells . OBJECTIVES : The mechanism underlying the regulation of glucolipotoxicity - induced apoptosis by MAPKs was examined in P01308 - 1 cells . METHODS : The rat insulinoma cell line P01308 - 1 was cotreated with glucose ( 30 mM ) and palmitic acid ( 0 . 2 mM ) ( GLU + PA ) . Apoptosis was assessed by cell morphology and detection of PARP cleavage . The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK , P27361 / 2 , and O75791 . RESULTS : ( 1 ) Live cell imaging studies showed that treatment with GLU + PA for 72 h induced significant cell death , concomitant with P09874 cleavage and caspase - 3 activation , which peaked at 96 h of treatment . ( 2 ) Western blot analysis of the activation of MAPKs during GLU + PA - induced P01308 - 1 cell apoptosis showed that phosphorylation of O75791 increased gradually and reached a peak at 96 h , which coincided with P09874 cleavage . A transient increase of P29323 activation was followed by a rapid decline at 96 h , whereas JNK phosphorylation status remained unchanged in response to GLU + PA . ( 3 ) Phosphorylation of insulin receptor substrate ( P41252 ) - 2 at 48 h of treatment triggered its degradation , which coincided with O75791 activation . ( 4 ) Inhibition of O75791 , but not JNK or P29323 , blocked GLU + PA - induced P01308 - 1 cell apoptosis . CONCLUSIONS : O75791 may be involved in the regulation of glucolipotoxicity - induced apoptosis through the phosphorylation of Q9Y4H2 .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"Accumulation of poly ( ADP - ribose ) polymerase inhibitors in children with chronic renal failure . DB02701 , N - methyl - 2 - pyridone - 5 - carboxamide ( Met2PY ) and N - methyl - 4 - pyridone - 3 - carboxamide ( Met4PY ) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide ( NAD ) that can potentially inhibit poly ( ADP - ribose ) polymerase 1 ( P09874 ; DNA repair enzyme ) . Our research was aimed at establishing whether chronic renal failure ( CRF ) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit P09874 activity . DB02701 , Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children . The effect of these NAD metabolites on P09874 activity was studied in vitro . We found that plasma concentration of all NAD metabolites ( nicotinamide , Met2PY , Met4PY ) in children with CRF could reach the concentration of 2 , 30 and 10 microM as compared to 0 . 2 , 1 and 0 . 5 microM , respectively , in healthy children . The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF . We found that Met2PY , Met4PY and nicotinamide inhibited in vitro P09874 activity with IC50 values of 2 . 1 , 0 . 18 and 0 . 12 mM , respectively . Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of P09874 activity . NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults .",
"NAD + and nicotinamide : sex differences in cerebral ischemia . BACKGROUND : Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes . While caspase - dependent mechanisms predominate in the female brain , caspase - independent cell death induced by the activation of poly ( ADP - ribose ) polymerase ( PARP ) predominates in the male brain . P09874 gene deletion decreases infarction volume in the male brain , but paradoxically increases damage in P09874 knockout females . PURPOSE : This study examined stroke - induced changes in NAD + , a key energy molecule involved in P09874 activation in both sexes . METHODS : Mice were subjected to middle cerebral artery occlusion and NAD + levels were assessed . P42574 activity and nuclear translocation were assessed 6h after ischemia . In additional cohorts , DB02701 ( 500 mg / kg i . p . ) a precursor of NAD + or vehicle was administered and infarction volume was measured 24h after ischemia . RESULTS : Males have higher baseline NAD + levels than females . Significant stroke - induced NAD + depletion occurred in males and ovariectomized females but not in intact females . P09874 deletion prevented the stroke - induced loss in NAD + in males , but worsened NAD + loss in P09874 deficient females . Preventing NAD + loss with nicotinamide reduced infarct in wild - type males and P09874 knockout mice of both sexes , with no effect in WT females . P42574 activity was significantly increased in P09874 knockout females compared to males and wild - type females , this was reversed with nicotinamide . CONCLUSIONS : Sex differences exist in baseline and stroke - induced NAD + levels . DB02701 protected males and PARP knockout mice , but had minimal effects in the wild - type female brain . This may be secondary to differences in energy metabolism between the sexes .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK90___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Changes in the response of the Q9HBH0 - 1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP - ribosyl transferase . The effect of inhibitors of nuclear ADP - ribosyl transferase ( P09874 ) on the cytotoxicity of melphalan ( DB01042 ) in the Q9HBH0 - 1 tumour in vivo was investigated . A large single dose of nicotinamide ( 1000 mg kg - 1 ) enhanced the tumour cell killing by DB01042 as measured by tumour cell survival . This enhancement was maximum when nicotinamide was administered within 1 h before injecting the DB01042 . When given at this time , the nicotinamide had a dose - modifying effect on all DB01042 doses tested , giving rise to a mean enhancement ratio ( ER ) of 2 . 2 . DB02701 did not appear to inhibit the recovery from DB01042 induced potentially lethal damage . DB01042 ( 6 mg kg - 1 ) produced a transient drop in mouse body temperature . This effect was both increased and prolonged by nicotinamide . In addition the inhibitor also delayed the clearance of DB01042 from the plasma of C3H mice , such that the half - life of the chemotherapeutic agent was extended from 41 min to 143 min . The effect of combining DB01042 with nicotinamide doses below 1000 mg kg - 1 was also investigated . The results showed that as the nicotinamide dose was decreased , the enhancement of the effects on body temperature , pharmacokinetics and white blood cell counts were reduced . However , a concomitant loss in the enhancement of tumour cell killing was also observed . Similar results were obtained using 3 - aminobenzamide , a more efficient inhibitor of P09874 .",
"Radiosensitizing effects of nicotinamide on a C3H mouse mammary adenocarcinoma . A study on per os drug administration . DB02701 is an inhibitor of adenosine diphosphate ribosyl transferase ( P09874 ) which is involved in the mechanism of DNA repair after high doses of ionizing radiation . C3H mice with transplanted mammary adenocarcinomas were treated with low doses of nicotinamide , 10 mg / kg , 5 days a week , and in combination with ionizing radiation , 30 Gy , using different drug dose schedules . Mice given nicotinamide in combination with irradiation took a longer time to reach a tumor volume of 1 , 000 mm3 and a higher complete response rate ( i . e . defined as total disappearance of the tumor for at least 7 days ) than those given radiation alone . This was true whether nicotinamide was given daily from one week before tumor transplantation until the animal was killed or from transplantation day until day of irradiation . In addition , nicotinamide given per os at a dose between the recommended maximum daily allowance for human subjects ( 20 mg / 70 kg ) , and the therapeutic allowance ( 1 g - 12 g daily ) 5 days a week for 9 weeks , showed a radiosensitizing effect without any histologically detectable damage to the normal tissues of the mouse , including bone marrow , intestine and the liver .",
"P09874 ( P09874 ) activation and NAD (+) in DNA repair and cell death . DB02701 adenine dinucleotide , NAD (+) , is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis , the tricarboxylic acid cycle ( TCA ) and mitochondrial respiration . These processes consume and produce both oxidative and reduced forms of NAD ( NAD (+) and DB00157 ) . NAD (+) is also important for ADP ( ribosyl ) ation reactions mediated by the ADP - ribosyltransferase enzymes ( ARTDs ) or deacetylation reactions catalyzed by the sirtuins ( SIRTs ) which use NAD (+) as a substrate . In this review , we highlight the significance of NAD (+) catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs . We summarize the current findings on the involvement of P09874 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by P09874 activation and energy depletion . By sharing the same substrate , the activities of ARTDs and SIRTs are tightly linked , are dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology , inflammatory diseases and ischaemia / reperfusion .",
"Further studies on the hypothesis of P09874 inhibition as a strategy for lessening the long - term effects produced by perinatal asphyxia : effects of nicotinamide and theophylline on P09874 activity in brain and peripheral tissue : nicotinamide and theophylline on P09874 activity . DB09140 interruption leads to death when re - oxygenation is not promptly re - established . Re - oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis . The effects observed long after perinatal asphyxia ( PA ) have been explained by over - expression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a therapeutic strategy . We studied the effects of nicotinamide and theophylline on P09874 activity assayed in brain and peripheral ( heart ) rat tissue 1 - 24 h after birth , as well as on changes in behaviour and monoamine neurotransmission in adult rats . PA was induced by immersing rat foetuses into a water bath for 0 or 21 min . After resuscitation , the pups were treated with nicotinamide ( 0 . 8 mmol / kg , i . p . ) , theophylline ( 0 . 14 mmol / kg , i . p . ) or saline ( 0 . 9 % NaCl ) and nurtured by surrogate dams , pending behavioural and microdialysis experiments , or euthanised after birth for assaying P09874 activity . To estimate the in vivo distribution of a single dose of nicotinamide or theophylline into brain and peripheral compartment , a series of animals were implanted with microdialysis probes , one into the brain and other subcutaneously , 1 h after birth , assaying the drugs with a HPLC - UV system . DB02701 , but not theophylline prevented the long - term effects induced by PA . Only nicotinamide produced a consistent decrease in P09874 activity in brain and heart , whether assayed in control or asphyxia - exposed pups . The present results support the idea that the long - term effects induced by PA imply P09874 over - activation .",
"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .",
"Poly ( ADP - ribose ) polymerase - 1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation : a potential specific effect on P05113 . We recently used a murine model of allergic airway inflammation to show that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays an important role in the pathogenesis of asthma - related lung inflammation . In this study , we show that P09874 inhibition , by a novel inhibitor ( TIQ - A ) or by gene deletion , prevented eosinophilic infiltration into the airways of OVA - challenged mice . Such impairment of eosinophil recruitment appeared to take place after IgE production . OVA challenge of wild - type mice resulted in a significant increase in P05112 , P05113 , P22301 , P35225 , and GM - P04141 secretions . Although P05112 production was moderately affected in OVA - challenged P09874 (-/-) mice , the production of P05113 , P22301 , P35225 , and GM - P04141 was completely inhibited in ex vivo OVA - challenged lung cells derived from these animals . A single TIQ - A injection before OVA challenge in wild - type mice mimicked the latter effects . The marked effect P09874 inhibition exerted on mucus production corroborated the effects observed on the Th2 response . Although P09874 inhibition by gene knockout increased the production of the Th1 cytokines P60568 and IL - 12 , the inhibition by TIQ - A exerted no effect on these two cytokines . The failure of lung cells derived from OVA - challenged P09874 (-/-) mice to synthesize GM - P04141 , a key cytokine in eosinophil recruitment , was reestablished by replenishment of P05113 . Furthermore , intranasal administration of P05113 restored the impairment of eosinophil recruitment and mucus production in OVA - challenged P09874 (-/-) mice . The replenishment of either P05112 or IgE , however , did not result in such phenotype reversals . Altogether , these results suggest that P09874 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to P05113 production .",
"Perinatal asphyxia : CNS development and deficits with delayed onset . Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted . The primary insult relates to the duration of the period lacking oxygenation , leading to death if not re - established . Re - oxygenation leads to a secondary insult , related to a cascade of biochemical events required for restoring proper function . Perinatal asphyxia interferes with neonatal development , resulting in long - term deficits associated to mental and neurological diseases with delayed clinical onset , by mechanisms not yet clarified . In the experimental scenario , the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy . Asphyxia induces transcriptional activation of pro - inflammatory factors , in tandem with P09874 overactivation , and pharmacologically induced P09874 inhibition also down - regulates the expression of proinflammatory cytokines . DB02701 has been proposed as a suitable P09874 inhibitor . Its effect has been studied in an experimental model of global hypoxia in rats . In that model , the insult is induced by immersing rat fetus into a water bath for various periods of time . Following asphyxia , the pups are delivered , treated , and nursed by surrogate dams , pending further experiments . DB02701 rapidly distributes into the brain following systemic administration , reaching steady state concentrations sufficient to inhibit P09874 activity for several hours , preventing several of the long - term consequences of perinatal asphyxia , supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles .",
"MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in P01308 - 1 pancreatic beta - cells . DB02701 has been reported to induce differentiation of precursor / stem cells toward a beta - cell phenotype , increase islet regeneration , and enhance insulin biosynthesis . Exposure of P01308 - 1 beta - cells to elevated glucose leads to reduced insulin gene transcription , and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 ( P52945 ) and mammalian homologue of avian MafA / l - Maf ( MafA ) . DB02701 and other low - potency poly ( ADP - ribose ) polymerase ( PARP ) inhibitors were thus tested for their ability to restore insulin promoter activity . The low - potency PARP inhibitors nicotinamide , 3 - aminobenzamide , or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose . In contrast , the potent P09874 inhibitors PJ34 or DB04335 - 1001 had no effect on promoter activity . Antioxidants , including DB06151 , lipoic acid , or quercetin , only minimally induced the insulin promoter . Site - directed mutations of the human insulin promoter mapped the low - potency PARP inhibitor response to the C1 element , which serves as a MafA binding site . P01308 - 1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels . Low - potency PARP inhibitors restored MafA mRNA and protein levels , but they had no affect on P52945 protein levels or binding activity . Increased MafA expression by low - potency PARP inhibitors was independent of increased MafA protein or mRNA stability . These data suggest that low - potency PARP inhibitors increase insulin biosynthesis , in part , through a mechanism involving increased MafA gene transcription .",
"Effect of growth factors on nuclear and mitochondrial ADP - ribosylation processes during astroglial cell development and aging in culture . Epidermal growth factor ( P01133 ) , basic fibroblast growth factor ( P09038 ) , insulin - like growth factor - I ( P05019 ) and insulin ( P01308 ) are powerful mitogens and may regulate gene expression in cultured astrocytes by ADP - ribosylation process . Nuclear poly - ADP ribose polymerase ( PARP ) and mitochondrial monoADP - ribosyltransferase ( P09874 ) are the key enzymes involved in poly - ADP - ribosylation and mono ADP - ribosylation , respectively . In this investigation the effect of P01133 , P09038 , P05019 or P01308 on nuclear PARP and mitochondrial P09874 activities were assessed in nuclei and mitochondria purified from developing ( 30 DIV ) or aging ( 90 and 190 DIV ) primary rat astrocyte cultures . A marked increase of PARP activity in P09038 or P05019 treated astroglial cell cultures at 30 DIV was found . Nuclear PARP and mitochondrial P09874 activities were greatly stimulated by treatment with P01133 or P01308 alone or together in astrocyte cultures at 30 DIV . Nuclear PARP and mitochondrial P09874 activities showed a more remarkable increase in control untreated astrocyte cultures at 190 DIV than at 90 DIV . These findings suggest that ADP - ribosylation process is involved in DNA damage and repair during cell differentiation and aging in culture . Twelve hours treatment with P01133 , P01308 or P09038 significantly stimulated nuclear PARP and mitochondrial P09874 activities in 190 DIV aging astrocyte cultures . The above results indicate that P01133 , P01308 and P09038 may play a crucial role in the post - translational modification of chromosomal proteins including ADP - ribosylation process in in vitro models . This suggests that growth factors regulate genomic stability in glial cells during development and maturation , stimulating nuclear and mitochondrial ADP - ribosylation processes in developing or aging astrocyte cultures .",
"Mass spectrometry and hydrogen / deuterium exchange measurements of alcohol - induced structural changes in cellular retinol - binding protein type I . To bind and release its ligand , cellular retinol - binding protein type I ( P09455 ) needs to undergo conformational and dynamic changes to connect the inner , solvent - shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water / alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo - and holo - P09455 , in either water / methanol or water / trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time - of - flight mass spectrometry ( P19957 - Q - TOFMS ) to identify the alcohol - induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen / deuterium ( H / D ) exchange monitored by continuous - labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo - P09455 exhibits a progressively more compact conformation , resulting in reduced H / D exchange with respect to the native protein in water . DB00162 dissociation from the holo - protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo - protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo - P09455 to a new alpha - helix conformation capable of exchanging all available hydrogen atoms .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK73___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"DB02701 : a potential addition to the anti - psoriatic weaponry . Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern . Increased expression of adhesion molecules , prominent neutrophil accumulation , and increased production of nitric oxide are characteristics of this disorder . Moreover , histamine and proteases are supposed to participate in the pathogenesis of psoriasis . DB02701 is an inhibitor of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) that , through enhancement of nuclear kappa B - mediated transcription , plays a pivotal role in the expression of inflammatory cytokines , chemokines , adhesion molecules , and inflammatory mediators . Through interaction with P28907 and inhibition of IL - 1 , IL - 12 , and P01375 production , nicotinamide produces a mild TH2 bias . DB02701 is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release . It inhibits nitric oxide synthase mRNA induction and suppresses antigen - induced lymphocyte transformation . DB02701 increases the biosynthesis of ceramides , which upon degradation produce sphingosine . DB03203 inhibits protein kinase C ( PKC ) and decreases basal cell proliferation dependent on PKC . Taken together , it can be reasoned that nicotinamide could be a useful addition to anti - psoriatic armamentarium . The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen - induced arthritis . DB02701 decreased the methotrexate - induced hepatotoxicity . The above combinations may prove to have a powerful anti - psoriatic effect as well . As PARP inhibitors could exert anti - retroviral effect , nicotinamide could also be of special value in the treatment of HIV - infected psoriatics .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"Chemotaxis of mouse bone marrow neutrophils and dendritic cells is controlled by adp - ribose , the major product generated by the P28907 enzyme reaction . The ectoenzyme P28907 catalyzes the production of cyclic ADP - ribose ( cADPR ) and ADP - ribose ( DB02059 ) from its substrate , NAD (+) . Both products of the P28907 enzyme reaction play important roles in signal transduction , as cADPR regulates calcium release from intracellular stores and DB02059 controls cation entry through the plasma membrane channel O94759 . We previously demonstrated that P28907 and the cADPR generated by P28907 regulate calcium signaling in leukocytes stimulated with some , but not all , chemokines and controls leukocyte migration to inflammatory sites . However , it is not known whether the other P28907 product , DB02059 , also regulates leukocyte trafficking In this study we characterize 8 - bromo ( 8Br ) - DB02059 , a novel compound that specifically inhibits DB02059 - activated cation influx without affecting other key calcium release and entry pathways . Using 8Br - DB02059 , we demonstrate that DB02059 controls calcium influx and chemotaxis in mouse neutrophils and dendritic cells activated through chemokine receptors that rely on P28907 and cADPR for activity , including mouse P21462 , P61073 , and P32248 . Furthermore , we show that the calcium and chemotactic responses of leukocytes are not dependent on poly - ADP - ribose polymerase 1 ( P09874 ) , another potential source of DB02059 in some leukocytes . Finally , we demonstrate that NAD (+) analogues specifically block calcium influx and migration of chemokine - stimulated neutrophils without affecting P09874 - dependent calcium responses . Collectively , these data identify DB02059 as a new and important second messenger of mouse neutrophil and dendritic cell migration , suggest that P28907 , rather than P09874 , may be an important source of DB02059 in these cells , and indicate that inhibitors of DB02059 - gated calcium entry , such as 8Br - DB02059 , have the potential to be used as anti - inflammatory agents .",
"Altered thyroxin and retinoid metabolic response to 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin in aryl hydrocarbon receptor - null mice . To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin ( TCDD ) can be mediated by the arylhydrocarbon receptor ( P35869 ) , pregnant P35869 - heterozygous ( P35869 +/- ) mice were administered a single oral dose of 10 microg kg (- 1 ) TCDD at gestation day 12 . 5 . Serum and liver were collected on postnatal day 21 from vehicle - treated control or TCDD - treated P35869 +/- and P35869 - null ( P35869 -/- ) mouse pups . Whereas TCDD exposure resulted in a marked reduction of total thyroxin ( TT4 ) and free DB00451 ( FT4 ) levels in the serum of P35869 +/- mice , TCDD had no effects on P35869 -/- mice . Gene expression of UDP - glucuronosyltransferase ( P78381 ) 1A6 , cytochrome P450 ( CYP ) 1A1 , and P05177 in the liver was induced markedly by TCDD in P35869 +/- but not P35869 -/- mice . Induction of P04798 in response to TCDD was confirmed by immunohistochemical evidence in that P04798 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region . Levels of retinyl palmitate were greatly reduced in the liver of TCDD - exposed P35869 +/- mice , but not in vehicle - treated P35869 +/- mice . No effects of TCDD on retinoid levels in the liver were found in P35869 -/- mice . We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via P35869 . Induction of P19224 is thought to be responsible at least partly for reduced serum thyroid hormone levels in TCDD - exposed mice .",
"p53 - , Q96EB6 - , and P09874 - independent downregulation of p21WAF1 expression in nicotinamide - treated cells . DB02701 at mM concentration is a potent inhibitor of certain key molecules involved in cell survival , such as Q96EB6 and P09874 , and affects cell survival in various conditions in vivo and in vitro . However , the effect of an acute treatment of nicotinamide on gene expression has rarely been closely examined . In our study , the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 - negative or Q96EB6 - knockdown cells indicating gene regulation not mediated by p53 or Q96EB6 . Meanwhile , in the nicotinamide - treated cells , Sp1 activity and protein level was substantially reduced due to increased proteasome - mediated degradation . Our results indicate that nicotinamide treatment attenuates p21WAF1 expression through Sp1 downregulation , and suggest a possible involvement of nicotinamide metabolism in cellular gene expression .",
"DB02701 uncouples hormone - dependent chromatin remodeling from transcription complex assembly . Sirtuins , homologs of the yeast SIR2 family , are protein deacetylases that require nicotinamide adenosine dinucleotide as cofactor . To determine whether the sirtuin family of deacetylases is involved in progesterone receptor ( PR ) - mediated transcription , the effect of sirtuin inhibitor , nicotinamide ( NAM ) , was monitored in T47D breast cancer cells . NAM suppressed hormone - dependent activation of PR - regulated genes in a dose - dependent manner . Surprisingly , NAM - mediated inhibition of PR - mediated transcription occurs independently of Q96EB6 and P09874 . Chromatin immunoprecipitation experiments did not show that PR binding nor that of the coactivators CBP and SRC3 was compromised . Consistent with the recruitment of the P51532 chromatin remodeling complex , promoter chromatin remodeling still occurs despite NAM inhibition of PR transactivation . Rather , we show that this inhibition of transcription is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter . These results show that NAM uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital NAM - regulated steps required for promoter chromatin remodeling and basal transcription complex communication .",
"P09874 inhibition - induced activation of P19957 - kinase - Akt pathway promotes resistance to taxol . PARP inhibitors combined with DNA - damage inducing cytostatic agents can lead to effective tumor therapy . However , inhibition of poly ( ADP - ribose ) polymerase ( P09874 ; EC 2 . 4 . 2 . 30 ) induces the activation of P19957 - kinase - Akt pathway , which can counteract the effectiveness of this therapy . To understand the role of Akt activation in the combined use of cytostatic agent and PARP inhibition , we used taxol ( paclitaxel ) as an antineoplastic agent , which targets microtubules and up - regulates mitochondrial ROS production , together with ( i ) pharmacological inhibition ( PJ - 34 ) , ( ii ) siRNA knock - down and ( iii ) transdominant expression of the DNA binding domain of P09874 . In all cases , P09874 inhibition leads to suppressed poly - ADP - ribosylation of nuclear proteins , prevention of NAD (+) depletion and significant resistance against taxol induced caspase - 3 activation and apoptotic cell death . Paclitaxel induced a moderate increase in Akt activation , which was significantly augmented by PARP inhibition , suggesting that PARP inhibition - induced Akt activation could be responsible for the cytostatic resistance . When activation of the P19957 - kinase - Akt pathway was prevented by LY - 294002 or Akt Inhibitor IV , the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of P19957 - kinase - Akt cascade had significantly contributed to the cytostatic resistance . Our study demonstrates that drug - induced drug resistance can be responsible for the reduced efficacy of antitumor treatment . Although inhibition of P09874 can promote cell death in tumor cells by the inhibition of DNA repair , PARP - inhibition promoted activation of the P19957 - kinase - Akt pathway can counteract this facilitating effect , and can cause cytostatic resistance . We suggest augmenting PARP inhibition by the inhibition of the P19957 - kinase - Akt pathway for antitumor therapy .",
"Role of nicotinamide in DNA damage , mutagenesis , and DNA repair . DB02701 is a water - soluble amide form of niacin ( nicotinic acid or vitamin B3 ) . Both niacin and nicotinamide are widely available in plant and animal foods , and niacin can also be endogenously synthesized in the liver from dietary tryptophan . DB02701 is also commercially available in vitamin supplements and in a range of cosmetic , hair , and skin preparations . DB02701 is the primary precursor of nicotinamide adenine dinucleotide ( NAD (+) ) , an essential coenzyme in DB00171 production and the sole substrate of the nuclear enzyme poly - ADP - ribose polymerase - 1 ( P09874 ) . Numerous in vitro and in vivo studies have clearly shown that P09874 and NAD (+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation . This paper will examine the role of nicotinamide in the protection from carcinogenesis , DNA repair , and maintenance of genomic stability .",
"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .",
"___MASK39___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK39___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK39___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .",
"Preventing NAD (+) depletion protects neurons against excitotoxicity : bioenergetic effects of mild mitochondrial uncoupling and caloric restriction . Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity , which involves energy depletion . By examining bioenergetic changes induced by glutamate , we found that the cellular nicotinamide adenine dinucleotide ( NAD (+) ) level is a critical determinant of neuronal survival . The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain . 2 , 4 - dinitrophenol ( DNP ) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons , which accelerates oxidation of NAD ( P ) H to NAD (+) in mitochondria . The NAD (+)- dependent histone deacetylase sirtulin 1 ( Q96EB6 ) and glucose transporter 1 ( P11166 ) mRNA are upregulated mouse brain under caloric restriction . To examine whether NAD (+) mediates neuroprotective effects , nicotinamide , a precursor of NAD (+) and inhibitor of Q96EB6 and poly ( ADP - ribose ) polymerase 1 ( P09874 ) ( two NAD (+)- dependent enzymes ) , was employed . DB02701 attenuated excitotoxic death and preserved cellular NAD (+) levels to support Q96EB6 and PARP 1 activities . Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress .",
"Zfp521 is a target gene and key effector of parathyroid hormone - related peptide signaling in growth plate chondrocytes . In the growth plate , the interplay between parathyroid hormone - related peptide ( P12272 ) and Indian hedgehog ( Ihh ) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth . We found that P12272 increases the expression of Zfp521 , a zinc finger transcriptional coregulator , in prehypertrophic chondrocytes . Mice with chondrocyte - targeted deletion of Zfp521 resembled P12272 (-/-) and chondrocyte - specific Q03431 (-/-) mice , with decreased chondrocyte proliferation , early hypertrophic transition , and reduced growth plate thickness . Deleting Zfp521 increased expression of Runx2 and Runx2 target genes , and decreased P12004 D1 and Bcl - 2 expression while increasing P42574 activation and apoptosis . Zfp521 associated with Runx2 in chondrocytes , antagonizing its activity via an P56524 - dependent mechanism . P12272 failed to upregulate P12004 D1 and to antagonize Runx2 , Ihh , and collagen X expression when Zfp521 was absent . Thus , Zfp521 is an important P12272 target gene that regulates growth plate chondrocyte proliferation and differentiation .",
"DB02701 inhibits alkylating agent - induced apoptotic neurodegeneration in the developing rat brain . BACKGROUND : Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system ( CNS ) . Administration of single dose of thiotepa in 7 - d postnatal ( Q0GE19 ) rat triggers activation of apoptotic cascade and widespread neuronal death . The present study was aimed to elucidate whether nicotinamide may prevent thiotepa - induced neurodegeneration in the developing rat brain . METHODOLOGY / PRINCIPAL FINDINGS : Neuronal cell death induced by thiotepa was associated with the induction of Bax , release of cytochrome - c from mitochondria into the cytosol , activation of caspase - 3 and cleavage of poly ( ADP - ribose ) polymerase ( P09874 ) . Post - treatment of developing rats with nicotinamide suppressed thiotepa - induced upregulation of Bax , reduced cytochrome - c release into the cytosol and reduced expression of activated caspase - 3 and cleavage of P09874 . Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus ; post - treatment with nicotinamide reduced the number of dead cells in these brain regions . Terminal deoxynucleotidyl transferase ( TdT ) - mediated dUTP nick end - labeling ( TUNEL ) and immunohistochemical analysis of caspase - 3 show that thiotepa - induced cell death is apoptotic and that it is inhibited by nicotinamide treatment . CONCLUSION : DB02701 ( Nic ) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat . These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants .",
"Poly ( ADP - ribose ) polymerase - 1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a NAD - consuming enzyme with an emerging key role in epigenetic regulation of gene transcription . Although P09874 expression is characteristically restricted to the nucleus , a few studies report the mitochondrial localization of the enzyme and its ability to regulate organelle functioning . Here , we show that , despite exclusive nuclear localization of P09874 , mitochondrial homeostasis is compromised in cell lines exposed to P09874 pharmacological inhibitors or small interfering RNA . P09874 suppression reduces integrity of mitochondrial DNA ( mtDNA ) , as well as expression of mitochondria - encoded respiratory complex subunits P23219 , P35354 , and ND - 2 . Accordingly , P09874 localizes at promoters of nuclear genes encoding both the mtDNA repair proteins P13051 , P12882 , and P27695 and the mtDNA transcription factors Q8WVM0 and Q9H5Q4 . It is noteworthy that poly ( ADP - ribosyl ) ation is required for nuclear gene expression of these mitochondrial proteins . Consistent with these findings , P09874 suppression impairs mitochondrial DB00171 production . Our results indicate that P09874 plays a central role in mitochondrial homeostasis by epigenetically regulating nuclear genes involved in mtDNA repair and transcription . These data might have important implications in pharmacology of P09874 inhibitors as well as clinical oncology and aging .",
"DB02701 pre - treatment ameliorates NAD ( H ) hyperoxidation and improves neuronal function after severe hypoxia . Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling ( between NAD (+) and DB00157 ) immediately after reoxygenation , resulting in DB00157 hyperoxidation . We test whether the addition of nicotinamide ( to enhance NAD (+) levels ) or P09874 inhibition ( to prevent consumption of NAD (+) ) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices . After severe , prolonged hypoxia ( maintained for 3min after spreading depression ) there was hyperoxidation of DB00157 following reoxygenation , an increased soluble NAD (+)/ DB00157 ratio , loss of neuronal field excitatory post - synaptic potential ( fEPSP ) and decreased DB00171 content . DB02701 incubation ( 5mM ) 2h prior to hypoxia significantly increased total NAD ( H ) content , improved neuronal recovery , enhanced DB00171 content , and prevented DB00157 hyperoxidation . The nicotinamide - induced increase in total soluble NAD ( H ) was more significant in the cytosolic compartment than within mitochondria . Prolonged incubation with PJ - 34 ( > 1h ) led to enhanced baseline DB00157 fluorescence prior to hypoxia , as well as improved neuronal recovery , DB00157 hyperoxidation and DB00171 content on recovery from severe hypoxia and reoxygenation . In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ - 34 prior to hypoxia improved recovery of neuronal function , enhanced DB00157 reduction and DB00171 content , but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation .",
"Protective effect of nicotinamide against poly ( ADP - ribose ) polymerase - 1 - mediated astrocyte death depends on its transporter - mediated uptake . AIM : Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a DNA repair enzyme , and its excessive activation , following ischemia , trauma , etc . , depletes cellular nicotinamide adenine dinucleotide ( NAD (+) ) as a substrate and eventually leads to brain cell death . DB02701 , an NAD (+) precursor and a P09874 inhibitor , is known to prevent P09874 - triggered cell death , but there is no available information on the mechanisms involved in its transport . Here we clarified the transport characteristics of nicotinamide in primary cultured mouse astrocytes . MAIN METHODS : Uptake characteristics of [( 14 ) C ] nicotinamide were assessed by a conventional method with primary cultured mouse astrocytes . Cell viability and P09874 activity were determined with intracellular LDH activity and immunocytochemical detection of PAR accumulation , respectively . KEY FINDINGS : P09874 activation was induced by treatment of astrocytes with N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) , an alkylating agent . MNNG - triggered astrocyte death and PAR accumulation were completely inhibited by treatment with nicotinamide as with DPQ ( 3 , 4 - dihydro - 5 -( 4 -( 1 - piperidinyl ) butoxy )- 1 ( 2H )- isoquinolinone ) , a second generation PARP inhibitor . The uptake of [( 14 ) C ] nicotinamide was time - , temperature - , concentration - and pH - dependent , and was inhibited and stimulated by co - and pre - treatment with N - methylnicotinamide , a representative substrate of an organic cation transport system , respectively . Co - treatment of astrocytes with nicotinamide and N - methylnicotinamide resulted in a decrease in PAR accumulation and absolute prevention of cell death . SIGNIFICANCE : These findings suggest that nicotinamide has a protective effect against P09874 - induced astrocyte death and that its transporter - mediated uptake , which is extracellular pH - sensitive and common to N - methylnicotinamide , is critical for prevention of P09874 - triggered cell death .",
"Poly ( ADP - ribose ) metabolism in X - irradiated Chinese hamster cells : its relation to repair of potentially lethal damage . DB02701 - adenine dinucleotide ( NAD + ) is the substrate used by cells in poly ( ADP - ribose ) synthesis . X - irradiation of log - phase Chinese hamster cells caused a rapid decrease in NAD + levels which was linearly dependent on radiation dose . The activity of ADP - ribosyl transferase ( P09874 ) also increased linearly with radiation dose . The decrease of NAD + was slower , and the increase in P09874 activity was less pronounced , in a radiation sensitive line , V79 - AL162 / S - 10 . An inhibitor of P09874 , m - aminobenzamide , largely prevented the depletion of cellular NAD + and reduced the rate at which P09874 activity disappeared during post - irradiation incubation . Post - irradiation treatment with hypertonic buffer or with medium containing D2O -- which inhibit repair of radiation - induced potentially lethal damage -- enhanced the depletion of NAD + and prevented the reduction in P09874 activity following irradiation . The characteristics of the effects of treatment with hypertonic buffer on NAD + metabolism were qualitatively similar to the effects that such treatment has on radiation - induced cell killing . These results suggest that poly ( ADP - ribose ) synthesis after irradiation plays a role in the repair of potentially lethal damage .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Rosemary ( Rosmarinus officinalis L . ) extract regulates glucose and lipid metabolism by activating AMPK and Q07869 pathways in HepG2 cells . An epidemic of metabolic disorders such as obesity and diabetes is rising dramatically . Using natural products as potential preventive and therapeutic interventions for these disorders has drawn worldwide attention . Rosemary has been shown to lower blood glucose and cholesterol levels and mitigate weight gain in several in vivo studies . However , the mechanisms are essentially unknown . We investigated the effects of rosemary extract on metabolism and demonstrated that rosemary extract significantly increased glucose consumption in HepG2 cells . The phosphorylation of AMP - activated protein kinase ( AMPK ) and its substrate , acetyl - DB01992 carboxylase ( ACC ) , was increased by rosemary extract . Rosemary extract also transcriptionally regulated the genes involved in metabolism , including Q96EB6 , PPARγ coactivator 1α ( PGC1α ) , glucose - 6 - phosphatase ( P35575 ) , ACC , and low - density lipoprotein receptor ( P01130 ) . Furthermore , the PPARγ - specific antagonist GW9662 diminished rosemary ' s effects on glucose consumption . Overall , our study suggested that rosemary potentially increases liver glycolysis and fatty acid oxidation by activating AMPK and Q07869 pathways .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .",
"Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .",
"P35354 inhibitor treatment enhances photodynamic therapy - mediated tumor response . Photodynamic therapy ( PDT ) continues to be used in the treatment of solid tumors . Clinical results are promising , but the therapy has not been optimized , and tumor recurrences can occur . Recently , it has been shown that inhibitors of cyclooxygenase ( P36551 ) - 2 can be effective in combination with conventional chemotherapy and radiation therapy . In the current study , we examined the parameters of PDT - mediated activation of P35354 expression . We also examined the tumoricidal effectiveness of combining PDT with the selective P35354 inhibitor NS - 398 . PDT induced the transcriptional activation of P35354 . Prolonged expression of P35354 protein was observed in PDT - treated mouse sarcoma and carcinoma cell lines , whereas P23219 was not inducible by PDT . Prostaglandin ( PG ) E2 synthesis was also increased in PDT - treated cells , and DB00917 levels were attenuated in cells coincubated with NS - 398 , indicating that PDT induced the expression of biologically active P35354 . Both porphyrin - and chlorin - based photosensitizers were able to elicit PDT - mediated P35354 expression . P35354 was also elevated in radiation - induced fibrosarcoma ( Q9HBH0 ) tumors after treatment with PDT . We also observed that systemic administration of NS - 398 decreased PDT induction of both DB00917 and vascular endothelial growth factor in treated Q9HBH0 tumors . Additionally , we demonstrated that NS - 398 enhanced PDT responsiveness in Q9HBH0 tumors without increasing toxicity to normal tissue . These results provide strong evidence that combination procedures involving selective P35354 inhibitors may improve the therapeutic effectiveness of PDT .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK35___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK35___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK35___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK35___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK35___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK35___ increased the protein expression of hepatic P05181 and ___MASK35___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK35___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK35___ and RFP - induced hepatotoxicity .",
"DB02701 - mechanisms of action and its topical use in dermatology . DB02701 , an amide of vitamin B3 ( niacin ) , is a hydrophilic endogenous substance . Its effects after epicutaneous application have long been described in the literature . Given a sufficient bioavailability , niacinamide has antipruritic , antimicrobial , vasoactive , photo - protective , sebostatic and lightening effects depending on its concentration . Within a complex metabolic system niacinamide controls the NFκB - mediated transcription of signalling molecules by inhibiting the nuclear poly ( ADP - ribose ) polymerase - 1 ( P09874 ) . DB02701 is a well - tolerated and safe substance often used in cosmetics . Clinical data for its therapeutic use in various dermatoses can increasingly be found in the literature . Although the existing data are not sufficient for a scientifically founded evaluation , it can be stated that the use of niacinamide in galenic preparations for epicutaneous application offers most interesting prospects .",
"DB02701 treatment reduces the levels of histone H3K4 trimethylation in the promoter of the mper1 circadian clock gene and blocks the ability of dexamethasone to induce the acute response . Circadian rhythms , which measure time on a scale of 24h , are generated by one of the most ubiquitous endogenous mechanisms , the circadian clock . Q96EB6 , a class III histone deacetylase , and P09874 , a poly ( ADP - ribose ) polymerase , are two NAD (+)- dependent enzymes that have been shown to be involved in the regulation of the clock . Here we present evidence that the metabolite nicotinamide , an inhibitor of Q96EB6 , P09874 and mono ( ADP - ribosyl ) transferases , blocks the ability of dexamethasone to induce the acute response of the circadian clock gene , mper1 , while it concomitantly reduces the levels of histone H3 trimethylation of lysine 4 ( H3K4me3 ) in the mper1 promoter . Moreover , application of alternative inhibitors of Q96EB6 and ADP - ribosylation did not lead to similar results . Therefore , inhibition of these enzymes does not seem to be the mode by which NAM exerts these effects . These results suggest the presence of a novel mechanism , not previously documented , by which NAM can alter gene expression levels via changes in the histone H3K4 trimethylation state .",
"The - 928 G / C and - 362 G / C single - nucleotide polymorphisms in the promoter of P13500 : Increased transcriptional activity and novel binding sites . BACKGROUND : The - 928 guanine ( G ) / cytosine ( C ) and - 362 G / C single - nucleotide polymorphisms ( SNPs ) in the proximal promoter region of the monocyte chemoattractant protein 1 gene have been associated with an increased risk for intimal medial thickness and carotid atherosclerosis , respectively . We characterized the transcriptional activity of these two SNPs in vitro and identified transcription factors that bind to them . METHODS : The proximal promoter region spanning bases - 2746 to + 440 was sequenced in subjects with carotid atherosclerosis . Two SNPs consisting of C - for - G substitution at bases - 928 and - 362 were characterized . Each observed haplotype was inserted into a luciferase reporter and transfected into mammalian cells . RESULTS : Stimulation with 12 - O - tetradecanoylphorbol 13 - acetate increased transcriptional activity of the - 928 C plasmid ( p = 0 . 005 ) . The basal transcription activities of the plasmids containing - 928 C and - 362 C were also increased ( p < 0 . 001 and p < 0 . 0001 , respectively ) . Electrophoretic mobility shift assay ( EMSA ) and DNA footprinting identified an P35869 nuclear translocator protein ( P27540 ) binding site at the - 928 C SNP . EMSA data indicated signal transducers and activators of transcription ( P35610 ) binding at the - 362 G SNP . A nuclear binding protein , poly ( ADP - ribose ) polymerase ( PARP ) 1 , was purified from the - 928 C SNP site and identified by mass spectroscopy . CONCLUSION : The - 928 C SNP and the - 362 C SNP are associated with increased transcriptional activity in vitro , but the - 362 G site is not . The - 928 C SNP is associated with P09874 and P27540 binding , and the - 362 G is associated with a P35610 binding site .",
"Differential effect of DB03932 , pravastatin , and fluvastatin on production of Q14116 and expression of P05362 and P25942 in human monocytes . A novel , proinflammatory cytokine , interleukin ( IL ) - 18 production was detected in the medium of human monocytes treated with 3 - hydroxy - 3 - methylglutaryl coenzyme - A ( HMG - DB01992 ) reductase inhibitors , pravastatin , and fluvastatin ( 0 . 1 and 1 muM ) but not with the statin - derived lymphocyte function - associated antigen - 1 ( LFA - 1 ) inhibitor DB03932 , which did not inhibit P04035 . ___MASK39___ and fluvastatin also induced the production of Q14116 , tumor necrosis factor alpha ( P01375 ) and interferon - gamma ( P01579 ) in human peripheral blood mononuclear cells ( PBMC ) in contrast to DB03932 . Q14116 production by PBMC is located upstream of the cytokine cascade activated by these statins . The Q14116 - induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes . In the absence and presence of lower concentrations ( 0 . 1 and 1 ng / ml ) of Q14116 , pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule ( ICAM ) - 1 and induced the expression of P25942 , whereas DB03932 had no effect . In the presence of higher concentrations ( 5 , 10 , and 100 ng / ml ) of Q14116 , pravastatin , fluvastatin , and DB03932 similarly inhibited the expression of P05362 and P25942 as well as the production of IL - 12 , P01375 , and P01579 in PBMC . The effects of pravastatin and fluvastatin but not DB03932 were abolished by the addition of mevalonate , indicating the involvement of P04035 in the action of pravastatin and fluvastatin . Thus , the effects of DB03932 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of Q14116 . It was concluded that DB03932 has the inhibitory effect on an Q14116 - initiated immune response without any activation on monocytes .",
"N - methyl - 2 - pyridone - 5 - carboxamide : a novel uremic toxin ? BACKGROUND : N - methyl - 2 - pyridone - 5 - carboxamide ( 2PY ) is one of the end products of nicotinamide - adenine dinucleotide ( NAD ) degradation . We recently found that serum 2PY concentrations in chronic renal failure ( CRF ) patients were enhanced to the values , which are potentially toxic . The aim of this study was to determine whether 2PY is an inhibitor of poly ( ADP - ribose ) polymerase , the nuclear enzyme that is highly involved in variety of physiologic events , including regulation of DNA replication and DNA repair . METHODS : High - performance liquid chromatography ( HPLC ) was used to determine 2PY and other NAD catabolite concentrations in serum of : nondialyzed patients ; patients chronically hemodialyzed ; patients after kidney transplantation ; and healthy individuals ( control group ) . Moreover , the effect of nicotinamide and 2PY on poly ( ADP - ribose ) polymerase ( P09874 ) in vitro was studied . RESULTS : The serum nicotinamide , 2PY , and 4PY ( N - methyl - 4 - pyridone - 3 - carboxamide ) concentrations are many times elevated in nondialyzed CRF patients when compared with controls . The direct correlations were found between serum 2PY ( as well as 4PY and nicotinamide ) concentrations and serum creatinine concentration , and negative correlations between serum concentrations of these compounds and creatinine clearance . The concentration of 2PY decreases considerably after hemodialysis ( HD ) session , but elevates back 48 hours later . It permanently declines after kidney transplantation . DB02701 and 2PY significantly inhibit P09874 activity in vitro . CONCLUSIONS : Increased serum 2PY concentration , along with a deterioration of kidney function and its toxic properties ( significant inhibition of P09874 by 2PY ) , suggest that it could be a novel uremic toxin .",
"MicroRNA Regulation of Q96EB6 . Q96EB6 is an NAD - dependent deacetylase that regulates stress response pathways . By deacetylating transcription factors and co - factors , Q96EB6 modulates metabolism , inflammation , hypoxic responses , circadian rhythms , cell survival , and longevity . Since Q96EB6 plays a key role in regulating pathways involved in cardiovascular diseases and metabolic diseases cancer , the regulation of Q96EB6 has received intense scrutiny . The post - transcriptional regulation of Q96EB6 is mediated by two classes of molecules , RNA - binding proteins ( RBPs ) and non - coding small RNAs . MicroRNAs ( miRNAs ) are short non - coding RNAs that regulate target gene expression in a post - transcriptional manner . More than 16 miRNAs modulate Q96EB6 expression , including miR - 34a . miR - 34a induces colon cancer apoptosis through Q96EB6 , and miR - 34a also promotes senescence in endothelial cells via Q96EB6 . This review describes the impact of miRNAs on Q96EB6 . The background of Q96EB6 and miRNAs will be summarized , followed by the mechanism by which several key miRNAs alter Q96EB6 levels , and how the P02753 Q15717 regulates Q96EB6 . MicroRNA regulation of Q96EB6 might affect a wide variety of pathways in humans , from metabolic diseases such as diabetes to cardiovascular diseases and cancer .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK84___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Red wine extract protects against oxidative - stress - induced endothelial senescence . Red wine polyphenols may preserve endothelial function during aging . Endothelial cell senescence enhances age - related endothelial dysfunction . We investigated whether RWE ( red wine extract ) prevents oxidative - stress - induced senescence in HUVECs ( human umbilical - vein endothelial cells ) . Senescence was induced by exposing HUVECs to tBHP ( t - butylhydroperoxide ) , and quantified by senescence - associated β - galactosidase staining . RWE ( 0 - 50 μg / ml ) concentration dependently decreased senescence by maximally 33 ± 7 . 1 % . RWE prevented the senescence - associated increase in P38936 protein expression , inhibited tBHP - induced DNA damage of endothelial cells and induced relaxation of PCAs ( porcine coronary arteries ) . Inhibition of Q96EB6 ( sirtuin 1 ) by sirtinol partially reversed the effect of RWE on tBHP - induced senescence , whereas both the NOS ( nitric oxide synthase ) inhibitor L - NMMA ( NG - monomethyl - L - arginine ) and the P36551 ( cyclo - oxygenase ) inhibitor indomethacin fully inhibited it . Furthermore , incubation of HUVECs with RWE increased P29474 ( endothelial NOS ) and P35354 mRNA levels as well as phosphorylation of P29474 at Ser1177 . RWE protects endothelial cells from tBHP - induced senescence . NO and P35354 , in addition to activation of Q96EB6 , play a critical role in the inhibition of senescence induction in human endothelial cells by RWE .",
"Poly ( ADP - ribose ) polymerase - 1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22 - 28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD + ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 overactivation may ensue , depleting cells of NAD + and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 expression and that administration of a P09874 inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty - four percent of control pups developed high - grade NEC ( grades 3 - 4 ) , whereas only 7 % of pups receiving nicotinamide developed high - grade NEC . DB02701 treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 overactivation in NEC may drive mucosal cell death in this disease and that P09874 may be a novel therapeutic target in NEC .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK28___ GITS , Diaprel MR ) . One daily dose of ___MASK28___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"P43490 regulates cell survival through autophagy in cardiomyocytes . DB02701 adenine dinucleotide ( NAD (+) ) acts as a transfer molecule for electrons , thereby acting as a key cofactor for energy production . NAD (+) also serves as a substrate for cellular enzymes , including poly ( ADPribose ) polymerase ( PARP ) - 1 and Sirt1 . Activation of P09874 by DNA damage depletes the cellular pool of NAD (+) , leading to necrotic cell death . NAD (+) in the nucleus enhances the activity of Sirt1 , thereby modulating transcription . NAD (+) is either synthesized de novo from amino acids , namely tryptophan and aspartic acid , or resynthesized from NAD (+) metabolites , such as nicotinamide ( NAM ) , through the salvage pathway . NAM phosphoribosyltransferase ( P43490 ) is a rate - limiting enzyme in the NAD (+) salvage pathway . We have recently demonstrated that P43490 is an important regulator of NAD (+) and autophagy in cardiomyocytes . Here we discuss the role of P43490 in regulating autophagy and potential mechanisms by which NAD (+) regulates autophagy in the heart .",
"UDP - glucuronosyltransferase 1A determinates intracellular accumulation and anti - cancer effect of β - lapachone in human colon cancer cells . β - lapachone ( β - lap ) , an NAD ( P ) H : quinone oxidoreductase 1 ( P15559 ) targeting antitumor drug candidate in phase II clinical trials , is metabolically eliminated via P15559 mediated quinone reduction and subsequent UDP - glucuronosyltransferases ( UGTs ) catalyzed glucuronidation . This study intends to explore the inner link between the cellular glucuronidation and pharmacokinetics of β - lap and its apoptotic effect in human colon cancer cells . HT29 cells S9 fractions exhibited high glucuronidation activity towards β - lap , which can be inhibited by O60656 competitive inhibitor propofol . P22309 siRNA treated HT29 cells S9 fractions displayed an apparent low glucuronidation activity . Intracellular accumulation of β - lap in HCT116 cells was much higher than that in HT29 cells , correlated with the absence of P22309 in HCT116 cells . The cytotoxic and apoptotic effect of β - lap in HT29 cells were much lower than that in HCT116 cells ; moreover , β - lap triggered activation of Q96EB6 - Q12778 apoptotic pathway was observed in HCT116 cells but not in HT29 cells . Pretreatment of HT29 cells with P22309 siRNA or propofol significantly decreased β - lap ' s cytotoxic and apoptotic effects , due to the repression of glucuronidation and the resultant intracellular accumulation . In conclusion , P22309 is an important determinant , via switching P15559 - triggered redox cycle to metabolic elimination , in the intracellular accumulation of β - lap and thereafter its cytotoxicity in human colon cancer cells . Together with our previous works , we propose that UGTs determined cellular pharmacokinetics is an important determinant in the apoptotic effects of P15559 targeting substrates serving as chemotherapeutic drugs .",
"DB02701 deficiency in human lymphocytes prevents the [ 3H ] thymidine - induced adaptive response for the repair of X - ray - induced chromosomal damage . Human lymphocytes treated with [ 3H ] thymidine ( [ 3H ] dThd ) become refractory to the induction of chromosomal aberrations by subsequent doses of X rays . This adaptive response to [ 3H ] dThd does not occur in the presence of 3 - aminobenzamide ( 3AB ) . 3AB inhibits the synthesis of poly ( ADP - ribose ) by the enzyme adenosine diphosphate ribosyl transferase ( P09874 ) , which requires NAD as a substrate . 3AB also prevents chromosomal repair , as measured in X - ray dose - fractionation studies . Because 3AB might interfere with metabolic reactions other than those mediated by P09874 , experiments were carried out to see if the adaptive response was also inhibited in nicotinamide - free medium , which prevents poly ( ADP - ribosyl ) ation by depleting cellular NAD . The experiments show that the incorporation of [ 3H ] dThd has no effect on the induction of chromosomal aberrations by subsequent doses of X rays if the cells are cultured in nicotinamide - free medium . DB02701 deficiency mimics the effects of 3AB on both the adaptive response and chromosome repair . The results indicate that P09874 activity itself , and not other metabolic processes affected by inhibitors of this enzyme , plays an essential role in the adaptive response .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK70___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )"
] |
[
"___MASK24___",
"___MASK28___",
"___MASK35___",
"___MASK39___",
"___MASK70___",
"___MASK73___",
"___MASK82___",
"___MASK84___",
"___MASK90___"
] |
___MASK39___
|
MH_train_343
|
interacts_with DB04817?
|
[
"Identification of the amino acid sequence motif of alpha - synuclein responsible for macrophage activation . P37840 ( Syn ) is implicated in the pathogenesis of PD and related neurodegenerative disorders . Recent studies have also shown that alpha - synuclein can activate microglia and enhance dopaminergic neurodegeneration . The mechanisms of microglia activation by alpha - synuclein , however , are not well understood . In this study , we found that not only alpha - synuclein but also beta - and gamma - synucleins activated macrophages ( RAW 264 . 7 ) in vitro . Macrophages treated with synuclein proteins secreted P01375 in a dose - dependent manner . Synuclein family proteins also increased mRNA transcription of P35354 and P35228 . Two alpha - synuclein deletion mutants , SynDeltaNAC and Syn61 - 140 , activated macrophages , while deletion mutants Syn1 - 60 and Syn96 - 140 did not significantly activate them . Finally , we demonstrated that macrophage activation by alpha - synuclein was accompanied by phosphorylation of P29323 . These results suggest that synuclein family proteins can activate macrophages , and that macrophage activation needs both the N - terminal and C - terminal domains of alpha - synuclein , but not the central Q9C000 region .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Nonsteroidal anti - inflammatory drugs ( NSAID ) sparing effects of glucosamine hydrochloride through N - glycosylation inhibition ; strategy to rescue stomach from NSAID damage . Gastrointestinal or cardiovascular complications limit nonsteroidal anti - inflammatory drugs ( NSAID ) prescription . ___MASK17___ hydrochloride ( GS - HCl ) alternatively chosen , but debates still exist in its clinical efficiency . P35354 instability through inhibiting P35354 N - glycosylation of GS - HCl raised the possibility of NSAID sparing effect . Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect . IEC - 6 cells were stimulated with P01375 - α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS - HCl by Western blotting and RT - PCR . C57BL / 6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS - HCl after 3 weeks . P01375 - α increased the expression of P35354 , P35228 and inflammatory cytokines , but GS - HCl significantly attenuated P01375 - α - induced P35354 expression . Decreased P35354 after GS - HCl was caused by N - glycosylation inhibition as much as tunicamycin . Combination of reduced dose of indomethacin and GS - HCl significantly reduced the expressions of P05362 , P19320 , P10145 , IL - 1β , P08253 , P09237 , P14780 , and P24347 mRNA as well as NF - κB activation better than high dose indomethacin alone . These NSAID sparing effect of GS - HCl was further proven in collagen - induced arthritis model . Combination of GS - HCl and 2 . 5 mg / kg indomethacin showed significant protection from gastric damages as well as efficacious anti - arthritic effect . Taken together , P35354 N - glycosylation inhibition by GS - HCl led to indomethacin sparing effects , based on which combination of GS - HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID - induced gastric damage as well as excellent anti - arthritic effects .",
"A comparative study of the antipyretic effects of indomethacin and dipyrone in rats . OBJECTIVE : Compare the antipyretic effects of dipyrone and indomethacin . MATERIALS AND METHODS : Fever was induced in rats by i . v . LPS or i . c . v . interleukins ( IL ) , prostaglandins ( PG ) , arachidonic acid ( AA ) , pre - formed pyrogenic factor ( PFPF ) , tumour necrosis factor - alpha ( P01375 ) or corticotrophin releasing hormone ( P06850 ) . DB04817 and indomethacin were administered i . p . , arginine vasopressin V1 - receptor antagonist , d ( CH2 ) 5 DB00135 ( Me ) AVP , into the ventral septal area . Cyclooxygenase ( P23219 /- 2 ) blocking activity was assessed in transfected COS - 7 cells . P06850 release from isolated hypothalami was determined by ELISA . RESULTS : Indomethacin or dipyrone reduced LPS , IL - 1beta , P05231 or P01375 induced fever and P06850 release from rat hypothalamus . Only dipyrone inhibited P10145 , PFPF or PGF2alpha fever . Only indomethacin inhibited fever induced by AA or IL - 1beta , plus AA . Neither antipyretic affected fever caused by DB00917 or P06850 . d ( CH2 ) 5Tyr ( Me ) AVP only blocked antipyresis induced by indomethacin . DB04817 at a very high concentration ( 10 mM ) inhibited only P23219 , while indomethacin ( 0 . 1 microM ) blocked P23219 and P35354 in COS - 7 cells . CONCLUSION : The antipyretic effect of dipyrone differs from that of indomethacin in that it does not depend on AVP release or inhibition of PG synthesis .",
"Synthesis and biological evaluation of novel pyrrolidine - 2 , 5 - dione derivatives as potential antidepressant agents . Part 1 . A series of 3 -( 1H - indol - 3 - yl ) pyrrolidine - 2 , 5 - dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 - HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5 - Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Effects of retroviral - mediated P08183 expression on hematopoietic stem cell self - renewal and differentiation in culture . Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications . Toward this goal , we have investigated whether retrovirally - transduced murine stem cells could be expanded in culture with hematopoietic cytokines . Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene ( HaMDR1 ) , a variant of human dihydrofolate reductase ( HaDHFR ) , or both P08183 and P00374 in an internal ribosomal entry site ( IRES ) - containing bicistronic vector ( HaMID ) . Cells were then expanded for 15 days in cultures stimulated with interleukin ( IL ) - 3 , P05231 , and stem cell factor . When very low marrow volumes were injected into lethally irradiated recipient mice , long - term reconstitution with 100 % donor cells was seen in all mice injected with HaMDR1 - or HaMID - transduced cells . By contrast , engraftment with HaDHFR - or mock - transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes . In addition , mice transplanted with expanded HaMDR1 - or HaMID - transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes . These results show that P08183 - transduced stem cells can be expanded in vitro with hematopoietic cytokines , but indicate that an increased stem cell division frequency can lead to stem cell damage .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK74___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK10___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK93___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"___MASK10___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK10___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK10___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK20___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone ( metamizol ) in mice . DB04817 is a common nonopioid analgesic and antipyretic , which , in many countries , is available over the counter and is more widely used than paracetamol or aspirin . However , the exact mechanisms by which dipyrone acts remain inconclusive . Two novel arachidonoyl - conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase ( FAAH ) , which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide . These arachidonoyl metabolites not only inhibit cyclooxygenase ( P23219 / P35354 ) but also bind to cannabinoid receptors at low micromolar concentrations . The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested . Accordingly , the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would ( a ) be blocked by cannabinoid receptor antagonists and ( b ) occur in FAAH mice . Here , we report that thermal antinociceptive , hypothermic , and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH . These findings indicate that FAAH - dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions .",
"Antiinflammatory steroid action in human ovarian surface epithelial cells . The human ovarian surface epithelium ( OSE ) is subject to serial injury and repair during ovulation , which is a natural inflammatory event . We asked whether there is a compensatory antiinflammatory component to this process , involving steroid hormones produced locally at the time of ovulation . Quantitative RT - PCR analysis of total RNA from cultured human OSE cell monolayers showed that exposure to proinflammatory IL1alpha ( 500 pg / ml ) increased mRNA levels of cyclooxygenase - 2 ( P35354 ) ( P < 0 . 01 ) at 48 h . The P35354 mRNA response to IL1alpha was associated with an approximate 18 - fold ( P < 0 . 01 ) increase in mRNA levels of 11beta - hydroxysteroid dehydrogenase type 1 ( 11betaHSD1 ) , encoding the steroid dehydrogenase that reversibly reduces cortisone to antiinflammatory cortisol . Addition of cortisol to OSE cell culture medium dose - dependently suppressed the P35354 mRNA response to IL1alpha ( P < 0 . 01 ) but reciprocally enhanced the 11betaHSD1 mRNA response ( P < 0 . 05 ) , with both effects strongest at 1 microm cortisol . Presence of glucocorticoid receptor - alpha mRNA and protein was established in OSE cell monolayers and treatment with IL1alpha shown to significantly up - regulate the glucocorticoid receptor - alpha mRNA level ( P < 0 . 05 ) . P04150 antagonist ( ___MASK8___ , 10 microm ) fully reversed the inhibitory effect of 1 microm cortisol on IL1alpha - stimulated P35354 mRNA expression . Progesterone also suppressed IL1alpha - induced P35354 mRNA expression but had no significant effect on IL1alpha - stimulated 11betaHSD1 expression . These data provide direct evidence for antiinflammatory actions of cortisol and progesterone in human OSE cells .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK63___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK63___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK63___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury . Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia , related in part to implantation injury . The cell - specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells ( EC ) and medial smooth muscle cells ( SMC ) from canine vein grafts , 2 hours ( H ) to 30 days ( D ) following surgery . Our results demonstrate a robust genomic response beginning at 2 H , peaking at 12 - 24 H , declining by 7 D , and resolving by 30 D . Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses , apoptosis , mitosis , and extracellular matrix reorganization in both cell types . Through backpropagation an integrated network was built , starting with genes differentially expressed at 30 D , followed by adding upstream interactive genes from each prior time - point . This identified significant enrichment of P05231 , P10145 , NF - κB , dendritic cell maturation , glucocorticoid receptor , and Triggering Receptor Expressed on Myeloid Cells ( Q9NP99 ) signaling , as well as PPARα activation pathways in graft EC and SMC . Interactive network - based analyses identified P05231 , P10145 , IL - 1α , and P01308 Receptor ( P06213 ) as focus hub genes within these pathways . Real - time PCR was used for the validation of two of these genes : P05231 and P10145 , in addition to Collagen 11A1 ( P12107 ) , a cornerstone of the backpropagation . In conclusion , these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury , and identifying novel targets for its prevention .",
"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .",
"A cyclooxygenase - 2 / prostaglandin E2 pathway augments activation - induced cytosine deaminase expression within replicating human B cells . Within inflammatory environments , B cells encountering foreign or self - Ag can develop tertiary lymphoid tissue expressing activation - induced cytosine deaminase ( Q9GZX7 ) . Recently , this DNA - modifying enzyme was detected in nonlymphoid cells within several inflamed tissues and strongly implicated in malignant transformation . This study examines whether a cyclooxygenase 2 ( P35354 ) pathway , often linked to inflammation , influences Q9GZX7 expression in activated B lymphocytes . In this paper , we report that dividing human B cells responding to surrogate C3d - coated Ag , P05112 , and Q9Y275 express Q9GZX7 , as well as P35354 . A progressive increase in Q9GZX7 with each division was paralleled by a division - related increase in a P35354 - linked enzyme , microsomal PGE ( 2 ) synthase - 1 , and the PGE ( 2 ) R , EP2 . Cells with the greatest expression of Q9GZX7 expressed the highest levels of EP2 . Although P35354 inhibitors diminished both Q9GZX7 expression and IgG class switching , exogenous PGE ( 2 ) and butaprost , a selective EP2 agonist , augmented Q9GZX7 mRNA / protein and increased the numbers of IgG (+) progeny . Despite the latter , the proportion of IgG (+) cells within viable progeny generally declined with PGE ( 2 ) supplementation . This was not due to PGE ( 2 )- promoted differentiation to plasma cells or to greater downstream switching . Rather , because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE ( 2 )- supplemented cultures , it appears more likely that PGE ( 2 ) facilitates Q9GZX7 - dependent DNA double - strand breaks that block B cell cycle progression or promote activation - induced cell death , or both . Taken together , the results suggest that a PGE ( 2 ) feed - forward mechanism for augmenting P35354 pathway proteins promotes progressively increased levels of Q9GZX7 mRNA , protein , and function .",
"The role of alpha - synuclein in neurodegenerative diseases : a potential target for new treatment strategies ? P37840 ( AS ) is the main constituent of Lewy bodies . There is an ongoing discussion if overexpression is already dangerous , or if toxicity is subjected to oligomers , protofibrils or mature aggregates . The facts that the central hydrophobic part of AS is also a constituent of amyloid plaques in Alzheimer ' s disease ( AD ) and that a majority of patients have Lewy bodies and Lewy neurites in specific brain areas raised our interest in the contribution of AS to AD pathogenesis . The N - terminal amino acid sequence 1 - 15 of beta - synuclein ( BS ) seems to be a natural antiaggregation factor for AS . We synthesized a library with different sequence variations . Several of these peptides displayed neuroprotective activity in tissue culture models of neurodegeneration induced by oxidative stress or beta - amyloid 1 - 42 . In spite of the fact that these peptides have a short half - life , a significant in vivo reduction in brain plaque load and improvement of behavior was demonstrated in amyloid precursor protein transgenic mice after intranasal treatment for 2 months . KEGV , the shortest sequence , was also active after intraperitoneal application . The in vitro effects can not be explained by the antiaggregatory potential , but most likely by interaction of BS derivates with antiapoptotic P19957 / Akt or antioxidative pathways . The possibility that BS - derived peptidomimetics act as neuroprotectants and prevent protein misfolding suggests therapeutic usefulness .",
"[ DB01373 signaling mediated by nicotine receptors in neurons ] . DB00184 has many acute and chronic pharmacological effects . DB00184 treatment activates neuronal nicotinic acetylcholine receptors ( nAChR ) in peripheral and central nervous systems leading to depolarization and elevation of intracellular calcium levels , which are considered to cause stimulation of neurotransmitter release , synaptic transmission , intracellular signal transduction and gene expression . Multiple subtypes of nAChRs display different sensitivity to nicotinic agonists and antagonists . Each of these subtypes has a unique distribution in peripheral and central nervous systems . Although presynaptic nAChRs have been extensively studied to modulate the release of neurotransmitters , the functional importance of nAChRs in somata is not sufficiently characterized . To clarify the mechanisms of calcium signaling and its stimulation of gene expression via nAChRs in somata , we have investigated nAChR - mediating calcium signaling mechanisms including phosphorylation of Q8NFH3 / 44 Q96HU1 kinase ( P29323 ) , CREB and Akt in PC12h cells . DB00184 transiently activates phosphorylation of P29323 - , CREB and Akt . DB00184 induces the activation of both P19957 kinase / Act and P29323 / CREB pathways via common pathways including non - alpha 7 - nAChRs , L - type VSCC , P62158 kinase and P00533 in PC12h cells , but Src family tyrosine kinases only participate in the pathway to activate Akt . Based on these results , we discuss nAChR signaling mechanisms in neurons .",
"P04150 interacting protein - 1 restores glucocorticoid responsiveness in steroid - resistant airway structural cells . Glucocorticoid ( GC ) insensitivity represents a profound challenge in managing patients with asthma . The mutual inhibition of transcriptional activity between GC receptor ( GR ) and other regulators is one of the mechanisms contributing to GC resistance in asthma . We recently reported that interferon regulatory factor ( Q969Q1 ) - 1 is a novel transcription factor that promotes GC insensitivity in human airway smooth muscle ( P17405 ) cells by interfering with GR signaling ( Tliba et al . , Am J Respir Cell Mol Biol 2008 ; 38 : 463 - 472 ) . Here , we sought to determine whether the inhibition of GR function by P10914 involves its interaction with the transcriptional co - regulator GR - interacting protein 1 ( Q9Y3R0 ) , a known GR transcriptional co - activator . We here found that siRNA - mediated Q9Y3R0 depletion attenuated P10914 - dependent transcription of the luciferase reporter construct and the mRNA expression of an P10914 - dependent gene , P28907 . In parallel experiments , Q9Y3R0 silencing significantly reduced GR - mediated transactivation activities . Co - immunoprecipitation and Q86UG4 pull - down assays showed that Q9Y3R0 , through its repression domain , physically interacts with P10914 identifying Q9Y3R0 as a bona fide transcriptional co - activator for P10914 . Interestingly , the previously reported inhibition of GR - mediated transactivation activities by either P01375 and P01579 treatment or P10914 overexpression was fully reversed by increasing cellular levels of Q9Y3R0 . Together , these data suggest that the cellular accumulation of P10914 may represent a potential molecular mechanism mediating altered cellular response to GC through the depletion of Q9Y3R0 from the GR transcriptional regulatory complexes .",
"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .",
"Catecholamine - producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti - inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) - positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH - positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type - II arthritis in DBA / 1J mice was induced . RESULTS : TH + cells were present only in inflamed tissue and not in controls . Catecholamine - storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β - adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine - producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti - inflammatory effects in vivo and in vitro .",
"A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not ___MASK8___ , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to ___MASK8___ . Unlike ___MASK8___ , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to ___MASK8___ or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK86___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK86___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"___MASK17___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK17___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK31___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"Novel bioactive metabolites of dipyrone ( metamizol ) . DB04817 is a common antipyretic drug and the most popular non - opioid analgesic in many countries . In spite of its long and widespread use , molecular details of its fate in the body are not fully known . We administered dipyrone orally to mice . Two unknown metabolites were found , viz . the arachidonoyl amides of the known major dipyrone metabolites , 4 - methylaminoantipyrine ( 2 ) and 4 - aminoantipyrine ( 3 ) . They were identified by P19957 - LC - MS / MS after extraction from the CNS , and comparison with reference substances prepared synthetically . The arachidonoyl amides were positively tested for cannabis receptor binding ( CB ( 1 ) and CB ( 2 ) ) and cyclooxygenase inhibition ( P23219 and P35354 in tissues and as isolated enzymes ) , suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain ."
] |
[
"___MASK10___",
"___MASK17___",
"___MASK20___",
"___MASK31___",
"___MASK63___",
"___MASK74___",
"___MASK86___",
"___MASK8___",
"___MASK93___"
] |
___MASK20___
|
MH_train_344
|
interacts_with DB00193?
|
[
"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .",
"DB00193 and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects , but decreased analgesic effects , in genetically deficient serotonin transporter ( P31645 ) mice . The serotonin syndrome is a potential side - effect of serotonin - enhancing drugs , including antidepressants such as selective serotonin reuptake inhibitors ( SSRIs ) and monoamine oxidase inhibitors ( MAOIs ) . We recently reported a genetic mouse model for the serotonin syndrome , as serotonin transporter ( P31645 ) - deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5 - hydroxy - l - tryptophan ( 5 - HTP ) . As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome , we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in P31645 wild - type ( +/+ ) , heterozygous ( +/- ) and knockout ( -/- ) mice . Comparisons were made with P31645 mice treated with either vehicle or morphine , an opioid not implicated in the serotonin syndrome in humans . Here we show that tramadol and meperidine , but not morphine , induce serotonin syndrome - like behaviours in mice , and we show that this response is exaggerated in mice lacking one or two copies of P31645 . The exaggerated response to tramadol in P31645 -/- mice was blocked by pretreatment with the P08908 antagonist WAY 100635 . Further , we show that morphine - , meperidine - and tramadol - induced analgesia is markedly decreased in P31645 -/- mice . These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side - effects may occur during concurrent use of tramadol and similar agents . These findings suggest that it is conceivable that there might be increased vulnerability in individuals with P31645 polymorphisms that may reduce P31645 by more than 50 % , the level in P31645 +/- mice .",
"P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time .",
"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .",
"___MASK54___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK54___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"Dexamethasone reverses adrenalectomy - induced neuronal de - differentiation in midbrain raphe - hippocampus axis . Differentiation leads to specific morphological and biochemical characteristics . We examined whether epigenetic factors ( e . g . , glucocorticoids ) are required to maintain neuronal differentiation in the adult brain . In the midbrain , adrenalectomy ( P10109 ) ( 1 - 2 wk ) reduced the size of tryptophan hydroxylase ( WH ) - immunoreactive ( IR ) neurons . P10109 rats exposed to short - term ( 24 - 72 - h ) dexamethasone ( ST - DEX ) in the drinking saline ( 10 mg / l ) showed an increase in WH protein , somal area and dendritic size of WH - IR neurons . In the hippocampus , P10109 for 2 - 3 mo ( long - term ; LT ) reduced Nissl staining , calbindin ( DB09061 ) - IR and P08908 receptor mRNA in the granular cell layer , and the size of the molecular layer and its DB09061 - IR dendrites . Small vimentin ( Vim ) - IR glial cells emerged in the granular layer . ST - DEX after LT - P10109 rapidly induced a recovery of P08908 mRNA , Nissl labeling and DB09061 - IR in the granule cell layer . In the molecular layer , there was an increase in the area and in the number of DB09061 - IR dendrites . Furthermore , the Vim - IR glial cells were enlarged in size and branching . The rate of cell proliferation was studied in these animals . Immunostaining with antibodies against proliferating cell nuclear antigen ( P12004 ) and use of bromouridine argue against enhanced neurogenesis after ST - DEX in LT - P10109 . We propose that glucocorticoids induce and maintain differentiation of serotonergic and DB09061 - IR neurons in the midbrain - hippocampal axis . A neuronotrophic role for the glial P08908 receptor is suggested .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK93___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence . Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations . Using a case - control design this study ' s purpose was to explore , among a population of methamphetamine - dependent Caucasians , six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations . A total of 193 non - psychotic males ( 117 methamphetamine - dependent and 76 controls ) were genotyped for variants located in six genes ( P31749 , P32121 , P23560 , P21964 , P09211 , P35372 ) . Genotypic and allelic frequencies , odds ratios , and 95 % confidence intervals were calculated . None of the putative gene associations was significantly replicated in our sample of Caucasian men . Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 ( P32121 ) and glutathione S - transferase P1 ( P09211 ) and allelic convergence for brain - derived neurotrophic factor ( P23560 ) . Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms ( SNPs ) for methamphetamine ( METH ) dependence reported among Asian populations across other ethnic / ancestral groups .",
"Differential expression of the alternatively spliced P35372 isoform μ - opioid receptor - 1K in HIV - infected individuals . OBJECTIVE : We previously examined the expression of specific C - terminal μ - opioid receptor ( MOR ) splice variants in human central nervous system cell types and HIV - infected brain tissue from individuals with neurocognitive impairment ± HIV encephalitis ( HIVE ) . In the present study , we examined the N - terminal splice variant MOR - 1K , which mediates excitatory cellular signaling . METHODS AND RESULTS : We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C - terminal MOR splice variants using the real - time polymerase chain reaction ( RT - PCR ) . Expression of MOR - 1K mRNA was also increased in HIV - infected individuals with combined neurocognitive impairment and HIVE compared with the other groups . MOR - 1K expression correlated with the level of patient neurocognitive impairment , whereas the pool of C - terminal MOR splice variants did not . HIVE was also associated with increased expression of the inflammatory mediators P13500 , P80075 , and RANTES , but not the host HIV coreceptors P61073 and P51681 or the P01730 receptor using qRT - PCR . Network analysis of microarray data from these same patients revealed filamin A ( P21333 ) as a possible interaction partner with MOR - 1K , and P21333 gene expression was also found to be upregulated in HIVE using qRT - PCR . Overexpression of P21333 in HEK293 cells redistributed MOR - 1K from intracellular compartments to the cell surface . CONCLUSION : These results suggest that HIVE , and neurocognitive impairment depending on its severity , are associated with enhanced MOR - 1K signaling through both increased expression and trafficking to the cell surface , which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS .",
"Inhibition of Akt / P31749 by a P35354 inhibitor induces apoptosis in gastric cancer cells . BACKGROUND / AIM : Inhibition of cyclooxygenase - 2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti - inflammatory drugs . This study investigates the mechanisms by which the cyclooxygenase - 2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway . METHODS : Two gastric cancer cell lines , AGS and MKN28 , were treated with SC236 and assessed for cell growth and apoptosis . The involvement of mitogen - activated protein kinase and Akt kinase / protein kinase B ( Akt / P31749 ) pathways and their downstream signalings were studied in the AGS cell line . RESULTS : SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress - activated protein kinase / jun kinase , but down - regulated Akt / P31749 . The specific p38 inhibitor SB203580 and the dominant - negative stress - activated protein kinase / jun kinase both failed , while the constitutively active form of Akt / P31749 was able to block SC236 - induced apoptosis . SC236 - induced apoptosis was coupled with release of cytochrome c and activation of caspases . CONCLUSION : One of the pathways involved in SC - 236 - induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c .",
"Role of serotonin in the regulation of interferon - gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter - current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon - gamma ( P01579 ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time - dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 mRNA in the presence of elutriated monocytes . Monocyte - induced inhibition of P01579 production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 production in the presence of monocytes . We conclude that serotonergic P08908 receptors transduce signals that are required for NK cells to produce P01579 in response to P60568 .",
"Activation of P08908 receptors expressed in NIH - 3T3 cells induces focus formation and potentiates P01133 effect on DNA synthesis . NIH - 3T3 fibroblasts have been transfected with human serotonin P08908 receptors . Clonal cell lines expressed between 40 and 500 fmol receptor / mg . P08908 agonists strongly inhibited nonstimulated - as well as forskolin - or isoproterenol - stimulated adenylyl cyclase . The effects of P08908 receptor activation on cell growth were investigated . P08908 agonists accelerated cell division , generated foci , and increased DNA synthesis . The stimulation of [ 3H ] thymidine incorporation was much stronger when tyrosine kinase receptors were activated concomitantly . DB02527 ( DB02527 ) elevating agents inhibited DNA synthesis induced by all mitogens tested . The mitogenic activity of P08908 agonists did not seem to be linked to adenylyl cyclase inhibition because 1 ) we were not able to measure any decrease in intracellular DB02527 levels under the conditions of DNA synthesis assay and 2 ) 2 ', 5 '- dideoxyadenosine , which strongly inhibited adenylyl cyclase , was not mitogenic and did not modify the mitogenic effects of P08908 agonists . Pertussis toxin completely blocked potentiation of epidermal growth factor effect induced by 8 - hydroxy - di -( n - propyl ) aminotetralin , a P08908 agonist , but only partially blocked the one induced by insulin . In conclusion , in transfected NIH - 3T3 cells , transforming and mitogenic effects of P08908 agonists involve a pertussis toxin - sensitive G protein but do not seem to be linked to adenylyl cyclase inhibition .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK42___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK42___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK42___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK42___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK42___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK42___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK42___ .",
"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .",
"___MASK27___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK93___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK15___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Molecular basis of functional gastrointestinal disorders . There are a number of abnormalities of gastrointestinal function , including sensory and motor dysfunction , which are believed to play a role in the manifestation of symptoms in patients with functional gastrointestinal disorders ( FGID ) . In addition , there is a remarkable psychiatric comorbidity . Family and twin studies have provided strong evidence for a clustering of FGID in families and an increased concordance in monozygotic compared to dizygotic twins . This points towards the role of one or more hereditary ( genetic ) factors . Considering these disorders of function and the psychiatric comorbidity , polymorphisms of adrenergic , opioidergic or serotonergic receptors as well as G - protein beta3 ( P16520 ) subunit gene polymorphisms ( C825T ) and polymorphisms of 5 - HT transporter genes are suitable causes . In addition , mediators or regulators of mucosal inflammation may trigger events that ultimately result in the manifestation of FGID . Thus , relevant polymorphisms of genes with immunmodulating and / or neuromodulating features ( P35372 , P05112 , IL - 4R , TNFalpha ) may also play a role in the manifestation of FGIDs .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK4___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"FK506 - binding protein 12 modulates μ - opioid receptor phosphorylation and protein kinase C ( ε )- dependent signaling by its direct interaction with the receptor . Protein kinase C ( PKC ) activation plays an important role in morphine - induced μ - opioid receptor ( P35372 ) desensitization and tolerance development . It was recently shown that receptor phosphorylation by G protein - coupled receptor kinase regulates agonist - dependent selective signaling and that inefficient phosphorylation of P35372 leads to PKCε activation and subsequent responses . Here , we demonstrate that such receptor phosphorylation and PKCε activation can be modulated by FK506 - binding protein 12 ( P62942 ) . Using a yeast two - hybrid screen , P62942 was identified as specifically interacting with P35372 at the Pro ( 353 ) residue . In human embryonic kidney 293 cells expressing P35372 , the association of P62942 with P35372 decreased the agonist - induced receptor phosphorylation at DB00133 ( 375 ) . The morphine - induced PKCε activation and the recruitment of PKCε to the P35372 signaling complex were attenuated both by P62942 short interfering RNA ( siRNA ) treatment and in cells expressing P35372 with a P353A mutation ( OPRM1P353A ) , which leads to diminished activation of PKC - dependent extracellular signal - regulated kinases . Meanwhile , the overexpression of P62942 enabled etorphine to activate PKCε . Further analysis of the receptor complex demonstrated that morphine treatment enhanced the association of P62942 and calcineurin with the receptor . The blockade of the P62942 association with the receptor by the siRNA - mediated knockdown of endogenous P62942 or the mutation of Pro ( 353 ) to Ala resulted in a reduction in PKCε and calcineurin recruitment to the receptor signaling complex . The receptor - associated calcineurin modulates P35372 phosphorylation , as demonstrated by the ability of the calcineurin autoinhibitory peptide to increase the receptor phosphorylation . Thus , the association of P62942 with P35372 attenuates the phosphorylation of the receptor and triggers the recruitment and activation of PKCε .",
"P35372 - dependent and independent components in effects of tramadol . DB00193 is thought to induce analgesia via both opioid and non - opioid pathways , although the precise mechanisms remain to be elucidated . In this study , we investigated the roles of the mu - opioid receptor ( MOP ) in analgesic and rewarding effects of tramadol by using MOP knockout ( KO ) mice . DB00193 - induced antinociception , assessed by hot - plate and tail - flick tests , was significantly reduced in heterozygous and homozygous MOP - KO mice when compared with that in wild - type mice . Interestingly , however , tramadol retained its ability to induce significant antinociception in homozygous MOP - KO mice . The tramadol - induced antinociception remaining in homozygous MOP - KO mice was not significantly affected by methysergide , a serotonin receptor antagonist , but was partially blocked by yohimbine , an adrenaline alpha2 receptor antagonist , and both naloxone , a non - selective opioid receptor antagonist , and yohimbine . In addition , antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP - KO mice . On the other hand , neither wild - type nor homozygous MOP - KO mice showed significant place preference for tramadol in a conditioned place preference test , although there were slight tendencies toward preference in wild - type mice and avoidance in homozygous MOP - KO mice . These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha2 receptor mediate most of the analgesic properties of tramadol .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK27___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"P35372 expression is increased in inflammatory bowel diseases : implications for homeostatic intestinal inflammation . BACKGROUND AND AIMS : Recent studies with mu opioid receptor ( MOR ) deficient mice support a physiological anti - inflammatory effect of MOR at the colon interface . To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases ( Q9UKU7 ) , we ( 1 ) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation ; and ( 2 ) tested the potential anti - inflammatory function of a specific opiate ( DALDA ) in inflamed and resting human mucosa . PATIENTS AND METHODS : Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues , isolated peripheral blood mononuclear cells and purified monocytes , and P01730 + and CD8 + T cells from healthy donors and Q9UKU7 patients . The effect of cytokines and nuclear factor kappaB ( NFkappaB ) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed . Finally , DALDA induced anti - inflammatory effect was investigated in mucosal explants from controls and Q9UKU7 patients . RESULTS : MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and P01730 + and CD8 + T cells . Overexpressed in active Q9UKU7 mucosa , MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines . Furthermore , ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active Q9UKU7 patients . CONCLUSIONS : Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active Q9UKU7 , natural and / or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK19___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Loss of the mu opioid receptor on different genetic backgrounds leads to increased bromodeoxyuridine labeling in the dentate gyrus only after repeated injection . The endogenous opioid system is involved in various physiological processes , including neurogenesis in the dentate gyrus ( DG ) of the hippocampus . In the current study , we investigated the role of the mu opioid receptor ( P35372 ) on DG neurogenesis and measured glucocorticoid levels following several injection paradigms to supplement the neurogenesis experiments . P35372 knockout ( KO ) mice on C57BL / 6 and 129S6 backgrounds were injected with bromodeoxyuridine ( BrdU ) using either a single injection or two different repeated injection protocols and then sacrificed at different time points . The total number of BrdU and proliferating cell nuclear antigen ( P12004 ) positive cells in the DG is significantly increased in P35372 KO mice compared with wild type ( WT ) on both strains after repeated injection , but not after a single injection . Plasma corticosterone ( O00230 ) levels increased similarly in P35372 KO and WT mice following both single and repeated injection , indicating that the stress response is activated following any injection protocol , but that the mechanism responsible for the increase in BrdU labeling in P35372 KO mice is O00230 - level independent . Finally , WT 129S6 mice , independent of genotype , showed higher levels of plasma O00230 compared with WT C57BL / 6 mice in both noninjected controls and following injection at two separate time points ; these levels were inversely correlated with low numbers of BrdU cells in the DG in 129S6 mice compared with C57BL / 6 mice . In summary , these data demonstrate that loss of P35372 increases BrdU labeling in the DG independent of O00230 levels , but only following a repeated injection , illustrating the capability of injection paradigms to influence cell - proliferative responses in a genotype - dependent manner .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK26___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK5___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Presynaptic serotonergic inhibition of GABAergic synaptic transmission in mechanically dissociated rat basolateral amygdala neurons . 1 . The basolateral amygdala ( P00519 ) nuclei contribute to the process of anxiety . GABAergic transmission is critical in these nuclei and serotonergic inputs from dorsal raphe nuclei also significantly regulate GABA release . In mechanically dissociated rat P00519 neurons , spontaneous miniature inhibitory postsynaptic currents ( mIPSCs ) arising from attached GABAergic presynaptic nerve terminals were recorded with the nystatin - perforated patch method and pharmacological isolation . 2 . 5 - HT reversibly reduced the GABAergic mIPSC frequency without affecting the mean amplitude . The serotonergic effect was mimicked by the P08908 specific agonist 8 - OH DPAT ( 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ) and blocked by the P08908 antagonist spiperone . 3 . The GTP - binding protein inhibitor N - ethylmaleimide removed the serotonergic inhibition of mIPSC frequency . In either K +- free or Ca2 +- free external solution , 5 - HT could inhibit mIPSC frequency . 4 . High K + stimulation increased mIPSC frequency and 8 - OH DPAT inhibited this increase even in the presence of Cd2 + . 5 . DB02587 , an activator of adenylyl cyclase ( AC ) , significantly increased synaptic GABA release frequency . Pretreatment with forskolin prevented the serotonergic inhibition of mIPSC frequency in both the standard and high K + external solution . 6 . Ruthenium Red ( RR ) , an agent facilitating the secretory process in a Ca2 +- independent manner , increased synaptic GABA release . 5 - HT also suppressed RR - facilitated mIPSC frequency . 7 . We conclude that 5 - HT inhibits GABAergic mIPSCs by inactivating the AC - DB02527 signal transduction pathway via a G - protein - coupled P08908 receptor and this intracellular pathway directly acts on the GABA - releasing process independent of K + and Ca2 + channels in the presynaptic nerve terminals ."
] |
[
"___MASK15___",
"___MASK19___",
"___MASK26___",
"___MASK27___",
"___MASK42___",
"___MASK4___",
"___MASK54___",
"___MASK5___",
"___MASK93___"
] |
___MASK27___
|
MH_train_345
|
interacts_with DB00831?
|
[
"[ P62158 - dependent regulation of Ca , Mg - ATPase activity in plasma membranes of the swine myometrium ] . Highly purified plasma membrane ( PM ) preparations of pig myometrium were found to contain 0 . 91 +/- 0 . 22 microgram calmodulin per mg of PM protein . Treatment of membranes with 1 mM EGTA in the presence of 0 . 2 M NaCl causes the diminution of the calmodulin content down to 3 % of the original level . The activity of Ca , Mg - ATPase is thereby decreased by 40 % . Exogenous calmodulin restores the enzyme activity up to 1 . 94 +/- +/- 0 . 30 mumol Pi / mg protein / hour . The maximal activation of Ca , Mg - ATPase is observed with 10 (- 7 ) M calmodulin . P62158 increases the total ATPase activity of myometrium PM without affecting the Mg - ATPase activity . DB00831 ( 20 microM ) diminishes the activating effect of exogenous calmodulin on Ca , Mg - ATPase . P62158 stimulates Ca , Mg - ATPase at low concentrations of Ca2 + ( 10 (- 8 )- 10 (- 6 ) M ) by decreasing Km for Ca2 + from 0 . 4 . 10 (- 6 ) M to 2 . 10 (- 8 ) M as well as by increasing Vmax -- from 0 , 8 to 1 . 42 mumol Pl / mg protein / hour . It is supposed that the activating effect of calmodulin on Ca , Mg - ATPase is based on electrostatic interactions of Ca2 +- free calmodulin with the enzyme .",
"___MASK100___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .",
"Stimulation of type 1 and type 8 Ca2 +/ calmodulin - sensitive adenylyl cyclases by the Gs - coupled 5 - hydroxytryptamine subtype 5 - HT7A receptor . The neurotransmitter serotonin ( 5 - hydroxytryptamine , 5 - HT ) plays an important regulatory role in developing and adult nervous systems . With the exception of the 5 - Q9H205 receptor , all of the cloned serotonin receptors belong to the G protein - coupled receptor superfamily . Subtypes P50406 and P34969 couple to stimulation of adenylyl cyclases through Gs and display high affinities for antipsychotic and antidepressant drugs . In the brain , mRNA for P50406 is found at high levels in the hippocampus , striatum , and nucleus accumbens . P34969 mRNA is most abundant in the hippocampus , neocortex , and hypothalamus . To better understand how serotonin might control DB02527 levels in the brain , we coexpressed P50406 or 5 - HT7A receptors with specific isoforms of adenylyl cyclase in P29320 293 cells . The P50406 receptor functioned as a typical Gs - coupled receptor in that it stimulated O95622 , a Gs - sensitive adenylyl cyclase , but not Q99440 or P40145 , calmodulin ( P62158 ) - stimulated adenylyl cyclases that are not activated by Gs - coupled receptors in vivo . Surprisingly , serotonin activation of 5 - HT7A stimulated Q99440 and P40145 by increasing intracellular Ca2 + . 5 - HT also increased intracellular Ca2 + in primary neuron cultures . These data define a novel mechanism for the regulation of intracellular DB02527 by serotonin .",
"Recombinant human prothrombin kringles have potent anti - angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases . P00734 , a protein involved in blood coagulation , is a plasma glycoprotein composed of the Gla domain , two adjacent kringle domains , and a serine protease domain . Kringles are triple - disulfide - loop folding domains , which are found in several other blood proteins . In this study , we showed that recombinant human prothrombin kringle - 1 , - 2 . and - 1 - 2 ( rk - 1 , - 2 , - 1 - 2 ) all have potent anti - angiogenic activities , which inhibit Lewis lung carcinoma ( LLC ) tumor growth and metastases . Recombinant human prothrombin kringles were expressed by an E . coli expression system and purified to apparent homogeneity from crude E . coli extracts . Purified rk - 1 , - 2 , - 1 - 2 migrated with a molecular mass of 14 , 19 , and 31 kDa , respectively , on sodium dodecyl sulfate - polyacrylamide gel electrophoresis ( SDS - PAGE ) under reducing conditions . rk - 1 , - 2 , - 1 - 2 exhibited potent inhibitory effects on P09038 - stimulated bovine capillary endothelial cell growth with half - maximal concentrations ( ED50 ) of approximately 41 , 55 , and 156 nM , respectively . All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane ( P62158 ) of chick embryos at a dose of 20 microg . Systemic administration of rk - 1 , - 2 , - 1 - 2 at a dose of 0 . 5 mg / kg / day suppressed the growth of primary LLC and at dose of 0 . 5 and 1 . 0 mg / kg / day inhibited LLC metastases in C57BL6 / J mice lungs through their anti - angiogenic effects .",
"Independent regulation of cyclo - oxygenase 2 expression by Q8NFH3 / 44 mitogen - activated protein kinases and Ca2 +/ calmodulin - dependent kinase . 5 - Hydroxytryptamine ( 5 - HT , ' serotonin ' ) is a potent inducer of the early response gene cyclo - oxygenase 2 ( Cox - 2 ; prostaglandin G / H synthase ) in mesangial cells . Protein kinase C ( PKC ) , Ca2 +- dependent enzymes and mitogen - activated protein kinase ( Q8NFH3 / 44 MAPK ) have previously been shown to be essential modules of the signalling pathway leading from the pertussis - insensitive 5 - Q13049 receptor to the induction of Cox - 2 mRNA expression . In the present study , PKC activation was linked to the 5 - HT - mediated phosphorylation and thus the activation of Q8NFH3 / 44 MAPK : the inhibition of PKC by the specific inhibitor GF109203x prevented Q8NFH3 / 44 MAPK activation . Ca2 +/ calmodulin - dependent ( P62158 ) kinase II delta2 was detected in mesangial cells by Western blot analysis . The inhibition of P62158 kinase by the inhibitors KN62 or KN93 led to a partial inhibition of 5 - HT - induced Cox - 2 mRNA expression and decreased basal , but not PMA - mediated , Cox - 2 expression . The 5 - HT - mediated activation of MAPK was not decreased by KN62 or KN93 , excluding P62158 kinase as a signalling module upstream of Q8NFH3 / 44 MAPK . Taken together , these results indicate a modulatory involvement of P62158 kinase in the regulation of 5 - HT - mediated Cox - 2 mRNA expression in addition to the main pathway that consists of the activation of PKC and Q8NFH3 / 44 MAPK .",
"Peptide - mediated disruption of calmodulin - cyclin E interactions inhibits proliferation of vascular smooth muscle cells and neointima formation . RATIONALE : Cell cycle progression in vascular smooth muscle cells ( VSMCs ) is a therapeutic target for restenosis . OBJECTIVE : Having discovered that calmodulin ( P62158 ) - dependent cyclin E / P24941 activity underlies Ca ( 2 +)- sensitive G ( 1 )- to - S phase transitions in VSMCs , we sought to explore the physiological importance of the P62158 - cyclin E interaction . METHODS AND RESULTS : A peptide based on the P62158 binding sequence ( P35520 ) of cyclin E was designed to interfere with P62158 - cyclin E binding . Compared with control peptides , P35520 blocked activating Thr160 phosphorylation of P24941 , decreased basal cyclin E / P24941 activity , and eliminated Ca ( 2 +)- sensitive cyclin E / P24941 activity in nuclear extracts from mouse VSMCs . Nucleofection with P35520 , or treatment with P35520 conjugated to the HIV - 1 TAT protein transduction domain to improve bioavailability , inhibited G ( 1 )- to - S cell cycle progression in a dose - dependent manner . These effects were not observed with control peptides . TAT - P35520 inhibited ( 3 ) H - thymidine incorporation in primary human aortic SMCs ( HA - SMCs ) in vitro , manifested greater transduction into HA - SMCs compared with endothelial cells in vitro , and limited decreased SM22α expression , neointima formation , and medial thickening without affecting collagen deposition or reendothelialization in a mouse model of carotid artery injury in vivo . The antiproliferative effects of P35520 remained evident in mouse embryonic fibroblasts derived from wild - type mice but not cyclin E1 / E2 double knockout mice . CONCLUSIONS : A synthetic peptide designed to disrupt P62158 - cyclin E binding inhibits Ca ( 2 +)/ P62158 - dependent P24941 activity , cell cycle progression , and proliferation in VSMCs and limits arterial remodeling following injury . Importantly , this effect appears to be cyclin E - dependent and may form the basis of a potentially novel therapeutic approach for restenosis .",
"Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2 + , calmodulin , DB02527 , the catalytic subunit of DB02527 - dependent protein kinase ( CSU ) and some Ca2 + antagonists were studied in chemically ( Triton X - 100 ) skinned coronary smooth muscle . P62158 increased the Ca2 + responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half - maximal activating Ca2 + concentration . DB00831 , a calmodulin antagonist , inhibited Ca2 +- calmodulin - induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2 + concentration . DB08980 , a Ca2 +- antagonist , at 2 x 10 (- 4 ) M produced a significant inhibitory effect , which was reduced by increasing the Ca2 + concentration . From other Ca2 + antagonists tested , W - 7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2 + , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK15___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK66___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .",
"P06850 - induced adrenocorticotropin hormone release and synthesis is blocked by incorporation of the inhibitor of cyclic AMP - dependent protein kinase into anterior pituitary tumor cells by liposomes . P06850 ( CRF ) is the most potent and effective natural stimulant of corticotropin ( DB01285 ) secretion . In a tumor cell line of the mouse anterior pituitary ( AtT - 20 / D16 - 16 ) consisting of a homogeneous population of corticotrophs , CRF is known to increase adenylate cyclase and DB02527 - dependent protein kinase activities as well as to release DB01285 . To determine whether activation of DB02527 - dependent protein kinase is essential for CRF to evoke the secretion of DB01285 , an inhibitor ( PKI ) of this kinase was inserted into AtT - 20 cells . This was accomplished by first encapsulating PKI into liposomes and then covalently coupling them to protein A for binding to antibodies directed against an AtT - 20 cell surface antigen , N - P62158 ( neural cell adhesion molecule ) . The binding of the liposomes to the anti - N - P62158 antibodies led to the internalization of the PKI into the tumor cells . The PKI treatment greatly attenuated CRF - stimulated DB01285 release as well as the secretory response to beta - adrenergic agonists . However , DB01285 release in response to caerulein , an agonist of cholecystokinin 8 receptors , was not altered by the PKI treatment . CRF treatment also increased the levels of mRNA for proopiomelanocortin ( P01189 ) , the precursor for DB01285 in AtT - 20 cells . Application of liposomes containing PKI to AtT - 20 cells blocked the ability of CRF and 8 - bromo - DB02527 , but not phorbol ester , to increase P01189 mRNA levels . The results revealed an essential role for DB02527 in mediating the effect of CRF on DB01285 release and P01189 gene expression .",
"Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 - mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator - activated receptor - gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) - induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 - induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro - angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0 . 001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0 . 001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti - angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients .",
"Discovery and structure - activity relationship of ( 1R ) - 8 - chloro - 2 , 3 , 4 , 5 - tetrahydro - 1 - methyl - 1H - 3 - benzazepine ( ___MASK87___ ) , a selective serotonin P28335 receptor agonist for the treatment of obesity . The synthesis and SAR of a novel 3 - benzazepine series of P28335 agonists is described . Compound 7d ( lorcaserin , APD356 ) was identified as one of the more potent and selective compounds in vitro ( pEC50 values in functional assays measuring [( 3 ) H ] phosphoinositol turnover : P28335 = 8 . 1 ; 5 - Q13049 = 6 . 8 ; P41595 = 6 . 1 ) and was potent in an acute in vivo rat food intake model upon oral administration ( ED50 at 6 h = 18 mg / kg ) . ___MASK87___ was further characterized in a single - dose pharmacokinetic study in rat ( t1 / 2 = 3 . 7 h ; F = 86 % ) and a 28 - day model of weight gain in growing Sprague - Dawley rat ( 8 . 5 % decrease in weight gain observed at 36 mg / kg b . i . d . ) . ___MASK87___ was selected for further evaluation in clinical trials for the treatment of obesity .",
"___MASK62___ binding to human and rat dopamine and 5 - HT receptors . ___MASK62___ ( ___MASK62___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK62___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK62___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK62___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK73___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"___MASK19___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK19___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK44___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"P16035 fusion protein with human serum albumin potentiates anti - angiogenesis - mediated inhibition of tumor growth by suppressing P08253 expression . P16035 protein has been intensively studied as a promising anticancer candidate agent , but the in vivo mechanism underlying its anticancer effect has not been clearly elucidated by previous works . In this study , we investigated the mechanism underlying the anti - tumor effects of a P16035 fusion protein conjugated with human serum albumin ( HSA / P16035 ) . Systemic administration of HSA / P16035 effectively inhibited tumor growth at a minimum effective dose of 60 mg / kg . The suppressive effect of HSA / P16035 was accompanied by a marked reduction of in vivo vascularization . The anti - angiogenic activity of HSA / P16035 was directly confirmed by P62158 assays . In HSA / P16035 - treated tumor tissues , P08253 expression was profoundly decreased without a change in P50281 expression of P16284 - positive cells . P08253 mRNA was also decreased by HSA / P16035 treatment of human umbilical vein endothelial cells . Zymographic analysis showed that HSA / P16035 substantially decreased extracellular pro - P08253 activity ( 94 - 99 % reduction ) and moderately decreased active P08253 activity ( 10 - 24 % reduction ) , suggesting P50281 - independent P08253 modulation . Furthermore , HSA / P16035 had no effect on in vitro active P08253 activity and in vivo P08253 activity . These studies show that HSA / P16035 potentiates anti - angiogenic activity by modulating P08253 expression , but not P08253 activity , to subsequently suppress tumor growth , suggesting an important role for P08253 expression rather than P08253 activity in anti - angiogenesis .",
"P62158 interacts with the platelet ADP receptor P47900 . P47900 [ P2 ( purinergic type - 2 ) - receptor 1 ] is a G - protein - coupled ADP receptor that regulates platelet activation and ADP - induced Ca2 + signalling . Studies using P47900 - knockout mice , G ( q )- deficient mice or P47900 - selective inhibitors have previously identified a key role for P47900 in pathophysiological thrombus formation at high shear stress . We provide evidence that a positively charged juxtamembrane sequence within the cytoplasmic C - terminal tail of P47900 can bind directly to the cytosolic regulatory protein calmodulin . Deletion by mutagenesis of the calmodulin - binding domain of P47900 inhibits intracellular Ca2 + flux in transfected cells . These results suggest that the interaction of calmodulin with the P47900 C - terminal tail may regulate P47900 - dependent platelet aggregation .",
"___MASK83___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response ."
] |
[
"___MASK100___",
"___MASK15___",
"___MASK19___",
"___MASK44___",
"___MASK62___",
"___MASK66___",
"___MASK73___",
"___MASK83___",
"___MASK87___"
] |
___MASK87___
|
MH_train_346
|
interacts_with DB00275?
|
[
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK66___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK5___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"___MASK59___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK59___ is the first of a new class of antihypertensive agents . ___MASK59___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK59___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Cooperative regulation of extracellular signal - regulated kinase activation and cell shape change by filamin A and beta - arrestins . beta - Arrestins ( betaarr ) are multifunctional adaptor proteins that can act as scaffolds for G protein - coupled receptor activation of mitogen - activated protein kinases ( MAPK ) . Here , we identify the actin - binding and scaffolding protein filamin A ( P21333 ) as a betaarr - binding partner using Son of sevenless recruitment system screening , a classical yeast two - hybrid system , coimmunoprecipitation analyses , and direct binding in vitro . In P21333 , the betaarr - binding site involves tandem repeat 22 in the carboxyl terminus . betaarr binds P21333 through both its N - and C - terminal domains , indicating the presence of multiple binding sites . We demonstrate that betaarr and P21333 act cooperatively to activate the MAPK extracellular signal - regulated kinase ( P29323 ) downstream of activated muscarinic M1 ( M1MR ) and angiotensin II type 1a ( P30556 ) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr - P28482 complex formation by P21333 . In Hep2 cells , stimulation of M1MR or P30556 results in the colocalization of receptor , betaarr , P21333 , and active P29323 in membrane ruffles . Reduction of endogenous levels of betaarr or P21333 and a catalytically inactive dominant negative Q02750 , which prevents P29323 activation , inhibit membrane ruffle formation , indicating the functional requirement for betaarr , P21333 , and active P29323 in this process . Our results indicate that betaarr and P21333 cooperate to regulate P29323 activation and actin cytoskeleton reorganization .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK47___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK47___ who were treated with a single dose of mifepristone .",
"Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK38___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Angiotensin II ( ATII ) - inducible platelet - derived growth factor A - chain gene expression is Q8NFH3 / 44 extracellular signal - regulated kinase - 1 / 2 and Egr - 1 - dependent and mediated via the ATII type 1 but not type 2 receptor . Induction by ATII antagonized by nitric oxide . Angiotensin II ( ATII ) and platelet - derived growth factor ( PDGF ) are two vasoconstrictors implicated in the maintenance of normal vascular homeostasis . PDGF A - chain levels increase in cultured vascular smooth muscle cells ( SMCs ) exposed to ATII . The molecular mechanisms underlying this induction are not known . We used transient transfection analysis to show that ATII can increase reporter gene activity driven by fragments of the PDGF - A promoter bearing recognition elements for the transcription factor , Egr - 1 . Nuclear run - off experiments indicate that ATII induces Egr - 1 expression at the level of transcription . Gel shift and supershift studies show that Egr - 1 protein accumulates in the nuclei of SMCs exposed to ATII and binds to the proximal region of the PDGF - A promoter in a specific , time - dependent manner . ATII induced extracellular - signal regulated kinase ( Q8NFH3 / 44 P29323 ) activity as did phorbol 12 - myristate 13 - acetate . The specific Q02750 / 2 inhibitor , PD98059 , suppressed both PDGF - A and Egr - 1 endogenous and promoter - dependent expression inducible by ATII . The ATII type 1 receptor ( AT1 ) antagonist , Losartan , inhibited ATII - induction of Q8NFH3 / 44 P29323 , as well as Egr - 1 and PDGF - A , whereas neither PD123319 , an P50052 receptor antagonist , nor wortmannin , an inhibitor of phosphatidylinositol 3 - kinase and c - Jun N - terminal kinase , had any effect . ATII - induction of Egr - 1 and PDGF - A was blocked by SIN - 1 , a NO donor . In addition , this pathway was blocked by overexpression of NO synthase . Collectively , these findings demonstrate that ATII activation of the PDGF - A promoter is mediated via the MEK / P29323 / Egr - 1 pathway and AT1 receptor and that this process is antagonized by NO .",
"Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early - stage type - 2 diabetics with hypertension . P30556 blockers ( ARBs ) are regarded as first - line treatments for type - 2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open - label prospective crossover study , we compared the effects of olmesartan ( 20 mg / day ) and telmisartan ( 40 mg / day ) . Twenty Japanese early - stage type - 2 diabetes patients with hypertension treated with valsartan ( 80 mg / day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg / day ) or telmisartan ( 40 mg / day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24 - h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . DB00275 lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA1c and adiponectin , the decreases in serum interleukin - 6 and highly sensitive P02741 were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti - inflammatory effects than telmisartan .",
"P00797 - angiotensin system revisited . New components and functions of the renin - angiotensin system ( DB01367 ) are still being unravelled . The classical DB01367 as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin - converting enzyme ( P12821 ) . Ang II , still considered the main effector of DB01367 was believed to act only as a circulating hormone via angiotensin receptors , AT1 and P50052 . Since then , an expanded view of DB01367 has gradually emerged . Local tissue DB01367 systems have been identified in most organs . Recently , evidence for an intracellular DB01367 has been reported . The new expanded view of DB01367 therefore covers both endocrine , paracrine and intracrine functions . Other peptides of DB01367 have been shown to have biological actions ; angiotensin 2 - 8 heptapeptide ( Ang III ) has actions similar to those of Ang II . Further , the angiotensin 3 - 8 hexapeptide ( Ang IV ) exerts its actions via insulin - regulated amino peptidase receptors . Finally , angiotensin 1 - 7 ( Ang 1 - 7 ) acts via mas receptors . The discovery of another Q9BYF1 was an important complement to this picture . The recent discovery of renin receptors has made our view of DB01367 unexpectedly complex and multilayered . The importance of DB01367 in cardiovascular disease has been demonstrated by the clinical benefits of P12821 inhibitors and AT1 receptor blockers . Great expectations are now generated by the introduction of renin inhibitors . Indeed , DB01367 regulates much more and diverse physiological functions than previously believed .",
"p300 regulates p63 transcriptional activity . The transcriptional co - activator p300 has been reported to regulate the tumor suppressor p53 and its ortholog p73 . Here we describe a study showing that this coactivator also regulates the transcriptional function of p63 . p300 bound to the N - terminal domain of p63gamma , and p63gamma bound to the N terminus of p300 in vitro and in cells . p300 , but not its acetylase - defective mutant P50052 , stimulated p63gamma - dependent transcription and induction of P38936 in cells , consequently leading to P55008 arrest . Inversely , the deltaN - p63gamma isoform as well as p300AT2 inhibited the induction of P38936 by p63gamma . These results suggest that p300 regulates p63 - dependent transcription of P38936 .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Blockade of P30556 reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation . Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease ( CKD ) associated with metabolic syndrome . The aim of this study was to determine the effects of treatment with angiotensin II ( Ang II ) type - 1 receptor blocker ( ARB ) on the regulation of adipocytokines . DB00275 , an ARB , significantly blunted the age - and body weight - associated falls in plasma adiponectin both in genetically and diet - induced obese mice , without affecting body weight , but had no effect on plasma adiponectin levels in lean mice . DB00275 also ameliorated dysregulation of adipocytokines in obesity , such as tumor necrosis factor - alpha , plasminogen activator inhibitor - 1 , monocyte chemotactic protein - 1 , and serum amyloid A3 . DB00275 significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue . In cultured adipocytes , olmesartan acted as an antioxidant and improved adipocytokine dysregulation . Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated , at least in part , by targeting oxidative stress in obese adipose tissue . Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome - based CKD .",
"Expression of renin - angiotensin system components in the early bovine embryo . The renin - angiotensin system ( DB01367 ) , mainly associated with the regulation of blood pressure , has been recently investigated in female reproductive organs and the developing foetus . Angiotensin II ( Ang II ) influences oviductal gamete movements and foetal development , but there is no information about DB01367 in the early embryo . The aim of this study was to determine whether DB01367 components are present in the pre - implantation embryo , to determine how early they are expressed and to investigate their putative role at this stage of development . Bovine embryos produced in vitro were used for analysis of DB01367 transcripts ( RT - PCR ) and localisation of the receptors P30556 and P50052 ( immunofluorescent labelling ) . We also investigated the effects of Ang II , DB00275 ( P30556 antagonist ) and PD123319 ( P50052 antagonist ) on oocyte cleavage , embryo expansion and hatching . Pre - implanted embryos possessed P30556 and P50052 but not the other DB01367 components . Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst . P30556 was mainly localised in granular - like structures in the cytoplasm , suggesting its internalisation into clathrin - coated vesicles , and P50052 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells . Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control . These results , the first on DB01367 in the early embryo , suggest that the pre - implanted embryo responds to Ang II from the mother rather than from the embryo itself . This may be a route by which the maternal DB01367 influences blastocyst hatching and early embryonic development .",
"Angiotensin II blockers in obstructive pulmonary disease : a randomised controlled trial . In chronic obstructive pulmonary disease ( P48444 ) , the sympathetic nervous system , as well as the renin - angiotensin system , is activated with possible negative systemic effects on skeletal muscles . P30556 blockers inhibit the sympathetic and renin - angiotensin systems and might improve skeletal and respiratory muscle strength in patients in whom these systems are activated . The effects of the angiotensin receptor blocker irbesartan given over 4 months was evaluated in 60 patients with P48444 and a forced expiratory volume in one second of < 50 % of the predicted value and without obvious cardiovascular disease that would necessitate the administration of an angiotensin - converting enzyme inhibitor or an angiotensin receptor blocker . Irbesartan was well tolerated , but did not exert a significant effect on the primary end - point maximum inspiratory pressure . Spirometric results were not affected , but total lung capacity was reduced . Irbesartan led to a significant decrease in haematocrit ( 46 . 4 +/- 3 . 6 to 43 . 9 +/- 4 . 3 % versus 47 . 5 +/- 2 . 4 to 48 . 7 +/- 3 . 0 % with placebo ) . In conclusion , respiratory muscle strength in chronic obstructive pulmonary disease patients was not influenced by angiotensin II receptor blockade . However , the changes in haematocrit and total lung capacity following irbesartan raise the possibility that well - known cardiovascular drugs can produce unanticipated beneficial effects in chronic obstructive pulmonary disease patients .",
"Foxp3 + regulatory T cells promote lung epithelial proliferation . Acute respiratory distress syndrome ( ARDS ) causes significant morbidity and mortality each year . There is a paucity of information regarding the mechanisms necessary for ARDS resolution . Foxp3 (+) regulatory T cells ( Foxp3 (+) T ( reg ) cells ) have been shown to be an important determinant of resolution in an experimental model of lung injury . We demonstrate that intratracheal delivery of endotoxin ( lipopolysaccharide ) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair . Epithelial proliferation coincided with an increase in Foxp3 (+) T ( reg ) cells in the lung during the course of resolution . To dissect the role that Foxp3 (+) T ( reg ) cells exert on epithelial proliferation , we depleted Foxp3 (+) T ( reg ) cells , which led to decreased alveolar epithelial proliferation and delayed lung injury recovery . Furthermore , antibody - mediated blockade of CD103 , an integrin , which binds to epithelial expressed P12830 decreased Foxp3 (+) T ( reg ) numbers and decreased rates of epithelial proliferation after injury . In a non - inflammatory model of regenerative alveologenesis , left lung pneumonectomy , we found that Foxp3 (+) T ( reg ) cells enhanced epithelial proliferation . Moreover , Foxp3 (+) T ( reg ) cells co - cultured with primary type II alveolar cells ( P50052 ) directly increased P50052 cell proliferation in a CD103 - dependent manner . These studies provide evidence of a new and integral role for Foxp3 (+) T ( reg ) cells in repair of the lung epithelium .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK55___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Angiotensin II type 2 receptor inhibits vascular endothelial growth factor - induced migration and in vitro tube formation of human endothelial cells . Endothelial cell migration and tube formation in response to vascular endothelial growth factor ( P15692 ) play an important role in the process of angiogenesis . Recent data indicate that angiotensin type 2 ( P50052 ) receptor stimulation is antiangiogenic . Therefore , we studied the effect of angiotensin II ( Ang II ) on P15692 - induced migration and in vitro tube formation of human endothelial cells . Ang II inhibited P15692 - induced migration of EA . hy926 cells , human coronary artery ( HCA ) and human dermal microvascular ( HDM ) endothelial cells ( ECs ) as well as tube formation by HDMECs . The P50052 receptor antagonist PD123 , 319 but not the AT1 receptor antagonist losartan blocked the inhibitory effect of Ang II . The inhibitory effect of Ang II on P15692 - induced migration of endothelial cells was mimicked by the specific P50052 receptor agonist CGP - 42112A . The phosphorylation of Akt and its downstream effector endothelial NO synthase ( P29474 ) is pivotal to P15692 - induced angiogenesis . We therefore investigated the effect of Ang II on P15692 - induced Akt and P29474 phosphorylation . Ang II diminished the P15692 - induced phosphorylation of Akt and P29474 in endothelial cells , whereas the autophosphorylation of P15692 receptors was unaffected . CGP - 42112A again mimicked and PD123 , 319 but not losartan blocked the inhibitory effect of Ang II . Treatment of endothelial cells with pertussis toxin ( PTX ) totally abolished the P50052 receptor - mediated inhibition of P15692 - induced endothelial cell migration and blocked the inhibition of Akt and P29474 phosphorylation . In conclusion , this study indicates that P50052 receptor stimulation inhibits P15692 - induced endothelial cell migration and tube formation via activation of a PTX - sensitive G protein . These findings may explain the reported antiangiogenic properties of the P50052 receptor .",
"Angiotensin II regulates vascular and endothelial dysfunction : recent topics of P30556 signaling in the vasculature . Accumulating evidence strongly implicates angiotensin II ( AngII ) intracellular signaling in mediating cardiovascular diseases such as hypertension , atherosclerosis and restenosis after vascular injury . In vascular smooth muscle cells ( VSMCs ) , through its G - protein - coupled AngII Type 1 receptor ( AT ( 1 ) ) , AngII activates various intracellular protein kinases , such as receptor or non - receptor tyrosine kinases , which includes epidermal growth factor receptor ( P00533 ) , platelet - derived growth factor receptor ( P09619 ) , c - Src , Q14289 , Q05397 , O60674 . In addition , AngII activates serine / threonine kinases such as mitogen - activated protein kinase ( MAPK ) family , P08133 S6 kinase , Akt / protein kinase B and various protein kinase C isoforms . In VSMCs , AngII also induces the generation of intracellular reactive oxygen species ( ROS ) , which play critical roles in activation and modulation of above signal transduction . Less is known about endothelial cell ( EC ) AngII signaling than VSMCs , however , recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide ( NO ) signaling pathway and thereby induces endothelial dysfunction . Moreover , in both VSMCs and ECs , AngII signaling cross - talk with insulin signaling might be involved in insulin resistance , an important risk factor in the development of cardiovascular diseases . In fact , clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT ( 1 ) receptor blockers improve insulin sensitivity . In this review , we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes , such as activation of receptor or non - receptor tyrosine kinases and ROS , as well as cross - talk between insulin and NO signal transduction in VSMCs and ECs .",
"___MASK4___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK4___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK25___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK25___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects ."
] |
[
"___MASK25___",
"___MASK38___",
"___MASK47___",
"___MASK4___",
"___MASK55___",
"___MASK59___",
"___MASK5___",
"___MASK66___",
"___MASK97___"
] |
___MASK59___
|
MH_train_347
|
interacts_with DB08868?
|
[
"The receptor P21453 overrides regulatory T cell - mediated immune suppression through Akt - P42345 . Regulatory T cells ( T ( reg ) cells ) are critically involved in maintaining immunological tolerance , but this potent suppression must be ' quenched ' to allow the generation of adaptive immune responses . Here we report that sphingosine 1 - phosphate ( Q14703 ) receptor type 1 ( P21453 ) delivers an intrinsic negative signal to restrain the thymic generation , peripheral maintenance and suppressive activity of T ( reg ) cells . Combining loss - and gain - of - function genetic approaches , we found that P21453 blocked the differentiation of thymic T ( reg ) precursors and function of mature T ( reg ) cells and affected T ( reg ) cell - mediated immune tolerance . P21453 induced selective activation of the Akt - P42345 kinase pathway to impede the development and function of T ( reg ) cells . Dynamic regulation of P21453 contributed to lymphocyte priming and immune homeostasis . Thus , by antagonizing T ( reg ) cell - mediated immune suppression , the lipid - activated P21453 - Akt - P42345 pathway orchestrates adaptive immune responses .",
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"Proangiogenesis action of the thyroid hormone analog 3 , 5 - diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (- 8 )- 10 (- 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3 , 5 - diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three - dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 )- agarose , as well as basic fibroblast growth factor ( b - FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three - dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b - FGF was blocked by PD 98059 , an inhibitor of the P27361 / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b - FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta3 , and are MAPK dependent .",
"The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .",
"The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of P27361 / 2 . Somatostatin ( P61278 ) controls the proliferation of a variety of cell types . Its effects are mediated by five G protein - coupled receptors ( P30872 - P35346 ) , variably expressed in normal and cancer tissues . P61278 inhibition of cell proliferation can be exploited by both direct and indirect mechanisms : the main direct pathway involves the modulation of phosphotyrosine phosphatase ( PTP ) activity . Here we show that P61278 cytostatic activity is mediated by the activation of a receptor - like PTP , named PTPeta . The role of this PTP in the antiproliferative activity of P61278 in five glioma cell lines ( P13671 , U87MG , U373MG , DBTRG05MG , and CAS1 ) and in four postsurgical human glioblastoma specimens , has been studied . P61278 inhibited growth only in P13671 and U87MG that express PTPeta . In P13671 cells , P61278 antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate , indicating the involvement of G proteins and PTPs . The role of PTPeta in the P61278 inhibitory effects was demonstrated by testing the PTPeta activity : it was increased by P61278 treatment and paralleled by inhibition of P27361 / 2 activation . Since basic fibroblast growth factor - dependent MEK phosphorylation was not affected by P61278 , we propose a direct effect of P61278 - activated PTPeta on P27361 / 2 phosphorylation . Finally , the SSTR mRNAs were identified in all of the 36 gliomas analyzed , whereas PTPeta expression was found in 33 % of cases . Culturing four gliomas , a precise correlation between the expression of PTPeta and the P61278 antiproliferative effects was identified . In conclusion , in glioma cells , P61278 antiproliferative activity requires the expression and activation of PTPeta , which directly dephosphorylates P27361 / 2 .",
"___MASK59___ down - regulates LDL - receptor expression independently of Q12772 . As a key regulator of cholesterol homeostasis , sterol - regulatory element binding protein - 2 ( Q12772 ) up - regulates expression of genes involved in cholesterol synthesis ( e . g . , 3 - hydroxy - 3 - methyl - glutaryl - coenzyme A ( HMG - DB01992 ) Reductase ) and uptake ( the low density lipoprotein ( LDL ) - receptor ) . Previously , we showed that Akt , a critical kinase in cell growth and proliferation , contributes to Q12772 activation . However , the specific Akt target involved is unknown . A potential candidate is the mammalian target of rapamycin , P42345 . ___MASK59___ can cause hyperlipidaemia clinically , and we hypothesised that this may be mediated via an effect of P42345 on Q12772 . Herein , we found that Q12772 activation and HMG - DB01992 Reductase gene expression were unaffected by rapamycin treatment . However , LDL - receptor gene expression was decreased by rapamycin , suggesting that this may contribute to the hyperlipidaemia observed in rapamycin - treated patients . ___MASK59___ did not affect mRNA stability , so the decrease in LDL - receptor gene expression is likely to be occurring at the transcriptional level , although independently of Q12772 .",
"Sphingosylphosphorylcholine as a novel calmodulin inhibitor . Q14703 ( sphingosine 1 - phosphate ) and Q969E3 ( sphingosylphosphorylcholine ) have been recently recognized as important mediators of cell signalling , regulating basic cellular processes such as growth , differentiation , apoptosis , motility and Ca2 + homoeostasis . Interestingly , they can also act as first and second messengers . Although their activation of cell - surface G - protein - coupled receptors has been studied extensively , not much is known about heir intracellular mechanism of action , and their target proteins are yet to be identified . We hypothesized that these sphingolipids might bind to P62158 ( calmodulin ) , the ubiquitous intracellular Ca2 + sensor . Binding assays utilizing intrinsic tyrosine fluorescence of the protein , dansyl - labelled P62158 and surface plasmon resonance revealed that Q969E3 binds to both apo - and Ca2 +- saturated P62158 selectively , when compared with the related lysophospholipid mediators Q14703 , P08519 ( lysophosphatidic acid ) and Q16549 ( lysophosphatidylcholine ) . Experiments carried out with the model P62158 - binding domain melittin showed that Q969E3 dissociates the P62158 - target peptide complex , suggesting an inhibitory role . The functional effect of the interaction was examined on two target enzymes , phosphodiesterase and calcineurin , and Q969E3 inhibited the Ca2 +/ P62158 - dependent activity of both . Thus we propose that P62158 might be an intracellular receptor for Q969E3 , and raise the possibility of a novel endogenous regulation of P62158 .",
"Porcine natriuretic peptide type B ( pNPPB ) maintains mouse oocyte meiotic arrest via natriuretic peptide receptor 2 ( P20594 ) in cumulus cells . In mouse ovarian follicles , the oocyte is maintained in meiotic prophase arrest by natriuretic peptide type C ( P23582 ) acting via its cognate receptor , natriuretic peptide receptor 2 ( P20594 ) . As there is a marked species difference in the receptor selectivity of the natriuretic peptide family , this study examined the functional effect of other natriuretic peptides , type A ( P01160 ) and type B ( P16860 ) , acting via P20594 on mouse - oocyte meiotic arrest . The results by quantitative , reverse - transcriptase PCR showed that Npr2 was the predominant natriuretic peptide receptor transcript , and that Npr1 and Npr3 mRNA levels were negligible in cumulus cells isolated from equine chorionic gonadotropin ( eCG ) - primed , immature female mice . While P01160 and P16860 from human and rat had no effect on oocyte maturation , porcine P16860 ( pNPPB ) maintained oocyte meiotic arrest in a dose - dependent manner . Furthermore , pNPPB - mediated meiotic arrest and cGMP production could be completely blocked by the P20594 inhibitor sphingosine - 1 - phosphate ( Q14703 ) . Neither the P16066 antagonist anantin or Npr1 knockout had an effect on pNPPB - mediated meiotic arrest . Thus , pNPPB can functionally maintain mouse - oocyte meiotic arrest by the receptor P20594 of cumulus cells . These findings demonstrate that pNPPB may be used as a probe to identify the essential amino acid sequences for activation of P20594 .",
"Exogenous sphingosine 1 - phosphate protects murine splenocytes against hypoxia - induced injury . DB03203 - 1 - phosphate ( Q14703 ) , a biologically active pleiotropic lipid , is involved in several physiological processes especially in the area of vascular biology and immunology encompassing cell survival , angiogenesis , vascular tone , immune response etc . by interacting with specific cell surface receptors . Hypoxia , a condition common to innumerable pathologies , is known to lethally affect cell survival by throwing off balance global gene expression , redox homeostasis , bioenergetics etc . Several molecular events of cellular adaptations to hypoxia have been closely linked to stabilization of hypoxia inducible factor - 1α ( HIF - 1α ) . Signalling functions of Q14703 in physiological events central to hypoxia - induced pathologies led us to investigate efficacy of exogenous Q14703 in preconditioning murine splenocytes to sustain during cellular stress associated with sub - optimal oxygen . The present study recapitulated the pro - survival benefits of exogenous Q14703 under normobaric hypoxia . Results indicate a direct effect of Q14703 supplementation on boosting cellular adaptive responses via HIF - 1α stabilization and , activation of pro - survival mediators P29323 and Akt . Overwhelming anti - oxidative and anti - inflammatory benefits of Q14703 preconditioning could also be captured in the present study , as indicated by improved redox homeostasis , reduced oxidative damage , balanced anti / pro - inflammatory cytokine profiles and temporal regulation of nitric oxide secretion and intra - cellular calcium release . Hypoxia induced cell death and the associated stress in cellular milieu in terms of oxidative damage and inflammation could be alleviated with exogenous Q14703 preconditioning .",
"DB03203 - 1 - phosphate receptors control B - cell migration through signaling components associated with primary immunodeficiencies , chronic lymphocytic leukemia , and multiple sclerosis . BACKGROUND : Five different G protein - coupled sphingosine - 1 - phosphate ( Q14703 ) receptors ( P21453 - Q9H228 ) regulate a variety of physiologic and pathophysiologic processes , including lymphocyte circulation , multiple sclerosis ( MS ) , and cancer . Although B - lymphocyte circulation plays an important role in these processes and is essential for normal immune responses , little is known about Q14703 receptors in human B cells . OBJECTIVE : To explore their function and signaling , we studied B - cell lines and primary B cells from control subjects , patients with leukemia , patients with Q14703 receptor inhibitor - treated MS , and patients with primary immunodeficiencies . METHODS : Q14703 receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR . Transwell assays were used to study cell migration . Q14703 receptor internalization was visualized by means of time - lapse imaging with fluorescent Q14703 receptor fusion proteins expressed by using lentiviral gene transfer . B - lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy . RESULTS : Showing that different B - cell populations express different combinations of Q14703 receptors , we found that P21453 promotes migration , whereas O95977 modulates and O95136 inhibits P21453 signals . Expression of Q07108 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited Q14703 - induced migration . Studying B - cell lines , normal B lymphocytes , and B cells from patients with primary immunodeficiencies , we identified Q06187 , β - arrestin 2 , LPS - responsive beige - like anchor protein , dedicator of cytokinesis 8 , and P42768 as critical signaling components downstream of P21453 . CONCLUSION : Thus Q14703 receptor signaling regulates human B - cell circulation and might be a factor contributing to the pathology of MS , chronic lymphocytic leukemia , and primary immunodeficiencies .",
"The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse . Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy . In peripheral neuropathy , defects in neurofilament and microtubules have been demonstrated . In this study , we examined the effects of insulin deficiency within the brain in insulin knockout mice ( I -/- ) . The I -/- exhibited hyperphosphorylation of tau , at threonine 231 , and neurofilament . In addition , we showed hyperphosphorylation of c - Jun N - terminal kinase ( JNK ) and glycogen synthase kinase 3 beta ( P49841 ) at serine 9 . P27361 ( P29323 1 ) showed decrease in phosphorylation , whereas P29323 2 showed no changes . Ultrastructural examination demonstrated swollen mitochondria , endoplasmic reticulum , and Golgi apparatus , and dispersion of the nuclear chromatin . Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches . Thus , lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament , and ultrastructural cellular damage , that over time may induce decrease in cognition and learning disabilities .",
"Synthesis and evaluation of fluorinated fingolimod ( FTY720 ) analogues for sphingosine - 1 - phosphate receptor molecular imaging by positron emission tomography . DB03203 - 1 - phosphate ( Q14703 ) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G - protein coupled receptors ( GPCRs ) : P21453 - Q9H228 . Q14703 and its receptors ( S1PRs ) play important roles in the immune , cardiovascular , and central nervous systems and have also been implicated in carcinogenesis . Recently , the Q14703 analogue DB08868 ( FTY720 ) has been approved for the treatment of patients with relapsing multiple sclerosis . This work presents the synthesis of various fluorinated structural analogues of FTY720 , their in vitro and in vivo biological testing , and their development and application as [( 18 ) F ] radiotracers for the study of S1PR biodistribution and imaging in mice using small - animal positron emission tomography ( PET ) .",
"Q9NYA1 mediates head & neck squamous cell carcinoma invasion through sphingosine 1 - phosphate receptor 1 . BACKGROUND : Head and neck squamous cell carcinoma ( HNSCC ) is characterized by aggressive loco - regional invasion . DB03203 kinase1 ( SphK1 ) , an enzyme in sphingolipid metabolism , is emerging as a key player in HNSCC pathology . The observation that SphK1 is overexpressed in all HNSCC stages and is associated with depth of tumor invasion , metastasis and clinical failure underscores the importance of SphK1 in HNSCC pathology . Still , the mechanisms underlying SphK1 regulation of invasion have not been delineated . Therefore , we sought to mechanistically describe how SphK1 regulates invasion in HNSCC . METHODS : Invasion assays were used to measure invasive ability of SphK1 overexpressing human tongue squamous cell carcinoma ( SCC - 25 cells ) . Western blotting , quantitative qPCR , ELISA and zymography were used to measure the effect of SphK1 and sphingosine 1 - phoshate receptor 1 ( P21453 ) on invasion measures , P08253 / 9 , P12830 , P00533 , P05231 / P40763 , in SCC - 25 cells . RESULTS : SphK1 expression is elevated in cells with an invasive phenotype as compared to non - invasive phenotype . We show SphK1 overexpression increased P01133 - induced P00533 / P29323 and AKT activity , increased matrix metalloproteinase ( MMP ) - 2 / 9 mRNA and reduced P12830 . SphK1 overexpression also increased P05231 concentration and P01133 - induced P40763 phosphorylation , exemplifying that SphK1 modulates P05231 / P40763 signaling . Notably , we show that P21453 knockdown reduced P05231 / P40763 signaling , representing another pathway by which SphK1 / Q14703 regulates invasion . CONCLUSIONS : Taken together , our data suggest that SphK1 sits at the hub of multiple key signaling cascades , all which have been implicated in the regulation of invasiveness , making SphK1 an attractive target for the development of HNSCC therapies .",
"Non - phosphorylated FTY720 induces apoptosis of human microglia by activating Q12772 . A synthetic analog of sphingosine named FTY720 ( DB08868 ) , phosphorylated by sphingosine kinase - 2 , interacts with sphingosine - 1 - phosphate ( Q14703 ) receptors expressed on various cells . FTY720 suppresses the disease activity of multiple sclerosis ( MS ) chiefly by inhibiting Q14703 - dependent egress of autoreactive T lymphocytes from secondary lymphoid organs , and possibly by exerting anti - inflammatory and neuroprotective effects directly on brain cells . However , at present , biological effects of FTY720 on human microglia are largely unknown . We studied FTY720 - mediated apoptosis of a human microglia cell line HMO6 . The exposure of HMO6 cells to non - phosphorylated FTY720 ( FTY720 - non - P ) induced apoptosis in a dose - dependent manner with IC50 of 10 . 6 ± 2 . 0 μM , accompanied by the cleavage of caspase - 7 and caspase - 3 but not of caspase - 9 . The apoptosis was inhibited by Z - DQMD - FMK , a caspase - 3 inhibitor , but not by Pertussis toxin , a Gi protein inhibitor , suramin , a Q99500 / Q9H228 inhibitor , or W123 , a P21453 competitive antagonist , although HMO6 expressed P21453 , O95136 , and Q99500 . Furthermore , both phosphorylated FTY720 ( FTY720 - P ) and SEW2871 , P21453 selective agonists , did not induce apoptosis of HMO6 . Genome - wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element - binding protein ( SREBP ) in FTY720 - non - P - treated HMO6 cells . Western blot verified activation of Q12772 in these cells , and apoptosis was enhanced by pretreatment with simvastatin , an activator of Q12772 , and by overexpression of the N - terminal fragment of Q12772 . These observations suggest that FTY720 - non - P - induced apoptosis of HMO6 human microglia is independent of Q14703 receptor binding , and positively regulated by the Q12772 - dependent proapoptotic signaling pathway .",
"Inflammatory stress exacerbates lipid - mediated renal injury in ApoE / P16671 / SRA triple knockout mice . Both lipids and inflammation play important roles in the progression of kidney disease . This study was designed to investigate whether inflammation exacerbates lipid accumulation via LDL receptors ( LDLr ) , thereby causing renal injury in C57BL / 6J mice , apolipoprotein E ( ApoE ) knockout ( KO ) mice , and ApoE / P16671 / scavenger receptor A triple KO mice . The mice were given a subcutaneous casein injection to induce inflammatory stress . After 14 wk , terminal blood samples were taken for renal function , lipid profiles , amyloid A ( P0DJI8 ) , and P05231 assays . Lipid accumulation in kidneys was visualized by oil red O staining . Fibrogenic molecule expression in kidneys was examined . There was a significant increase in serum P0DJI8 and P05231 in the all casein - injected mice compared with respective controls . Casein injection reduced serum total cholesterol , LDL cholesterol , and HDL cholesterol and caused lipid accumulation in kidneys from three types of mice . The expression of LDLr and its regulatory proteins sterol - responsive element - binding protein ( SREBP ) 2 and Q12770 ( SCAP ) were upregulated in inflamed mice compared with controls . Casein injection induced renal fibrosis accompanied by increased expression of fibrogenic molecules in the triple KO mice . These data imply that inflammation exacerbates lipid accumulation in the kidney by diverting lipid from the plasma to the kidney via the SCAP - Q12772 - LDLr pathway and causing renal injury . Low blood cholesterol levels , resulting from inflammation , may be associated with high risk for chronic renal fibrosis .",
"Transduction of multiple effects of sphingosine 1 - phosphate ( Q14703 ) on T cell functions by the P21453 G protein - coupled receptor . DB03203 1 - phosphate ( Q14703 ) in blood , lymph , and immune tissues stimulates and regulates T cell migration through their Q14703 ( 1 ) ( endothelial differentiation gene encoded receptor - 1 ) G protein - coupled receptors . We show now that Q14703 ( 1 ) Rs also mediate suppression of T cell proliferation and cytokine production . Uptake of [( 3 ) H ] thymidine by mouse P01730 T cells stimulated with anti - CD3 mAbs plus either anti - P10747 or P13232 was inhibited up to 50 % by 10 (- 9 )- 10 (- 6 ) M Q14703 . Suppression by Q14703 required Ca ( 2 +) signaling and was reduced by intracellular DB02527 . Q14703 decreased P01730 T cell generation of P01579 and P05112 , without affecting P60568 . A Th1 line from D011 . 10 TCR transgenic mice without detectable Q14703 ( 1 ) was refractory to Q14703 until introduction of Q14703 ( 1 ) by retroviral transduction . Q14703 then evoked chemotaxis , inhibited chemotaxis to DB00833 - 5 and DB00833 - 21 , and suppressed Ag - stimulated proliferation and P01579 production . Thus , Q14703 ( 1 ) signals multiple immune functions of T cells as well as migration and tissue distribution .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK93___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"The sphingosine - 1 - phosphate receptor agonist FTY720 prevents the development of anti - glomerular basement membrane glomerulonephritis . The sphingosine - 1 - phosphate ( Q14703 ) agonist FTY720 prolongs the survival of organ allograft and attenuates autoimmune - mediated injury in experimental models . Most cases of glomerulonephritis ( GN ) in human appear to be immunologically initiated . In this study , we evaluated the potential therapeutic role of FTY720 in GN via a mouse anti - glomerular basement membrane ( GBM ) model . Mice were immunized with rabbit IgG in complete Freund ' s adjuvant ( O75347 ) followed by an intravenous injection of a rabbit anti - mouse GBM serum . Disease and immune responses were assessed on day 14 . Mice were treated with FTY720 ( 0 . 3 or 3 mg / kg ) and prednisone ( 10 mg / kg ) from days 0 to 14 . The Q14703 modulator reduced proteinuria , serum creatinine , crescent formation and serum IgG level . The expressions of splenic Q14703 receptor and renal Th - 1 cytokine were also inhibited at the transcription stage . Treatment with FTY720 increased splenocyte production of protective Th2 cytokine P05112 and promoted the apoptosis of splenic P01730 + T cells in the animal models , which suggests that FTY720 played a protective role at the induction stage of GN by inhibiting mRNA expressions of splenic P21453 , O95136 , and Q9H228 .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK58___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK6___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Ceramide alters endothelial cell permeability by a nonapoptotic mechanism . Ceramide is a lipid second messenger that was recently identified as mediator of pulmonary edema in vivo . Here , we investigated the effect of ceramide on the permeability of confluent endothelial cell monolayers . In monolayers of bovine pulmonary artery and human microvascular pulmonary endothelial cells , incubation with P13671 - ceramide for 3 h elevated permeability in a concentration - dependent manner , whereas dihydroceramide was without effect . After 3 h of incubation with ceramide , we found no signs of necrosis ( release of lactate dehydrogenase , loss of thiazylyl blue reduction ) or apoptosis ( ssDNA , caspase - 8 activity ) . The increased endothelial permeability in response to ceramide was attenuated by the DB00133 / DB00156 protein kinase inhibitors K252a , K252b and H - 7 , as well as by the phosphatidylinositol - specific phospholipase C inhibitor L108 . Since in some systems sphingosine - 1 - phosphate ( Q14703 ) acts antagonistic to ceramide , the effect of Q14703 was studied . Q14703 transiently increased endothelial cell resistance , whether it was given together with ceramide or 90 min thereafter . These data provide a novel example of the antagonism between Q14703 and ceramide . Our findings further suggest that ceramide alters vascular permeability by activation of pathways dependent on unidentified phospholipase C and DB00133 / DB00156 kinase isoenzymes .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Distinct energy requirements for human memory P01730 T - cell homeostatic functions . Differentiation and activation of P01730 memory T cells ( T ( mem ) cells ) require energy from different sources , but little is known about energy sources for maintenance and surveillance activities of unactivated T ( mem ) cells . Mitochondrial fatty acid oxidation ( FAO ) in human unactivated P01730 T ( mem ) cells was significantly enhanced by inhibition of glycolysis , with respective means of 1 . 7 - and 4 . 5 - fold for subjects < 45 yr and > 65 yr , and by stimulation of AMP - activated protein kinase , with respective means of 1 . 3 - and 5 . 2 - fold . However , Q99731 and sphingosine 1 - phosphate ( Q14703 ) , which control homeostatic lymphoid trafficking of unactivated T ( mem ) cells , altered FAO and glycolysis only minimally or not at all . Inhibition of P01730 T ( mem )- cell basal FAO , but not basal glycolysis , significantly suppressed Q99731 - and Q14703 - mediated adherence to collagen by > 50 and 20 % , respectively , and chemotaxis by > 20 and 50 % . Apoptosis of unactivated T ( mem ) cells induced by P60568 deprivation or Q99731 was increased significantly by > 150 and 70 % , respectively , with inhibition of FAO and by > 110 and 30 % with inhibition of glycolysis . Anti - TCR antibody activation of T ( mem ) cells increased their chemotaxis to P13501 , which was dependent predominantly on glycolysis rather than FAO . The sources supplying energy for diverse functions of unactivated T ( mem ) cells differ from that required for function after immune activation .",
"DB08868 ( FTY720 ) enhances remyelination following demyelination of organotypic cerebellar slices . Remyelination , which occurs subsequent to demyelination , contributes to functional recovery and is mediated by oligodendrocyte progenitor cells ( OPCs ) that have differentiated into myelinating cells . Therapeutics that impact remyelination in the CNS could be critical determinants of long - term functional outcome in multiple sclerosis ( MS ) . DB08868 is a Q14703 receptor modulator in MS clinical trials due to systemic anti - inflammatory properties , yet may impact cells within the CNS by crossing the blood - brain barrier . Previous studies using isolated dissociated cultures indicate that neural cells express Q14703 receptors and respond to receptor engagement . Our objective was to assess the effects of fingolimod on myelin - related processes within a multicellular environment that maintains physiological cell - cell interactions , using organotypic cerebellar slice cultures . DB08868 treatment had no impact on myelin under basal conditions . DB08868 treatment subsequent to lysolecithin - induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes , while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein . The number of phagocytosing microglia was not increased by fingolimod . Using Q14703 receptor specific agonists and antagonists , we determined that fingolimod - induced effects on remyelination and astrogliosis were mediated primarily through Q99500 and Q9H228 , whereas enhanced microgliosis was mediated through P21453 and Q9H228 . Taken together , these data demonstrate that fingolimod modulates multiple neuroglial cell responses , resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain .",
"DB03203 1 - phosphate ( Q14703 ) induces shape change in rat P13671 glioma cells through the O95136 receptor : development of an agonist for Q14703 receptors . Treatment with isoprenaline led to a change in the cell morphology of rat P13671 glioma cells . This morphological change was reverted by the addition of sphingosine 1 - phosphate ( Q14703 ) . Using this morphological change as a response marker we determined that DS - SG - 44 ( ( 2S , 3R ) - 2 - amino - 3 - hydroxy - 4 -( 4 - octylphenyl ) butyl phosphoric acid ) was an agonist of Q14703 receptors . The DS - SG - 44 - induced morphological reversion was not observed with such structurally related molecules as DS - SG - 45 ( ( 2S , 3R ) - 2 - amino - 3 - hydroxy - 4 -( 3 - octylphenyl ) butyl phosphoric acid ) and DS - SG - 12 ( ( 2S , 3R ) - 2 - amino - 4 -( 4 - octylphenyl ) butane - 1 , 3 - diol ) . The Q14703 - and DS - SG - 44 - induced shape changes were neither reproduced with the P21453 / Q99500 receptor agonist VPC24191 nor inhibited by the P21453 / Q99500 receptor antagonist , VPC23019 . Transfection with small interfering RNA ( siRNA ) for the O95136 receptor greatly inhibited the DS - SG - 44 - induced shape change , and in part an Q14703 - induced response . In the presence of VPC23019 , siRNA transfection for the O95136 receptor almost completely blocked the Q14703 - and DS - SG - 44 - induced shape changes . Our results suggested that DS - SG - 44 , a newly - synthesized Q14703 analogue , acted as an Q14703 receptor agonist and that the Q14703 - induced shape change in rat P13671 glioma cells was mediated mainly through the O95136 receptor , and cooperatively through the P21453 / Q99500 receptors .",
"Characterization of ibrutinib - sensitive and - resistant mantle lymphoma cells . ___MASK33___ inhibits Q06187 ( Q06187 ) , a key component of early B - cell receptor ( P11274 ) signalling pathways . A multicentre phase 2 trial of ibrutinib in patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) demonstrated a remarkable response rate . However , approximately one - third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance . Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance . In this study , we investigated cell lines and primary Q8WXI8 cells that display differential sensitivity to ibrutinib . We found that the primary cells display a higher Q06187 activity than normal B cells and Q8WXI8 cells show differential sensitivity to Q06187 inhibition . Genetic knockdown of Q06187 inhibits the growth , survival and proliferation of ibrutinib - sensitive but not resistant Q8WXI8 cell lines , suggesting that ibrutinib acts through Q06187 to produce its anti - tumour activities . Interestingly , inhibition of P27361 / 2 and AKT , but not Q06187 phosphorylation per se , correlates well with cellular response to Q06187 inhibition in cell lines as well as in primary tumours . Our study suggests that , to prevent primary resistance or to overcome secondary resistance to Q06187 inhibition , a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK100___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK63___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK63___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK63___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK63___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK63___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"DB08868 : direct CNS effects of sphingosine 1 - phosphate ( Q14703 ) receptor modulation and implications in multiple sclerosis therapy . DB08868 is the first oral disease - modifying therapy approved for relapsing forms of multiple sclerosis ( MS ) . Following phosphorylation in vivo , the active agent , fingolimod phosphate ( fingolimod - P ) , acts as a sphingosine 1 - phosphate ( Q14703 ) receptor modulator , binding with high affinity to four of the five known Q14703 receptors ( P21453 , Q99500 , O95977 and Q9H228 ) . The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory , whereby fingolimod - P modulates P21453 on lymphocytes , selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system ( CNS ) . However , emerging evidence indicates that fingolimod has direct effects in the CNS in MS . For example , in the MS animal model of experimental autoimmune encephalomyelitis ( EAE ) , fingolimod is highly efficacious in both a prophylactic and therapeutic setting , yet becomes ineffective in animals selectively deficient for P21453 on astrocytes , despite maintained normal immunologic receptor expression and functions , and Q14703 - mediated immune activities . Here we review Q14703 signaling effects relevant to MS in neural cell types expressing Q14703 receptors , including astrocytes , oligodendrocytes , neurons , microglia and dendritic cells . The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair . The therapeutic implications of Q14703 modulation in the CNS are considered in terms of the clinical outcomes of MS , such as reducing MS - related brain atrophy , and other CNS disorders . Additionally , we briefly outline other existing and investigational MS therapies that may also have effects in the CNS .",
"The combination of rapamycin and MAPK inhibitors enhances the growth inhibitory effect on Nara - H cells . The inhibition of the mammalian target of rapamycin ( P42345 ) signaling pathway promotes the initiation of autophagy , and the mitogen - activated protein kinase ( MAPK ) / extracellular signal - regulated protein kinase ( P29323 ) is well known to induce autophagy . Autophagy is a self - defense mechanism of cancer cells that are subjected to antitumor agents , and blocking autophagy can trigger apoptosis . In the present study , we demonstrate that an P42345 inhibitor , rapamycin , induces autophagy in the Nara - H malignant fibrous histiocytoma ( Q9H334 ) cell line through the activation of P27361 / 2 . ___MASK59___ - induced apoptosis was enhanced following the inhibition of the MEK / P29323 pathway . In the Nara - H cells , we examined the effects of rapamycin treatment on cell proliferation and on the phosphorylation of the P42345 pathway components and autophagy by western blot analysis . Furthermore , we examined the effects of rapamycin with or without the MEK inhibitor , U0126 , on the induction of apoptosis by using fluorescence microscopy . ___MASK59___ inhibited Nara - H cell proliferation and decreased the phosphorylation of the P42345 pathway in the Nara - H cells . ___MASK59___ induced the apoptosis of Nara - H cells , and this apoptosis was enhanced by U0126 . Simultaneously , phospho - P27361 / 2 was activated by rapamycin . The present study demonstrates that rapamycin induces autophagy in Nara - H cells by activating the MEK / P29323 signaling pathway , and the rapamycin - induced apoptosis can be enhanced by the MEK inhibitor , U0126 . These results suggest that self ‑ protective mechanisms involving P42345 inhibitors in Nara - H cells are prevented by the inhibition of the MEK / P29323 pathway . The combination of an P42345 inhibitor ( e . g . , rapamycin ) and an MEK inhibitor ( e . g . , U0126 ) may offer effective treatment for Q9H334 , as this combination effectively activates apoptotic pathways .",
"DB03203 1 - phosphate receptors regulate chemokine - driven transendothelial migration of lymph node but not splenic T cells . Chemokines and chemokine receptors are required for T cell trafficking and migration . Recent evidence shows that sphingosine 1 - phosphate ( Q14703 ) and S1PRs are also important for some aspects of T cell migration , but how these two important receptor - ligand systems are integrated and coregulated is not known . In this study , we have investigated Q99731 - P32248 and P48061 - P61073 - driven migration of both splenic and peripheral lymph node ( P26678 ) nonactivated and naive T cells , and used both Q14703 and the S1PR ligand , FTY720 , to probe these interactions . The results demonstrate that splenic T cell migration to Q99731 or P48061 is enhanced by , but does not require , S1PR stimulation . In contrast , P26678 T cell migration to P48061 , but not Q99731 , requires both chemokine and S1PR stimulation , and the requirement for dual receptor stimulation is particularly important for steps involving transendothelial migration . The results also demonstrate that : 1 ) splenic and P26678 nonactivated and naive T cells use different molecular migration mechanisms ; 2 ) P32248 and P61073 stimulation engage different migration mechanisms ; and 3 ) Q14703 and FTY720 have distinct S1PR agonist and antagonist properties . The results have important implications for understanding naive T cell entry into and egress from peripheral lymphoid organs , and we present a model for how Q14703 and chemokine receptor signaling may be integrated within a T cell .",
"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK59___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .",
"Cyclical and dose - dependent responses of adult human mature oligodendrocytes to fingolimod . DB08868 is a sphingosine - 1 - phosphate ( Q14703 ) analogue that has been used in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis . DB08868 readily accesses the central nervous system , raising the issue of its direct effects on neural cells . We assessed the effects of active fingolimod on dissociated cultures of mature , myelin - producing oligodendrocytes ( OLGs ) derived from adult human brain . Human OLGs express Q14703 receptor transcripts in relative abundance of Q9H228 > Q99500 > P21453 , with undetectable levels of O95977 . Low doses of fingolimod ( 100 pmol / L to 1 nmol / L ) induced initial membrane elaboration ( 2 days ) , subsequent retraction ( 4 days ) , and recurrence of extension with prolonged treatment ( 8 days ) . Higher doses ( 10 nmol / L to 1 mumol / L ) caused the opposite modulation of membrane dynamics . Retraction was rescued by co - treatment with the Q99500 / Q9H228 pathway antagonist , suramin , and was associated with RhoA - mediated cytoskeletal signaling . Membrane elaboration was mimicked using the P21453 agonist SEW2871 . DB08868 rescued human OLGs from serum and glucose deprivation - induced apoptosis , which was reversed with suramin co - treatment and mimicked using an Q9H228 agonist . High doses of fingolimod induced an initial down - regulation of Q9H228 mRNA levels relative to control ( 4 hours ) , subsequent up - regulation ( 2 days ) , and recurrent down - regulation ( 8 days ) . P21453 mRNA levels were inversely regulated compared with Q9H228 . These results indicate that fingolimod modulates maturity - and species - specific OLG membrane dynamics and survival responses that are directly relevant for myelin integrity .",
"The role of sphingosine 1 - phosphate receptors in the trafficking of hematopoietic progenitor cells . DB03203 1 - phosphate ( Q14703 ) is an ubiquitously present extracellular lipid mediator that is released by several cell types , particularly by activated platelets . The effects of Q14703 are mediated by a specific family of G protein - coupled sphingosine 1 - phosphate receptors ( P21453 - Q9H228 ) . We demonstrate that Q14703 acts on hematopoietic progenitor cells as a chemotactic factor , attracting peripheral blood P28906 (+) cells in vitro . Furthermore , constant activation of Q14703 receptors augments P61073 - mediated signal transduction induced by stromal cell - derived factor 1 ( P48061 ) . These effects are most likely mediated by the P21453 receptor consistently expressed in both primitive and committed P28906 (+) hematopoietic progenitor cells ( HPCs ) . In vivo , sustained activation of P21453 by a receptor agonist during the homing process resulted in increased engraftment . Given the fact that activated platelets represent a major source of extracellular Q14703 , P48061 - mediated stem cell homing may occur at sites of tissue injury in addition to the bone marrow . This could explain the previously observed contribution of primary hematopoietic stem cells to tissue repair in myocardial infarction and other diseases .",
"Functional consequences of Q14703 receptor modulation in rat oligodendroglial lineage cells . DB08868 ( FTY720 ) and its phosphorylated form FTY720P are modulators of sphingosine - 1 - phosphate ( Q14703 ) receptors , which are G - protein coupled receptors linked to cell migration and vascular maturation . The efficacy of FTY720 in autoimmune diseases such as multiple sclerosis and its animal models has been attributed to its inhibition of lymphocyte trafficking to target organs . In this study , we examined the role of Q14703 receptors in cultured rat oligodendrocytes ( OLGs ) and OLG progenitor cells ( OPCs ) using the active phosphorylated form of FTY720 . We found that ( 1 ) FTY720P improves the survival of neonatal rat OLGs during serum withdrawal , which is associated with the phosphorylation of extracellular signal regulated kinases ( P27361 / 2 ) and Akt ; ( 2 ) FTY720P regulates OPC differentiation into OLGs in a concentration - dependent manner ; and ( 3 ) Q14703 receptors are differentially modulated by platelet - derived growth factor ( PDGF ) resulting in downregulation of Q9H228 and upregulation of P21453 in OPCs . In addition , siRNA studies revealed that P21453 participates in PDGF - induced OPC mitogenesis . We conclude that P21453 and Q9H228 serve different functions during oligodendroglial development , and possibly during remyelination .",
"DB03843 - or adjuvant - induced peripheral inflammation increases neurokinin - 1 receptor gene expression in the mouse . Substance P ( SP ) has been widely studied as a mediator of nociception . The release of SP from primary afferent neurons is increased during nociception , and SP activates neurokinin - 1 ( NK - 1 ) receptors in the spinal cord and periphery . Nociception - evoked alterations in P25103 gene expression have been studied in rat models of persistent pain but have not been characterized in any murine models of peripheral inflammation . This study assessed behavioral responses and P25103 mRNA gene expression in mice receiving formalin or Freund ' s complete adjuvant ( O75347 ) as an inflammatory stimulus . Mechanical withdrawal thresholds were measured before injection of formalin or O75347 and hind paw licking / biting timed during the late - phase of the formalin response . Two and 24 hours after formalin or O75347 injection , mechanical withdrawal thresholds were measured and the mice euthanized . Solution hybridization - nuclease protection assays were used to quantify P25103 mRNA levels . Results demonstrated that inflamed hind paws were edematous , and the withdrawal thresholds of the inflamed hind paws were significantly lower after formalin or O75347 injection . Neurokinin - 1 receptor mRNA levels in the ipsilateral dorsal spinal cords of mice were higher at 24 h after formalin injection or 4 days after O75347 injection . These results confirm that mice are hyperalgesic at late time points after formalin or adjuvant injection when P25103 gene expression is elevated in the dorsal spinal cord . This supports the hypothesis that increased P25103 gene expression contributes to the development and maintenance of a hyperalgesic state .",
"Phytosphingosine - 1 - phosphate stimulates chemotactic migration of L2071 mouse fibroblasts via pertussis toxin - sensitive G - proteins . Phytosphingosine - 1 - phosphate ( PhS1P ) was found to stimulate an intracellular calcium increase via phospholipase C but not pertussis toxin ( PTX ) - sensitive G - proteins in L2071 mouse fibroblasts . PhS1P also activated P29323 and p38 kinase , and these activations by PhS1P were inhibited by PTX . Moreover , PhS1P stimulated the chemotactic migration of L2071 cells via PTX - sensitive Gi protein ( s ) . In addition , the PhS1P - induced chemotactic migration of L2071 cells was also dramatically inhibited by LY294002 and SB203580 ( inhibitors of phosphoinositide 3 - kinase and p38 kinase , respectively ) . L2071 cells are known to express four Q14703 receptors , i . e . , P21453 , O95136 , Q99500 , and O95977 , and pretreatment with an P21453 and Q99500 antagonist ( VPC 23019 ) did not affect on PhS1P - induced chemotaxis . This study demonstrates that PhS1P stimulates at least two different signaling cascades , one is a PTX - insensitive but phospholipase C dependent intracellular calcium increase , and the other is a PTX - sensitive chemotactic migration mediated by phosphoinositide 3 - kinase and p38 kinase .",
"Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .",
"Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK33___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .",
"P21453 as a useful target for treatment of multiple sclerosis . DB03203 1 - phosphate ( Q14703 ) , a lysophospholipid mediator , is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors . P21453 ( P21453 ) plays an essential role in lymphocyte egress from secondary lymphoid organs ( Q12791 ) , as evinced by the inability of lymphocytes to exit from the Q12791 in mice lacking lymphocytic P21453 . DB08868 hydrochloride ( FTY720 ) is a first - in - class , orally active , Q14703 receptor modulator with a structure closely related to sphingosine . FTY720 was first synthesized by chemical modification of a natural product , myriocin . FTY720 is effectively converted to an active metabolite , FTY720 phosphate ( FTY720 - P ) by sphingosine kinases . FTY720 - P shows high affinity to 4 of the Q14703 receptors ( P21453 , Q99500 , O95977 , and Q9H228 ) . In particular , FTY720 - P strongly induces internalization and degradation of P21453 , inhibits Q14703 responsiveness of lymphocytes in the Q12791 , and acts as a functional antagonist at lymphocytic P21453 . Consequently , FTY720 inhibits P21453 - dependent lymphocyte egress from the Q12791 to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis ( EAE ) , an animal model of multiple sclerosis ( MS ) . Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon - β - 1a ( Avonex ® ) , P21453 is presumed to be a useful target for the therapy of MS .",
"Cyclosporin a affects signaling events differentially in human gingival fibroblasts . Gingival overgrowth is a common side - effect of the administration of cyclosporin A ( Q13216 ) , phenytoin , and calcium blockers . To identify the signaling mechanisms possibly involved in the overgrowth , we examined how Q13216 affects the activities of Q96HU1 kinases and transcription factors in human gingival fibroblasts ( P14210 ) . The P14210 were treated with Q13216 and P01375 or PDGF . DNA - binding activity of NFAT , NFkappaB , and AP - 1 transcription factors was determined by gel shift assay , and JNK , p38 , and P27361 and P28482 activation was assessed by Western blot analysis of immunoprecipitates . The Q13216 inhibited NFAT , NFkappaB , and p38 and JNK activities ; however , P27361 and P28482 were not affected significantly . AP - 1 activity increased approximately 4 . 5 - fold . Our results indicate that Q13216 affects signaling molecules in P14210 differently from other cell types , and that a Q13216 - induced increase in AP - 1 activity may affect the expression of fibrogenic molecules in gingiva and promote gingival overgrowth .",
"___MASK65___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK86___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK65___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK65___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK65___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"Cyclophosphamide and other new agents for the treatment of severe aplastic anemia . Severe aplastic anemia ( P0DJI8 ) has a poor prognosis in the absence of treatment . Current accepted therapeutic strategies include allogeneic stem - cell transplantation and immunosuppression , both resulting in long - term survival in the majority of patients . Although human leukocyte antigen ( HLA ) - matched sibling stem - cell transplantation is highly effective , the 25 % probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients . Transplantation using HLA - matched , unrelated donors carries a high risk of treatment failure along with considerable toxicity . While combined immunosuppression with both antithymocyte globulin ( ATG ) and cyclosporine A ( Q13216 ) produces hematologic improvement in most patients , relapse is common . Late evolution of aplastic anemia to other serious hematologic disorders , including paroxysmal nocturnal hemoglobinuria ( PNH ) , myelodysplasia , and acute leukemia , is also a significant problem following treatment with ATG / Q13216 . Recently , results of immunosuppression in P0DJI8 with another potent immunosuppressive agent , cyclophosphamide , were reported in a small number of patients . The overall response rate was similar to that seen with ATG / Q13216 , but relapse and late clonal disease were not observed during a long period of follow - up . A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG / Q13216 or high - dose cyclophosphamide and Q13216 is now underway ; secondary end points include response duration , event - free survival , and overall survival . Additionally , a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed .",
"Signalling mechanisms in sphingosine 1 - phosphate - promoted mesangial cell proliferation . BACKGROUND : The bioactive sphingolipid sphingosine 1 - phosphate ( Q14703 ) is formed by the activation of sphingosine kinase ( Q9NYA1 ) in diverse stimuli , such as platelet - derived growth factor ( PDGF ) . Q14703 acts not only as an extracellular mediator but also as an intracellular second messenger , resulting in the proliferation of various different types of cells . However , the signal transduction mechanism in Q14703 - induced proliferation of mesangial cells is poorly known . RESULTS : We examined the signalling mechanisms by which Q14703 and dihydro - Q14703 ( DHS1P ) , another Q14703 receptor agonist , induce mesangial cell proliferation . We first observed that exogenous Q14703 / DHS1P had additive effects on the PDGF - promoted proliferation of mesangial cells . Treatment of mesangial cells with pertussis toxin almost completely inhibited Q14703 - and DHS1P - induced , and slightly inhibited PDGF - induced cell proliferation . Additionally , the P29323 kinase inhibitor PD98059 partially blocked the proliferation of mesangial cells induced by all these ligands . N , N - dimethylsphingosine , a competitive inhibitor of Q9NYA1 , reduced PDGF - induced mesangial cell proliferation , whereas over - expression of Q9NYA1 promoted it . We also revealed that PDGF induces Q9NYA1 mRNA expression and Q9NYA1 activity , suggesting that Q9NYA1 , which links the PDGF to the Q14703 signalling cascade , is , at least in part , involved in PDGF - induced mesangial cell proliferation . Moreover , we found that extracellular Q14703 stimulates two Q14703 receptors , Q99500 and O95136 , which leads to cell proliferation and survival . CONCLUSIONS : The data show that Q14703 - induced mesangial cell proliferation is mediated by EDG - dependent and - independent signalling pathways . Q14703 may cooperate with PDGF to increase the proliferation of mesangial cells during pathophysiological processes ."
] |
[
"___MASK100___",
"___MASK33___",
"___MASK58___",
"___MASK59___",
"___MASK63___",
"___MASK65___",
"___MASK6___",
"___MASK86___",
"___MASK93___"
] |
___MASK93___
|
MH_train_348
|
interacts_with DB00918?
|
[
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK9___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"___MASK25___ : kinetic and dynamic profile in the treatment of pain . ___MASK25___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK25___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK25___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK25___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Safety profile of almotriptan , a new antimigraine agent . Effects on central nervous system , renal function and respiratory dynamics . DB00918 ( 3 - [ 2 -( dimethylamino ) ethyl ] - 5 -( pyrrolidin - 1 - ylsulfonylmethyl )- 1H - indole , CAS 154323 - 57 - 6 ) is a new P28222 / 1D agonist whose clinical efficacy has been demonstrated in Phase III clinical trials . This study aimed to evaluate the safety of almotriptan with respect to the central nervous system , renal function and respiratory dynamics using preclinical animal models . The results indicate that almotriptan does not cross the blood - brain barrier , since no effects on / interaction with spontaneous locomotor activity , hexobarbital - induced sleeping time , caffeine - induced increase of spontaneous locomotor activity , or hypothermia ( caused by stimulation of central P28221 receptors ) was observed following treatment . DB00918 had a mild antiemetic effect and a slight , transient diuretic effect in dogs , although the latter effect is probably of no clinical relevance . In addition , no effect on the respiratory system of conscious guinea pigs was observed following almotriptan treatment . These results indicate that almotriptan has a favourable safety profile with respect to the central nervous , renal and respiratory systems .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .",
"DB00918 is an effective and well - tolerated treatment for migraine pain : results of a randomized , double - blind , placebo - controlled clinical trial . DB00918 is a novel and specific serotonin P28222 / 1D agonist for the acute treatment of migraine . This randomized , single - dose , double - blind , multicentre , study assessed the efficacy and safety of oral almotriptan ( 12 . 5 mg and 25 mg ) in patients with migraine , and compared it with the standard treatment ( sumatriptan 100 mg ) and placebo . A total of 668 patients treated one migraine attack of moderate or severe intensity with study medication . The primary efficacy assessment was migraine pain relief , improvement from severe or moderate pain to mild or no pain , at 2 h after treatment . Response rates , stratified for variation in baseline pain levels , for both almotriptan doses were equivalent to sumatriptan and significantly better than placebo . Other efficacy assessments confirmed the equivalence of the almotriptan groups with the sumatriptan group . DB00918 12 . 5 mg was as well tolerated as placebo ( P = 0 . 493 ) and significantly better tolerated than sumatriptan ( P < 0 . 001 ) , in terms of the overall incidence of adverse events . There was no statistically significant difference in the incidence of adverse events between almotriptan 25 mg and sumatriptan 100 mg ( P = 0 . 376 ) . The results from this large clinical study indicate that the new , specific P28222 / 1D agonist , almotriptan , is an effective and well - tolerated treatment for migraine pain .",
"___MASK57___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK57___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"To press or not to press ? Differential receptor expression and response to novelty in rats learning an operant response for reward . Learning to perform instrumental tasks is an ability of all animals . In a population of rats , not all individuals will acquire an operant response for reward . We hypothesized that there could be a genetic explanation for differences between High Consumers ( those that acquired the lever press response ) and Low Consumers ( lever press response is low ) . Additionally , we proposed that this genetic difference could produce measurable changes in response to novelty . Wistar rats were trained to lever press for a 0 . 2 % saccharin reward and on the 10th day they were placed in a novel open field for 30 min to record locomotor activity . The prefrontal cortex and hippocampus were dissected and qPCR was used to measure mRNA expression . A significant difference ( p =. 048 ; 2 - way Q9UNW9 ) in gene expression was observed between Low and High Consumers . A principal component analysis ( DB11245 ) , to cluster which genes represent this difference , identified 4 genes ; 5 - Q13049 and mGlu1 in the hippocampus and AMPA GluR1 and adrenergic alpha2A in the prefrontal cortex . Response to a novel open field also differed since Low Consumers displayed a higher Total Distance in comparison to High Consumers . Additionally , Low Consumers could be subdivided into Low - Lever ( with lever press response only when water deprived ) and Low - Non - Lever ( lever press response is low throughout training ) . DB11245 with this subdivision identified an additional nine genes differing within the divisions ; DB01221 Q13224 and GABAAalpha3 in the prefrontal cortex and adrenergic alpha2B and alpha2A , AMPA GluR1 , GluR2 and GluR3 , P28222 and GABAAalpha5 in the hippocampus .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK21___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"___MASK15___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK15___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Desmopressin ( ___MASK32___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK32___ ) also has strong vasodilatory effects . ___MASK32___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK32___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK32___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK32___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK32___ - induced vasodilation .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK100___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK58___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers . OBJECTIVE : To assess the interaction between almotriptan , a P28222 / 1D - receptor agonist used to treat migraine , and verapamil , an agent for migraine prophylaxis . METHODS : Twelve healthy volunteers received the following treatments in a crossover design : ( 1 ) 120 - mg sustained - release verapamil tablet twice daily for 7 days and one 12 . 5 - mg almotriptan tablet on day 7 and ( 2 ) one 12 . 5 - mg almotriptan tablet alone on day 7 . Serial plasma and urine samples were obtained on day 7 . DB00918 plasma concentrations were determined by liquid chromatography - tandem mass spectrometry ; urine samples were analyzed by ultraviolet HPLC . Safety measures included blood pressure and pulse measurements , electrocardiography , and adverse event monitoring . Statistical comparisons of pharmacokinetic parameters and vital sign data were made by Q9UNW9 . RESULTS : Mean almotriptan peak concentration and area under the plasma concentration - time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone . The magnitudes of these differences were approximately 20 % . Renal clearance was unaffected by verapamil coadministration . No significant effects of treatment on blood pressure or pulse were detected , with the exception of sitting systolic blood pressure at 2 hours after administration . However , the difference in mean change from baseline at this time point was only 8 mm Hg . CONCLUSIONS : Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of P08684 to almotriptan metabolism . This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted .",
"DB00918 : a novel P28222 / D agonist for the symptomatic treatment of migraine . Currently available oral triptans are not ideal , at least for 20 - 30 % of migraine patients , due to either response failure or adverse events . DB00918 is a novel selective P28222 / D receptor agonist exhibiting the highest bioavailability among triptans , both outside and within a migraine attack . The tolerability of the therapeutic oral dose of almotriptan , 12 . 5 mg , is similar to that of placebo , with a remarkably low incidence of chest symptoms . At this dose , efficacy parameters remain comparable to those of sumatriptan 100 mg , while the recurrence rate is in the lower range . This balanced profile makes almotriptan 12 . 5 mg a good choice for the symptomatic treatment of the typical migraine patient .",
"Estrogen regulation of uterine genes in vivo detected by complementary DNA array . INTRODUCTION : In the present study , our aim was to identify differentially expressed genes involved in estrogen actions at the endometrium level in rats . METHODS : Thirty adult rats were ovariectomized four days prior to drug administration for 48 days . Rats were divided in 2 groups : I , control and II , conjugated equine estrogens ( CCE ) . Total RNA was isolated from uterus , and differential expression was analyzed by array technology and RT - PCR . RESULTS : A total of 32 candidate genes were shown to be upregulated or downregulated in groups I or II . Among them , differential expression was already confirmed by RT - PCR for P24593 , P28222 , c - kit , and P15692 , genes whose expression was up regulated during CCE therapy , and casein kinase II and serine kinase expression was the same level in both groups . CONCLUSION : We have demonstrated that cDNA array represents a powerful approach to identify key molecules in the estrogens therapy . A number of the candidates reported here should provide new markers that may contribute to the detection of target estrogen receptor . This information may also aid the development of new approaches to therapeutic intervention .",
"Antibody to ras proteins in patients with colon cancer . The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated P38936 ras protein was present . Studies focused on the aspartic acid substitution at amino acid position 12 ( denoted D12 ) , one of the most common mutations in colon adenocarcinoma . IgA antibodies directed against mutated P38936 ras - D12 protein were detected in 51 ( 32 % ) of 160 colon cancer patients , but only in 1 ( 2 . 5 % ) of 40 normal individuals . The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy . Examination of sera for antibody reactivity to wild - type P38936 ras protein ( denoted P38936 ras - G12 ) as well as P38936 ras proteins bearing the D12 , V12 , P28222 , or L61 mutations showed that antibody detected was largely to normal segments of the P38936 ras protein . Epitope mapping , using peptide neutralization assays with mutated or normal ras peptides as competitors , demonstrated that in 10 ( 67 % ) of 15 sera examined the antibody reactivity to P38936 ras - G12 protein was neutralized by peptides near the carboxyl terminus of P38936 ras protein , but not by peptides spanning the specific point mutation region . Antibody reactivities correlated with peripheral blood lymphocyte count , but did not correlate with patient age , sex , histology , stage , tumor locus , lymph node metastasis , or serum carcinoembryonic antigen .",
"Dose finding , placebo - controlled study of oral almotriptan in the acute treatment of migraine . OBJECTIVE : To assess the efficacy and tolerability of oral almotriptan , a selective serotonin receptor ( P28222 / 1D ) agonist , when used at different doses in the treatment of acute migraine . METHODS : This was a placebo controlled , double - blind , parallel - group , dose - finding study . Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2 , 6 . 25 , 12 . 5 , or 25 mg at the onset of moderate or severe pain . Patients graded pain intensity on a 4 - point verbal scale from 0 ( no pain ) to 3 ( severe pain ) and recorded adverse events . The primary efficacy variable was headache response at 2 hours . Data were analyzed on an intent - to - treat basis . RESULTS : Nine hundred and three patients were randomized , and 742 were included in the evaluation of the efficacy and tolerability . Headache response at 2 hours was 32 . 5 % with placebo , and 30 % , 56 . 3 % , 58 . 5 % , and 66 . 5 % with almotriptan 2 , 6 . 25 , 12 . 5 , and 25 mg doses ( p < 0 . 05 for 6 . 25 , 12 . 5 , and 25 mg vs placebo ) . A dose - dependent decrease in the incidence of migraine - associated symptoms and the need for escape medication was observed . The incidence of adverse events with the almotriptan 2 - mg , 6 . 25 - mg , and 12 . 5 - mg groups was comparable to that with the placebo group . CONCLUSION : DB00918 12 . 5 mg demonstrated the most favorable ratio between efficacy and tolerability , offering equivalent efficacy and better tolerability compared with the 25 mg dose . The minimum effective dose of almotriptan was 6 . 25 mg .",
"The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .",
"DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .",
"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK80___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 / 1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69 . 1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first - pass metabolism ( 18 . 7 - 79 . 6 % ) . The elimination half - life was short and ranged between 0 . 7 and 3 h . The main route of elimination of almotriptan was urine with 75 . 6 % and 80 . 4 % of the dose recovered over a 168 - h period in rats and dogs , respectively . The gamma - aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N - oxide metabolite were the main metabolites in dog .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .",
"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .",
"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC ."
] |
[
"___MASK100___",
"___MASK15___",
"___MASK21___",
"___MASK25___",
"___MASK32___",
"___MASK57___",
"___MASK58___",
"___MASK80___",
"___MASK9___"
] |
___MASK15___
|
MH_train_349
|
interacts_with DB00523?
|
[
"___MASK69___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK69___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK48___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"Human chromosome 3 and pig chromosome 13 show complete synteny conservation but extensive gene - order differences . A comparative map of human chromosome 3 ( HSA 3 ) and pig chromosome 13 ( SSC 13 ) was constructed using physically assigned pig sequence - tagged sites ( STSs ) . Pig STSs representing 11 HSA 3 genes , including v - P04049 murine leukemia viral oncogene homolog 1 ( P04049 ) , retinoic acid beta receptor ( P10826 ) , cholecystokinin ( CCK ) , pituitary transcription factor 1 ( P28069 ) , ceruloplasmin ( CP ) , guanine nucleotide binding protein , alpha - inhibiting polypeptide 2 ( P04899 ) , sucrase - isomaltase ( SI ) , rhodopsin ( P08100 ) , dopamine receptor D3 ( P35462 ) , growth - associated protein 43 ( P17677 ) , and somatostatin ( P61278 ) , were developed . Ten pig STSs were regionally mapped using a somatic cell hybrid panel ( SCHP ) to SSC 13 with 80 - 100 % concordance . Large - insert probes were obtained by screening a pig yeast artificial chromosome ( YAC ) library with primers for each STS . Several YACs were identified for P35462 , P17677 , P28069 , P08100 , SI , and P61278 for fluorescence in situ hybridization ( Q5TCZ1 ) mapping . Single gene and bi - color Q5TCZ1 with each pairwise combination were used to further define the gene order on SSC 13 . While these data confirm chromosome painting results showing that HSA 3 probes hybridize to a major portion of SSC 13 , they also demonstrate extensive gene - order differences between man and pig within this large conserved synteny group . Interestingly , several conserved chromosomal regions have been detected between pig and mouse that are not conserved between man and mouse , suggesting that the SSC 13 gene arrangement may be the closest to that of the ancestral eutherian chromosome .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK29___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"The expression of the solute carriers Q14973 and O75051 - 1 is regulated by cholesterol in HepG2 cells . Drug disposition and response are greatly determined by the activities of drug - metabolizing enzymes and transporters . While the knowledge in terms of CYP enzymes and efflux ABC transporters ( such as P08183 , P - glycoprotein ) is quite extensive , influx transporters are increasingly being unveiled as key contributors to the process of drug disposition . There is little information on the regulation of these proteins in human cells , especially as regards the effect of endogenous compounds . In this study , we analysed the expression of P08684 and three uptake transporters Q14973 ( Q14973 ) , P46721 / P46721 ( P46721 ) and O75051 - 1 ( O15245 ) in HepG2 cells following treatment with cholesterol . While P08684 and P46721 expression was unaffected , cholesterol treatment led to increased levels of Q14973 and O75051 - 1 mRNAs . Alterations in the functional characteristics and / or expression levels of drug transporters in the liver may conceivably contribute to the variability in drug oral bioavailability often observed in the clinical settings .",
"Retinoic acid regulates the development of oligodendrocyte precursor cells in vitro . Cultures of oligodendrocyte precursor cells can be grown from brain hemispheres of newborn rats . These cells , also called O - 2A progenitor cells , can differentiate in vitro into oligodendrocytes or type 2 astrocytes . Basic FGF and PDGF are known to stimulate their proliferation and delay their differentiation . Lack or excess of retinoic acid ( RA ) has been known for a long time to alter brain development suggesting that this compound is involved in normal brain development . Here we report that RA partially inhibits both the proliferation and the differentiation of oligodendrocyte precursor cells . It also down - regulates the mitogenic effect of P09038 on these cells while keeping them in an immature stage . RA is more effective than P09038 in inhibiting myelin basic protein mRNA expression in these cells , and like P09038 , it preserves their bipotential character . RA nuclear receptors P10276 and their transcripts are expressed in oligodendrocyte precursor cells as seen by Western blot , Northern blot and in situ hybridization . The expression of P10276 transcripts is stimulated transiently by RA alone or associated to P09038 . The expression of P10826 transcripts is not constitutive and is induced by RA alone or associated to P09038 and to a lesser extent by P09038 alone . These results suggest that retinoids participate in the control of the development of glial cells of the oligodendrocyte lineage .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK49___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK49___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK49___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK49___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Genome - wide association studies identify P30532 / 3 and Q13639 in the development of airflow obstruction . RATIONALE : Genome - wide association studies ( GWAS ) have identified loci influencing lung function , but fewer genes influencing chronic obstructive pulmonary disease ( P48444 ) are known . OBJECTIVES : Perform meta - analyses of GWAS for airflow obstruction , a key pathophysiologic characteristic of P48444 assessed by spirometry , in population - based cohorts examining all participants , ever smokers , never smokers , asthma - free participants , and more severe cases . METHODS : Fifteen cohorts were studied for discovery ( 3 , 368 affected ; 29 , 507 unaffected ) , and a population - based family study and a meta - analysis of case - control studies were used for replication and regional follow - up ( 3 , 837 cases ; 4 , 479 control subjects ) . Airflow obstruction was defined as Q99581 ( 1 ) and its ratio to FVC ( Q99581 ( 1 )/ FVC ) both less than their respective lower limits of normal as determined by published reference equations . MEASUREMENTS AND MAIN RESULTS : The discovery meta - analyses identified one region on chromosome 15q25 . 1 meeting genome - wide significance in ever smokers that includes A2RU49 , P48200 , and P30532 / P32297 genes . The region was also modestly associated among never smokers . Gene expression studies confirmed the presence of P30532 / 3 in lung , airway smooth muscle , and bronchial epithelial cells . A single - nucleotide polymorphism in Q13639 , a gene previously related to Q99581 ( 1 )/ FVC , achieved genome - wide statistical significance in combined meta - analysis . Top single - nucleotide polymorphisms in Q9H013 , P10826 , O14495 , and Q8TE59 were nominally replicated in the P48444 meta - analysis . CONCLUSIONS : These results suggest an important role for the P30532 / 3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the Q13639 gene in the etiology of airflow obstruction .",
"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK81___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .",
"DNA hypermethylation and clinicopathological features in breast cancer : the Western New York Exposures and Breast Cancer ( WEB ) Study . Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in carcinogenesis . We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors among 803 incidence breast cancer cases from a large population - based case - control study conducted in Western New York State . DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the P12830 , p16 , and P10826 ( 2 ) genes using real time methylation - specific polymerase chain reaction . The frequencies of hypermethylation were 20 . 0 % for P12830 , 25 . 9 % for p16 , and 27 . 5 % for P10826 ( 2 ) genes . For postmenopausal women , hypermethylation of P12830 tended to be more likely in progesterone receptor ( PR ) negative than in PR - positive tumors ( odds ratio ( OR ) , 1 . 41 ; 95 % confidence interval ( CI ) , 0 . 91 - 2 . 18 ) . Hypermethylation of p16 tended to be more frequent among estrogen receptor ( ER ) negative cases than ER - positive cases ( OR , 1 . 51 ; 95 % CI , 1 . 01 - 2 . 32 ) . Hypermethylation of P10826 ( 2 ) gene was inversely associated with histological and nuclear grade of breast cancer .",
"Anti - tumor effect of vitamin A and D on head and neck squamous cell carcinoma . OBJECTIVES : DB00162 and D ( 3 ) have a very strong differentiation induction effect . STUDY DESIGN : We examined the anti tumor effect on head and neck squamous cell carcinoma ( HNSCC ) by treatment with several vitamins having strong differentiation induction effects in vitro . METHODS : We used KB cell that an oral floor squamous cell carcinoma , vitamins as all - trans retinoic acid ( DB00755 ) , 4 - [ 3 , 5 - bis ( trimethylsilyl ) benzamido ] benzoic acid ( TAC - 101 ) , 1alpha , 25 ( OH )( 2 ) D ( 3 ) ( calcitriol ) and 22 - oxa - 1 , 25 -( OH )( 2 ) D ( 3 ) ( O75051 ) . We determined receptors of vitamin A and D ( 3 ) using RT - PCR . Furthermore , we investigated the proliferation of tumor cells in concentration dependency using [ 3H ] TdR uptake method , apoptosis and apoptosis related factors using TUNEL method and real - time PCR , cell cycle changes using flow cytometry , changing of the sensitivity of using MTT method , cytokine production and the angiogenesis factor using ELISA , by treatment with these vitamins . RESULTS : The deficit of P10826 was found in the KB cell . Each vitamin suppressed the cell proliferation , induced apoptosis , and cell cycle arrest , upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor ; survivin . CONCLUSIONS : These results support the idea that vitamin A , D ( 3 ) and their derivatives are useful for preventing and / or treating patients with HNSCC .",
"P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK58___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .",
"Associations between single nucleotide polymorphisms in cellular viral receptors and attachment factor - related genes and humoral immunity to rubella vaccination . BACKGROUND : Viral attachment and cell entry host factors are important for viral replication , pathogenesis , and the generation and sustenance of immune responses after infection and / or vaccination , and are plausible genetic regulators of vaccine - induced immunity . METHODS : Using a tag - SNP approach in candidate gene study , we assessed the role of selected cell surface receptor genes , attachment factor - related genes , along with other immune genes in the genetic control of immune response variations after live rubella vaccination in two independent study cohorts . RESULTS : Our analysis revealed evidence for multiple associations between genetic variants in the P15151 , Q92692 , Q9NNX6 / Q9NNX6 , P10826 , Q16653 , P05231 and other immune function - related genes and rubella - specific neutralizing antibodies after vaccination ( meta p - value < 0 . 05 ) . CONCLUSION : Our results indicate that multiple SNPs from genes involved in cell adhesion , viral attachment , and viral entry , as well as others in genes involved in signaling and / or immune response regulation , play a role in modulating humoral immune responses following live rubella vaccination .",
"Induction of retinoic acid receptor - beta suppresses cyclooxygenase - 2 expression in esophageal cancer cells . Since retinoic acid receptor ( RAR ) - beta mRNA is frequently lost during esophageal carcinogenesis and esophageal cancer cells that do not express P10826 are resistant to retinoic acid ( RA ) , we stably transfected P10826 expression vector into an esophageal cancer cell line TE - 8 and an antisense P10826 into TE - 3 cells . Transfection of P10826 decreased cell growth and colony formation and induced apoptosis in TE - 8 cells . Antisense P10826 - transfected TE - 3 cells had a shorter doubling time and became resistant to RA . Induction of P10826 decreased P35354 expression in P10826 transfected TE - 8 cells , whereas antisense P10826 transfected TE - 3 cells increased P35354 expression . The inhibitory effect of P10826 on P35354 expression was further enhanced in the presence of RA , which was blocked by an RAR antagonist . The synthetic retinoid N -( 4 - hydroxyphenyl ) retinamide , which does not bind effectively to P10826 , had no effect on P35354 suppression . Furthermore , RA blocked bile acid - induced P35354 expression and prostaglandin E ( 2 ) production only in the P10826 positive cells . Our data demonstrated that anticancer effect of P10826 may be related to its ability to suppress P35354 expression and support that the loss of P10826 expression may contribute to esophageal carcinogenesis .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK89___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK89___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Novel real - time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia . The recent World Health Organization classification recognizes different subtypes of acute myeloid leukemia ( AML ) according to the presence of several recurrent genetic abnormalities . Detection of these abnormalities and other molecular changes is of increasing interest because it contributes to a refined diagnosis and prognostic assessment in AML and enables monitoring of minimal residual disease . These genetic abnormalities can be detected using single RT - PCR , although the screening is still labor intensive and costly . We have developed a novel real - time RT - PCR assay to simultaneously detect 15 AML - associated rearrangements that is a simple and easily applicable method for use in clinical diagnostic laboratories . This method showed 100 % specificity and sensitivity ( 95 % confidence interval , 91 % to 100 % and 92 % to 100 % , respectively ) . The procedure was validated in a series of 105 patients with AML . The method confirmed all translocations detected using standard cytogenetics and fluorescence in situ hybridization and some additional undetected rearrangements . Two patients demonstrated two molecular rearrangements simultaneously , with P11274 - P00519 implicated in both , in addition to Q01196 - MECOM in one patient and P29590 - P10276 in another . In conclusion , this novel real - time RT - PCR assay for simultaneous detection of multiple AML - associated fusion genes is a versatile and sensitive method for reliable screening of recurrent rearrangements in AML .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK33___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK33___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"Expression of human all - trans - retinoic acid receptor beta and its ligand - binding domain in Escherichia coli . DB00755 , one of the hormonally active derivatives of vitamin A , occurs physiologically in plasma at a concentration below 10 nmol / l . The methods currently used for its quantification are based on HPLC , need about 1 ml of serum , are relatively laborious and thus not well suited for mass analysis . The affinity and specificity of retinoic acid receptors for all - trans - retinoic acid encouraged us to express both the entire human retinoic acid receptor beta ( P10826 ) and two versions of its retinoic acid - binding domain in Escherichia coli in the hope that these recombinant proteins might be used as binders in a ligand - binding assay for all - trans - retinoic acid . The recombinant receptors , the whole receptor [ P10826 -( Q93033 - Q448 ) ] , corresponding to domains A - F , and the ligand - binding domain [ P10826 -( E149 - Q448 ) ] , corresponding to domains D - F , were expressed in the vector pET 3d / BL21 ( DE3 ) as inclusion bodies , solubilized with guanidinium chloride , renatured and purified by ion - exchange chromatography . P10826 -( P193 - Q448 ) , corresponding to domains E - F , was expressed in the vector pET 3d / BL21 ( DE3 ) pLysS , and purified by reversed - phase chromatography . Under non - denaturing conditions , the expressed whole receptor [ P10826 -( Q93033 - Q448 ) ] and the D - F construct ( P10826 -( E149 - Q448 ) ] behaved chromatographically as monomeric proteins whereas the E - F construct [ P10826 -( P193 - Q448 ) ] had a strong tendency to aggregate . P10826 -( Q93033 - Q448 ) and P10826 -( E149 - Q448 ) had similar Kd values for all - trans - retinoic acid ( 1 . 4 and 0 . 6 nmol / l respectively ) whereas P10826 -( P193 - Q448 ) bound all - trans - retinoic acid less avidly ( Kd 9 . 6 nmol / l ) . DB00523 bound to P10826 -( E149 - Q448 ) and P10826 -( Q93033 - Q448 ) as avidly as all - trans - retinoic acid . Competition experiments showed weak or no binding of 4 - oxo - all - trans - retinoic acid , 4 - oxo - 13 - cis - retinoic acid , 13 - cis - retinoic acid , acitretin and retinol by P10826 -( E149 - Q448 ) .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Retinoic acid - induced modulation of P60568 mRNA production and P60568 receptor expression on T cells . BACKGROUND : Retinoic acid ( RA ) has important immune - modulating effects on both T and B cell function . Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin ( Ig ) response . Investigating cytokines known to affect B cell differentiation , we have recently shown that P05231 production is augmented by RA . In the present study we have examined the immune modulating effects of RA on P60568 mRNA , another important cytokine for B cell immunoglobulin production , the expression of P60568 receptors on T cells , and the RA nuclear receptors . METHODS : Purified T cells were obtained from adenoidal tissues , and incubated with RA ( 10 (- 7 ) M ) or DB01093 solvent / media control for 0 , 6 - 8 , and 24 h . Total mRNA was extracted from T cells , and using RT - PCR , changes in the production of P60568 and RA receptors ( RAR ) - alpha , beta , gamma mRNA were determined . The effects of RA on P60568 - alpha receptor expression was determined by flow cytometry on T cells . CONCLUSION : These studies suggest that RA can augment P60568 mRNA production by T cells with a possible paracrine effect on IL - 2R - alpha expression . These changes appear to be mediated by P10276 . Thus , P60568 may be another important cytokine modulated by RA in the immune response .",
"Synergism between bosutinib ( ___MASK25___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Dynamic network of transcription and pathway crosstalk to reveal molecular mechanism of MGd - treated human lung cancer cells . Recent research has revealed various molecular markers in lung cancer . However , the organizational principles underlying their genetic regulatory networks still await investigation . Here we performed Network Component Analysis ( P40199 ) and Pathway Crosstalk Analysis ( DB11245 ) to construct a regulatory network in human lung cancer ( A549 ) cells which were treated with 50 uM DB05428 ( MGd ) , a metal cation - containing chemotherapeutic drug for 4 , 12 , and 24 hours . We identified a set of key TFs , known target genes for these TFs , and signaling pathways involved in regulatory networks . Our work showed that putative interactions between these TFs ( such as P03372 / Sp1 , Q01094 / Sp1 , c - MYC - P03372 , P84022 / c - Myc , and P19838 / Q04206 ) , between TFs and their target genes ( such as BMP41 / Est1 , P49815 / Myc , P27695 / Sp1 / p53 , P10276 / P49639 , and SP1 / Q15853 ) , and between signaling pathways ( such as Q07869 signaling pathway and Adipocytokines signaling pathway ) . These results will provide insights into the regulatory mechanism of MGd - treated human lung cancer cells .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5 - HT 2C , P50406 , and P34969 serotonin receptors : implications for extrapyramidal side effects of serotonin reuptake inhibitors . The striatum is richly innervated by serotonergic afferents from the raphe nucleus . We explored the effects of this input on striatal cholinergic interneurons from rat brain slices , by means of both conventional intracellular and whole - cell patch - clamp recordings . Bath - applied serotonin ( 5 - HT , 3 - 300 microM ) , induced a dose - dependent membrane depolarization and increased the rate of spiking . This effect was mimicked by the 5 - HT reuptake blockers citalopram and fluvoxamine . In voltage - clamped neurons , 5 - HT induced an inward current , whose reversal potential was close to the K (+) equilibrium potential . Accordingly , the involvement of K (+) channels was confirmed either by increasing extracellular K (+) concentration and by blockade of K (+) channels with barium . Single - cell reverse transcriptase - polymerase chain reaction ( RT - PCR ) profiling demonstrated the presence of P28335 , P50406 , and P34969 receptor mRNAs in identified cholinergic interneurons . The depolarization / inward current induced by 5 - HT was partially mimicked by the 5 - HT2 receptor agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine and antagonized by both ketanserin and the selective P28335 antagonist RS102221 , whereas the selective 5 - Q9H205 and Q13639 receptor antagonists tropisetron and RS23597 - 190 had no effect . The depolarizing response to 5 - HT was also reduced by the selective P50406 and P34969 receptor antagonists SB258585 and SB269970 , respectively , and mimicked by the P34969 agonist , 5 - CT . Accordingly , activation of either P50406 or P34969 receptor induced an inward current . The 5 - HT response was attenuated by U73122 , blocker of phospholipase C , and by SQ22 , 536 , an inhibitor of adenylyl cyclase . These results suggest that 5 - HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons .",
"Gene expression profiling in chronic myeloid leukemia patients treated with hydroxyurea . Using array technology that allows the simultaneous detection of gene expression of hundreds of genes , four patients with chronic myeloid leukemia ( CML ) were investigated at diagnosis and after starting administration of hydroxyurea . To detect the gene expression of peripheral blood mononuclears and granulocytes Human Cancer cDNA Array ( CLONTECH ) with 588 gene probes was used . Gene expression mononuclear and granulocyte profiles of patients at diagnosis were compared with the control profiles . The significant expression changes observed in most patients seemed to be important . Increased expression of c - jun N - terminal kinase 2 ( P45984 ) , integrin alpha E , P22894 , P14780 was detected in both fractions of most patients . In some samples P12004 , P51858 , MAPK p38 , P13987 increased expressions were found . Significant down - regulation of expression in patients was detected in genes P11802 inhibitor A , Q00577 , notch1 in mononuclears ; P52630 , P42229 , P10276 , Q8WXI8 - 1 , junB , caspase 4 in granulocytes ; Q00534 , P35638 , P00533 - 3 , cadherin 5 in both fractions . Expression profiles detected in patients at diagnosis did not differ markedly from those after one - week treatment with hydroxyurea . Only in a few genes were significant changes after hydroxyurea administration observed and inter - individual expression differences were rather common .",
"Induction of cyclooxygenase - 2 by benzo [ a ] pyrene diol epoxide through inhibition of retinoic acid receptor - beta 2 expression . Benzo [ a ] pyrene diol epoxide ( BPDE , a carcinogen present in tobacco smoke and environmental pollution ) has been shown to suppress retinoic acid receptor - beta2 ( P10826 ( 2 ) ) and induce cyclooxygenase - 2 ( P35354 ) expression . Restoration of P10826 ( 2 ) inhibited growth and colony formation of esophageal cancer cells , which was correlated with P35354 suppression . In this study , we investigated the molecular mechanisms for P10826 ( 2 )- mediated suppression of P35354 expression using BPDE as a tool . We found that BPDE - induced P35354 expression was through inhibition of P10826 ( 2 ) and consequently , induction of epidermal growth factor receptor ( P00533 ) , extracellular signal - regulated protein kinases 1 / 2 ( Erk1 / 2 ) phosphorylation , and c - Jun expression . Esophageal cancer cells that do not express P10826 ( 2 ) did not respond to BPDE for induction of P35354 . BPDE was also unable to induce P35354 expression after P10826 ( 2 ) expression was manipulated in these esophageal cancer cells . Furthermore , BPDE induced time - dependent methylation of P10826 ( 2 ) gene promoter in esophageal cancer cells . Transfection of P10826 ( 2 ) expression vector into esophageal cancer cells suppressed expression of P00533 , Erk1 / 2 phosphorylation , c - Jun , and P35354 . In addition , co - treatment of P10826 ( 2 )- positive cells with BPDE and the Q02750 / 2 inhibitor U0126 caused little change in c - Jun and P35354 expression . This study demonstrated that BPDE - suppressed expression of P10826 ( 2 ) results in P35354 induction and restoration of P10826 ( 2 ) expression reduces P35354 protein in esophageal cancer cells , thereby further supporting our previous finding that P10826 ( 2 ) plays an important role in suppressing esophageal carcinogenesis .",
"Growth - inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells . Retinoids and vitamin D are important factors that regulate cellular growth and differentiation . An additive growth - inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma , leukaemic and breast cancer cells . We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all - trans - and 9 - cis - retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T . The cell lines investigated expressed vitamin D receptor , retinoic acid receptor ( RAR ) - alpha and gamma as determined by polymerase chain reaction after reverse transcription . P10826 was expressed only in Hs766T cells . Addition of all - trans - retinoic acid increased the amount of P10276 mRNA in the three cell lines and induced P10826 mRNA in Capan 1 and Capan 2 cells . All - trans - retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40 % relative to controls . DB00523 was less effective . Neither all - trans - retinoic acid nor 9 - cis - retinoic acid affected the growth of Hs766T cells . EB1089 , if added alone to the cells , did not significantly inhibit growth . However , the combination of 1 nM EB1089 with 10 nM all - trans - retinoic acid exerted a growth - inhibitory effect of 90 % in Capan 1 cells and of 70 % in Capan 2 cells . Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells . However , in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer .",
"Dexamethasone inhibits interleukin - 1β - induced matrix metalloproteinase - 9 expression in cochlear cells . OBJECTIVES : To investigate the effect of interleukin ( IL ) - 1β on matrix metalloproteinase ( MMP ) - 9 expression in cochlea and regulation of IL - 1β - mediated P14780 expression by dexamethasone and the molecular and signaling mechanisms involved . METHODS : House ear institute - organ of Corti 1 ( HEI - OC1 ) cells were used and exposed to IL - 1β with / without dexamethasone . P04150 antagonist , ___MASK58___ , was used to see the role of dexamethasone . PD98059 ( an extracellular signal - regulated kinases [ ERKs ] inhibitor ) , SB203580 ( a p38 mitogen - activated protein kinases [ MAPK ] inhibitor ) , SP600125 ( a c - Jun N - terminal kinase [ JNK ] inhibitor ) were also used to see the role of MAPKs signaling pathway ( s ) in IL - 1β - induced P14780 expression in HEI - OC1 cells . Reverse transcription - polymerase chain reaction and gelatin zymography were used to measure mRNA expression level of P14780 and activity of P14780 , respectively . RESULTS : Treatment with IL - 1β - induced the expression of P14780 in a dose - and time - dependent manner . IL - 1β ( 1 ng / mL ) - induced P14780 expression was inhibited by dexamethasone . Interestingly , p38 MAPK inhibitor , SB203580 , significantly inhibited IL - 1β - induced P14780 mRNA and P14780 activity . However , inhibition of JNKs and ERKs had no effect on the IL - 1β - induced P14780 expression . CONCLUSION : These results suggest that the pro - inflammatory cytokine IL - 1β strongly induces P14780 expression via activation of p38 MAPK signaling pathway in HEI - OC1 cells and the induction was inhibited by dexamethasone ."
] |
[
"___MASK25___",
"___MASK29___",
"___MASK33___",
"___MASK48___",
"___MASK49___",
"___MASK58___",
"___MASK69___",
"___MASK81___",
"___MASK89___"
] |
___MASK58___
|
MH_train_350
|
interacts_with DB06663?
|
[
"O95760 augments DB05875 - induced P15692 secretion from human mast cells and is increased in psoriatic skin . The peptide DB05875 ( SP ) has been implicated in inflammatory conditions , such as psoriasis , where mast cells and P15692 are increased . A relationship between SP and P15692 has not been well studied , nor has any interaction with the proinflammatory cytokines , especially O95760 . Here we report that SP ( 0 . 1 - 10 microM ) induces gene expression and secretion of P15692 from human LAD2 mast cells and human umbilical core blood - derived cultured mast cells ( hCBMCs ) . This effect is significantly increased by coadministration of O95760 ( 5 - 100 ng / mL ) in both cell types . The effect of SP on P15692 release is inhibited by treatment with the P25103 antagonist 733 , 060 . SP rapidly increases cytosolic calcium , and so does O95760 to a smaller extent ; the addition of O95760 augments the calcium increase . SP - induced P15692 production involves calcium - dependent PKC isoforms , as well as the P29323 and JNK MAPKs . Gene expression of O95760 and histidine decarboxylase ( HDC ) , an indicator of mast cell presence / activation , is significantly increased in affected and unaffected ( at least 15 cm away from the lesion ) psoriatic skin , as compared with normal control skin . Immunohistochemistry indicates that O95760 is associated with endothelial cells in both the unaffected and affected sites , but is stronger and also associated with immune cells in the affected site . These results imply that functional interactions among SP , O95760 , and mast cells leading to P15692 release contribute to inflammatory conditions , such as the psoriasis , a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component .",
"Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .",
"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .",
"Gene - environment interactions in obesity . Obesity is a global and growing problem . The detrimental health consequences of obesity are significant and include co - morbidities such as diabetes , cancer and coronary heart disease . The marked rise in obesity observed over the last three decades suggests that behavioural and environmental factors underpin the chronic mismatch between energy intake and energy expenditure . However , not all individuals become obese , suggesting that there is considerable variation in responsiveness to ' obesogenic ' environments . Some individuals defend easily against a propensity to accumulate fat mass and become overweight whilst others are predisposed to gain weight , possibly as a function of genotype . The genetic contribution to obesity is well established . Common obesity is polygenic , involving complex gene - gene and gene - environment interactions , and it is these interactions that produce the multi - factorial obese phenotypes . Candidate gene variants for polygenic obesity appear to disrupt pathways involved in the regulation of energy intake and expenditure and include adrenergic receptors , uncoupling proteins , P37231 , P01189 , P32245 and a set of single nucleotide polymorphisms in the Q9C0B1 locus . Notably , the Q9C0B1 gene is the most robust gene for common obesity characterised to date , and recent data shows that the Q9C0B1 locus seems to confer risk of obesity through increasing energy intake and reduced satiety . Gene variants involved in pathways regulating addiction and reward behaviours may also play a role in predisposition to obesity . Understanding the routes through which the genotype is expressed will ultimately provide opportunities for developing strategies to intervene , as the interaction between genotype and environment is potentially modifiable through behaviour change .",
"Cerebrospinal fluid and plasma corticotropin - releasing hormone in senile dementia . Cerebrospinal fluid ( P04141 ) levels of corticotropin - releasing hormone ( P06850 ) and DB01285 , and plasma levels of P06850 , DB01285 and cortisol were determined in samples taken simultaneously from 28 patients with dementia including senile dementia of the Alzheimer type ( SDAT ) , multi - infarct dementia ( MID ) , dementia following a cerebrovascular accident ( CVD ) , and the borderline - to - normal state . P06850 levels in P04141 were significantly reduced in patients with SDAT and CVD , but not in those with MID , as compared with the borderline cases . DB01285 levels in P04141 were significantly reduced in the patients with SDAT compared to those with MID . Reduced P06850 levels in P04141 were found in the patients who showed severe dementia and poor activities of daily living ( Q16586 ) . Plasma levels of P06850 , DB01285 and cortisol were normal and were not significantly different among the four groups of patients . P06850 levels in P04141 were positively correlated with DB01285 levels in P04141 , but not with the levels of plasma P06850 , DB01285 or cortisol . Plasma P06850 levels were positively correlated with plasma DB01285 levels . These results suggest that : 1 ) abnormalities in the extrahypothalamic P06850 system play a role in the pathophysiology of senile dementia , which may not be specific to SDAT ; 2 ) P04141 P06850 is correlated with the severity of dementia and Q16586 ; 3 ) the levels of P06850 in P04141 and plasma are independent , and 4 ) the plasma P06850 reflects , at least in part , the activity of the hypothalamic P06850 regulating the secretion of pituitary DB01285 .",
"Modulation of expression of somatostatin receptor subtypes in Graves ' ophthalmopathy orbits : relevance to novel analogs . Apart from evaluating orbital inflammation in Graves ' ophthalmopathy ( GO ) , somatostatin ( P61278 ) analogs have been proposed as a therapy , but recent trials were disappointing . We aimed to measure somatostatin receptor ( SSTR ) expression in orbital tissues ex vivo and determine whether the new broad - affinity analog DB06663 might be of therapeutic use . Orbital adipose / connective tissues from 29 GO patients and 10 normal individuals were analyzed . Transcripts were quantified using SYBR Green and a light cycler . In vitro models were used to investigate whether thyrotropin receptor activation ( as occurs via thyroid stimulating antibodies ) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and DB06663 in their modulation . The expression of P30872 was significantly higher in GO patients than normal controls ( P = 0 . 024 ) . Although differences in the expression of P30874 were not significant , 39 % of GO samples had levels above the 97th percentile of the controls . P32745 , - 4 , and - 5 were at or below the limit of detection ( LOD ) . The lymphocyte contribution was minimal , since CD3alpha transcripts were at the LOD . DB00024 receptor activation did not modulate SSTR expression . An in vitro model of adipogenesis indicated upregulation of P30872 and P30874 during differentiation . DB06663 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide . Ex vivo analysis of orbital tissues reveals upregulation of P30872 and - 2 in a group of GO patients . Adipogenesis , a process occurring in GO orbits , provides one possible explanation for some of the observed increase .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK5___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Taiwanofungus camphoratus activates peroxisome proliferator - activated receptors and induces hypotriglyceride in hypercholesterolemic rats . Taiwanofungus camphoratus ( T . camphoratus ) , a fungus and a Taiwan - specific , well - known traditional Chinese medicine , has long been used to treat diarrhea , hypertension , itchy skin , and liver cancer . To gain a large amount of T . camphoratus , several culture techniques have been developed , including solid - state culture and liquid - state fermentation . P37231 ( PPARgamma ) has been described as a hypoglycemic agent that increases insulin sensitivity in peripheral tissues and results in reduced blood glucose , insulin , and triglyceride levels in insulin - resistant animals and in type - 2 ( non - insulin - dependent ) diabetic patients . In this study , we investigate the possibility that T . camphoratus might activate PPARgamma in vitro and hypolipidemic activity in vivo . The results show that an aqueous extract of the wild fruiting bodies of T . camphoratus was able to increase the PPARgamma activity in cells transfected with the PPARgamma expression plasmid and the AOx - TK reporter plasmid . Based on the cell experiment , we examined the hypolipidemic effect of wild fruiting bodies ( WFT ) and a solid - state culture ( P61278 ) of T . camphoratus on SD rats fed on a high - cholesterol ( HC ) diet . The results show that WFT significantly decreased the serum triglyceride level , but could not affect the cholesterol level . P61278 only slightly decreased the serum triglyceride level . In addition , both WFT and P61278 significantly decreased the serum alanine transaminase ( ALT ) level and protected against the liver damage induced by the HC diet from the results of a histological examination . These results suggest that T . camphoratus might contain PPARgamma ligands and result in a hypotriglyceridemic effect , and that it also exhibits a liver protective activity .",
"DB00104 prevents growth factor - induced proliferation of bovine retinal endothelial cells under hypoxia . Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries . The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation . Particularly , hypoxia and growth factors , such as P15692 , DB01277 , P09038 and TGF beta ( 2 ) , show a complex interaction in the onset and progression of the diseases . Therefore , to date , most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors . Recently , a synthetic analog of somatostatin , octreotide , has been shown to inhibit the proliferation of various cells in vitro , including endothelial cells . In this study , we have investigated the proliferative response of bovine retinal endothelial cells ( BREC ) to growth factors under hypoxic conditions and the modulation by octreotide . We found a dose - dependent increase of cell proliferation with P15692 , DB01277 and P09038 , and inhibition of hypoxia - induced cell proliferation with TGF beta ( 2 ) . Moreover , growth factor - induced , but not hypoxia - induced , cell proliferation was attenuated in the presence of octreotide . In contrast , TGF beta ( 2 ) abolished hypoxia - induced BREC proliferation . Similar to octreotide BIM23027 , a somatastatin receptor subtype 2 ( P30874 ) receptor agonist was able to attenuate the growth factor - induced proliferation of BREC expressing mRNA and protein for P30874 . Therefore , we postulate that octreotide exerts its effects mainly through binding to the P30874 . Taken together , our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor - dependent proliferation of endothelial cells .",
"Pharmacogenomics of methadone maintenance treatment . ___MASK64___ is the major opioid substitution therapy for opioid dependence . Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines . Nevertheless many genetic factors have been investigated including those affecting its metabolism ( P20813 - consistent results ) , efflux transport ( P - gp - inconsistent results ) , target μ - opioid receptor ( μ - opioid receptor - inconsistent results ) and a host of other receptors ( P14416 ) and signaling elements ( P48051 and P32121 ; not replicated ) . None by themselves have been able to substantially explain dosage variation ( the major but not sole end point ) . When multiple genes have been combined such as P08183 , P20813 , P35372 and P14416 a greater contribution to dosage variation was found but not as yet replicated . As stabilization of dosage needs to be made rapidly , it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed , which may or may not tailor to different ethnic groups and each country ' s policy towards an outcome that benefits all .",
"Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy . The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors ( GEP - NETs ) have increased in the past 20 years . GEP - NETs are heterogeneous tumors , in terms of clinical and biological features , that originate from the pancreas or the intestinal tract . Some GEP - NETs grow very slowly , some grow rapidly and do not cause symptoms , and others cause hormone hypersecretion and associated symptoms . Most GEP - NETs overexpress receptors for somatostatins . Somatostatins inhibit the release of many hormones and other secretory proteins ; their effects are mediated by G protein - coupled receptors that are expressed in a tissue - specific manner . Most GEP - NETs overexpress the somatostatin receptor P30874 ; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone - related symptoms and also have antitumor effects . Long - acting formulations of somatostatin analogues stabilize tumor growth over long periods . The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP - NETs . Peptide receptor radiotherapy has significant antitumor effects , increasing overall survival times of patients with tumors that express a high density of SSTRs , particularly P30874 and P35346 . The multi - receptor somatostatin analogue DB06663 ( pasireotide ) and chimeric molecules that bind P30874 and the dopamine receptor D2 are also being developed to treat patients with GEP - NETs . Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways , such as mammalian target of rapamycin ( P42345 ) and vascular endothelial growth factor , might be the most effective therapeutics for GEP - NETs .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Inhibitory effects of DB06663 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo . DB01285 ( DB01285 ) production by pituitary corticotroph adenomas is the main cause of Cushing ' s disease . A drug that targets pituitary DB01285 - secreting adenomas would aid treatment of Cushing ' s disease . DB00104 , a somatostatin receptor type 2 ( P30874 ) - preferring somatostatin analogue , has no effect on DB01285 secretion in patients with Cushing ' s disease . The multiligand DB06663 ( pasireotide ) displays a much higher affinity for P30872 and P35346 than octreotide and suppresses DB01285 secretion in cultures of human corticotroph tumors to a greater extent than octreotide . In the present in vitro and in vivo study , we determined the effect of DB06663 on DB01285 production and cell proliferation of AtT - 20 corticotroph tumor cells . DB06663 decreased proopiomelanocortin ( P01189 ) mRNA levels in AtT - 20 cells and DB01285 levels in the culture medium of these cells , suggesting that DB06663 suppresses DB01285 synthesis and secretion in corticotroph tumor cells . DB06663 also decreased cell proliferation and both cyclic adenosine monophosphate response element - binding protein and Akt phosphorylation in AtT - 20 cells . P35346 knockdown inhibited the DB06663 - induced decreases in cell proliferation . Fluorescence - activated cell sorting analyses revealed that DB06663 did not attenuate cell cycle progression . Tumor weight in mice xenografted with AtT - 20 cells and treated with DB06663 was significantly lower than in AtT - 20 - xenografted control mice . DB06663 also significantly decreased plasma DB01285 levels , and P01189 and pituitary tumor transforming gene mRNA levels in the tumor cells . Thus , DB06663 inhibits DB01285 production and corticotroph tumor cell proliferation in vitro and in vivo .",
"P30872 and P35346 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors . The effectiveness of the long acting somatostatin analogues like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells . The immunohistochemical method performed on surgically removed tumors searches the expression of receptors at the level of receptor protein and gives us insight into receptor ' s cellular localization . The aim of study was to assess the presence of all the 5 subtypes of SSTR 1 - 5 ( including 2A and 2B SSTR isoforms ) in surgically treated human neuroendocrine tumors ( NETs ) to establish which receptor subtype is the dominant form of somatostatin receptor in particular tumor and thus to be able to predict which somatostatin analog will be effective in NETs treatment . 18 samples of neuroendocrine tumors ( surgically excised tumors or biopsies ) were immunostained with specific antibodies . Expression of SSTR was scored semiquantitatively . Only strong or moderate immunostaining was considered as positive reaction . The summarized expression pattern of SSTR in the investigated neuroendocrine tumors in our material was : SSTR 1 > SSTR 5 > SSTR 3 > SSTR 2A > SSTR 2B . The receptors were distributed mainly in the area of cells cytoplasm with a few specimens showing only membranous or mixed : membranous -- cytoplasmic localization . The observed pattern suggests that apart from octreotide and lanreotide , newly synthesized multiligand analogs such as DB06663 , KE 108 or SSTR 1 and SSTR 5 selective analogs could be effective in NETs treatment .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK16___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK16___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .",
"Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .",
"Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune - mediated arthritis . OBJECTIVE : Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties . However , it is not known which of the 5 somatostatin receptor subtypes ( SSTRs 1 - 5 ) is involved in these actions . The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide ( DB06663 ) in a mouse model of antigen - induced arthritis ( AIA ) . METHODS : Studies were performed in P30874 - deficient mice ( P30874 (-/-) ) and their wild - type littermates ( P30874 (+/+) ) . The expression of P30872 , SSTR2A , P32745 , and P35346 in dorsal root ganglia was examined by immunohistochemistry . RESULTS : Untreated P30874 (-/-) mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in P30874 (+/+) mice . In wild - type mice , both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone . In P30874 (-/-) mice , the antiinflammatory effects of both octreotide and pasireotide were completely abrogated . Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions . In addition , both octreotide and pasireotide reduced inflammatory hyperalgesia . The antinociceptive actions of octreotide were abolished in P30874 (-/-) mice , but those of pasireotide were retained . In dorsal root ganglia of naive wild - type mice , only P30872 and SSTR2A , but not P32745 or P35346 , were detected in a subset of small - and medium - diameter neurons . CONCLUSION : Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the P30874 receptor . In addition , we identified the P30872 receptor as a novel pharmacologic target for somatostatin - mediated peripheral analgesia in inflammatory pain .",
"Expression of somatostatin receptors in human melanoma cell lines : effect of two different somatostatin analogues , octreotide and DB06663 , on cell proliferation . Somatostatin analogues ( SAs ) are potential anticancer agents . This study was designed to investigate the expression of somatostatin receptors ( SSTRs ) in melanoma cells and the effect of two SAs on cell proliferation and viability . Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and DB06663 . Expression of P30872 , P30874 , P32745 and P35346 was assessed by real - time polymerase chain reaction . Proliferation , viability and cell death were assessed using standard assays . Inhibition was modelled by mixed - effect regression . Melanoma cells expressed one or more SSTR . Both SAs inhibited proliferation of most melanoma cell lines , but inhibition was < 50 % . Neither SA affected cell viability or induced cell death . The results suggest that melanoma cell lines express SSTRs . The SAs investigated , under the conditions used in this study , did not , however , significantly inhibit melanoma growth or induce cell death . Novel SAs , combination therapy with SAs and their anti - angiogenic properties should be further investigated .",
"Pro12Ala sequence variant of the P37231 gene is associated with postprandial hypertriglyceridemia in non - E3 / E3 patients with the metabolic syndrome . BACKGROUND : Postprandial hypertriglyceridemia , a component of the metabolic syndrome , has varied etiology and involves many genes related to triglyceride metabolism . Variations in these genes may affect postprandial hypertriglyceridemia in the context of the metabolic syndrome . METHODS : We orally administered 60 g of fat overload to 74 patients with the metabolic syndrome . We then measured baseline concentrations of cholesterol , triglycerides , HDL cholesterol , apolipoprotein AI , apolipoprotein B , uric acid , and uric acid excretion ; we also performed homeostasis model assessments of insulin resistance and insulin sensitivity . At 3 h , we measured triglycerides , cholesterol , apolipoprotein AI , and apolipoprotein B . Patients were considered to have postprandial hypertriglyceridemia if the difference in plasma triglycerides between baseline and 3 h after the test was 1 . 71 mmol / L or more . We also measured anthropometrical variables and classified the patients according to their peroxisome proliferative activated receptor , gamma ( P37231 ) gene and apolipoprotein E ( P02649 ) genotype . RESULTS : Postprandial hypertriglyceridemia occurred in 64 . 7 % of patients with the Ala12 allele vs 19 . 9 % of the Pro12Pro patients , ( P = 0 . 00032 ; odds ratio , 7 . 6 ) , and in 87 . 5 % of the patients with both the Ala12 allele and the non - E3 / E3 P02649 genotype ( odds ratio , 23 . 8 ) . Logistic regression analysis showed that P37231 and P02649 sequence variants were associated with the presence of postprandial hypertriglyceridemia . CONCLUSION : The Pro12Ala P37231 sequence variant together with a non - E3 / E3 P02649 genotype is associated with a high risk for postprandial hypertriglyceridemia in patients with the metabolic syndrome , indicating a close association between these genes and the regulation of lipoproteinase clearance .",
"A case of a sclerosing stromal ovarian tumor that expresses P15692 . A case of a sclerosing stromal tumor ( P61278 ) of the ovary is presented . One of the tumor ' s characteristics was its high vascularity . On immunohistochemical staining , the vascular endothelial growth factor ( P15692 ) was positive for both cellular and edematous areas in the tumor . P15692 was thought to be a factor that affected the clinicopathological features of this tumor .",
"A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK62___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK96___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK49___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK49___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"Effect of DB06663 ( pasireotide ) on corticotropic cells : action in dogs with Cushing ' s disease . DB06663 ( pasireotide ) is a multiligand somatostatin ( SRIF ) analog able to bind to somatostatin receptor ( SSTR ) subtypes 1 , 2 , 3 and 5 , and trigger antisecretory and antiproliferative signaling cascades . Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing ' s disease in a spontaneous manner , due to adrenocorticotropic hormone ( DB01285 ) - producing pituitary adenomas . Different levels of expression of P30874 and P35346 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells . The objective of this study was to evaluate whether DB06663 controls both tumor cell growth and hormone synthesis , therefore controlling the disease . DB06663 was tested in dogs suffering from Cushing ' s disease ( 10 animals were treated continuously during 6 months , and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2 - month rest period ) . A significant decrease in DB01285 , urinary cortisol creatinine ratio , adenoma size ( magnetic nuclear resonance ) and improvement of clinical signs were obtained , without side effects . AtT20 cells treated with DB06663 suppressed pro - opiomelanocortin ( P01189 ) promoter activity through P30874 , via the G ( i ) α - subunit , and reduced P22736 / Nurr1 transcriptional activity . We conclude that DB06663 , in addition to its well - described antisecretory effects , inhibits , as shown in AtT20 cells , DB01285 synthesis at the P01189 transcriptional level , an effect mediated mainly through P30874 , and limits tumor growth . The controlled Cushing ' s disease in the dogs that received the treatment indicates that DB06663 has a potential therapeutic use in humans suffering from Cushing ' s disease .",
"Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog DB06663 on hormone secretion in vitro and in ex vivo adrenal cells . BACKGROUND : Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion , cell proliferation , and apoptosis by 5 somatostatin receptors ( P30872 - 5 ) . The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and / or secretion of growth factors and growth - promoting hormones . AIM : Very little information is available on the effect of somatostatin analogs on adrenal tumors , so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog ( DB06663 ) on hormone secretion and cell viability in adrenal cells . MATERIAL / SUBJECTS AND METHODS : SSTR expression was analyzed by real - time PCR in 13 adrenocortical carcinomas ( ACC ) , 24 aldosterone - producing adenomas ( APA ) , 11 cortisol - producing adenomas ( P15085 ) , and 7 normal adrenals ( NA ) , and verified by immunohistochemistry ( IHC ) in 14 samples . The effect of DB06663 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay , and its effect on viability in H295R and SW13 using the MTT test . RESULTS : P30872 and P30874 mRNA was expressed in 100 % of adrenal tumors . Compared to NA , ACC revealed an increase in almost all SSTR , while only some APA over - expressed P32745 and P30872 . P15085 expressed SSTR similar to NA . IHC confirmed the mRNA expression data . At nanomolar concentrations , DB06663 inhibited hormone secretion in primary adrenal cultures and H295R cells , but had no evident effect on cell viability . CONCLUSIONS : The evidence of SSTR over - expression ( particularly in ACC ) and of hormone secretion being inhibited by DB06663 suggests a potential therapeutic role for this broad - spectrum somatostatin analog in adrenal tumors .",
"DB06663 , a multiple somatostatin receptor subtypes ligand , reduces cell viability in non - functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion . Somatostatin ( SRIF ) analogs have been employed in medical therapy of non - functioning pituitary adenomas ( DB04552 ) , with contrasting results . Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor ( P15692 ) secretion and action , and that P15692 expression may be related to pituitary tumor growth . The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on P15692 secretion and cell proliferation in human DB04552 primary cultures . We assessed the expression of SRIF receptors ( P30872 - 5 ) , the in vitro effects on P15692 secretion , and on cell viability of SRIF and of the stable SRIF analog pasireotide ( DB06663 ) , which activates P30872 , 2 , 3 , and 5 . Twenty - five DB04552 were examined by RT - PCR for expression of alpha - subunit , SSTR , P15692 , and P15692 receptors 1 ( P15692 - Q96GN5 ) and 2 ( P15692 - R2 ) . Primary cultures were tested with SRIF and with pasireotide . All DB04552 samples expressed alpha - sub , P15692 and P17948 and 2 , while SSTR expression pattern was highly variable . Two different groups were identified according to P15692 secretion inhibition by SRIF . P15692 secretion and cell viability were reduced by SRIF and pasireotide in the ' responder ' group , but not in the ' non - responder ' group , including DB04552 expressing P35346 . SRIF and pasireotide completely blocked forskolin - induced P15692 secretion . In addition , SRIF and pasireotide completely abrogated the promoting effects of P15692 on DB04552 cell viability . Our data demonstrate that pasireotide can inhibit DB04552 cell viability by inhibiting P15692 secretion , and suggest that the multireceptor - SSTR agonist pasireotide might be useful in medical therapy of selected DB04552 .",
"Genome - wide association study of monoamine metabolite levels in human cerebrospinal fluid . Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype - phenotype correlations . Metabolic traits pertinent to the central nervous system ( CNS ) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms . We therefore conducted a genome - wide association study ( GWAS ) of monoamine metabolite ( MM ) levels in cerebrospinal fluid ( P04141 ) of 414 human subjects from the general population . In a linear model correcting for covariates , we identified one locus associated with MMs at a genome - wide significant level ( standardized β = 0 . 32 , P = 4 . 92 × 10 (- 8 ) ) , located 20 kb from P30872 , a gene involved with brain signal transduction and glutamate receptor signaling . By subsequent whole - genome expression quantitative trait locus ( eQTL ) analysis , we provide evidence that this variant controls expression of O76083 ( β = 0 . 21 ; P unadjusted = 5 . 6 × 10 (- 7 ) ; P corrected = 0 . 014 ) , a gene previously implicated in monoaminergic transmission , major depressive disorder and antidepressant response . A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at Q96PZ7 , a schizophrenia susceptibility locus , plays a role in the ratio between dopamine and serotonin metabolites in P04141 . The presented DNA and mRNA analyses yielded genome - wide and suggestive associations in biologically plausible genes , two of which encode proteins involved with glutamate receptor functionality . These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes .",
"Genetic Association between Akt1 Polymorphisms and Alzheimer ' s Disease in a Japanese Population . A recent paper reported that Aβ oligomer causes neuronal cell death through the phosphatidylinositol - 3 - OH kinase ( PI3K ) - Akt - P42345 signaling pathway . Intraneuronal Aβ , a main pathological finding of Alzheimer ' s disease ( AD ) , is also known as inhibiting activation of Akt . This study aims to investigate whether single nucleotide polymorphisms ( SNPs ) of the Akt1 gene are associated with AD . SNPs genotyped using TaqMan technology was analyzed using a case - control study design . Our case - control dataset consisted of 180 AD patients and 130 age - matched controls . Although two SNPs showed superficial positive , Hardy - Weinberg equilibrium ( HWE ) tests , and linkage disequilibrium ( LD ) analyses suggested that genetic regions of the gene are highly polymorphic . We failed to detect any synergetic association among Akt1 polymorphisms , P02649 ( APO E ) , and AD . Further genetic studies are needed to clarify the relationship between the Akt1 and AD .",
"Cyclopentenone prostaglandins induce caspase activation and apoptosis in dendritic cells by a P37231 - independent mechanism : regulation by inflammatory and T cell - derived stimuli . OBJECTIVE : Dendritic cells ( DC ) are professional antigen - presenting cells playing a pivotal role in the induction of immunological responses . There is evidence that DC survival during ongoing immune responses is finite . However , little is known about the mechanisms regulating apoptosis in these cells . Here , we have investigated the effects of the anti - inflammatory cyclopentenone prostaglandins on human monocyte - derived DC . MATERIALS AND METHODS : Phenotype of DC was determined by flow cytometry and their allostimulatory potential in mixed leukocyte reaction . Induction of apoptosis in DC was monitored by staining with annexin - V - FITC and propidium iodide , propidium iodide staining of cell nuclei , and fluorimetric assay of caspase activity . Induction of maturation in DC was obtained by stimulation with P01375 , LPS , P01579 , P25942 - ligand , or different combinations of these stimuli . P37231 expression in DC was determined by RT - PCR . RESULTS : Exposure of immature DC to cyclopentenone prostaglandins blunted their allostimulatory capacity and skewed their phenotype by downregulating CD1a and costimulatory molecules . These effects were due to activation of caspases and induction of apoptotic cell death in DC by cyclopentenone prostaglandins . Mature DC showed enhanced susceptibility to apoptosis via cyclopentenone prostaglandins as compared with immature DC . Although DC express P37231 , the corresponding receptor for some of these metabolites , P37231 activation by a synthetic high - affinity agonist failed to impair DC viability . CONCLUSIONS : Cyclopentenone prostaglandins induce apoptosis of human DC by a P37231 - independent mechanism . Since these compounds are released during an inflammatory event and show anti - inflammatory properties , they may contribute to the downregulation of DC function through apoptotic cell death .",
"Filamin A in somatostatin and dopamine receptor regulation in pituitary and the role of DB02527 / PKA dependent phosphorylation . Molecular mechanisms underlying resistance of pituitary tumors to somatostatin ( SS ) and dopamine ( DA ) analogues treatment are not completely understood . Resistance has been associated with defective expression of functional somatostatin and dopamine receptors P30874 , P35346 , and P14416 , respectively . Recently , a role of cytoskeleton protein filamin A ( P21333 ) in P14416 and SSTR receptors expression and signaling in PRL - and GH - secreting tumors , respectively , has been demonstrated , first revealing a link between P21333 expression and responsiveness of pituitary tumors to pharmacological therapy . No molecular events underlying the reduction of P21333 levels in resistant tumors have been so far identified . P21333 can be phosphorylated by PKA on Ser2152 , with increased P21333 resistance to cleavage by calpain and conformational changes affecting P21333 regions involved in P30874 and P14416 binding and signal transduction . In this respect , the effect of DB02527 / PKA pathway in the regulation of P21333 stability and / or function by modulating its phosphorylation status could assume particular importance in pituitary , where DB02527 cascade plays a crucial role in pituitary cell functions and tumorigenesis . This review will discuss the role of P21333 in the regulation of the main GPCRs target of pharmacological treatment of pituitary tumors , that is , P30874 and P14416 , focusing on the effects of DB02527 / PKA - mediated P21333 phosphorylation on P21333 biological functions .",
"Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 and Q9Y6Q9 coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co - administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down - regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 and Q9Y6Q9 coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR - A and PR - B ) , P00533 , P15692 and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 and Q9Y6Q9 and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .",
"Eighteen insulin - like growth factor pathway genes , circulating levels of P05019 and its binding protein , and risk of prostate and breast cancer . BACKGROUND : Circulating levels of insulin - like growth factor I ( P05019 ) and its main binding protein , IGF binding protein 3 ( P17936 ) , have been associated with risk of several types of cancer . Heritable factors explain up to 60 % of the variation in P05019 and P17936 in studies of adult twins . METHODS : We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of P05019 and P17936 . A total of 302 single nucleotide polymorphisms ( SNP ) were genotyped in > 5 , 500 Caucasian men and 5 , 500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium . RESULTS : After adjusting for multiple testing , SNPs in the IGF1 and P35346 genes were significantly associated with circulating P05019 ( P < 2 . 1 × 10 (- 4 ) ) ; SNPs in the P17936 and P35858 genes were significantly associated with circulating P17936 . Multi - SNP models explained R ( 2 ) = 0 . 62 % of the variation in circulating P05019 and 3 . 9 % of the variation in circulating P17936 . We saw no significant association between these multi - SNP predictors of circulating P05019 or P17936 and risk of prostate or breast cancers . CONCLUSION : Common genetic variation in the IGF1 and P35346 genes seems to influence circulating P05019 levels , and variation in P17936 and P35858 seems to influence circulating P17936 . However , these variants explain only a small percentage of the variation in circulating P05019 and P17936 in Caucasian men and women . Q9P2X3 : Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK16___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK27___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb . PURPOSE : We hypothesized that sustained delivery of vascular endothelial growth factor ( P15692 ) using a polymer [ 85 : 15 poly ( lactide - co - glycolide ) ( P00747 ) ] would enhance angiogenesis and improve perfusion of ischemic tissue . METHODS : C57BL / 6J mice ( n = 20 / group ) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation ( 0 - Implant ) , unloaded scaffold implantation ( Empty - P00747 ) , or implantation of scaffolds incorporating 3 microg of VEGF165 ( P00747 - P15692 ) . Endpoints included laser Doppler perfusion imaging ( LDPI , ischemic / nonischemic limb , % ) , local vessel counts , immunohistochemistry for CD31 , and alpha - smooth muscle actin . In vitro release kinetics of P15692 from P00747 was also measured . RESULTS : P00747 - P15692 resulted in improved lower extremity perfusion vs . controls as measured by LDPI % at 7 , 14 , 21 , and 28 days ( p < 0 . 05 ) . P00747 - P15692 was associated with significantly greater percentage of vessels staining for CD31 and alpha - smooth muscle actin compared to the Empty - P00747 or 0 - Implant ( p < 0 . 05 for both ) . CONCLUSIONS : The P00747 - P15692 scaffolds resulted in sustained P15692 delivery , improved tissue perfusion , greater capillary density , and more mature vasculature compared to the controls . The sustained - release P00747 polymer vehicle is a promising delivery system for therapeutic neovascularization applications .",
"[ New medical treatments in Cushing disease ] . The standard treatment of Cushing disease is surgery . Radiotherapy and steroïdogenesis inhibitors are second - line treatments . The new multi - ligand somatostatin analogs , such as DB06663 , having a much higher affinity with several receptors of somatostatin ( P30872 , 3 , and 5 ) than octreotid ( mostly a P30874 receptor ) have been synthetized . Some studies have shown that P35346 is predominantly expressed in corticotroph pituitary adenomas and that DB06663 has more efficacy than octreotid in the treatment of Cushing disease . It has been suggested that the thiazolinidinediones , P37231 agonists , might also be useful in the treatment of this disease , but studies are still limited and give conflicting results . In a recent study conducted on dogs , Castillo et al have shown that the retinoïds give encouraging results and might open a new pathway in the treatment of Cushing disease . But further studies , especially on humans , are necessary before conclusions can be reached . Labeur and his team have contributed a study on the use of gamma - interferon on murine pituitary cells and on human and murine corticotroph pituitary adenoma cells , and they have evidenced a 20 to 60 % decrease in the production of DB01285 in 5 cases out of 7 in the tumoral cells treated -- versus the non - treated ones . Eventually , Pivonello and his team have confirmed the D2 dopaminergic receptor expression in corticotroph pituitary cells , mainly in the intermediary zone . Thus they have suggested that the dopaminergic agonists -- such as cabergoline - could be used in corticotroph pituitary adenomas derivated from the intermediary zone .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of P27361 / 2 . Somatostatin ( P61278 ) controls the proliferation of a variety of cell types . Its effects are mediated by five G protein - coupled receptors ( P30872 - P35346 ) , variably expressed in normal and cancer tissues . P61278 inhibition of cell proliferation can be exploited by both direct and indirect mechanisms : the main direct pathway involves the modulation of phosphotyrosine phosphatase ( PTP ) activity . Here we show that P61278 cytostatic activity is mediated by the activation of a receptor - like PTP , named PTPeta . The role of this PTP in the antiproliferative activity of P61278 in five glioma cell lines ( P13671 , U87MG , U373MG , DBTRG05MG , and CAS1 ) and in four postsurgical human glioblastoma specimens , has been studied . P61278 inhibited growth only in P13671 and U87MG that express PTPeta . In P13671 cells , P61278 antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate , indicating the involvement of G proteins and PTPs . The role of PTPeta in the P61278 inhibitory effects was demonstrated by testing the PTPeta activity : it was increased by P61278 treatment and paralleled by inhibition of P27361 / 2 activation . Since basic fibroblast growth factor - dependent MEK phosphorylation was not affected by P61278 , we propose a direct effect of P61278 - activated PTPeta on P27361 / 2 phosphorylation . Finally , the SSTR mRNAs were identified in all of the 36 gliomas analyzed , whereas PTPeta expression was found in 33 % of cases . Culturing four gliomas , a precise correlation between the expression of PTPeta and the P61278 antiproliferative effects was identified . In conclusion , in glioma cells , P61278 antiproliferative activity requires the expression and activation of PTPeta , which directly dephosphorylates P27361 / 2 .",
"Regulatory roles of sex hormones in cutaneous biology and immunology . Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin . Pregnancy , menstruation and the menopause modulate the natural course of psoriasis , indicating a female hormone - induced regulation of skin inflammation . Estrogen in vitro down - regulates the production of the neutrophil , type 1 T cell and macrophage - attracting chemokines , P10145 , P02778 , P13501 , by keratinocytes , and suppresses IL - 12 production and antigen - presenting capacity while enhancing anti - inflammatory P22301 production by dendritic cells . These data indicate that estrogen may attenuate inflammation in psoriatic lesions . Estrogen , alone or together with progesterone , prevents or reverses skin atrophy , dryness and wrinkles associated with chronological or photo - aging . Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy . Estrogen also enhances collagen synthesis , and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts , thereby maintaining skin thickness . Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis . Progesterone increases sebum secretion . Estrogen accelerates cutaneous wound healing stimulating P01138 production in macrophages , GM - P04141 production in keratinocytes and P09038 and TGF - beta1 production in fibroblasts , leading to the enhancement of wound re - innervation , re - epithelialization and granulation tissue formation . In contrast , androgens prolong inflammation , reduce deposition of extracellular matrix in wounds , and reduce the rate of wound healing . Estrogen enhances P15692 production in macrophages , an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy . These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis , aging , chronic wounds or granuloma pyogenicum .",
"Overexpression of the μ - opioid receptor in human non - small cell lung cancer promotes Akt and P42345 activation , tumor growth , and metastasis . BACKGROUND : Recent epidemiologic studies suggesting that there were differences in cancer recurrence contingent on anesthetic regimens have raised the possibility that μ - opioid agonists can influence cancer progression . Based on our previous studies indicating the μ - opioid receptor ( MOR ) is up - regulated in several types of non - small cell lung cancer , this study examined the functional significance of MOR overexpression to elucidate a possible mechanism for the epidemiologic findings . METHODS : Stable vector control and P35372 overexpressing human bronchioloalveolar carcinoma cells were evaluated using immunoblot analysis , proliferation and transendothelial extravasation assays with or without Akt inhibitor , P42345 inhibitor ( temsirolimus ) , or the peripheral MOR antagonist , methylnaltrexone . In human lung cancer xenograft models , primary tumor growth rates and lung metastasis were analyzed using consecutive tumor volume measurements and nestin immunoreactivity in lungs of the nude mouse model . RESULTS : The authors provide evidence that MOR is an important regulator of lung cancer progression . MOR overexpression increased Akt and P42345 activation , proliferation , and extravasation in human bronchioloalveolar carcinoma cells . In vivo , overexpression of MOR in human bronchoalveolar carcinoma cells increased primary tumor growth rates in nude mice by approximately 2 . 5 - fold and lung metastasis by approximately 20 - fold compared with vector control cells ( n = 4 per condition ) . CONCLUSIONS : The overexpression data suggest a possible direct effect of MOR on Akt and P42345 activation and lung cancer progression . Such an effect provides a plausible explanation for the epidemiologic findings . The authors ' observations further suggest that exploration of MOR in non - small cell lung carcinoma merits further study both as a diagnostic and therapeutic option .",
"Role of the steroid receptor coactivator Q9Y6Q9 in cell growth . Steroid receptor coactivator 3 ( Q9Y6Q9 / p / CIP / Q9Y6Q9 / Q9Y6Q9 / RAC3 / Q9Y6Q9 ) is a member of the P52701 family of nuclear receptor coactivators , which includes Q15788 ( Q15788 ) and P12931 - 2 ( Q15596 / GRIP1 / NCoA2 ) . Previous studies indicate that Q9Y6Q9 is required for normal animal growth and is often amplified or overexpressed in many cancers , including breast and prostate cancers . However , the mechanisms of Q9Y6Q9 - mediated growth regulation remain unclear . In this study , we show that overexpression of Q9Y6Q9 stimulates cell growth to increase cell size in prostate cancer cell lines . Furthermore , our results indicate that overexpression of Q9Y6Q9 can modulate the AKT signaling pathway in a steroid - independent manner , which results in the activation of AKT / P42345 signaling concomitant with an increase in cell size . In contrast , down - regulation of Q9Y6Q9 expression in cells by small interfering RNA decreases cell growth , leading to a smaller cell size . Similarly , in Q9Y6Q9 null mutant mice , AKT signaling is down - regulated in normally Q9Y6Q9 - expressing tissues . Taken together , these results suggest that Q9Y6Q9 is an important modulator for mammalian cell growth .",
"Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors . OBJECTIVES : Pancreatic endocrine tumors ( PETs ) share numerous features with gastrointestinal neuroendocrine ( carcinoid ) tumors . Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs ( 44 cases ) . METHODS : Activating mutations in P00533 , P10721 , and P16234 and nonresponse mutations in P01116 were evaluated . Copy number of P00533 and HER - 2 / neu was quantified by fluorescence in situ hybridization . Expression of P00533 , P16234 , P17948 , P36897 , Hsp90 , SSTR2A , P35346 , P08069 , P42345 , and P16455 was measured immunohistochemically . RESULTS : Elevated P00533 copy number was found in 38 % of cases but no P01116 nonresponse mutations . P17948 , P36897 , P16234 , P35346 , SSTR2A , and P08069 exhibited the highest levels of expression in the largest percentages of PETs . Anticancer drugs BMS - 754807 ( selective for P08069 / IR ) , 17 -( allylamino )- 17 - demethoxygeldanamycin ( 17 - P29372 , targeting Hsp90 ) , and axitinib ( directed toward P17948 - 3 / P16234 - B / P10721 ) induced growth inhibition of human QGP - 1 PET cells with IC50 values ( nM ) of 273 , 723 , and 743 , respectively . At growth - inhibiting concentrations , BMS - 754807 inhibited P08069 phosphorylation ; 17 - P29372 induced loss of P00533 , P08069 , and P35968 ; and axitinib increased P38936 ( P38936 ) expression without inhibiting P35968 phosphorylation . CONCLUSIONS : Results encourage further research into multidrug strategies incorporating inhibitors targeting P08069 or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest .",
"Effects of chimeric somatostatin - dopamine molecules on human peripheral blood lymphocytes activation . O43521 23A761 , selective for somatostatin receptors subtypes 2 , 5 and the dopamine receptor subtype 2 , and O43521 23A757 with affinity for P30874 and DAR2 were studied on human PBL proliferation and activation . O43521 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen , while O43521 23A757 was more potent than specific P30874 and DAR2 agonists in suppressing antigen induced proliferation only . Both molecules displayed enhanced potency in suppressing IFNgamma and P05231 secretion compared with the SSTR and DAR2 analogs , while only O43521 23A761 was able to inhibit P60568 secretion and its effect is more potent than the control analogs . Furthermore O43521 23A761 inhibit cell progression into the S phase and then into the G2 / M , while O43521 23A757 inhibited bromodeoxyuridine incorporation only during the S phase . Both chimeric molecules resulted significantly more effective than the respective controls .",
"Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up - regulated genes were further validated by quantitative real - time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n = 5 ) . Selected genes up - regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin - 2 receptor beta ) ; Q92843 ( P10415 - like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF - hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator - activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras - like 2 ) ; P05112 ( interleukin - 4 ) ; IL - 4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 - related protein A1 ) ; P24522 ( growth arrest and DNA - damage - inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide - 3 - kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member - associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) .",
"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK16___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .",
"Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"The opioid system in alcohol and drug dependence : family - based association study . Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin , cocaine , and alcohol . In an earlier study , we reported that variation in the genes encoding the kappa - opioid receptor ( P41145 ) and its peptide ligand ( P01213 ) were associated with the risk for alcoholism . We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro - and delta - opioid receptors and their peptide ligands . We analyzed 18 P35372 SNPs , 18 P41143 SNPs , 7 P01210 SNPs , and 7 P01189 SNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families . Employing a family - based test of association , we found no evidence that these four genes were significantly associated with alcohol dependence . We also did not find association between these genes and illicit drug dependence . Secondary analyses employing the narrower phenotype of opioid dependence ( 83 affected individuals ) demonstrated association with SNPs in P01210 and P01189 , but not in P35372 or P41143 . Haplotype analyses provided further support for the association of P01210 and P01189 with opioid dependence . Therefore , our data provide no support for the idea that variations in P35372 , P41143 , P01210 and P01189 are associated with alcohol dependence or general illicit drug dependence , but variations in P01210 and P01189 appear to be associated with the narrower phenotype of opioid dependence in these families .",
"DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK96___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK96___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .",
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"Modulation of the P06850 system by DB05875 / P20366 in an animal model of depression . It has been suggested by studies in animals and humans that DB05875 ( SP ) and its receptor neurokinin 1 ( P25103 ) play an important role in the pathology of depression . The pharmacological blockade or genetic deletion of the NK1 receptor , or the DB05875 coding gene tac1 led to a decreased emotionality and a reduction of depression - related behaviours in different animal models . In order to characterize molecular changes associated with reduced SP - NK1 signalling in animal models of depression , we assessed the regulation of the P06850 system . First , tac1 (-/-) animals and tac1 (+/+) controls were subjected to bulbectomy , which induces physiological and behavioural changes that are relevant to depression . We demonstrate that tac1 (-/-) animals , in contrast to tac1 (+/+) controls , do not show anhedonia in the saccharine preference test after bulbectomy . Next , we studied expression levels of P06850 , the receptors P34998 and Q13324 , and the binding protein P24387 in the cortex and paraventricular nucleus using real - time RT - PCR . Our results show a strong induction of P06850 , P24387 and P34998 expression in the cortex of tac1 (-/-) , but not in tac1 (+/+) animals . In the PVN , bulbectomized tac1 (-/-) mice showed an elevated expression of P34998 and Q13324 . These results show that DB05875 / P20366 is involved in modulating P06850 signalling in an animal model of depression .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK64___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Changes in somatostatin receptor expression of the pancreas and effectiveness of octreotide in rats with acute necrotizing pancreatitis . OBJECTIVE : To investigate changes in the expression of the somatostatin receptor ( SSTR ) of the pancreas and of pancreatic blood flow , and its relationship to the metabolism of eicosanoids in order to elucidate the effectiveness of octreotide , an analog of somatostatin , in acute necrotizing pancreatitis ( P01160 ) . METHODS : A model of P01160 was induced in rats with injection of sodium taurocholate via the pancreaticobiliary duct . The SSTR was detected using a radioligand binding assay ( RBA ) with 125I - somatostatin - 14 , and the P30874 mRNA of the pancreas was analyzed using in situ hybridization . Pancreatic blood flow and the metabolites of eicosanoids were also determined . RESULTS : The SSTR of the pancreas was 109 . 70 +/- 58 . 32 fmol / mg protein in normal rats . A significant decrease in the SSTR , together with the signals of P30874 mRNA , was shown at 3 , 6 and 12 h after onset of P01160 . Pancreatic blood flow was reduced and thromboxin - 2 was increased significantly in the course of P01160 . In the P01160 group treated with octreotide , both the decrease in pancreatic blood flow and the abnormal metabolism of eicosanoids were corrected , and the pathological damage was relieved . CONCLUSION : SSTR expression of the pancreas is significantly reduced in P01160 . Correction of the abnormal metabolism of eicosanoids and improvement in pancreatic microcirculation may be the major mechanism of somatostatin analogs in the treatment of P01160 and inhibition of pancreatic enzymes via their receptors plays a minor role .",
"___MASK2___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK2___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Hypothalamic neuronal toll - like receptor 2 protects against age - induced obesity . Toll - like receptors ( TLRs ) are traditionally associated with immune - mediated host defense . Here , we ascribe a novel extra - immune , hypothalamic - associated function to O60603 , a TLR - family member known to recognize lipid components , in the protection against obesity . We found that O60603 - deficient mice exhibited mature - onset obesity and susceptibility to high - fat diet ( HFD ) - induced weight gain , via modulation of food intake . Age - related obesity was still evident in chimeric mice , carrying comparable O60603 (+) immune cells , suggesting a non - hematopoietic - related involvement of this receptor . O60603 was up - regulated with age or HFD in pro - opiomelanocortin ( P01189 ) neurons in the arcuate nucleus of the hypothalamus , a brain area participating in central - metabolic regulation , possibly modulating the hypothalamic - anorexigenic peptide , α - melanocyte - stimulating hormone ( α - MSH ) . Direct activation of O60603 in a hypothalamic - neuronal cell - line via its known ligands , further supports its capacity to mediate non - immune related metabolic regulation . Thus , our findings identify O60603 expressed by hypothalamic neurons as a potential novel regulator of age - related weight gain and energy expenditure .",
"Differential increases in catecholamine metabolizing enzymes in amyotrophic lateral sclerosis . The activity of three catecholamine - metabolizing enzymes , monoamine oxidase type A and type B ( P21397 and P27338 ) as well as catechol - O - methyltransferase ( P21964 ) , were estimated in homogenates of human spinal cord using radiometric assays . The enzyme activities were determined in postmortem spinal cord tissue from controls and cases with amyotrophic lateral sclerosis ( P35858 ) . The activity of P21397 was below the limit of detectability in both controls and P35858 cases . The activities of P27338 and P21964 were evenly distributed at the various spinal levels . The P27338 activity was substantially elevated in P35858 spinal homogenates , whereas only a slight , but not statistically significant , increase in P21964 activity was observed . A significant correlation between P21964 and P27338 activities was observed for controls . However , this covariation was not apparent for the P35858 cases . These results suggest that the two enzyme proteins are regulated by more complex mechanisms in the spinal cord in amyotrophic lateral sclerosis than simple general increases caused by elevated astroglial cell numbers . In addition , the P21397 , P27338 , and P21964 activities were estimated in spinal cords from rats treated with the selective P27338 inhibitor L - deprenyl , a drug with putative neuroprotective effects in neurodegenerative disorders . After 3 weeks of L - deprenyl treatment ( 0 . 25 mg / kg / day , sc ) , the spinal P21397 and P27338 activities were decreased by 50 and 80 % , respectively . In contrast , the P21964 activity was not altered by L - deprenyl administration .",
"The somatostatin immunoregulatory circuit present at sites of chronic inflammation . Somatostatin is part of an immunoregulatory circuit that helps limit interferon - gamma ( IFNgamma ) production at sites of chronic inflammation . In murine schistosomiasis . parasite eggs induce focal , chronic granulomatous inflammation in the liver and intestines . These granulomas produce somatostatin 1 - 14 and express somatostatin receptor subtype number 2 ( P30874 ) , which is the exclusive somatostatin receptor present in this inflammation . Granuloma and splenic macrophages as well as macrophage cell lines make somatostatin . There appears to be no other inflammatory cell source of the peptide . Various inflammatory mediators induce this expression , whereas DB05875 inhibits somatostatin production . Somatostatin can suppress P01579 secretion from T cells via interaction with the P30874 receptor expressed on these cells . Other cells within the granuloma also display P30874 . The effect of somatostatin on these other cell types remains unknown . The thymus of normal mice has a complete somatostatin regulatory circuit . The thymic epithelial and dendritic cells make somatostatin . Like the granulomas of murine schistosomiasis , the thymus expresses only P30874 . Somatostatin likely has an important role in thymic T cell education and selection .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK8___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK8___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK8___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Growth of V79 cells as xenograft tumors promotes multicellular resistance but does not increase spontaneous or radiation - induced mutant frequency . A Chinese hamster V79 xenograft model was developed to determine whether cells subjected to a hypoxic tumor microenvironment would be more likely to undergo mutation at the P00492 locus . V79 - 171b cells stably transfected with P15692 and EGFP were grown subcutaneously in immunodeficient NOD / SCID mice . V79 - VE tumors were characterized for host cell infiltration , doubling time , hypoxic fraction , vascular perfusion , and response to ionizing radiation . When irradiated in vitro , the mutant frequency for a given surviving fraction did not differ for cells grown in vivo or in vitro . Similar results were obtained using HCT116 human colorectal carcinoma cells grown as xenografts . However , V79 - VE cells grown as xenografts were significantly more resistant to killing than monolayers . The background mutant frequency and the radiation - induced mutant frequency did not differ for tumor cells close to or distant from blood vessels . Similarly , tumor cells from well - perfused regions showed the same rate of strand break rejoining and the same rate of loss of phosphorylated histone P16104 as cells sorted from poorly perfused regions . Therefore , deleterious effects of the tumor microenvironment on DNA repair efficiency or mutation induction could not be demonstrated in these tumors . Rather , development of multicellular resistance in V79 - VE tumors acted to reduce mutant frequency for a given dose of radiation .",
"Interferon - gamma inhibits cellular proliferation and DB01285 production in corticotroph tumor cells through a novel janus kinases - signal transducer and activator of transcription 1 / nuclear factor - kappa B inhibitory signaling pathway . Interferon - gamma ( P01579 ) is a cytokine that exerts potent antiproliferative and tumoricidal effects in a variety of cancers . Moreover , P01579 modulates normal pituitary hormone secretion , and was shown to inhibit the expression of the DB01285 precursor P01189 in murine DB01285 - secreting AtT - 2010 / 21 / 2008 tumor cells . We have studied the functional role of P01579 on pituitary tumor cells , focusing on the involvement of P01579 in the molecular events leading to the control of P01189 transcriptional repression . Herein , it is shown that P01579 inhibits AtT - 20 tumor cell proliferation without inducing apoptosis . Unexpectedly , an activated janus kinases - signal transducer and activator of transcription ( JAK - P42224 ) cascade is required for P01579 inhibitory action on P01189 promoter activity . Factor - kappa B ( NF - kappaB ) is necessary for the inhibitory action of P01579 on Pomc transcription , since loss of NF - kappaB activity with IkappaB super - repressor abolishes this effect . In addition , 1 and 2 P01579 receptor immunoreactivity was detected in human corticotropinoma cells . Interestingly , P01579 inhibits DB01285 production from these cells in primary cell culture , without affecting basal DB01285 biosynthesis in normal non - tumoral pituitary cells . In conclusion , our data show for the first time that P01189 transcription can be negatively regulated by a JAK - P42224 and NF - kappaB - dependent pathway .",
"Synovial Fluid α - MSH Levels are Inversely Correlated with Articular Cartilage Degeneration in Anterior Cruciate Ligament Deficient Knees . BACKGROUND : Secondary osteoarthritis after ligament or meniscus injury generally causes great burdens to patients . Alpha - melanocyte - stimulating hormone ( α - MSH ) , a 13 amino acid neuropeptide produced by intracellular cleavage of the proopiomelanocortin ( P01189 ) hormone , has been proven to suppress inflammation and protect cartilage from damage . The present study was carried out to explore the relationship between synovial fluid α - MSH levels and articular cartilage degeneration in patients with anterior cruciate ligament ( P53396 ) deficiency . METHODS : 51 patients with P53396 deficiency admitted to our hospital were enrolled . The Noyes score method was used to assess articular cartilage damage arthroscopically . Synovial fluid α - MSH levels were examined using a double antibody radioimmunoassay method . Inflammation markers such as P05231 , P08254 , and degradation biomarker of collagen type II ( CTX - II ) were also explored by enzyme - linked immunosorbent assay ( ELISA ) . RESULTS : The articular cartilage in P53396 deficiency patients deteriorated significantly with time after injury ( r = 0 . 673 , p < 0 . 001 ) . Synovial fluid α - MSH levels are inversely associated with Noyes scores ( r = - 0 . 682 , p < 0 . 001 ) , levels of inflammation markers P05231 ( r = - 0 . 302 , p = 0 . 035 ) , P08254 ( r = - 0 . 652 , p < 0 . 001 ) and degradation biomarker CTX - II ( r = - 0 . 584 , p < 0 . 001 ) . CONCLUSIONS : Synovial fluid α - MSH levels showed an independent and negative correlation with articular cartilage degeneration in patients with knee P53396 deficiency . Supplementing with a - MSH may serve as a possible adjuvant therapy for delaying cartilage degeneration after P53396 injury ."
] |
[
"___MASK16___",
"___MASK27___",
"___MASK2___",
"___MASK49___",
"___MASK5___",
"___MASK62___",
"___MASK64___",
"___MASK8___",
"___MASK96___"
] |
___MASK8___
|
MH_train_351
|
interacts_with DB00480?
|
[
"Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand up - regulation via prostaglandin E2 synthesis . Previously , we discovered that periodontal ligament ( PDL ) cells not only support osteoclastogenesis through cell - to - cell contact , but also inhibit the formation of tartrate - resistant acid phosphatase - positive ( TRAP + ) multinucleated cells by a producing soluble factor ( s ) . Furthermore , PDL cells express both receptor activator of nuclear factor kappaB ligand ( O14788 ) and osteoprotegerin ( O00300 ) messenger RNA ( mRNA ) . Clinically , \" ankylosed teeth , \" which lack periodontal ligament , can not be moved with orthodontic tooth treatment . From this , we hypothesized that PDL cells under mechanical stress should play a pivotal role in osteoclast formation during orthodontic tooth movement . This study examined how mechanical stress affects the osteoclastogenesis - supporting activity of PDL cells . PDL cells were compressed continuously and then cocultured with peripheral blood mononuclear cells ( PBMCs ) for 4 weeks . PDL cells under mechanical stress up - regulated osteoclastogenesis from PBMCs . Furthermore , the expression of O14788 mRNA and protein in PDL cells increased with compressive force in parallel with the change in the number of osteoclasts . In addition , cyclo - oxygenase 2 ( P35354 ) mRNA expression was induced by compressive force , and indomethacin inhibited the O14788 up - regulation resulting from compressive force . PDL cells under compressive force exhibited significantly increased prostaglandin E2 ( DB00917 ) production in comparison with control PDL cells . Exogenous DB00917 treatment increased O14788 mRNA expression in PDL cells . Interestingly , O00300 expression remained constant throughout compressive force or DB00917 treatment . In conclusion , compressive force up - regulated O14788 expression in PDL cells . Furthermore , O14788 up - regulation in mechanically stressed PDL cells was dependent on DB00917 .",
"P01730 (+) regulatory T cells in autoimmunity and allergy . Regulatory T cells ( also referred to as suppressor T cells ) are important components of the homeostasis of the immune system , as impaired regulatory T cell activity can cause autoimmune diseases and atopy . It is now clear that the phrase ' regulatory T cells ' encompasses more than one cell type . For instance , P01730 (+) CD25 (+) regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo , but in several instances it has been shown that P01730 (+) CD25 (-) T cell populations also contain potent regulatory activity . Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor ( TNFR ) family members ( Q9Y5U5 and O14788 - R / Q9Y6Q6 ) in Treg biology , the improved understanding of the role of co - stimulatory molecules and cytokines P22301 and P60568 in the induction and function of Tregs , and the generation of CD25 (+) and CD25 (-) regulatory T cells in vivo through high - avidity T cell receptor interactions .",
"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .",
"___MASK21___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"Immunohistochemical analysis of low - grade and high - grade prostate carcinoma : relative changes of parathyroid hormone - related protein and its parathyroid hormone 1 receptor , osteoprotegerin and receptor activator of nuclear factor - kB ligand . AIM : To investigate multiple bone cytokines produced by prostate carcinoma ( PCa ) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis . METHODS : A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution ( Fundación Jiménez Díaz ( Grupo Capio ) , Madrid , Spain ) between January 1991 and June 1998 were identified as low - grade ( < or = 4 ; n = 22 ) or high - grade ( > or = 7 , excluding 7 ( 3 + 4 ) cases ; n = 25 ) PCa according to Gleason grade . PCa specimens were immunostained for : parathyroid hormone ( PTH ) - related protein ( P12272 ) , the Q03431 , osteoprotegerin and receptor activator of nuclear factor - kappa B ligand ( O14788 ) , as well as Ki67 ( a proliferation marker ) and P28906 ( an angiogenesis marker ) . RESULTS : PCa samples showed an increased immunostaining for both osteoprotegerin and O14788 , associated with tumour grade and P12272 positivity , in the tumoral epithelium . Using a score value of 4 - corresponding to moderate staining - as cut - off , the best sensitivity value was for P12272 ( with C - terminal antiserum P13671 ; 100 % ) ; wheras the best specificity value was for O14788 ( 95 % ) . CONCLUSIONS : All the evaluated factors are overexpressed mainly in the high - grade tumours . Our findings indicate that , in most patients with PCa ( with Ki67 values between 1 % and 9 % ) , sequential determination of C - terminal P12272 and O14788 immunoreactivities is a useful approach to discriminate low - grade and high - grade tumours .",
"NF - Y is essential for the recruitment of RNA polymerase II and inducible transcription of several CCAAT box - containing genes . O14788 ( O14788 ) / receptor activator of NF - kappaB ligand is essential for inducing the differentiation of mature osteoclasts . We find that nuclear factor Y ( NF - Y ) binds to the CCAAT box on the O14788 promoter and regulates its basal transcriptional activity . The CCAAT box on the O14788 gene is required for its transcriptional induction by vitamin D3 , suggesting that NF - Y coregulates this promoter along with P11473 . Chromatin immunoprecipitation analysis reveals that NF - Y is required for the recruitment of RNA polymerase II ( RNAPII ) and TATA box binding protein on the O14788 promoter . Stimulation with vitamin D3 facilitates the recruitment of P11473 and p300 onto the O14788 promoter , resulting in acetylation of histone H4 in an NF - Y - independent manner . O14788 gene induction by parathyroid hormone or prostaglandin E is also dependent on NF - Y . Furthermore , NF - Y is essential for the recruitment of RNAPII onto other CCAAT box - containing promoters , such as those of osteopontin , Q07973 , and Q01094 . These results suggest that NF - Y recruits RNAPII and general transcription factors onto various CCAAT box - containing promoters in response to various inductions to permit strong transcriptional activation independently of histone modifications .",
"Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and / or physiological stress . When people feel stress , the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin - releasing hormone ( P06850 ) , adrenocorticotropic hormone ( ___MASK23___ ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of ___MASK23___ and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20 - 240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma ___MASK23___ - like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma ___MASK23___ - IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress - related disease .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK20___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"17 ___MASK6___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK41___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK41___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK41___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"___MASK41___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK48___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Development of an osteoblast / osteoclast co - culture derived by human bone marrow stromal cells and human monocytes for biomaterials testing . The communication of bone - forming osteoblasts and bone - resorbing osteoclasts is a fundamental requirement for balanced bone remodelling . For biomaterial research , development of in vitro models is necessary to investigate this communication . In the present study human bone marrow stromal cells and human monocytes were cultivated in order to differentiate into osteoblasts and osteoclasts , respectively . Finally , a cultivation regime was identified which firstly induces the differentiation of the human bone marrow stromal cells followed by the induction of osteoclastogenesis through the osteoblasts formed -- without the external addition of the factors O14788 and P09603 . As a feedback on osteoblasts enhanced gene expression of P21815 was detected for modifications which facilitated the formation of large multinuclear osteoclasts . Phenotype characterization was performed by biochemical methods ( DNA , LDH , ALP , TRAP 5b ) , gene expression analysis ( ALP , P21815 , O14788 , P05231 , VTNR , P43235 , TRAP , Q8IYS5 , P30988 ) as well as light microscopy , confocal laser scanning microscopy , and scanning electron microscopy . After establishing this model on polystyrene , similar positive results were obtained for cultivation on a relevant bone substitution material -- a composite xerogel of silica , collagen , and calcium phosphate .",
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK9___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"P14780 inhibition suppresses wear debris - induced inflammatory osteolysis through downregulation of Q9Y6Q6 / O14788 in a murine osteolysis model . Wear debris - induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty . P14780 ( P14780 ) is expressed in osteoclast cells that surround loosening peri - implant tissue , but the molecular mechanism of P14780 action in wear debris - induced osteolysis remains ambiguous . We used a murine osteolysis model to examine the hypothesis that administration of an P14780 inhibitor reduces the expression of receptor activator of nuclear factor - κB ( Q9Y6Q6 ) and nuclear factor - κB ligand ( O14788 ) and , thereby , suppressesdebris - induced inflammatory osteolysis . Experiments were performed in 3 groups of 15 mice : a control , a titanium ( Ti ) and a Ti plus tetracycline group . To provoke inflammatory osteolysis , calvarial bone was implanted from syngeneic littermates , followed by injection of Ti particles into established air pouches for all groups except the control . DB00759 was administered daily by intraperitoneal ( i . p . ) injection , and PBS was administered by i . p . injection to the control and Ti groups . Mice were sacrificed 14 days after bone - Ti implantation . Pouch membranes with the intact bone implants were collected for histological and molecular analysis . DB00759 had minimum effect on the expression of P14780 and tumor necrosis factor - α ( P01375 - α ) but it decreased gene activation and inhibited the expression of Q9Y6Q6 and O14788 , thereby inhibiting Ti - particle - induced inflammatory osteolysis . DB00759 decreased the number of tartrate - resistant acid phosphatase ( TRAP ) - positive cells in the pouch tissues . Our results in the murine osteolysis model suggest that through the downregulation of Q9Y6Q6 / O14788 , tetracycline significantly inhibits debris - induced inflammatory osteolysis . Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty .",
"Immunomodulatory drugs inhibit expression of cyclooxygenase - 2 from P01375 , IL - 1beta , and LPS - stimulated human PBMC in a partially P22301 - dependent manner . Immunomodulatory drugs ( IMiDs ) are potent inhibitors of P01375 and IL - 1beta and elevators of P22301 production in LPS - stimulated human PBMC . They are currently in clinical trials for various diseases , including multiple myeloma , myelodysplastic syndrome , and melanoma . In the present study , we have investigated the effects of thalidomide , DB00480 and CC - 4047 on the expression of P35354 by stimulated PBMC . Our results show that thalidomide and IMiDs inhibited the expression of P35354 but not the P23219 protein in LPS - P01375 and IL - 1beta stimulated PBMC and shortened the half - life of P35354 mRNA in a dose - dependent manner . They also inhibited the synthesis of prostaglandin E2 from LPS - stimulated PBMC . While anti - P01375 or IL - 1beta neutralizing antibodies had no effect on P35354 expression , anti - P22301 neutralizing antibody elevated the expression of P35354 mRNA , and protein from treated PBMC . These data suggest that the anti - inflammatory and anti - tumor effects of IMiDs may be due in part to elevation of P22301 production and its subsequent inhibition of P35354 expression .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Parathyroid - hormone - related protein induces expression of receptor activator of NF -{ kappa } B ligand in human periodontal ligament cells via a DB02527 / protein kinase A - independent pathway . Periodontal ligament ( PDL ) cells play important roles in root resorption of human deciduous teeth by odontoclasts ( osteoclast - like cells ) . However , it is unclear how PDL cells regulate osteoclastogenesis . We examined the effects of P12272 , TGF - beta , and P01133 , which are all secreted by the tooth germ , on tartrate - resistant acid - phosphatase - positive ( TRAP + ) cell formation using co - cultures of human PDL cells and mouse spleen cells . Only P12272 promoted TRAP + cell formation in co - cultures . P12272 induced receptor activator of NF - kappaB ligand ( O14788 ) mRNA expression and slightly reduced osteoprotegerin ( O00300 ) expression in PDL cells . The DB02527 / PKA inhibitors Rp - DB02527 , H89 , and PKI did not affect P12272 - induced TRAP + cell formation . The PKC inhibitor , Ro - 32 - 0432 , suppressed O14788 expression in PDL cells and P12272 - induced TRAP + cell formation . However , this inhibitor directly modulated the number of osteoclast precursors . Thus , P12272 induces osteoclastogenesis by increasing the relative expression level of O14788 vs . O00300 in PDL cells via a DB02527 / PKA - independent pathway . ABBREVIATIONS : P12272 , parathyroid - hormone - related protein ; TGF - beta , transforming growth factor - beta ; P01133 , epidermal growth factor ; O14788 , receptor activator of NF - kappaB ligand ; O00300 , osteoprotegerin ; PDL , periodontal ligament ; TRAP , tartrate - resistant acid phosphatase ; PKA , protein kinase A ; PKC , protein kinase C ; Q96HU1 , mitogen - activated protein ; P29323 , extracellular signal - regulated kinase ; DB02527 , cyclic DB00640 3 ' 5 '- Monophosphate .",
"Interleukins 1α and 1β as regulators of steroidogenesis in human NCI - H295R adrenocortical cells . Inflammatory cytokines interleukin - 1 ( IL - 1 ) and tumor necrosis factor - α ( P01375 - α ) regulate the activity of the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis at several levels . Although hypothalamic P06850 secretion may be the primary mechanism by which these cytokines activate the Q9Y251 axis , IL - 1 expression is increased within the adrenal glands in models for systemic inflammation , and IL - 1 may augment adrenal glucocorticoid production . Our aim was to investigate the direct effects of IL - 1α and IL - 1β on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI - H295R cell line as a model . mRNAs encoding receptors for IL - 1 , P01375 - α , and leukemia inhibitory factor ( P15018 ) were detectable in the cell line ( Affymetrix microarray analysis ) . Both IL - 1α and IL - 1β increased cortisol , androstenedione , dehydroepiandrosterone and DB05804 production , and the accumulation of mRNAs for steroidogenic acute regulatory protein ( STAR ) , 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and 3β - hydroxysteroid dehydrogenase 2 ( P26439 ) in these cells ( P < 0 . 05 for all ) . Both ILs augmented P01375 - α - and P15018 - induced STAR and P05093 mRNA accumulation , and P01375 - α - induced cortisol production ( P < 0 . 05 for all ) . Both ILs also increased the apoptotic index of the cells ( P < 0 . 05 ) , which was efficiently neutralized by their specific antibodies . The IL - induced changes in the STAR , P26439 , and P05093 protein levels were not as evident as those in the respective mRNA levels . In conclusion , the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production , and thus explain the observed discrepancy between the cortisol and ___MASK23___ concentrations sometimes seen in sepsis and chronic inflammatory states .",
"Invasion and metastasis of renal cell carcinoma . Renal cell carcinoma ( RCC ) represents over 80 % of kidney cancer , and about 30 % of the patients with RCC develop metastasis after the surgery . Invasion of basement membrane ( BM ) and extracellular matrix ( Q13201 ) is an essential event in tumor invasion and metastasis . Matrix metalloproteinases ( MMPs ) , which digest the main components of BM and Q13201 , are expressed in RCC . Q9Y251 , which degrades heparan sulfate proteoglycans , is predominantly expressed in high - grade RCCs with a positive correlation with pathological tumor stage and poor prognosis . Bone metastasis is common among the patients with RCC , and increased osteoclastic activity was observed at metastatic sites . Receptor activator of nuclear factor κB ligand ( O14788 ) , which plays an important role in osteoclastogenesis , is predominantly expressed in high - grade RCC and its expression level is associated with bone metastasis and prognosis . Epithelial - mesenchymal transition ( EMT ) , a switch of epithelial cells to sarcomatoid phenotype , is considered to be critical step during metastasis , and Snail , a major regulator of EMT , is predominantly expressed in high - grade RCC , and high Snail expression is a worse prognostic factor . Accordingly , heparanase , O14788 and Snail may be targets for the development of anti - tumor therapies for RCCs .",
"Effect of active smoking on the human bronchial epithelium transcriptome . BACKGROUND : Lung cancer is the most common cause of cancer - related deaths . Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer . In this study , using serial analysis of gene expression ( Q9NXZ1 ) , we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current , former and never smokers , and identified genes showing both reversible and irreversible expression changes upon smoking cessation . RESULTS : Twenty - four Q9NXZ1 profiles of the bronchial epithelium of eight current , twelve former and four never smokers were generated and analyzed . In total , 3 , 111 , 471 Q9NXZ1 tags representing over 110 thousand potentially unique transcripts were generated , comprising the largest human Q9NXZ1 study to date . We identified 1 , 733 constitutively expressed genes in current , former and never smoker transcriptomes . We have also identified both reversible and irreversible gene expression changes upon cessation of smoking ; reversible changes were frequently associated with either xenobiotic metabolism , nucleotide metabolism or mucus secretion . Increased expression of Q07654 , O75952 , and Q5MY95 were found to be reversible upon smoking cessation . Expression of P49841 , which regulates P35354 expression , was irreversibly decreased . P98088 expression was only partially reversed . Validation of select genes was performed using quantitative RT - PCR on a secondary cohort of nine current smokers , seven former smokers and six never smokers . CONCLUSION : Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking , while expression of others appears to be permanently altered despite prolonged smoking cessation . These irreversible changes may account for the persistent lung cancer risk despite smoking cessation .",
"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .",
"Engineering the response to vascular injury : divergent effects of deregulated Q01094 expression on vascular smooth muscle cells and endothelial cells result in endothelial recovery and inhibition of neointimal growth . P01375 - alpha ( P01375 ) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells ( ECs ) , thereby delaying reendothelialization . Prior studies have shown that direct antagonism of P01375 , using a systemically administered soluble receptor , can enhance endothelial recovery and reduce neointimal thickening . These studies have also shown that downregulation of the transcription factor Q01094 was a key mechanism of P01375 ' s effect on ECs . We now show that Ad - Q01094 overexpression at sites of balloon injury accelerates functional endothelial recovery , consistent with the prior in vitro findings . Moreover these studies also reveal divergent effects of P01375 and overexpression of Q01094 on ECs versus VSMCs . P01375 exposure of VSMCs had no affect on proliferation or apoptosis , in contrast to the effect seen in ECs . In Ad - Q01094 - transduced VSMCs , however , P01375 - induced marked apoptosis in contrast to the survival effect seen in ECs . Finally , these studies suggest that differential activation of NF - kappaB may play a key role in mediating these opposing effects . Nuclear translocation and transcriptional activity of NF - kappaB was markedly attenuated in Ad - Q01094 - transduced VSMCs , whereas it remained active in similarly treated ECs when the cells were exposed to P01375 . These studies reveal that overexpression of Ad - Q01094 primes VSMCs to P01375 - induced apoptosis . Furthermore , Q01094 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF - kappaB activation . The divergent responses of VSMCs and ECs to Q01094 overexpression provide unique therapeutic possibilities : simultaneously targeting the cell cycle of two different cell types , within same tissue microenvironment resulting in opposite and biologically complimentary effects .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK74___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"P62158 is a critical regulator of osteoclastic differentiation , function , and survival . Increased osteoclastic resorption and subsequent bone loss are common features of many debilitating diseases including osteoporosis , bone metastases , Paget ' s disease , and rheumatoid arthritis . While rapid progress has been made in elucidating the signaling pathways directing osteoclast differentiation and function , a comprehensive picture is far from complete . Here , we explore the role of the Ca ( 2 +)- activated regulator calmodulin in osteoclastic differentiation , functional bone resorption , and apoptosis . During active bone resorption , calmodulin expression is increased , and calmodulin concentrates at the ruffled border , the organelle utilized for acid transport and bone dissolution . Pharmacologic inhibitors of calmodulin , several of which are already used clinically as anti - cancer and anti - psychotic agents , inhibit osteoclastic acid transport , suggesting their potential as bone - sparing drugs . Recent studies also implicate calmodulin in osteoclast apoptosis through a mechanism involving its direct interaction with the death receptor Fas . During osteoclastogenesis , O14788 - induction stimulates a rise in intracellular Ca2 + , which in turn activates calmodulin and its downstream effectors . In particular , the Ca ( 2 +)/ calmodulin - dependent phosphatase calcineurin and its targets , the NFAT family of transcription factors , have been posited as the master regulators of osteoclastogenesis . However , recent in vivo and in vitro studies demonstrate that another Ca ( 2 +)/ calmodulin - regulated effector protein , CaMKII , is also involved . CaMKII (+/-) mutant mice have reduced osteoclast numbers , and CaMKII antagonists inhibit osteoclastogenesis in vitro . Furthermore , CaMKII is known to activate AP - 1 transcription factors , which are also required for O14788 - induced osteoclast gene transcription , and recent findings suggest that CaMKII can down - regulate P40189 , a cytokine receptor involved in bone remodeling and implicated in numerous osteo - articular diseases .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK9___ and Tissue P00747 Activator in Occluded Arteries .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK65___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"DB00480 inhibits osteoclastogenesis , survival factors and bone - remodeling markers in multiple myeloma . Osteolytic bone disease in multiple myeloma ( MM ) is caused by enhanced osteoclast ( OCL ) activation and inhibition of osteoblast function . DB00480 and bortezomib have shown promising response rates in relapsed and newly diagnosed MM , and bortezomib has recently been reported to inhibit OCLs . We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib . Both drugs decreased alpha V beta 3 - integrin , tartrate - resistant acid phosphatase - positive cells and bone resorption on dentin disks . In addition , both agents decreased receptor activator of nuclear factor - kappaB ligand ( O14788 ) secretion of bone marrow stromal cells ( BMSCs ) derived from MM patients . We identified PU . 1 and pERK as major targets of lenalidomide , and nuclear factor of activated T cells of bortezomib , resulting in inhibition of osteoclastogenesis . Furthermore , downregulation of cathepsin K , essential for resorption of the bone collagen matrix , was observed . We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein - alpha , B - cell activating factor and a proliferation - inducing ligand . Importantly , in serum from MM patients treated with lenalidomide , the essential bone - remodeling factor O14788 , as well as the O14788 / O00300 ratio , were significantly reduced , whereas osteoprotegerin ( O00300 ) was increased . We conclude that both agents specifically target key factors in osteoclastogenesis , and could directly affect the MM - OCL - BMSCs activation loop in osteolytic bone disease ."
] |
[
"___MASK20___",
"___MASK21___",
"___MASK23___",
"___MASK41___",
"___MASK48___",
"___MASK65___",
"___MASK6___",
"___MASK74___",
"___MASK9___"
] |
___MASK6___
|
MH_train_352
|
interacts_with DB01166?
|
[
"Antiinflammatory and analgesic efficacy of P35354 specific inhibition : from investigational trials to clinical experience . Research strongly indicates that increased expression of the isoenzyme cyclooxygenase - 2 ( P35354 ) is responsible for elevated production of prostaglandins in inflamed joint tissues and is involved in the mediation of pain . In contrast , P23219 is a constitutively produced isoenzyme that is involved in the synthesis of eicosanoids that have important homeostatic functions , for example , in the gastric mucosa and platelets . This new knowledge led to the development of drugs that are highly specific inhibitors of P35354 while not inhibiting P23219 at maximally efficacious dosages . The first P35354 specific agent approved for clinical use in the United States was celecoxib . Large multicenter trials have shown that celecoxib at dosages of 100 mg P55957 and 200 mg P55957 is as effective as naproxen 500 mg P55957 in patients with osteoarthritis of the knee or hip . Another large multicenter trial also demonstrated that celecoxib 200 mg P43251 and 400 mg P55957 is as effective as naproxen 500 mg P55957 in patients with rheumatoid arthritis ( RA ) . A comparative trial showed that celecoxib 200 mg P55957 is as effective as diclofenac SR 75 mg P55957 in patients with RA . The potential of P35354 specific inhibitors to provide antiinflammatory and analgesic efficacy equivalent to that of conventional nonsteroidal antiinflammatory drugs without the adverse gastrointestinal mucosal and platelet effects associated with nonspecific P36551 inhibitors promises to revolutionize the clinical care of arthritis patients .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK45___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK55___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .",
"NT - 702 ( parogrelil hydrochloride , DB05505 ) , a novel and potent phosphodiesterase inhibitor , improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model . NT - 702 ( parogrelil hydrochloride , DB05505 ) , 4 - bromo - 6 -[ 3 -( 4 - chlorophenyl ) propoxy ]- 5 -[( pyridin - 3 - ylmethyl ) amino ] pyridazin - 3 ( 2H )- one hydrochloride , a novel phosphodiesterase ( PDE ) inhibitor synthesized as a potent vasodilatory and antiplatelet agent , is being developed for the treatment of intermittent claudication ( IC ) in patients with peripheral arterial disease . We assessed the efficacy of NT - 702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo . NT - 702 selectively inhibited PDE3 ( IC ( 50 )= 0 . 179 and 0 . 260 nM for Q14432 and 3B ) more potently than cilostazol ( IC ( 50 )= 231 and 237 nM for Q14432 and 3B ) among recombinant human PDE1 to PDE6 . NT - 702 inhibited in vitro human platelet aggregation induced by various agonists ( IC ( 50 )= 11 to 67 nM ) and phenylephrine - induced rat aortic contraction ( IC ( 50 )= 24 nM ) . Corresponding results for cilostazol were 4 . 1 to 17 microM and 1 . 0 microM , respectively . NT - 702 ( 3 mg / kg or more ) significantly inhibited ex vivo rat platelet aggregation after a single oral dose . For cilostazol , 300 mg / kg was effective . In a rat femoral artery ligation model , NT - 702 at 5 and 10 mg / kg repeated oral doses twice a day ( P55957 ) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2 . 5 mg / kg and more . DB01166 also improved the walking distance and surface temperature at 300 mg / kg P55957 but significant difference was only observed for surface temperature on day 8 . These results suggest that NT - 702 can be expected to have therapeutic advantage for IC .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK49___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK84___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"Calcineurin - inhibitor - free immunosuppression based on the JAK inhibitor CP - 690 , 550 : a pilot study in de novo kidney allograft recipients . This randomized , pilot study compared the Janus kinase inhibitor CP - 690 , 550 ( 15 mg P55957 [ CP15 ] and 30 mg P55957 [ CP30 ] , n = 20 each ) with tacrolimus ( n = 21 ) in de novo kidney allograft recipients . Patients received an P60568 receptor antagonist , concomitant mycophenolate mofetil ( DB00688 ) and corticosteroids . CP - 690 , 550 doses were reduced after 6 months . Due to a high incidence of BK virus nephropathy ( BKN ) in CP30 , DB00688 was discontinued in this group . The 6 - month biopsy - proven acute rejection rates were 1 of 20 , 4 of 20 and 1 of 21 for CP15 , CP30 and tacrolimus groups , respectively . BKN developed in 4 of 20 patients in CP30 group . The 6 - month rates of cytomegalovirus disease were 2 of 20 , 4 of 20 and none of 21 for CP15 , CP30 and tacrolimus groups , respectively . Estimated glomerular filtration rate was > 70 mL / min at 6 and 12 months ( all groups ) . NK cells were reduced by </= 77 % in CP - 690 , 550 - treated patients . In the CP - 690 , 550 arms , there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months . These data suggest that coadministration of CP - 690 , 550 30 mg P55957 with DB00688 is associated with overimmunosuppression . At 15 mg P55957 , the efficacy / safety profile was comparable to the tacrolimus control group , excepting a higher rate of viral infection . Further dose - ranging evaluation of CP - 690 , 550 is warranted .",
"Comparison of the micro - and macro - vascular effects of glimepiride and gliclazide in metformin - treated patients with Type 2 diabetes : a double - blind , crossover study . AIMS : To compare the metabolic and vascular effects of two sulphonylureas ( SU ) , gliclazide ( specific for the pancreatic [ Q09428 ] receptor ) and glimepiride ( a nonspecific agent that also binds to vascular and cardiac [ SUR2 ] receptors ) , during chronic administration in metformin - treated patients with Type 2 diabetes ( T2DM ) . METHODS : A randomized , double - blind , crossover study of gliclazide 80 mg P55957 and glimepiride 2 mg OD , each for 4 weeks as add - on therapy to metformin , with a 4 - week washout period . Patients attended four study mornings after first dose and 4 weeks ' SU treatment for measurements of arterial distensibility ( Ax ) , pressor responsiveness to i . v . angiotensin II ( ANGII ) , and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) . RESULTS : Glycaemic responses were similar ( e . g . serum fructosamine was 315 vs 329 micro mol l - 1 after 4 weeks ) , and there was no change in augmentation index during treatment with either SU ( 9 . 1 vs 9 . 8 mmHg after 4 weeks [ 95 % confidence interval - 8 . 1 , 10 . 5 ] ) . Similarly , there were no differences between treatments in pressor responsiveness ( e . g . PD10 [ dose of agonist required to increase mean BP by 10 mmHg ] for ANGII was 1 . 37 vs 1 . 68 ng kg - 1 min - 1 [ - 4 . 3 , 6 . 9 ] ) or cutaneous microvascular vasodilator responses ( peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [ - 82 . 7 , 79 . 1 ] ) . CONCLUSIONS : There is no evidence that Q09428 - specific and nonspecific SUs have differential effects on arterial distensibility , endothelial function or vasodilator mechanisms in metformin - treated patients with T2DM .",
"___MASK57___ : kinetic and dynamic profile in the treatment of pain . ___MASK57___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK57___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK57___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK57___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK67___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK29___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Survivin expression in glioblastomas correlates with proliferation , but not with apoptosis . BACKGROUND : Survivin is expressed in proliferating tissues and in tumors . It is a member of the inhibitory apoptosis protein ( IAP ) family known to regulate mitosis and to inhibit apoptosis . It has therefore been regarded as a target for therapies . In malignant gliomas it increases with malignancy , even though in glioblastomas it does not seem to correlate with outcome . MATERIALS AND METHODS : Survivin was immunohistochemically studied in 39 selected viable glioblastoma areas belonging to 20 cases which were assayed for apoptosis , using a TUNEL assay , caspase - 3 , poly ( ADP - ribose ) polymerase 1 ( P09874 ) , Bid ( P55957 ) and with the proliferation index Ki - 67 / MIB - 1 and mitotic index ( MI ) . RESULTS : A positive linear correlation was found between the survivin labelling index ( LI ) and the Ki - 67 / MIB - 1 LI and MI . No inverse correlation was found with apoptosis . CONCLUSION : This double behavior can be attributed to mechanisms mediating survivin activity , either as a mitosis regulator and apoptosis inhibitor , and should be taken into account in therapeutic strategies using survivin .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK56___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK21___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Efficacy and safety of apremilast , an oral phosphodiesterase 4 inhibitor , in ankylosing spondylitis . OBJECTIVES : To evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor , apremilast , in treatment of ankylosing spondylitis ( AS ) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of DB05876 inhibition on blood biomarkers of bone biology . METHODS : In this double - blind , placebo - controlled , single - centre , Phase II study , patients with symptomatic AS with active disease on Q9BWK5 were randomised to apremilast 30 mg P55957 or placebo over 12 weeks . Bath Indices were monitored serially . Patients were followed for 4 weeks after stopping medication . Bone biomarkers were assessed at baseline and day 85 . RESULTS : 38 subjects were randomised and 36 subjects completed the study . Although the primary end - point ( change in BASDAI at week 12 ) was not met , apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI ( - 1 . 59 ± 1 . 48 vs - 0 . 77 ± 1 . 47 ) , BASFI ( - 1 . 74 ± 1 . 91 vs - 0 . 28 ± 1 . 61 ) and BASMI ( - 0 . 51 ± 1 . 02 vs - 0 . 21 ± 0 . 67 ) ; however , differences did not achieve statistical significance . The clinical indices returned to baseline values by 4 weeks after cessation of apremilast . Six apremilast patients ( 35 . 3 % ) vs 3 placebo ( 15 . 8 % ) achieved ASAS20 responses ( p = 0 . 25 ) . There were statistically significant decreases in serum O14788 and O14788 : osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK - 1 , bone alkaline phosphatase , TRAP5b , P08254 , osteoprotegrin , or osteocalcin . CONCLUSIONS : Although a small pilot study , these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology . These data support further research of apremilast in axial inflammation .",
"Expression of angiogenesis - and apoptosis - related genes in chorionic villi derived from recurrent pregnancy loss patients . Angiogenesis takes place during embryogenesis , characterized by the formation of new blood vessels from pre - existing ones . This biological process is also found in the female reproductive system , wound healing , and cancer development . Apoptosis , programmed cell death , is a physiological process in development , tissue homeostasis , and disease . Apoptosis is a normal event in several reproductive tissues including human placenta . In these studies , we investigated whether aberrant angiogenesis and apoptosis are associated with recurrent pregnancy loss ( RPL ) . We compared the gene expression level for angiogenesis - and apoptosis - related genes in chorionic villi from RPL patients and those from normal controls . Semi - quantitative reverse transcriptase - polymerase chain reaction ( RT - PCR ) analysis revealed that 7 angiogenesis - and 12 apoptosis - related genes were abnormally expressed in chorionic villi from RPL patients . Angiogenesis - related genes that showed aberrant expression level are matrix metalloproteinase - 2 ( P08253 ) , plasminogen activator inhibitor ( P05121 ) , integrin , transforming growth factor - beta ( TGF - beta ) , vascular endothelial growth factor ( P15692 ) , basic fibroblast growth factor ( P09038 ) , and leptin receptor . Expression levels for these genes , except for leptin receptor , showed less in chorionic villi from RPL patients than those from normal controls . In contrast , higher expression levels of 12 apoptosis - related genes ( caspase 3 , 6 , 7 , 8 , 9 , 10 , 12 , Q92934 , Q07812 , P55957 , Fas , and P48023 ) were shown in chorionic villi from RPL patients than those from normal controls . Taken all together , it is likely that the lower expression of angiogenesis - related genes and the excessive expression of apoptosis - related genes are associated with RPL .",
"Modulation of GSK - 3β activity in Venezuelan equine encephalitis virus infection . Alphaviruses , including Venezuelan Equine Encephalitis Virus ( VEEV ) , cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases . Features of the host immune response and tissue - specific responses may contribute to fatal outcomes as well as the development of encephalitis . It has previously been shown that VEEV infection of mice induces transcription of pro - inflammatory cytokines genes ( e . g . , IFN - γ , P05231 , IL - 12 , P35228 and P01375 - α ) within 6 h . GSK - 3β is a host protein that is known to modulate pro - inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer ' s . Hence inhibition of GSK - 3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity . Small molecule GSK - 3β inhibitors and GSK - 3β siRNA experiments indicated that GSK - 3β was important for VEEV replication . Thirty - eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor , with an IC ( 50 ) of ∼ 0 . 5 µM and a CC ( 50 ) of > 100 µM . BIOder was a more potent inhibitor of GSK - 3β than BIO , as demonstrated through in vitro kinase assays from uninfected and infected cells . Size exclusion chromatography experiments demonstrated that GSK - 3β is found in three distinct complexes in VEEV infected cells , whereas GSK - 3β is only present in one complex in uninfected cells . Cells treated with BIOder demonstrated an increase in the anti - apoptotic gene , survivin , and a decrease in the pro - apoptotic gene , P55957 , suggesting that modulation of pro - and anti - apoptotic genes contributes to the protective effect of BIOder treatment . Finally , BIOder partially protected mice from VEEV induced mortality . Our studies demonstrate the utility of GSK - 3β inhibitors for modulating VEEV infection ."
] |
[
"___MASK21___",
"___MASK29___",
"___MASK45___",
"___MASK49___",
"___MASK55___",
"___MASK56___",
"___MASK57___",
"___MASK67___",
"___MASK84___"
] |
___MASK49___
|
MH_train_353
|
interacts_with DB00910?
|
[
"Examination of ceramic restorative material interfacial debonding using acoustic emission and optical coherence tomography . OBJECTIVE : CAD / P62158 ceramic restorative material is routinely bonded to tooth substrates using adhesive cement . This study investigates micro - crack growth and damage in the ceramic / dentin adhesive interface under fatigue shear testing monitored using the acoustic emission ( AE ) technique with optical coherence tomography ( O75051 ) . METHODS : Ceramic / dentin adhesive samples were prepared to measure the shear bond strength ( SBS ) under static load . Fatigue shear testing was performed using a modified ISO14801 method . Loads in the fatigue tests were applied at 80 % , 70 % , and 60 % of the SBS to monitor interface debonding . The AE technique was used to detect micro - crack signals in static and fatigue shear bond tests . RESULTS : The results showed that the average SBS value in the static tests was 10 . 61 ± 2 . 23MPa ( mean ± standard deviation ) . The average number of fatigue cycles in which ceramic / dentin interface damage was detected in 80 % , 70 % and 60 % of the SBS were 152 , 1962 and 9646 , respectively . The acoustic behavior varied according to the applied load level . Events were emitted during 60 % and 70 % fatigue tests . A good correlation was observed between crack location in O75051 images and the number of AE signal hits . SIGNIFICANCE : The AE technique and O75051 images employed in this study could potentially be used as a pre - clinical assessment tool to determine the integrity of cemented load bearing restored ceramic material . Sustainable cyclic load stresses in ceramic / dentin - bonded specimens were substantially lower than the measured SBS . Predicted S - N curve showed that the maximum endured load was 4 . 18MPa passing 10 ( 6 ) fatigue cyclic .",
"A requirement for breast - cancer - associated gene 1 ( P38398 ) in the spindle checkpoint . P38398 - associated breast cancer exhibits significantly higher levels of chromosomal abnormalities than sporadic breast cancers . However , the molecular mechanisms regarding the roles of P38398 in maintaining genome integrity remain elusive . By using a mouse model deficient for Brca1 full - length isoform ( Brca1 ( Delta11 / Delta11 ) ) , we found that Brca1 ( Delta11 / Delta11 ) cells displayed decreased expression of a number of genes that are involved in the spindle checkpoint , including Mad2 , which is a key component of spindle checkpoint that inhibits anaphase - promoting complex . We showed that Brca1 ( Delta11 / Delta11 ) cells failed to arrest at metaphase in the presence of DB08313 and underwent apoptosis because of activation of p53 . Consistently , reconstitution of Mad2 in Brca1 ( Delta11 / Delta11 ) cells partially restored the spindle checkpoint and attenuated apoptosis . By using UBR60 cells , which carry tetracycline - regulated expression of P38398 , we demonstrated that P38398 binds to transcription factor O75051 - 1 and up - regulates the transcription of Q13257 . Furthermore , we showed that the induction of P38398 to endogenous Q13257 or transfected Q13257 luciferase reporter in UBR60 cells was completely inhibited by acute suppression of P38398 by RNA interference . These data reveal a role of P38398 in maintaining genome integrity by interplaying with p53 and genes that are involved in the spindle checkpoint and apoptosis .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK27___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"[ ___MASK91___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .",
"The Concept of Divergent Targeting through the Activation and Inhibition of Receptors as a Novel Chemotherapeutic Strategy : Signaling Responses to Strong DNA - Reactive Combinatorial Mimicries . Recently , we reported the combination of multitargeted ErbB1 inhibitor - DNA damage combi - molecules with O75051 in order to downregulate ErbB1 and activate SSTRs . Absence of translation to cell kill was believed to be partially due to insufficient ErbB1 blockage and DNA damage . In this study , we evaluated cell response to molecules that damage DNA more aggressively and induce stronger attenuation of ErbB1 phosphorylation . We used three cell lines expressing low levels ( U87MG ) or transfected to overexpress wildtype ( U87 / P00533 ) or a variant ( U87 / EGFRvIII ) of ErbB1 . The results showed that ___MASK94___ ± P0CJ69 and the combi - molecules , ZRBA4 and ZR2003 , significantly blocked ErbB1 phosphorylation in U87MG cells . Addition of O75051 significantly altered cell cycle distribution . Analysis of the DNA damage response pathway revealed strong upregulation of p53 by P0CJ69 and the combi - molecules . Apoptosis was only induced by a 48 h exposure to P0CJ69 . All other treatments resulted in cell necrosis . This is in agreement with Akt - Bad pathway activation and survivin upregulation . Despite strong DNA damaging properties and downregulation of ErbB1 phosphorylation by these molecules , the strongest effect of SSTR activation was on cell cycle distribution . Therefore , any enhanced antiproliferative effects of combining ErbB1 inhibition with SSTR activation must be addressed in the context of cell cycle arrest .",
"Vitamin D analogues . The plethora of actions attributed to 1 , 25 ( OH ) 2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1 , 25 ( OH ) 2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19 - nor - 1 , 25 ( OH ) 2D2 ( DB00910 from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 ) , the serum vitamin D binding protein ( DBP ) , the vitamin D - 24 - hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22 - oxacalcitriol ( O75051 ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19 - nor - 1 , 25 ( OH ) 2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders .",
"The role of tyrosine metabolism in the pathogenesis of chronic migraine . OBJECTIVE : The pathogenesis of chronic migraine ( CM ) remains largely unknown . We hypothesized that anomalies of tyrosine metabolism , found in migraine without aura ( MwwA ) patients , play an important role in the transformation of MwwA into CM , since the increase in the number of MwwA attacks is the most predisposing factor for the occurrence of CM . METHODS : To test our hypothesis we measured the plasma levels of dopamine ( DA ) , noradrenaline ( NE ) and trace amines , including tyramine ( P14679 ) and octopamine ( O75051 ) , in a group of 73 patients with CM , 13 patients with chronic tension - type headache ( CTTH ) and 37 controls followed in the Headache Centers of the Neurology Departments of Asti , Milan and Vicenza hospitals in Italy . RESULTS : The plasma levels of DA and NE were several - fold higher in CM patients compared with control subjects ( P > 0 . 001 ) . The plasma levels of P14679 were also extremely elevated ( P > 0 . 001 ) ; furthermore , these levels progressively increased with the duration of the CM . CONCLUSIONS : Our data support the hypothesis that altered tyrosine metabolism plays an important role in the pathogenesis of CM . The high plasma levels of P14679 , a potent agonist of the trace amine associated receptors type 1 ( Q96RJ0 ) , may ultimately down - regulate this receptor because of loss of inhibitory presynaptic regulation , therein resulting in uncontrolled neurotransmitter release . This may produce functional metabolic consequences in the synaptic clefts of the pain matrix implicated in CM .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK18___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK18___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir , a HIV integrase inhibitor . DB08930 ( DTG ; S / GSK1349572 ) is a potent HIV - 1 integrase inhibitor with a distinct resistance profile and a once - daily dose regimen that does not require pharmacokinetic boosting . This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug - drug interactions . DTG is a substrate for the efflux transporters P - glycoprotein ( Pgp ) and human breast cancer resistance protein ( Q9UNQ0 ) . Its high intrinsic membrane permeability limits the impact these transporters have on DTG ' s intestinal absorption . UDP - glucuronosyltransferase ( P78381 ) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo , with cytochrome P450 ( P450 ) 3A4 being a notable pathway and P35503 and O60656 being only minor pathways . DTG demonstrated little or no inhibition ( IC ( 50 ) values > 30 μM ) in vitro of the transporters Pgp , Q9UNQ0 , multidrug resistance protein 2 , organic anion transporting polypeptide 1B1 / 3 , organic cation transporter ( O75051 ) 1 , or the drug metabolizing enzymes P05177 , 2A6 , 2B6 , 2C8 , 2C9 , 2C19 , 2D6 , 3A4 , P22309 , or 2B7 . Further , DTG did not induce P05177 , 2B6 , or 3A4 mRNA in vitro using human hepatocytes . DTG does inhibit the renal OCT2 ( IC ( 50 ) = 1 . 9 μM ) transporter , which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies . These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine - related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine - related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine - related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .",
"Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK61___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK24___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK24___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK24___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Immunohistochemical analysis in ethinylestradiol - treated breast cancers after prior long - term estrogen - deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER - positive patients become resistant to hormone therapy after long - term hormone treatment . ___MASK42___ ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well - known breast cancer - related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down - regulated ER and up - regulated PgR while nuclear and cytosolic AR were oppositely down - and up - regulated , respectively . Cytosolic staining of P38398 was significantly up - regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non - responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non - genomic pathway and this may be reflected in their sensitivity to EE2 treatment .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK51___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK51___ who were treated with a single dose of mifepristone .",
"New analogs of vitamin D3 . Calcitriol , the most active metabolite of vitamin D , controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone ( PTH ) . However , because of its potent effects on intestinal calcium absorption and bone mobilization , calcitriol treatment can induce hypercalcemia , often precluding its use at therapeutic doses . Hyperphosphatemia is also a persistent problem among patients undergoing chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol . Several pharmaceutical companies were able to modify the side - chain of the 1 , 25 ( OH ) 2D3 , allowing some of these new analogs to retain the action on the parathyroid glands while decreasing their hypercalcemic and hyperphosphatemic effects . The structure - activity relationship for ligand - mediated transcriptional regulation has been studied in detail . In some analogs the serum binding protein ( DBP ) plays a key role in determining the pharmacokinetics of the vitamin D compound . The affinity to DBP for 22 - oxacalcitriol ( O75051 ) , an analog of calcitriol for the treatment of secondary hyperparathryoidism , is approximately 300 - 400 times lower than that of calcitriol and the analog is rapidly cleared from the circulation . The mechanisms for the selectivity of 19 - nor - 1 , 25 ( OH ) 2D2 ( paricalcitol ) ( DB00910 ) another analog of calcitriol , is clearly different from O75051 . Although the mechanisms of action is not completely known , it does appear that paricalcitol down - regulates the P11473 in the intestine . It is likely that the unique biological profiles of vitamin D analogs in vivo are due to multiple mechanisms . Understanding the molecular basis of the analog selectivity will not only provide an explanation for their unique actions but allow intelligent design of more effective analogs in the future .",
"Uptake of DB06704 and catecholamines in noradrenaline - and organic cation transporter - expressing cells : potential use of corticosterone for a preferred uptake in neuroblastoma - and pheochromocytoma cells . For imaging of neuroblastoma and phaeochromocytoma , [( 123 ) I ] meta - iodobenzylguanidine ( [( 123 ) I ] DB06704 ) is routinely used , whereas [( 18 ) F ] 6 - fluorodopamine ( [( 18 ) F ] 6 - FDA ) is sporadically applied for positron emission tomography in pheochromocytoma . Both substances are taken up by catecholamine transporters ( CATs ) . In competition , some other cell types are able to take up catecholamines and related compounds probably by organic cation ( O75051 ) [ extraneuronal monoamine ( EMT ) ] transporters ( OCT1 , OCT2 , OCT3 = EMT ) . In this study , we investigated the uptake of radioiodine - labeled meta - iodobenzylguanidine ( DB06704 ) as well as [( 3 ) H ] dopamine ( mimicring 6 - fluorodopamine ) and [( 3 ) H ] noradrenaline . SK - N - SH ( neuroblastoma ) and PC - 12 ( phaeochromocytoma ) cells were used and compared with P29320 - 293 cells transfected with OCT1 , OCT2 and OCT3 , respectively . In order to gain a more selective uptake in CAT expressing tumor cells , different specific inhibitors were measured . Uptake of DB06704 into O75051 - expressing cells was similar or even better as into both CAT - expressing cell lines , whereas dopamine and noradrenaline uptake was much lower in O75051 - expressing cells . In presence of corticosterone ( f . c . 10 (- 4 ) M ] , catecholamine and DB06704 uptake into SK - N - SH and PC - 12 cells was only slightly reduced . In contrast , this process was significantly inhibited in OCT2 and OCT3 transfected P29320 - 293 as well as in Caki - 1 cells , which naturally express OCT3 . We conclude that the well - known corticosteroid corticosterone might be used in combination with [( 18 ) F ] 6 - FDA or [( 123 ) I ] DB06704 to improve specific imaging of neuroblastoma and pheochromocytoma and to reduce irradiation dose to nontarget organs in [( 131 ) I ] DB06704 treatment .",
"Swept - source optical coherence tomography of lower limb wound healing with histopathological correlation . Direct noninvasive visualization of wound bed with depth information is important to understand the tissue repair . We correlate skin swept - source - optical coherence tomography ( O75051 ) with histopathological and immunohistochemical evaluation on traumatic lower limb wounds under honey dressing to compare and assess the tissue repair features acquired noninvasively and invasively . Analysis of optical biopsy identifies an uppermost brighter band for stratum corneum with region specific thickness ( p < 0 . 0001 ) and gray - level intensity ( p < 0 . 0001 ) variation . Below the stratum corneum , variation in optical intensities is remarkable in different regions of the wound bed . Correlation between O75051 and microscopic observations are explored especially in respect to progressive growth and maturation of the epithelial and subepithelial components . Characteristic transition of uniform hypolucid band in O75051 image for depigmented zone to wavy highly lucid band in the pigmented zone could be directly correlated with the microscopic findings . The transformation of prematured epithelium of depigmented area , with low expression of P12830 , to matured epithelium with higher P12830 expression in pigmented zone , implicated plausible change in their optical properties as depicted in O75051 . This correlated evaluation of multimodal images demonstrates applicability of swept - source - O75051 in wound research and importance of integrated approach in validation of new technology .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK97___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 ."
] |
[
"___MASK18___",
"___MASK24___",
"___MASK27___",
"___MASK42___",
"___MASK51___",
"___MASK61___",
"___MASK91___",
"___MASK94___",
"___MASK97___"
] |
___MASK61___
|
MH_train_354
|
interacts_with DB00107?
|
[
"DB00107 and vasopressin receptor polymorphisms interact with circulating neuropeptides to predict human emotional reactions to stress . DB00107 ( OT ) and a polymorphism ( rs53576 ) in the oxytocin receptor gene ( P30559 ) have been independently associated with stress reactivity , whereas oxytocin ' s sister peptide , arginine vasopressin ( AVP ) and polymorphisms in the vasopressin receptor gene ( P37288 ) have been independently associated with aggressive behavior . In this study , 68 men and 98 women were genotyped for the P30559 rs53576 polymorphism and the P37288 O15537 polymorphism . Baseline and poststressor levels of plasma OT , plasma AVP , positive affect , and anger were assessed . Women , but not men , with high levels of poststressor OT and the GG genotype of rs53576 felt the most positive affect after the stressor . Men , but not women , with high levels of poststressor AVP and the 320 allele of the O15537 polymorphism reported more poststressor anger than noncarriers . These data constitute the first evidence that oxytocin and vasopressin receptor genes interact with levels of OT and AVP to predict sex - specific emotional stress responses .",
"Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK4___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .",
"Newborn Analgesia Mediated by DB00107 during Delivery . The mechanisms controlling pain in newborns during delivery are poorly understood . We explored the hypothesis that oxytocin , an essential hormone for labor and a powerful neuromodulator , exerts analgesic actions on newborns during delivery . Using a thermal tail - flick assay , we report that pain sensitivity is two - fold lower in rat pups immediately after birth than 2 days later . P30559 antagonists strongly enhanced pain sensitivity in newborn , but not in 2 - day - old rats , whereas oxytocin reduced pain at both ages suggesting an endogenous analgesia by oxytocin during delivery . Similar analgesic effects of oxytocin , measured as attenuation of pain - vocalization induced by electrical whisker pad stimulation , were also observed in decerebrated newborns . DB00107 reduced GABA - evoked calcium responses and depolarizing GABA driving force in isolated neonatal trigeminal neurons suggesting that oxytocin effects are mediated by alterations of intracellular chloride . Unlike GABA signaling , oxytocin did not affect responses mediated by P56373 and Q8NER1 receptors . In keeping with a GABAergic mechanism , reduction of intracellular chloride by the diuretic P55011 chloride co - transporter antagonist bumetanide mimicked the analgesic actions of oxytocin and its effects on GABA responses in nociceptive neurons . Therefore , endogenous oxytocin exerts an analgesic action in newborn pups that involves a reduction of the depolarizing action of GABA on nociceptive neurons . Therefore , the same hormone that triggers delivery also acts as a natural pain killer revealing a novel facet of the protective actions of oxytocin in the fetus at birth .",
"P30559 gene associated with the efficiency of social auditory processing . DB00107 has been shown to facilitate social aspects of sensory processing , thereby enhancing social communicative behaviors and empathy . Here we report that compared to the AA / AG genotypes , the presumably more efficient GG genotype of an oxytocin receptor gene polymorphism ( P30559 rs53576 ) that has previously been associated with increased sensitivity of social processing is related to less self - reported difficulty in hearing and understanding people when there is background noise . The present result extends associations between oxytocin and social processing to the auditory and vocal domain . We discuss the relevance of our findings for autistic spectrum disorders ( P51689 ) , as P51689 seems related to specific impairments in the orienting to , and selection of speech sounds from background noise , and some social processing impairments in patients with P51689 have been found responsive to oxytocin treatment .",
"Effect of undernutrition on the uterine environment during maternal recognition of pregnancy in sheep . The effects of pregnancy and undernutrition on endometrial gene expression were investigated in ewes fed all or half their maintenance requirements and killed on Day 14 of pregnancy or of the oestrous cycle . The endometrial expression of progesterone , oestrogen , oxytocin and interferon receptors ( PR , ERalpha , P30559 and P17181 , respectively ) , cyclo - oxygenase ( P36551 ) - 2 , proliferating cell nuclear antigen ( P12004 ) , insulin - like growth factors ( IGF ) - I and - II , and DB01277 receptor ( IGF - 1R ) was studied by immunohistochemistry or real - time reverse transcription - polymerase chain reaction . The luminal epithelium of cyclic control ewes was devoid of PR staining and had relatively high levels of ERalpha , P30559 , P35354 and P48551 . The presence of a conceptus decreased the in vitro uterine secretion of prostaglandin ( PG ) F ( 2alpha ) and the expression of P48551 in most cell types , and increased the gene expression of P05019 and P01344 . Undernutrition tended to increase ERalpha protein and gene , but decreased in vitro uterine secretion of PGE ( 2 ) and the gene expression of P48551 in cyclic ewes . There was no effect of undernutrition on pregnancy rates or the number of conceptuses recovered . Consistent with this , undernutrition of pregnant ewes did not have any effect on uterine gene expression . Moreover , in cases where changes were observed in cyclic ewes , these changes were negated when a conceptus was present .",
"P30559 is expressed in the penis and mediates an estrogen - dependent smooth muscle contractility . DB00107 ( OT ) is released by the posterior pituitary during male orgasm and is supposed to participate in the ejaculatory process . We now report evidence demonstrating the presence of an OT receptor gene ( real - time RT - PCR and Northern blot ) and protein ( immunohistochemistry , Western blot , and binding studies ) expression in the rabbit and human corpus cavernosum ( CC ) and its possible involvement in postorgasmic penile detumescence . OT receptor is expressed in the penis at a concentration similar to that present in other portions of the male genital tract and mediates CC contractility . OT - induced CC contractility is clearly regulated by the changing sex steroid milieu . In fact , we found that in a rabbit model of hypogonadotropic hypogonadism ( induced by a single administration of the long - acting DB00644 agonist triptorelin pamoate , 2 . 9 mg / kg ) , OT responsiveness was strongly reduced and was completely restored by estradiol valerate ( 3 . 3 mg / kg weekly ) , but not by testosterone enanthate ( 30 mg / kg weekly ) . As we found that CC expresses both subtypes of estrogen receptors and P450 aromatase , we hypothesized a physiological role for endogenous estrogens in regulating OT responsiveness . We therefore treated adult rabbits with an aromatase inhibitor ( letrozole , 2 . 5 mg / kg ) or an antiestrogen ( tamoxifen , 0 . 25 mg / kg ) for 3 wk . Both treatments significantly reduced CC responsiveness to OT stimulation . In conclusion , these findings indicate that OT might participate in inducing postorgasmic penile flaccidity and suggest a new role for estrogens in the male : regulation of CC responsiveness to OT .",
"Associations between oxytocin receptor gene ( P30559 ) polymorphisms and self - reported aggressive behavior and anger : Interactions with alcohol consumption . DB00107 has been implicated in the regulation of social as well as aggressive behaviors , and in a recent study we found that the effect of alcohol on aggressive behavior was moderated by the individual ' s genotype on an oxytocin receptor gene ( P30559 ) polymorphism ( Johansson et al . , 2012 ) . In this study we wanted to deepen and expand the analysis by exploring associations between three ( rs1488467 , rs4564970 , rs1042778 ) P30559 polymorphisms and aggressive behavior , trait anger as well as anger control in a population - based sample of Finnish men and women ( N = 3577 ) aged between 18 and 49 years ( M = 26 . 45 years , SD = 5 . 02 ) . A specific aim was to investigate if the polymorphisms would show interactive effects with alcohol consumption on aggressive behavior and trait anger , as well as to explore whether these polymorphisms affect differences in anger control between self - reported sober and intoxicated states . The results showed no main effects of the polymorphisms , however , three interactions between the polymorphisms and alcohol consumption were found . The effect of alcohol consumption on aggressive behavior was moderated by the genotype of the individual on the rs4564970 polymorphism , in line with previous results ( Johansson et al . , 2012 ) . For trait anger , both the rs1488467 and the rs4564970 polymorphisms interacted with alcohol consumption . It appears that the region of the P30559 gene including both the rs4564970 and the rs1488467 polymorphisms may be involved in the regulation of the relationship between alcohol and aggressive behavior as well as between alcohol and the propensity to react to situations with elevated levels of anger .",
"___MASK32___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK32___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK32___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"Involvement of P21453 receptor pathway in angiogenic effects of a novel adenosine - like nucleic acid analog COA - Cl in cultured human vascular endothelial cells . COA - Cl ( 2Cl - C . P01178 - A ) is a recently developed adenosine - like nucleic acid analog that promotes angiogenesis via the mitogen - activated protein ( Q96HU1 ) kinases P27361 / 2 . Endothelial P21453 receptor plays indispensable roles in developmental angiogenesis . In this study , we examined the functions of P21453 in COA - Cl - induced angiogenic responses . Antagonists for P21453 , W146 , and VPC23019 , substantially but still partly inhibited the effects of COA - Cl with regard to P27361 / 2 activation and tube formation in cultured human umbilical vein endothelial cells ( HUVEC ) . Antagonists for adenosine A1 receptor and purinergic P47900 receptor were without effect . Genetic knockdown of P21453 with siRNA , but not that of Q99500 , attenuated COA - Cl - elicited P27361 / 2 responses . The signaling properties of COA - Cl showed significant similarities to those of sphingosine 1 - phosphate , an endogenous P21453 ligand , in that both induced responses sensitive to pertussis toxin ( Gα i / o inhibitor ) , 1 , 2 - bis ( 2 - aminophenoxy ) ethane - N , N , N ', N '- tetraacetic acid tetrakis ( acetoxymethyl ester ) ( BAPTA - AM ) , ( calcium chelator ) , and Q99463 ( c - Src tyrosine kinase inhibitor ) . COA - Cl elevated intracellular Ca ( 2 +) concentration and induced tyrosine phosphorylation of p130Cas , a substrate of c - Src , in HUVEC . COA - Cl displaced [( 3 ) H ] Q14703 in a radioligand - binding competition assay in chem - 1 cells overexpressing P21453 . However , COA - Cl activated P27361 / 2 in CHO - P04264 cells that lack functional P21453 receptor , suggesting the presence of additional yet - to - be - defined COA - Cl target in these cells . The results thus suggest the major contribution of P21453 in the angiogenic effects of COA - Cl . However , other mechanism such as that seen in CHO - P04264 cells may also be partly involved . Collectively , these findings may lead to refinement of the design of this nucleic acid analog and ultimately to development of small molecule - based therapeutic angiogenesis .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Platelet aggregometry and receptor binding to predict the magnitude of antithrombotic and bleeding time effects of clopidogrel in rabbits . Target levels of ex vivo inhibition of platelet aggregation ( IPA ) induced by adenosine diphosphate ( ADP ) that produce clinically relevant effects of clopidogrel , a Q9H244 antagonist , are unclear . We examined standard and modified IPA and Q9H244 receptor occupancy as predictors of antithrombotic ( % thrombus weight reduction ) and bleeding time ( BT , fold - increase over control ) effects of clopidogrel in rabbit models of carotid artery thrombosis and cuticle bleeding , respectively . Standard and modified IPA with 20 microM ADP were measured in the absence and presence of partial P47900 blockade , respectively . ___MASK86___ maximally produced standard IPA of 57 % +/- 5 % , antithrombotic effect of 85 % +/- 1 % , BT increase of 6 . 0 +/- 0 . 4 - fold and Q9H244 receptor occupancy of 87 % +/- 5 % . Surprisingly , a clopidogrel dose that produced a low standard IPA of 17 % +/- 4 % and Q9H244 receptor occupancy of 39 % +/- 5 % achieved a significant antithrombotic activity of 55 % +/- 2 % with a moderate increase in BT of 2 . 0 +/- 0 . 1 - fold . This underestimation of clopidogrel efficacy by standard IPA was improved by measuring either modified IPA or Q9H244 receptor occupancy . These results suggest that in clopidogrel - treated rabbits , low standard IPA is associated with significant antithrombotic effects . Moreover , modified IPA and Q9H244 receptor occupancy appear to better predict the magnitude of clopidogrel ' s efficacy compared with standard IPA , which may be a better predictor of BT .",
"A 9 - year - old male with a duplication of chromosome 3p25 . 3p26 . 2 : clinical report and gene expression analysis . We describe a 9 - year - old male referred for genetic evaluation for Prader - Willi syndrome ( PWS ) . PWS is the most common genetically defined cause of life - threatening obesity and results from a functional loss of paternally expressed genes from the chromosome 15q11 - q13 region . The patient presented with pervasive developmental disorder , delayed speech , and rapid onset of obesity at age 4 years , all features similar to PWS . However , chromosome 15q11 - q13 methylation testing and fragile X studies were normal . GTG - banding and fluorescence in situ hybridization ( Q5TCZ1 ) with whole chromosome 3 paint probe ( WCP3 ) and a chromosome 3p subtelomeric probe suggested a duplication of 3p25 . 3p26 . 2 , a finding supported by comparative genomic hybridization ( CGH ) . This region of chromosome 3p contains genes which contribute to obesity and behavioral problems , most notably , ghrelin ( Q9UBU3 ) , an oxytocin receptor ( P30559 ) , solute carrier family six members ( gamma - aminobutyric acid ( GABA ) neurotransmitter transporters , P30531 and P48066 ) , and peroxisome proliferator - activated receptor gamma ( P37231 ) . To characterize these obesity and behavior related genes in our subject , we performed quantitative RT - PCR and compared expression levels with similarly aged male subjects ( four non - obese males , four obese males , and four PWS males - two with 15q11 - q13 deletions and two with maternal disomy 15 ) . Our studies suggest increased expression of several genes in the 3p duplication region , including Q9UBU3 and P37231 , which may contribute to the phenotypic features in our 3p duplication subject .",
"Pre - clinical evaluation of an in vitro selection protocol for the enrichment of transduced P28906 + cell - derived human dendritic cells . The efficient genetic modification of P28906 + cell - derived dendritic cells ( DC ) will provide a significant advancement towards the development of immunotherapy protocols for cancer , autoimmune disorders and infectious diseases . Recent reports have described the transduction of P28906 + cells via retrovirus - and lentivirus - based gene transfer vectors and subsequent differentiation into functional DC . Since there is significant apprehension regarding the clinical uses of HIV - based vectors , in this report , we compare a murine leukemia virus ( MLV ) - and a human immunodeficiency virus ( HIV ) - based bicistronic vector for gene transfer into human P28906 + cells and subsequent differentiation into mature DC . Each vector expressed both EGFP and the dominant selectable marker P00374 ( L22Y ) allowing for the enrichment of marked cells in the presence of the antifolate drug trimetrexate ( TMTX ) . Both MLV - based and HIV - based vectors efficiently transduced cytokine mobilized human peripheral blood P28906 + cells . However , in vitro expansion and differentiation in the presence of GM - P04141 , P01375 , Flt - 3L , P21583 and P05112 resulted in a reduction in the percentage of DC expressing the transgene . Selection with TMTX during differentiation increased the percentage of marked DC , resulting in up to 79 % ( MLV vector ) and up to 94 % ( lentivirus - vector ) transduced cells expressing EGFP without loss of DC phenotype . Thus , MLV - based vectors and in vitro selection of transduced human DC show great promise for immunotherapy protocols .",
"Reduced nerve growth factor levels in stress - related brain regions of folate - deficient mice . DB00158 deficiency has been linked to neurodegenerative and stress - related diseases such as stroke , dementia and depression . The role of the neurotrophins nerve growth factor ( P01138 ) and neurotrophin - 3 ( P20783 ) in stress - related disorders and neurodegeneration has garnered increasing attention in recent years . DB03419 misincorporation is involved in the neuropsychiatric dysfunction induced by experimental folate deprivation . However , the effects of folate deficiency on the expression of P01138 and P20783 in brain tissue have not yet been investigated . In a 2 × 2 design , aged mice lacking uracil - DNA N - glycosylase ( Ung (-/-) ) versus wild - type ( Ung (+/+) ) controls were subjected to a folate - deficient diet versus a regular diet for three months . Independent of genotype , folate deficiency led to decreased P01138 protein levels in the frontal cortex and amygdala . In the hippocampus , P01138 levels were increased in P13051 (-/-) mice on the normal diet , but not under folate deficiency , while in P13051 (+/+) mice , folate deprivation did not affect hippocampal P01138 content . P20783 protein concentrations were neither affected by genotype nor by folate deficiency . Altogether , the results of our study show that folate deficiency affects P01138 levels in the frontal cortex , amygdala and hippocampus . The decrease in P01138 content in the hippocampus in response to folate deficiency in Ung (-/-) mice may contribute to their phenotype of enhanced anxiety and despair - like behavior as well as to selective hippocampal neurodegeneration .",
"Central administration of oxytocin reduces hyperalgesia in mice : implication for cannabinoid and opioid systems . The neuropeptide oxytocin ( P01178 ) contributes to the regulation of diverse cognitive and physiological functions including nociception . Indeed , P01178 has been reported to be analgesic when administered directly into the brain , the spinal cord , or systemically . Although many authors have reported the analgesic effects of P01178 , its mechanism has not been well elucidated . Recently , it has been also hypothesize that P01178 , increasing intracellular concentration of calcium , could regulate the production of mediators , like endocannabinoids ( eCB ) . It has been well documented that eCB are able to suppress pain pathways . The present study investigates the effect of P01178 in paw carrageenan - induced pain . Intracerebroventricular ( icv ) administration of P01178 , but neither intraperitoneal nor intraplantar route , induces an antihyperalgesic effect increasing paw withdrawal latency to mechanical or thermal stimuli . Our results clearly demonstrate that 3 and 6h following carrageenan challenge , central administration of P01178 ( 30 ng / mouse ) shows a significant antihyperalgesic activity . Moreover , for the first time , we demonstrate that P21554 receptor plays a key role in the antihyperalgesic effect of P01178 . In fact our results show P21554 antagonist , but not the specific CB2 antagonist reduce P01178 - induced antihyperalgesic effect . In addition , our data show that central P01178 administration is able to reduce carrageenan - induced hyperalgesia but does not modify carrageenan - induced paw edema . Finally , using opioid antagonists we confirm an important role of opioid receptors . In conclusion , our experiments suggest that central administration of P01178 reduces hyperalgesia induced by intraplantar injection of carrageenan , and this effect may work via cannabinoid and opioid systems .",
"DB00107 and tumor necrosis factor alpha stimulate expression of prostaglandin E2 synthase and secretion of prostaglandin E2 by luminal epithelial cells of the porcine endometrium during early pregnancy . DB00107 ( P01178 ) and tumor necrosis factor α ( P01375 ) have been implicated in the control of luteolysis by stimulating endometrial secretion of luteolytic prostaglandin F ( 2α ) ( P49763 ( 2α ) ) . Nevertheless , P01178 concentration in porcine uterine lumen increases markedly on days 11 - 12 of pregnancy , and P01375 is expressed in endometrium during pregnancy . The objective of the study was to determine the effect of P01178 and P01375 on expression of the enzymes involved in PG synthesis : PG - endoperoxide synthase 2 ( P35354 ) , PGE ( 2 ) synthase ( mPGES - 1 ) and P49763 synthase , and PGE ( 2 ) receptor ( PTGER2 ) , as well as on PG secretion by endometrial luminal epithelial cells ( LECs ) on days 11 - 12 of the estrous cycle and pregnancy . LECs isolated from gilts on days 11 - 12 of the estrous cycle ( n = 8 ) and pregnancy ( n = 7 ) were treated with P01178 ( 100 nmol / l ) and P01375 ( 0 . 6 nmol / l ) for 24 h . P01178 increased P35354 mRNA and mPGES - 1 protein contents , as well as PGE ( 2 ) secretion but only on days 11 - 12 of pregnancy . P01375 stimulated P35354 and mPGES - 1 mRNA , as well as mPGES - 1 protein expression and PGE ( 2 ) release on days 11 - 12 of pregnancy and the estrous cycle . In addition , expressions of PTGER2 and P35408 were determined in corpus luteum ( CL ) . Abundance of PTGER2 mRNA and P35408 protein in CL was upregulated on day 14 of pregnancy versus day 14 of the estrous cycle . This study indicates that P01375 and P01178 regulate PGE ( 2 ) synthesis in LECs during early pregnancy . PGE ( 2 ) secreted by LECs , after reaching ovaries , could have a luteoprotective effect through luteal PTGER2 and P35408 , or may directly promote uterine function and conceptus development .",
"DB00107 - immunoreactive innervation of identified neurons in the rat dorsal vagal complex . BACKGROUND : DB00107 ( P01178 ) has been implicated in reproduction and social interactions and in the control of digestion and blood pressure . P01178 - immunoreactive axons occur in the dorsal vagal complex ( DVC ; nucleus tractus solitarius , P30990 , dorsal motor nucleus of the vagus , DMV , and area postrema , AP ) , which contains neurons that regulate autonomic homeostasis . The aim of the present work is to provide a systematic investigation of the P01178 - immunoreactive innervation of dorsal motor nucleus of the vagus ( DMV ) neurons involved in the control of gastrointestinal ( GI ) function . METHODS : We studied DMV neurons identified by ( i ) prior injection of retrograde tracers in the stomach , ileum , or cervical vagus or ( ii ) induction of c - fos expression by glucoprivation with DB08831 . Another subgroup of DMV neurons was identified electrophysiologically by stimulation of the cervical vagus and then juxtacellularly labeled with biotinamide . We used two - or three - color immunoperoxidase labeling for studies at the light microscopic level . KEY RESULTS : Close appositions from P01178 - immunoreactive varicosities were found on the cell bodies , dendrites , and axons of DMV neurons that projected to the GI tract and that responded to DB08831 and juxtacellularly labeled DMV neurons . Double staining for P01178 and choline acetyltransferase revealed that P01178 innervation was heavier in the caudal and lateral DMV than in other regions . P01178 - immunoreactive varicosities also closely apposed a small subset of tyrosine hydroxylase - immunoreactive P30990 and DMV neurons . CONCLUSIONS & INFERENCES : Our results provide the first anatomical evidence for direct P01178 - immunoreactive innervation of GI - related neurons in the DMV .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"P30559 subtypes in the pregnant rat myometrium and decidua : pharmacological differentiations . DB00107 ( OT ) has a dual action in the uterus : a uterotonic action on myometrial cells and a prostaglandin ( PG ) - releasing action on endometrial / decidual cells . It had not been determined whether the OT - binding sites or receptors on the myometrial and the endometrial / decidual membranes are of the same type or may represent two subtypes . Our studies presented in this paper show that isolated day 19 - 22 pregnant rat uterine horns and myometrial tissues ( uterine horns with decidual tissues removed ) incubated in Kreb ' s buffer at 37 C released PGF2 alpha in sustained quantities into the bathing medium . OT stimulated PG release over the basal release rate in a dose - dependent manner in the whole uterine horn but not in the myometrial tissue . Two OT antagonists , P [ DB00120 ( Me ) 2 , Thr4 ] ornithine vasotocin ( antagonist A ) and desGly - NH2 ( 9 ), d ( CH2 ) 5 ( 1 )[ DB00135 ( Me ) 2 , Thr4 ] ornithine vasotocin ( antagonist B ) were found to have different effects on the PG - releasing action of OT . At antiuterotonic doses , antagonist A had no antagonism of the PG - releasing action of OT . On the contrary , antagonist A was found to stimulate uterine PG release . Antagonist B was a full OT antagonist . At equivalent antiuterotonic doses , antagonist B inhibited both the uterotonic action and the PG - releasing action of OT . These findings suggest that OT - sensitive PGs are synthesized / released principally in the endometrium / decidua . The myometrial uterotonic OT receptors and the endometrial / decidual PG - releasing OT receptors are two distinct subtypes and can be differentiated . The existence of two OT receptor subtypes in the uterus has important implications in the clinical application of OT antagonists as tocolytics for preterm labor . To be efficacious , OT antagonist therapy needs to block both the uterotonic and the PG - releasing action of OT .",
"DB00107 promotes long - term potentiation by enhancing epidermal growth factor receptor - mediated local translation of protein kinase Mζ . In addition to triggering the birthing process and milk release , the hypothalamic neuropeptide oxytocin ( P01178 ) plays an important role in the regulation of complex social cognition and behavior . Previous work has shown that P01178 can regulate hippocampal synaptic plasticity and improve hippocampus - dependent cognitive functions in the female mice , but the underlying mechanisms remain largely unclear . Here , we demonstrate that P01178 promotes the maintenance of long - term potentiation ( LTP ) induced by one train of tetanic stimulation ( TS ) in the P00915 region of hippocampal slices from both nulliparous female and male rats through a previously unknown mechanism involving P01178 receptor ( P30559 ) - dependent and epidermal growth factor receptor ( P00533 ) - mediated local translation of an atypical protein kinase C isoform , protein kinase Mζ ( PKMζ ) , in dendrites . Using pharmacological and biochemical approaches , we show that both the conventional P30559 - associated signaling pathway ( G ( q / 11 )- coupled phospholipase C ) and the transactivated P00533 downstream signaling pathways ( phosphatidylinositol 3 kinase and extracellular signal - regulated kinase 1 / 2 ) are involved in the regulation of P01178 . In addition , P01178 stimulates local dendritic PKMζ mRNA translation via activation of a mammalian target of rapamycin - regulated mechanism . Furthermore , blockade of P30559 results in a modest decrease in the ability to maintain late - phase LTP induced by three trains of TS . These results reveal a novel P30559 - to - P00533 communication to regulate the new synthesis of PKMζ , which functions to promote the maintenance of LTP at hippocampal P00915 synapses .",
"DB00107 attenuates amygdala reactivity to fear in generalized social anxiety disorder . Patients with generalized social anxiety disorder ( GSAD ) exhibit heightened activation of the amygdala in response to social cues conveying threat ( eg , fearful / angry faces ) . The neuropeptide oxytocin ( P01178 ) decreases anxiety and stress , facilitates social encounters , and attenuates amygdala reactivity to threatening faces in healthy subjects . The goal of this study was to examine the effects of P01178 on fear - related amygdala reactivity in GSAD and matched healthy control ( CON ) subjects . In a functional magnetic resonance imaging study utilizing a double - blind placebo - controlled within - subjects design , we measured amygdala activation to an emotional face matching task of fearful , angry , and happy faces following acute intranasal administration of P01178 ( 24 IU or 40 . 32 μg ) and placebo in 18 GSAD and 18 CON subjects . Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo , with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group . P01178 had no effect on amygdala activity to emotional faces in the CON group , but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group , such that the hyperactivity observed during the placebo session was no longer evident following P01178 ( ie , normalization ) . These findings suggest that P01178 has a specific effect on fear - related amygdala activity , particularly when the amygdala is hyperactive , such as in GSAD , thereby providing a brain - based mechanism of the impact of P01178 in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety .",
"DB00107 microinjected into the central amygdaloid nuclei exerts anti - aggressive effects in male rats . We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain P01178 levels induces potent anti - aggressive and pro - social explorative effects during social challenges . However , the exact anatomical location in the brain where P01178 exerts its action is still elusive . In the present study , we targeted two critical brain areas , i . e . the central amygdala ( CeA ) and the dorsal raphe ( DR ) , both containing high levels of P01178 receptors ( OXTRs ) and constituting important nodes of the neural circuitry related to aggression . Behavioral effects of local micro - infusion of P01178 and P30559 antagonist , L368 . 899 , ( alone and combined ) were evaluated in resident male rats during confrontations with an unfamiliar male intruder . Our results show that P01178 microinjected into the CeA markedly reduced resident ' s offensive behavior and facilitated social exploration , without affecting other non - aggressive behaviors . The receptor specificity of the behavioral effects was verified when a micro - infusion of a selective P30559 antagonist nullified the changes . Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous P01178 within the CeA does not play a major inhibitory role on offensiveness . Anatomical specificity was also supported by the absence of relevant behavioral effects when P01178 was microinjected into more medial sub - regions of the amygdala . Likewise , within the DR neither P01178 nor P30559 exerted significant effects on offensive aggression , while microinjection of the P08908 autoreceptor agonist in this region significantly suppressed aggression . In conclusion , our results point at the CeA as an important brain site of action for the anti - aggressive and pro - social explorative effects induced by exogenous enhancement of brain P01178 levels .",
"Expression and regulation of functional oxytocin receptors in bovine T lymphocytes . The corpus luteum ( CL ) produces oxytocin ( P01178 ) , which has been proposed to regulate the pulsatile release of prostaglandin F2alpha during luteolysis in ruminants . This action of P01178 is mediated via oxytocin receptors ( OXTRs ) present on uterine epithelial cells . It is hypothesized that luteal P01178 acts as a paracrine regulator of resident immune cells . In the present study , P30559 mRNA expression in bovine lymphocytes was analyzed , as well as its regulation during the estrous cycle . P30559 transcripts were observed in freshly purified bovine peripheral blood mononuclear cells and T lymphocytes . P30559 mRNA in bovine lymphocytes on Day 3 was numerically greater than but not significantly different from that of Day 19 of the estrous cycle ( P = 0 . 091 ) . In cultured T cells , estradiol ( E2 ) treatment significantly increased the steady - state concentrations of P30559 mRNA , but the stimulatory effect of E2 was inhibited by the addition of progesterone ( P4 ) . Each of the major T cell subsets ( P01730 + , CD8 + , and gamma delta + ) expressed P30559 mRNA , with no significant difference in expression among them . Western blot analyses demonstrated the presence of the bovine P30559 protein at about 45 kDa in lymphocytes , as well as expression of the 14 - kDa precursor of P01178 . When lymphocytes were treated with P01178 , intracellular concentrations of calcium ( [ Ca2 +] i ) were rapidly and dramatically increased . This study demonstrated that bovine lymphocytes express OXTRs and that this expression can be regulated in a steroid - dependent manner . Furthermore , P01178 elicited a functional [ Ca2 +] i response in T lymphocytes , supporting the possibility that P01178 within the CL could act as a paracrine or autocrine regulator of resident T lymphocytes .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK35___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"DB00107 induces the migration of prostate cancer cells : involvement of the Gi - coupled signaling pathway . Expression of genes that encode oxytocin ( P01178 ) and vasopressin ( AVP ) and their cognate receptors in normal and diseased prostates are only partially characterized . Reverse transcription and PCR were used to examine the expression of these genes in normal prostate epithelial and stromal cell lines , k - ras - transformed prostate epithelial cell lines , and in four prostate cancer cell lines . Secreted and cell - associated P01178 peptide was measured by an enzyme immunoassay . P01178 and its receptor ( P30559 ) were expressed in all eight prostate cell lines . Cell - associated P01178 peptide was also found in all prostate epithelial cell lines except in DU145 cells . Neither AVP nor its cognate receptors ( V1a receptor and V2 receptor ) were expressed in any prostate cell line examined . These data point to the P30559 as the primary target of P01178 and AVP , and suggest that P01178 might be an autocrine / paracrine regulator in human prostate . We found that P01178 induces the migration of PC3 and PC3M , but not DU145 prostate cancer cells . The effect of P01178 is distinct from the epidermal growth factor ( P01133 ) - induced migration of prostate cancer cells , in which P27361 / 2 and P01133 receptor kinase activities were required . When cells were pretreated with pertussis toxin , the effect of P01178 , but not P01133 , on cell migration was abolished . Pretreatment with the cyclic AMP analogue , 8 - Br - DB02527 , did not affect P01178 - induced cell migration , which eliminated the nonspecific effect of pertussis toxin . We conclude that a Gi - dependent mechanism is involved in P30559 - mediated migration of prostate cancer cells , and indicates a role for P30559 in prostate cancer metastasis .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK85___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK85___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"p38 Mitogen - activated protein kinase is required for glucosamine - induced endothelial nitric oxide synthase uncoupling and plasminogen - activator inhibitor expression . BACKGROUND : Hexosamine biosynthetic pathway ( HBP ) is implicated in increased plasminogen activator inhibitor - 1 ( P05121 ) , and endothelial nitric oxide synthase ( P29474 ) dysfunction in diabetes . ___MASK80___ ( GlcN ) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models . p38 mitogen - activated protein kinase ( p38mapk ) has been shown to be involved in HBP - mediated biological processes . The aim of the present study was to investigate the role of p38mapk in GlcN - induced endothelial P05121 expression and P29474 dysfunction . METHODS AND RESULTS : In cultured human endothelial cells , GlcN time - and concentration - dependently increased P05121 protein level that was further enhanced by tumor necrosis factor ( P01375 ) - α , which was accompanied by a transient synergistic activation of p38mapk . The stimulation of P05121 by GlcN alone or by GlcN and P01375 - α in combination was inhibited by the specific inhibitor of p38mapk , but not that of JNK or P27361 / 2 . Moreover , in isolated mouse aortas , GlcN caused P29474 uncoupling resulting in enhanced superoxide and decreased NO production , as well as impaired endothelium - dependent relaxations , which were also fully prevented by the p38mapk inhibitor . CONCLUSIONS : HBP activated by GlcN increases P05121 expression and P29474 uncoupling depending on p38mapk , which not only explains hyperglycemic vascular complications , but also may bring into question the clinical use of GlcN . The present results , support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease .",
"P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK35___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .",
"___MASK80___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK80___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Pathophysiological function of oxytocin secreted by neuropeptides : A mini review . DB00107 ( P01178 ) is well known for its ability to stimulate milk ejection and uterine contraction . P01178 is also involved in several physiological and pathological functions such as antinociception , anxiety , feeding , social recognition and stress responses . Previous studies showed that neuropeptides such as cholecystokinin ( CCK ) activate P01178 - secreting magnocellular neuron in the supraoptic ( P18583 ) and the paraventricular nuclei ( PVN ) of the hypothalamus and cause P01178 release from the axon terminal in the posterior pituitary into the systemic circulation . Our recent studies showed that central administration of adrenomedullin ( AM ) family ( AM , Q7Z4H4 ( identical to intermedin ) and AM5 ) induced the expression of the c - fos gene in the P18583 and the PVN and elicited the marked increase of plasma P01178 levels in conscious rats . Here , we review pathophysiological properties of P01178 in whole body and effects of novel peptides such as AM family as well as other peptides on P01178 release .",
"DB00107 neurones in the supraoptic nucleus ( P18583 ) are inhibited by endogenous opioids in late pregnant rats . Late pregnant rats exhibit endogenous opioid restraint of oxytocin cells since i . v . naloxone ( NLX opioid antagonist ) increases oxytocin ( P01178 ) secretion but P01178 nerve terminals become desensitised to opioids . We have studied central opioid inhibition of P01178 neurones in late pregnancy by measuring P18583 P01178 neurones firing rate , immediate early gene ( Fos ) expression and dendritic P01178 release under the influence of NLX On day 21 of pregnancy NLX strongly potentiated cholecystokinin ( CCK ) excitation of P01178 neurones increased Fos protein expression and increased intranuclear release of P01178 in the P18583 ; NLX was ineffective in virgin rats . The data indicate central endogenous opioid inhibition of P01178 neurone activity in late pregnancy which may restrain premature P01178 release .",
"The association between oxytocin receptor gene ( P30559 ) polymorphisms and affective temperaments , as measured by TEMPS - A . BACKGROUND : DB00107 is associated with social interaction , trust , and affectivity . Affective temperaments are traits based on Kraepelin ' s typological definition of the \" fundamental states \" of manic - depressive illness . These states can be measured by the Temperament Evaluation of Memphis , Pisa , Paris and San Diego - Autoquestionnaire version ( TEMPS - A ) . The objective of this study is to assess the association between oxytocin receptor gene ( P30559 ) polymorphisms and affective temperaments . METHODS : Participants consisted of 493 genetically unrelated , non - clinical Japanese subjects ( 307 males and 186 females ) . The Mini - International Neuropsychiatric Interview ( MINI ) was used to screen and exclude those who had a lifetime diagnosis of schizophrenia or other psychotic disorders . Fifteen P30559 tag single nucleotide polymorphisms ( SNPs ) were genotyped using TaqMan ® or direct sequencing . The Haploview 4 . 1 . software determined the haplotype block structure . Haplotype - based quantitative trait association analysis with Bonferroni correction using PLINK 1 . 06 software was used to assess the association between haplotypes and the following affective temperaments : depressive , cyclothymic , hyperthymic , irritable , and anxious . RESULTS : Two haplotype blocks were identified on the P30559 . The depressive temperament was significantly associated with the most frequent haplotype GGGTGTC ( rs11131149 / rs2243370 / rs2243369 / rs13316193 / rs2254298 / rs2268493 / rs2268491 ) ( corrected P < 0 . 05 ) . LIMITATIONS : This study consisted of participants from a corporation and the effect sizes were small . CONCLUSIONS : The findings suggest that an P30559 haplotype is associated with a discrete depressive temperament . Clarification of the biological basis of this temperamental trait may help to elucidate the pathophysiology of depressive disorder .",
"Early life stress modulates amygdala - prefrontal functional connectivity : implications for oxytocin effects . Recent evidence suggests that early life stress ( ELS ) changes stress reactivity via reduced resting state functional connectivity ( rs - FC ) between amygdala and the prefrontal cortex . DB00107 ( P01178 ) modulates amygdala connectivity and attenuates responses to psychosocial stress , but its effect appears to be moderated by ELS . Here we first investigate the effect of ELS on amygdala - prefrontal rs - FC , and examine whether ELS - associated changes of rs - FC in this neural circuit predict its response to psychosocial stress . Secondly , we explore the joint effect of P01178 and ELS on the amygdala - prefrontal circuit . Eighteen healthy young males participated in a resting - state fMRI study of P01178 effects using a double - blind , randomized , placebo - controlled , within - subject crossover design . We measured the rs - FC to bilateral amygdalae and subsequently assessed changes of state anxiety and prefrontal responses to psychosocial stress . Multiple linear regressions showed that ELS , specifically emotional abuse , predicted reduced rs - FC between the right amygdala and pregenual anterior cingulate cortex ( pgACC ) , which in turn predicted elevated state anxiety after psychosocial stress . In subjects with lower ELS scores , stronger pgACC - amygdala rs - FC predicted stronger pgACC deactivation during the psychosocial stress task , and this rest - task interaction was attenuated by P01178 . In subjects with higher ELS scores however , the rest - task interaction was altered and P01178 showed no significant effect . These findings highlight that ELS reduces pgACC - amygdala rs - FC and alters how rs - FC of this circuit predicts its stress responsiveness . Such changes in pgACC - amygdala functional dynamics may underlie the altered sensitivity to the effects of P01178 after ELS .",
"Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children ' s Cancer Group Study . PURPOSE : ___MASK66___ is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real - time RT - PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children ' s Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event - free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome .",
"A lentivirus - mediated genetic screen identifies dihydrofolate reductase ( P00374 ) as a modulator of beta - catenin / GSK3 signaling . The multi - protein beta - catenin destruction complex tightly regulates beta - catenin protein levels by shuttling beta - catenin to the proteasome . Glycogen synthase kinase 3beta ( GSK3beta ) , a key serine / threonine kinase in the destruction complex , is responsible for several phosphorylation events that mark beta - catenin for ubiquitination and subsequent degradation . Because modulation of both beta - catenin and GSK3beta activity may have important implications for treating disease , a complete understanding of the mechanisms that regulate the beta - catenin / GSK3beta interaction is warranted . We screened an arrayed lentivirus library expressing small hairpin RNAs ( shRNAs ) targeting 5 , 201 human druggable genes for silencing events that activate a beta - catenin pathway reporter ( BAR ) in synergy with 6 - bromoindirubin - 3 ' oxime ( BIO ) , a specific inhibitor of GSK3beta . Top screen hits included shRNAs targeting dihydrofolate reductase ( P00374 ) , the target of the anti - inflammatory compound methotrexate . Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity , reduction of beta - catenin phosphorylation at GSK3 - specific sites , and accumulation of nuclear beta - catenin . Furthermore , the observed synergy correlated with inhibitory phosphorylation of GSK3beta and was neutralized upon inhibition of phosphatidyl inositol 3 - kinase ( PI3K ) . Linking these observations to inflammation , we also observed synergistic inhibition of lipopolysaccharide ( LPS ) - induced production of pro - inflammatory cytokines ( TNFalpha , P05231 , and IL - 12 ) , and increased production of the anti - inflammatory cytokine P22301 in peripheral blood mononuclear cells exposed to GSK3 inhibitors and methotrexate . Our data establish P00374 as a novel modulator of beta - catenin and GSK3 signaling and raise several implications for clinical use of combined methotrexate and GSK3 inhibitors as treatment for inflammatory disease .",
"___MASK74___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"Switching brain serotonin with oxytocin . Serotonin ( 5 - HT ) and oxytocin ( P01178 ) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism . We asked whether these chemical messengers interact in the regulation of emotion - based behavior by administering P01178 or placebo to 24 healthy subjects and mapping cerebral 5 - HT system by using 2 '- methoxyphenyl -( N - 2 '- pyridinyl )- p -[( 18 ) F ] fluoro - benzamidoethylpiperazine ( [( 18 ) F ] MPPF ) , an antagonist of P08908 receptors . P01178 increased [( 18 ) F ] MPPF nondisplaceable binding potential ( BPND ) in the dorsal raphe nucleus ( DRN ) , the core area of 5 - HT synthesis , and in the amygdala / hippocampal complex , insula , and orbitofrontal cortex . Importantly , the amygdala appears central in the regulation of 5 - HT by P01178 : [( 18 ) F ] MPPF BPND changes in the DRN correlated with changes in right amygdala , which were in turn correlated with changes in hippocampus , insula , subgenual , and orbitofrontal cortex , a circuit implicated in the control of stress , mood , and social behaviors . P01178 administration is known to inhibit amygdala activity and results in a decrease of anxiety , whereas high amygdala activity and 5 - HT dysregulation have been associated with increased anxiety . The present study reveals a previously unidentified form of interaction between these two systems in the human brain , i . e . , the role of P01178 in the inhibitory regulation of 5 - HT signaling , which could lead to novel therapeutic strategies for mental disorders .",
"DB00107 and a C - terminal derivative ( Z - prolyl - D - leucine ) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain . The effects of oxytocin ( P01178 ) and of dipeptides derived from the C - terminal portion of oxytocin ( Z - prolyl - leucine and Z - prolyl - D - leucine ) on the development of acute and chronic tolerance to , and dependence on morphine were tested in the mouse . DB00107 and the dipeptides attenuated the development of acute and chronic tolerance to the antinociceptive effect of morphine and delayed the onset of the naloxone - precipitated withdrawal syndrome . Both oxytocin and Z - prolyl - D - leucine affected drug - induced behavioural responses related to dopamine ( DA ) in the brain . Thus , oxytocin potentiated the hypermotility induced by a large dose of apomorphine and decreased the supersensitivity of the DA receptors . Small doses of Z - prolyl - D - leucine inhibited the hypomotility elicited by a small dose of apomorphine and potentiated the hyperactivity induced by amphetamine . The data indicate that both oxytocin and Z - prolyl - D - leucine affect tolerance to and dependence on morphine . While oxytocin interacts mainly with postsynaptic DA - ergic neuronal elements , the dipeptide primarily affects DA - ergic neurotransmission at the presynaptic level .",
"Interaction between norepinephrine , oxytocin , and nitric oxide in the stimulation of gonadotropin - releasing hormone release from proestrous rat basal hypothalamus explants . In the proestrous female rat , norepinephrine , oxytocin and nitric oxide ( NO ) all participate in the regulation of the preovulatory gonadotropin - releasing hormone ( DB00644 ) surge . Recent studies from our laboratory have demonstrated that oxytocin induces dose - dependent release of DB00644 from proestrous basal hypothalamus explants . The present studies were undertaken to determine whether norepinephrine could also stimulate DB00644 release from similar explants , to identify the receptors responsible for this effect and to investigate interactions between norepinephrine , oxytocin and NO . Norepinephrine significantly stimulated DB00644 release from proestrous basal hypothalamus explants , and coadministration of the alpha ( 1 )- adrenergic antagonist prazosin blocked this effect . Combined administration of oxytocin and norepinephrine stimulated significantly more DB00644 release than either drug alone , and this stimulation was blocked by inhibition of NO synthase , or by an oxytocin receptor antagonist . NO production was measured from the same samples using a modified Griess reaction . DB00107 , but not norepinephrine , significantly increased NO production , as did norepinephrine and oxytocin in combination . P30559 antagonist administration attenuated the stimulation of NO production by norepinephrine / oxytocin . These results demonstrate for the first time that oxytocin and norepinephrine dramatically stimulate DB00644 release from basal hypothalamus explants harvested on the afternoon of proestrus , and indicate that this involves oxytocin receptor and NO - dependent mechanisms .",
"Variation in the oxytocin receptor gene is associated with increased risk for anxiety , stress and depression in individuals with a history of exposure to early life stress . BACKGROUND : DB00107 is a neuropeptide that is involved in the regulation of mood , anxiety and social biology . Genetic variation in the oxytocin receptor gene ( P30559 ) has been implicated in anxiety , depression and related stress phenotypes . It is not yet known whether P30559 interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression . METHODS : In this study , we examined genotypes in 653 individuals and tested whether SNP variation in P30559 correlates with severity of features of self - reported experience on the Depression Anxiety and Stress Scale ( DASS ) , and whether this correlation is enhanced when early life trauma is taken into account . We also assessed the effects of P30559 SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples . RESULTS : A significant effect of P30559 genotype on DASS anxiety , stress and depression scores was found and ELS events , in combination with several different P30559 SNPs , were significantly associated with differences in DASS scores with one SNP ( rs139832701 ) showing significant association or a trend towards association for all three measures . Several P30559 SNPs were correlated with alterations in P30559 RNA expression and rs3831817 replicated across both sets of tissues . CONCLUSIONS : These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders .",
"Nonsocial functions of hypothalamic oxytocin . DB00107 ( P01178 ) is a hypothalamic neuropeptide composed of nine amino acids . The functions of P01178 cover a variety of social and nonsocial activity / behaviors . Therapeutic effects of P01178 on aberrant social behaviors are attracting more attention , such as social memory , attachment , sexual behavior , maternal behavior , aggression , pair bonding , and trust . The nonsocial behaviors / functions of brain P01178 have also received renewed attention , which covers brain development , reproduction , sex , endocrine , immune regulation , learning and memory , pain perception , energy balance , and almost all the functions of peripheral organ systems . Coordinating with brain P01178 , locally produced P01178 also involves the central and peripheral actions of P01178 . Disorders in P01178 secretion and functions can cause a series of aberrant social behaviors , such as depression , autism , and schizophrenia as well as disturbance of nonsocial behaviors / functions , such as anorexia , obesity , lactation failure , osteoporosis , diabetes , and carcinogenesis . As more and more P01178 functions are identified , it is essential to provide a general view of P01178 functions in order to explore the therapeutic potentials of P01178 . In this review , we will focus on roles of hypothalamic P01178 on central and peripheral nonsocial functions .",
"Effect of cytokines and ovarian steroids on equine endometrial function : an in vitro study . Regulation of immune - endocrine interactions in the equine endometrium is not fully understood . The aims of the present study were to : ( 1 ) investigate the presence of tumour necrosis factor alpha ( P01375 ) , interferon gamma ( P01579 ) , P48023 ( P48023 ) and their receptors in the mare endometrium throughout the oestrous cycle ; and ( 2 ) assess endometrial secretory function ( prostaglandins ) , angiogenic activity and cell viability in response to P01375 , oestradiol ( E2 ) , progesterone ( P4 ) and oxytocin ( P01178 ) . Transcription of P01375 and P48023 mRNA increased during the early and late luteal phase ( LP ) , whereas P01579 mRNA increased in late LP . Transcription of the mRNA of both P01375 receptors was highest in the mid - LP . All cytokines and receptors were expressed in surface and glandular epithelium , as well as in the stroma . Expression of P01375 and its receptor P19438 increased during the follicular phase ( FP ) and mid - LP . P01579 was expressed in the mid - LP , whereas its receptor IFNR1 was expressed in the in mid - and late LP . The highest expression of P48023 and FAS occurred during the late LP . P01178 increased the secretion of prostaglandin ( PG ) E2 and PGF2α in the FP and mid - LP . In the mid - LP , E2 and P4 + E2 stimulated PGF2α secretion , whereas P01375 and P4 increased cell viability . All treatments , with the exception of P4 , increased nitric oxide and angiogenic activity in both phases . The coordinated action of cytokines and ovarian hormones may regulate secretory , angiogenic and proliferative functions in the equine endometrium .",
"P30559 ligand binding in embryonic tissue and postnatal brain development of the C57BL / 6J mouse . DB00107 ( P01178 ) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior . It has been suggested that P01178 plays an important role in the infant brain during caregiver attachment in nurturing familial contexts , but there is incomplete experimental evidence . Mouse models of P01178 system genes have been particularly informative for the role of the P01178 system in social behavior , however , the developing brain areas that could respond to ligand activation of the P01178 receptor ( P30559 ) have yet to be identified in this species . Here we report new data revealing dynamic ligand - binding distribution of P30559 in the developing mouse brain . Using male and female C57BL / 6J mice at postnatal days ( P ) 0 , 7 , 14 , 21 , 35 , and 60 we quantified P30559 ligand binding in several brain areas which changed across development . Further , we describe P30559 ligand binding in select tissues of the near - term whole embryo at E18 . 5 . Together , these data aid in the interpretation of findings in mouse models of the P01178 system and generate new testable hypotheses for developmental roles for P01178 in mammalian systems . We discuss our findings in the context of developmental disorders ( including autism ) , attachment biology , and infant physiological regulation . SUMMARY : Quantitative mapping of selective P30559 ligand binding during postnatal development in the mouse reveals an unexpected , transient expression in layers II / III throughout the mouse neocortex . P30559 are also identified in several tissues in the whole late embryo , including the adrenal glands , brown adipose tissue , and the oronasal cavity .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK40___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"DB00107 affects nitric oxide and cytokine production by sepsis - sensitized macrophages . BACKGROUND / AIM : DB00107 ( P01178 ) secretion during cecal ligation puncture ( CLP ) - induced sepsis has not yet been examined . Although immune properties have been attributed to P01178 , its effect on CLP - sensitized macrophages has never been investigated . We analyzed P01178 secretion during CLP and its effect in CLP - sensitized macrophage cultures . METHODS : Male Wistar rats were decapitated 4 , 6 or 24 h after CLP surgery or sham operation and blood , brain and neurohypophyses were collected for P01178 measurements . In another set of animals we studied the effect of P01178 on nitrite , tumor necrosis factor ( P01375 - α ) , interleukin ( IL ) - 1β and P22301 production of peritoneal macrophages harvested at 6 and 24 h after CLP . RESULTS : In the early phase of sepsis ( 4 - 6 h ) , P01178 levels increased in plasma and decreased in hypothalamus and neurohypophysis . In the late phase ( 24 h ) , plasma and neurohypophyseal levels remained basal . In the paraventricular , the P01178 content remained low , but in the supraoptic increased . Macrophages of the early phase of sepsis pretreated with P01178 and stimulated with lipopolysaccharide showed decreased nitrite , P01375 - α and IL - 1β levels , but no alteration in P22301 production . In the late phase , they showed reduction only on IL - 1β . CONCLUSIONS : P01178 secretion during sepsis may represent a neuroendocrine response contributing to the overall host response to infection by decreasing the proinflammatory response and oxidative stress .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK66___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"Dysregulation of leukocyte gene expression in women with medication - refractory depression versus healthy non - depressed controls . BACKGROUND : Depressive Disorders ( DD ) are a great financial and social burden . Females display 70 % higher rate of depression than males and more than 30 % of these patients do not respond to conventional medications . Thus medication - refractory female patients are a large , under - served , group where new biological targets for intervention are greatly needed . METHODS : We used real - time quantitative polymerase chain reaction ( qPCR ) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes , including immune , Q9Y251 - axis , ion channels , and growth and transcription factors . Our sample included 23 females with medication refractory DD : 13 with major depressive disorder ( MDD ) , 10 with bipolar disorder ( BPD ) . Our comparison group was 19 healthy , non - depressed female controls . We examined differences in mRNA expression in DD vs . controls , in MDD vs . BPD , and in patients with greater vs . lesser depression severity . RESULTS : DD patients showed increased expression for P22301 , P05231 , P30559 , Q99572 , P47900 , and Q8NER1 . BPD patients showed increased P05067 , P16220 , P19838 , P04150 , and P09486 and decreased P01375 expression . Depression severity was related to increased P22301 , P47900 , P51575 , and Q9HBA0 expression . CONCLUSIONS : These results support prior findings of dysregulation in immune genes , and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication - refractory depression , and in transcription and growth factors in those with BPD . If replicated in future research examining protein levels as well as mRNA , these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"P30559 ligands induce changes in cytoskeleton in neuroblastoma cells . Aim of the present study was to evaluate effects of ligands of oxytocin receptors on gene expression of neurofilament proteins ( nestin and microtubule - associated protein 2 ( P11137 ) ) associated with neuronal differentiation and growth factors ( brain - derived neurotrophic factor ( P23560 ) and nerve growth factor ( P01138 ) ) related to neuronal growth . Fluorescent staining of F - actin was used to observe morphology of cells . Co - treatment with oxytocin and oxytocin receptor antagonist -- atosiban -- resulted in significant increase of P11137 gene expression in SK - N - SH cells . There was no effect of oxytocin on gene expression of growth factors P23560 and P01138 . Surprisingly , oxytocin with atosiban significantly increased mRNA levels for both P23560 and P01138 . Gene expression of vasopressin receptor ( P37288 ) significantly decreased in response to vasopressin . Atosiban decreased mRNA levels for oxytocin receptor ( P30559 ) and P37288 . DB00107 significantly decreased P30559 and nestin mRNA levels and increased mRNA levels for P23560 and P01138 in U - 87 MG cells . The densest recruitment of F - actin filaments was observed in apical parts of filopodia in SK - N - SH cells incubated in oxytocin presence . Present data demonstrate complex role of ligands of oxytocin receptors in regulation of gene expression of intermediate filaments and thus , oxytocin might be considered as a growth factor in neuronal type of cells .",
"P03372 ( ER ) expression and function in the pregnant human myometrium : estradiol via ERα activates P27361 / 2 signaling in term myometrium . DB00286 are thought to promote labor by increasing the expression of pro - contraction genes in myometrial cells . The specific estrogen receptors ( ( ERs : ERα and ERβ ( also known as P03372 and Q92731 ) ) and G protein - coupled receptor 30 ( Q99527 ; also known as Q99527 ) ) and signaling pathways that mediate these actions are not clearly understood . In this study , we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol ( E ( 2 ) ) modulates expression of the gene encoding the oxytocin receptor ( P30559 ) , a major pro - contraction protein . Using quantitative RT - PCR , we found that ERα and Q99527 mRNAs were expressed in the human pregnant myometrium while ERβ mRNA was virtually undetectable . While mRNA encoding ERα was the predominant ER transcript in the pregnant myometrium , ERα protein was largely undetectable in myometrial tissue by immunoblotting . Pharmacological inhibition of 26S proteasome activity increased ERα protein abundance to detectable levels in term myometrial explants , however , indicating rapid turnover of ERα protein by proteasomal processing in the pregnant myometrium . E ( 2 ) stimulated rapid extranuclear signaling in myometrial explants , as evidenced by increased extracellularly regulated kinase ( P27361 / 2 ) phosphorylation within 10 min . This effect was inhibited by pre - treatment with an ER antagonist , ICI 182 780 , indicating the involvement of ERα . Inhibition of P29323 signaling abrogated the ability of E ( 2 ) to stimulate P30559 gene expression in myometrial explants . We conclude that estrogenic actions in the human myometrium during pregnancy , including the stimulation of contraction - associated gene expression , can be mediated by extranuclear signaling through ERα via activation of the P29323 / mitogen - activated protein kinase pathway .",
"Characterization of the cyclic adenosine monophosphate target site in the oxytocin receptor gene in rabbit amnion . DB00107 ( P01178 ) is a potent stimulator of prostaglandin E ( 2 ) ( PGE ( 2 ) ) synthesis by rabbit amnion cells obtained near the end of pregnancy . Coincident with a marked increase in sensitivity of PGE ( 2 ) synthesis to P01178 , the concentration of P01178 receptors ( OXTRs ) is abruptly upregulated about 200 - fold at term . This increase can be mimicked in preterm amnion cells in primary culture by the synergistic action of agents that increase DB02527 synthesis and by glucocorticoids . To elucidate the mechanism of DB02527 action , we cloned the rabbit P30559 gene and isolated a 200 - base pair ( bp ) forskolin - responsive region about 4 . 7 kilobase upstream from the transcriptional start site using transient transfection assays . This region corresponds to a P24855 - hypersensitive site that appears in amnion tissue only near the end of pregnancy , when OXTRs are upregulated . The effects of forskolin were mediated in part by DB02527 response element binding protein ( CREB ) , as coexpression of reporter constructs with dominant negative CREB inhibited reporter expression . In addition , CREB was cross - linked to sites in the 200 - bp region only in chromatin isolated from cells near the end of pregnancy , as demonstrated by chromatin immunoprecipitation ( ChIP ) . Because the transient transfection results are consistent with work using tissue extracts ( P24855 hypersensitivity and ChIP ) , we conclude that DB02527 , acting through a specific upstream CREB binding site , is critical for the physiological upregulation of OXTRs in the amnion at the end of gestation .",
"DB00107 and oxytocin receptor gene polymorphisms and risk for schizophrenia : a case - control study . OBJECTIVES : Dysfunctions of the \" social brain \" belong to the core features of schizophrenia . The neurohormone oxytocin ( P01178 ) , mediated through its specific receptor ( P30559 ) , is involved in the regulation of social behaviour and social cognition . Previous research has suggested a role of P01178 system genes in disorders of social reciprocity . Preliminary evidence points to an association of peripheral P01178 levels as well as P01178 and P30559 gene polymorphisms with psychotic symptoms and treatment response in schizophrenia . This study aims to determine a possible contribution of P01178 and P30559 genetic variations to schizophrenia susceptibility . METHODS : Using n = 406 individuals diagnosed with schizophrenia according to DSM - IV and n = 406 healthy controls matched for age and gender in a case - control design , two single nucleotide polymorphisms ( SNPs ) within the P01178 gene ( rs2740204 , rs2740210 ) and four SNPs within the P30559 gene ( rs53576 , rs237880 , rs237885 , rs237902 ) that were previously investigated in other studies were genotyped . RESULTS : Chi ( 2 )- testing suggested significant associations of P30559 SNPs rs53576 ( A > G ) ( P = 0 . 008 ) and rs237885 ( T > G ) ( P = 0 . 025 ) with a diagnosis of schizophrenia . Post - hoc ANCOVA revealed significant associations of P30559 SNPs rs53576 with general psychopathology and rs237902 with negative symptom scores in schizophrenic patients . CONCLUSIONS : Our findings support hypotheses about an involvement of oxytocinergic gene variants in schizophrenia vulnerability and warrant independent replication ."
] |
[
"___MASK32___",
"___MASK35___",
"___MASK40___",
"___MASK4___",
"___MASK66___",
"___MASK74___",
"___MASK80___",
"___MASK85___",
"___MASK86___"
] |
___MASK35___
|
MH_train_355
|
interacts_with DB08896?
|
[
"Serotonin transporter interacts with the PDGFβ receptor in DB00102 - induced signaling and mitogenesis in pulmonary artery smooth muscle cells . The serotonin transporter ( P31645 ) and the platelet - derived growth factor receptor ( P09619 ) have been implicated in both clinical and experimental pulmonary hypertension ( PH ) and the facilitation of pulmonary artery smooth muscle cell ( PASMC ) growth . To gain a better understanding of the possible relationship of these two cell surface molecules we have explored interactions between P31645 and P09619 . We have previously demonstrated that P31645 transactivates PDGFRβ in serotonin - stimulated PASMC proliferation . We now provide evidence for a role for P31645 in DB00102 signaling and PASMC proliferation by using pharmacological inhibitors , genetic ablation , and construct overexpression of P31645 . The results show that four tested P31645 blockers dose dependently inhibit PDGF - stimulated human and bovine PASMC proliferation with comparable efficacy to that of P09619 inhibitors , whereas P28222 or 5 - Q13049 receptor inhibitors had no effect . Combinations of the P31645 and P09619 inhibitors led to synergistic / additive inhibition . Similarly , PDGF - induced PASMC proliferation was attenuated by small interfering RNA downregulation of P31645 . Inhibition of P31645 in PASMCs attenuated PDGF - induced phosphorylation of PDGFRβ , Akt , and p38 but not Erk . Overexpression of P31645 in HEK293 cells led to enhanced Akt phosphorylation by PDGF , which was blunted by a P31645 PDZ motif mutant , indicating the mechanistic need for the PDZ motif of P31645 in PDGF signaling . Furthermore , coimmunoprecipitation experiments showed that P31645 and PDGFRβ become physically associated upon PDGF stimulation . In total , the data show for the first time an important interactive relationship between P31645 and the PDGFRβ in the production of PASMC proliferation triggered by PDGF that may be important in PH .",
"Real - time US versus CT determination of pubic arch interference for brachytherapy . PURPOSE : Part 1 , to determine whether transrectal ultrasonography ( US ) enables accurate determination of pubic arch interference ( P05121 ) for prostate brachytherapy ( P10721 ) ; part 2 , to compare the accuracy of transrectal US with that of computed tomography ( CT ) for P05121 determination ; and part 3 , to determine the cost savings of P05121 determination with transrectal US versus that with CT . MATERIALS AND METHODS : Part 1 : The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage ( 14 patients ) . Part 2 : Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position ( nine patients ) . Part 3 : Cost savings were calculated for P05121 determination with transrectal US versus that with CT ( 32 patients per group ) . RESULTS : Part 1 : Transrectal US accurately showed the pubic arch relative to the prostate . Part 2 : CT resulted in P05121 overestimation by 11 . 8 mm . Part 3 : Cost savings with transrectal US were $ 1 , 465 per patient . CONCLUSION : Transrectal US P05121 determination is easily performed , intraoperatively useful , and accurate . CT can result in P05121 overestimation . Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false - positive P05121 will reduce expense and improve patient care . Transrectal US should replace CT for P05121 determination .",
"Order of genes on human chromosome 5q with respect to 5q interstitial deletions . Using ( a ) somatic cell hybrids retaining partial chromosome 5 and ( b ) clinical samples from patients with acquired deletions of the long arm of chromosome 5 , combined with chromosome 5 - linked DNA probes , some of which exhibited RFLPs , we have determined the order of a series of genes on chromosome 5 . The order established is 5pter ---- MLVI - 2 ---- cen ---- P07686 ---- P00374 ---- Pi227 - --- cp12 . 6 ---- ( P05113 , P05112 ) ---- P08700 ---- P04141 ---- P05230 ---- ( P07333 , P09619 ) ---- ( treC , ADRBR ) ---- ( Q5SW96 - Q13585 , P09603 ) ---- qter . The suggested order and orientation for the closely linked P08700 / P04141 gene pair is cen ---- 5 ' P08700 3 ' ---- 5 ' P04141 3 ' ---- qter , on the basis of analysis of the P04141 rearrangement in HL60 DNA . The map position of the GRL locus , which was consistent with both somatic cell hybrid and 5q - analyses , was telomeric to P04141 and centromeric to P07333 / P09619 , near P05230 . Long - range restriction - enzyme analysis of 5q - DNAs did not detect rearrangements of 5q - linked probes except in HL60 DNA , but it did reveal putative long - range RFLPs of several loci . RFLPs for GRL , Pi227 , cp12 . 6 , P08700 , and P07333 can detect deletions in bone marrow and in leukemia cells from patients with acquired 5q deletions .",
"___MASK7___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"DB08896 for treatment of advanced gastrointestinal stromal tumors . INTRODUCTION : Gastrointestinal stromal tumors ( GISTs ) are abdominal sarcomas which are extremely refractory to chemotherapy treatment . The treatment of GISTs has been revolutionized by use of P10721 / platelet - derived growth factor receptor - α ( P16234 ) kinase inhibitors . Unfortunately , most tumors develop resistance to front - line ( imatinib ) or second - line ( sunitinib ) therapy . DB08896 , a P10721 / P16234 / vascular endothelial growth factor receptor ( VEGFR ) oral kinase inhibitor , has been shown to improve progression - free survival in the third - or fourth - line setting . AREAS COVERED : This review covers the preclinical and clinical studies of regorafenib for treatment of GIST . A literature search on regorafenib was carried out using the PubMed database up to October 2013 . EXPERT OPINION : Currently , imatinib and sunitinib represent the only proven first - and second - line therapies , respectively , for advanced GISTs . Based on the results of a Phase III study , regorafenib is now established as the only proven third - line therapy . DB08896 activity in this setting is believed to be due to its activity against oncogenic forms of P10721 / P16234 . Although side effects are common with this agent , they can be effectively managed with a combination of supportive care , dose interruptions / reductions . The toxicity profile is similar to other oral kinase inhibitors with anti - VEGFR activity . DB08896 is mainly metabolized by P08684 , and concomitant use of strong inducers / inhibitors of this enzyme should be avoided .",
"Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .",
"___MASK12___ for joints and bones . ___MASK12___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK12___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK12___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK91___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Minimal FLAG sequence useful in the functional epitope tagging of H - Ras . Epitope tagging can interfere with normal protein function , indicating the need for an unobtrusive epitope tag . The FLAG epitope ( DYKDDDDK ) was examined for a minimal epitope useful in the tagging of H - Ras . The heptapeptide tag , P08709 ( MDYKDDD ) , was found to retain reactivity with M2 and M5 monoclonal antibodies in immunoprecipitation , Western blotting , and immunofluorescence microscopy . The P08709 tag did not interfere with Ras stability , P01133 stimulation of Ras activation , and downstream phosphorylation of MAPK Erk1 / 2 . Unlike the full FLAG sequence , the P08709 tag had minimal effect on the growth properties of H - Ras in a colony - forming assay . The P08709 tag may be useful when minimizing the effect of tagging on protein function is an important criterion in the selection of an N - terminal epitope tag .",
"The development of regorafenib and its current and potential future role in cancer therapy . DB08896 is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types , in preclinical and clinical studies . Preclinical data show inhibitory activity of angiogenic , stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1 , 2 and 3 , tyrosine - protein kinase receptor P35590 - 2 , platelet - derived growth factor receptor β , fibroblast growth factor receptor 1 , proto - oncogene tyrosine - protein kinase receptor Ret , mast / stem cell growth factor receptor Kit , P04049 and wild - type and V600E mutant serine / threonine - protein kinase B - raf . Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3 - weeks - on / 1 - week - off schedule , or 100 mg daily on a continuous schedule , with adverse effects typical of other multikinase inhibitors . Phase II studies demonstrated clinical benefit in a variety of tumor types , mostly associated with prolonged stable disease . Phase III studies include the CORRECT trial , which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies . There is still much work to be done to determine the role of regorafenib in the future of cancer therapy . This review will focus on the development of regorafenib , from early preclinical work through phase I , II and III trials , as well as highlighting the current role and potential future directions of this novel agent .",
"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK90___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK36___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK36___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK36___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK36___ among adults with ADHD .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK45___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Q9UEF7 , Q9GZV9 , and FGF receptors in chronic kidney disease : a yin - yang situation ? Secondary hyperparathyroidism in chronic kidney disease ( CKD ) develops in response to disturbances in calcium and phosphate metabolism associated with CKD , including Q9GZV9 and klotho . Q9GZV9 activates its receptor P11362 , splice variant IIIC , in the parathyroid gland via a klotho - dependent mechanism and suppresses parathyroid hormone ( PTH ) secretion . Q9UEF7 also may regulate PTH secretion in an Q9GZV9 - independent mode , by modulating parathyroid Na +/ K +- ATPase activity . The persistence of hyperparathyroidism with progressing CKD despite high serum Q9GZV9 is indicative of Q9GZV9 resistance .",
"DB09222 binding potentiates P09038 but not P15692 induced expression of u - PA , u - PAR , and P05121 in endothelial cells . Endothelial cell responses at sites of injury occur in a fibrin matrix and are regulated by growth factors including those of the FGF and P15692 families . The pericellular proteolytic balance is important in these responses , and P09038 and P15692 up - regulate endothelial cell u - PA , u - PAR and P05121 . Because both P15692 and P09038 bind to fibrinogen , we have examined the capacity of fibrinogen to modulate the up - regulation of these proteins by P09038 and P15692 . Confluent cultures of endothelial cells were exposed to P09038 , P15692 , and fibrinogen or to combinations of growth factors with fibrinogen . Changes in mRNA levels of u - PA , u - PAR and P05121 were measured by Northern blot . P09038 increased u - PA , u - PAR , and P05121 mRNA , but there was a significantly greater induction when fibrinogen was added to P09038 at all concentrations . The potentiation by fibrinogen was particularly evident at an P09038 concentration of 0 . 1 ng mL (- 1 ) , which resulted in non - significant change in transcript levels by itself , but significantly increased up to 2 . 6 - fold with fibrinogen . P15692 also increased endothelial cell expression of u - PA , u - PAR and P05121 , but this effect was not potentiated by fibrinogen . Addition of LM609 , a monoclonal antibody to alphaVbeta3 , significantly inhibited induction of u - PA mRNA and activity by fibrinogen - bound P09038 compared to P09038 . A monoclonal antibody to P11362 also inhibited u - PA mRNA expression induced by fibrinogen - bound P09038 . We conclude that fibrinogen increases the capacity of P09038 , but not of P15692 , to up - regulate u - PA , u - PAR , and P05121 in endothelial cells and that fibrinogen - bound P09038 requires alphaVbeta3 binding to up - regulate endothelial cell u - PA .",
"YAP modifies cancer cell sensitivity to P00533 and survivin inhibitors and is negatively regulated by the non - receptor type protein tyrosine phosphatase 14 . The Yes - associated protein ( YAP ) is a transcriptional factor involved in tissue development and tumorigenesis . Although YAP has been recognized as a key element of the Hippo signaling pathway , the mechanisms that regulate YAP activities remain to be fully characterized . In this study , we demonstrate that the non - receptor type protein tyrosine phosphatase 14 ( Q15678 ) functions as a negative regulator of YAP . We show that YAP forms a protein complex with Q15678 through the WW domains of YAP and the PPXY motifs of Q15678 . In addition , Q15678 inhibits YAP - mediated transcriptional activities . Knockdown of YAP sensitizes cancer cells to various anti - cancer agents , such as cisplatin , the P00533 tyrosine kinase inhibitor erlotinib and the small - molecule antagonist of survivin , P28222 . YAP - targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects .",
"Molecular profiling in the treatment of colorectal cancer : focus on regorafenib . Metastatic colorectal cancer ( mCRC ) is a highly heterogeneous disease . Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies , including anti - P00533 antibodies , cetuximab and panitumumab , and P15692 inhibitors , bevacizumab , ramucirumab , and aflibercept . The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments , such as DB01367 mutation profiling for P00533 antibodies . DB08896 is a multikinase inhibitor currently used as late line therapy for mCRC . The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized . Here , we review currently available clinical evidence of mCRC molecular profiling , such as DB01367 , P15056 , and P22897 testing , and its role in targeted therapies with special focus on regorafenib treatment .",
"[ Bone metastasis in prostate cancer ] . Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients . In addition to established bone - targeted therapies , new drugs such as endothelin A receptor antagonists , MET and P35968 antagonists or radiopharmaceuticals are in the focus of development . The standard care in prostate cancer patients with bone metastases to prevent skeletal - related events ( SRE ) are bisphosphonates . ___MASK12___ , a human monoclonal antibody against O14788 , appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases - free survival . In contrast to zoledronic acid , denosumab clearance is not dependent on kidney function and can be administered subcutaneously . Similar rates of toxicity were observed for both substances ; however , long - term data for denosumab are limited .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK43___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration . AflatoxinB1 ( AFB1 ) is well known as a potent carcinogen . Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans . AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1 - 8 , 9 - exo - epoxide , which acts as a mutagen to react with DNA . In addition , recent study demonstrates AFB1 positively regulates type I insulin - like growth factor receptor ( IGF - IR ) signaling in hepatoma cells . The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate ( P41252 ) in lung cancer cells and the effects of AFB1 on lung cancer cell migration . To this end , the effects of AFB1 on P41252 expression , Src , Akt , and P29323 phosphorylation were measured by Western blot analysis . The migration of lung cancer cells was detected by wound - healing assay . AFB1 downregulates P35568 but paradoxically upregulates Q9Y4H2 through positive regulation of the stability of Q9Y4H2 and the proteasomal degradation of P35568 in lung cancer cell lines A549 and P08709 - 1 . In addition , AFB1 induces Src , Akt , and P27361 / 2 phosphorylation . Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1 - induced Q9Y4H2 accumulation . Moreover , AFB1 stimulates lung cancer cell migration , which can be inhibited by saracatinib . We conclude that AFB1 may upregulate Q9Y4H2 and stimulate lung cancer cell migration through Src .",
"DB08896 for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi - target inhibitor . Intracellular signals for cancer cell growth , proliferation , migration , and survival are frequently triggered by protein tyrosine kinases ( TKs ) . The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes . However , intrinsic resistance may limit the benefit of these drugs , and multiple escape routes compensate for the inhibited signaling . The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents . In this scenario , regorafenib has emerged as a novel , orally active , multitarget compound with potent activity against a number of angiogenic and stromal TKs , including vascular endothelial growth factor receptor 2 ( P35968 ) , tyrosine kinase with immunoglobulin - like and P01133 - like domains 2 ( P35590 - 2 ) , fibroblast growth factor receptor 1 ( P11362 ) , and platelet - derived growth factor receptor ( P09619 ) . Moreover , the drug has the capability of blocking P10721 , P07949 and V600 mutant P15056 . Starting from interesting preclinical results , this review describes the clinical development of regorafenib in gastrointestinal malignancies , focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors .",
"DB08896 ( DB08896 ) : stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma . The introduction of targeted therapies , specifically those that target the P15692 receptor ( VEGFR ) , PDGF receptor ( P09619 ) and the P42345 pathways , has significantly changed the approach to patients with unresectable renal cell cancer ( RCC ) . However , drug resistance develops through bypassing of targeted pathways . DB08896 ( DB08896 ) is a novel bi - aryl urea compound that has potential anti - tumour activity in RCC , as along with targeting P15692 and PDGF receptors , it targets additional kinases associated with alternative pathways of angiogenesis and resistance to P15692 - targeted drugs . Based on a phase II clinical trial , the efficacy outcome of regorafenib in the first - line setting of unresectable RCC appears comparable that of other targeted first - line drugs . However , testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects . Further assessment of regorafenib should exploit the drug ' s ability to inhibit mechanisms of escape from anti - angiogenic treatment through biomarker - driven clinical trials .",
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK43___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK74___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .",
"Functional blockade of platelet - derived growth factor receptor - beta but not of receptor - alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E - deficient mice . BACKGROUND : The vascular smooth muscle cell ( VSMC ) is the central cell component involved in the fibroproliferative response in atherogenesis . As the lesion advances , VSMCs migrate from the media into the subendothelial space , thereby forming fibrous plaque lesions . Platelet - derived growth factor ( PDGF ) has been known to be a potent chemoattractant and mitogen for SMCs , but the pathophysiological role of the 2 PDGF receptors , receptor - alpha ( P16234 ) and receptor - beta ( P09619 ) in atherogenesis is poorly understood . To clarify this problem , we prepared antagonistic rat monoclonal antibodies , APA5 and APB5 , against murine P16234 and P09619 , respectively . METHODS AND RESULTS : P02649 - deficient mice were fed a high - fat diet containing 0 . 3 % cholesterol from 6 weeks of age and subjected to injection with 1 mg / d IP of either antibody from 12 to 18 weeks every other day . In the mice injected with APB5 , the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67 % and 80 % , respectively , compared with the control mice injected with irrelevant rat IgG . In contrast , the mice that received APA5 showed only minimal reduction of lesion size , and a large number of VSMCs were observed in the intima . In the intima of advanced lesions , APB5 immunolabeled VSMCs , whereas APA5 could detect VSMCs mainly in the media . CONCLUSIONS : These results indicate that P09619 plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through P09619 could affect atherogenesis in mice .",
"Biological and molecular effects of small molecule kinase inhibitors on low - passage human colorectal cancer cell lines . Low - passage cancer cell lines are versatile tools to study tumor cell biology . Here , we have employed four such cell lines , established from primary tumors of colorectal cancer ( CRC ) patients , to evaluate effects of the small molecule kinase inhibitors ( SMI ) vemurafenib , trametinib , perifosine , and regorafenib in an in vitro setting . The mutant P15056 ( V600E / V600K ) inhibitor vemurafenib , but also the Q02750 / 2 inhibitor trametinib efficiently inhibited DNA synthesis , signaling through P27361 / 2 and expression of genes downstream of P27361 / 2 in P15056 mutant cells only . In case of the AKT inhibitor perifosine , three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant . The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of P01116 , P15056 , P42336 , and P04637 mutations . DB08896 action was associated with broad - range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK / P29323 signaling . In vemurafenib - sensitive cells , the antiproliferative effect of vemurafenib was enhanced by the other SMI . Together , our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low - passage CRC cell lines as preclinical models .",
"DB08896 . DB08896 ( DB08896 , Stivarga ® ) is an oral diphenylurea multikinase inhibitor that targets angiogenic ( P17948 - 3 , Q02763 ) , stromal ( P09619 - β , FGFR ) , and oncogenic receptor tyrosine kinases ( P10721 , P07949 , and RAF ) . DB08896 is the first small - molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies . Consequently , regorafenib was FDA approved for this indication . In addition , regorafenib treatment resulted in a significant improvement in progression - free survival ( PFS ) compared with placebo in patients with metastatic gastrointestinal stromal tumors ( GIST ) after progression on standard treatments and is also an FDA approved indication . Currently , regorafenib is examined in several clinical trials ( mostly phase II ) in different tumor entities , including renal cell carcinoma ( RCC ) , hepatocellular carcinoma ( HCC ) , and soft tissue sarcoma ( STS ) .",
"Inhibition of proliferation and migration of luminal and claudin - low breast cancer cells by P09619 inhibitors . BACKGROUND : Platelet - derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 in murine and human luminal - like and claudin - low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal - like and claudin - low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells .",
"Inhibition of HCV by the serpin antithrombin III . BACKGROUND : Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection , interferon - α based therapy remains challenging for certain populations , including those with unfavorable Q8IZI9 genotypes , psychiatric co - morbidity , HIV co - infection , and decompensated liver disease . We have recently shown that P01008 , a serine protease inhibitor ( serpin ) , has broad antiviral properties . RESULTS : We now show that P01008 is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations . At a mechanistic level using gene - expression arrays , we found that P01008 treatment down - regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma , including Jun , Myc and P12643 . Using a protein interactive network analysis we found that changes in gene - expression caused by P01008 were dependent on three nodes previously implicated in HCV disease progression or HCV replication : NFκB , O75791 MAPK , and P27361 / 2 . CONCLUSIONS : Our findings suggest that P01008 stimulates a novel innate antiviral host cell defense different from current treatment options .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK45___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK66___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"A novel function for platelet - derived growth factor D : induction of osteoclastic differentiation for intraosseous tumor growth . Although increasing evidence suggests a critical role for platelet - derived growth factor ( PDGF ) receptor β ( β - P09619 ) signaling in prostate cancer ( PCa ) progression , the precise roles of β - P09619 and PDGF isoform - specific cell signaling have not been delineated . Recently , we identified the Q9GZP0 isoform as a ligand for β - P09619 in PCa and showed that Q9GZP0 is activated by serine protease - mediated proteolytic removal of the CUB domain in a two - step process , yielding first a hemidimer ( HD ) and then a growth factor domain dimer . Herein , we demonstrate that the expression of Q9GZP0 in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice . Histopathological analyses of bone tumors generated by Q9GZP0 - expressing LNCaP cells ( LNCaP - Q9GZP0 ) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases . Importantly , we discovered a novel function of Q9GZP0 in the regulation of osteoclast differentiation , independent of the O14788 / Q9Y6Q6 signaling axis . Although both PDGF - B and - D were able to activate β - P09619 , only Q9GZP0 was able to induce osteoclastic differentiation in vitro , and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1 , a master transcription factor for osteoclastogenesis . Taken together , these results reveal a new function of Q9GZP0 as a regulator of osteoclastic differentiation , an activity critical for the establishment of skeletal metastatic deposit in PCa patients .",
"Functional cross talk between P61073 and P09619 on glioblastoma cells is essential for migration . Glioblastoma ( GBM ) is the most common and aggressive form of brain tumor , characterized by high migratory behavior and infiltration in brain parenchyma which render classic therapeutic approach ineffective . The migratory behaviour of GBM cells could be conditioned by a number of tissue - and glioma - derived cytokines and growth factors . Although the pro - migratory action of P48061 on GBM cells in vitro and in vivo is recognized , the molecular mechanisms involved are not clearly identified . In fact the signaling pathways involved in the pro - migratory action of P48061 may differ in individual glioblastoma and integrate with those resulting from abnormal expression and activation of growth factor receptors . In this study we investigated whether some of the receptor tyrosine kinases commonly expressed in GBM cells could cooperate with P48061 / P61073 in their migratory behavior . Our results show a functional cross - talk between P61073 and P09619 which appears to be essential for GBM chemotaxis .",
"P15056 activation induces transformation and then senescence in human neural stem cells : a pilocytic astrocytoma model . PURPOSE : P15056 is frequently activated by gene fusion or point mutation in pilocytic astrocytoma , the most common pediatric brain tumor . We investigated the functional effect of constitutive P15056 activation in normal human neural stem and progenitor cells to determine its role in tumor induction in the brain . EXPERIMENTAL DESIGN : The constitutively active P15056 ( V600E ) allele was introduced into human neurospheres , and its effects on MAPK ( mitogen - activated protein kinase ) signaling , proliferation , soft agarose colony formation , stem cell phenotype , and induction of cellular senescence were assayed . Immunohistochemistry was used to examine p16 ( INK4a ) levels in pilocytic astrocytoma . RESULTS : P15056 ( V600E ) expression initially strongly promoted colony formation but did not lead to significantly increased proliferation . P15056 ( V600E )- expressing cells subsequently stopped proliferating and induced markers of oncogene - induced senescence including acidic β - galactosidase , P05121 , and p16 ( INK4a ) whereas controls did not . Onset of senescence was associated with decreased expression of neural stem cell markers including P48431 . Primary pilocytic astrocytoma cultures also showed induction of acidic β - galactosidase activity . Immunohistochemical examination of 66 pilocytic astrocytomas revealed p16 ( INK4a ) immunoreactivity in the majority of cases , but patients with tumors negative for p16 ( INK4a ) had significantly shorter overall survival . CONCLUSIONS : P15056 activation in human neural stem and progenitor cells initially promotes clonogenic growth in soft agarose , suggesting partial cellular transformation , but oncogene - induced senescence subsequently limits proliferation . Induction of senescence by P15056 may help explain the low - grade pathobiology of pilocytic astrocytoma , whereas worse clinical outcomes associated with tumors lacking p16 ( INK4a ) expression could reflect failure to induce senescence or an escape from oncogene - induced senescence .",
"P35354 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by P15056 inhibitors . Keratoacanthomas ( KAs ) and cutaneous squamous cell carcinomas ( cuSCCs ) develop in 15 - 30 % of patients with P15056 ( V600E ) metastatic melanoma treated with P15056 inhibitors ( BRAFi ) . These lesions resemble mouse skin tumors induced by the two - stage DMBA / TPA skin carcinogenesis protocol ; in this protocol BRAFi accelerates tumor induction . Since prior studies demonstrated cyclooxygenase 2 ( P35354 ) is necessary for DMBA / TPA tumor induction , we hypothesized that P35354 inhibition might prevent BRAFi - accelerated skin tumors . Celecoxib , a P35354 inhibitor , significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90 % . Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720 - induced gene signature . In PDV cuSCC cells , vemurafenib ( a clinically approved BRAFi ) increased P29323 phosphorylation and soft agar colony formation ; both responses were greatly decreased by celecoxib . In clinical trials trametinib , a MEK inhibitor ( MEKi ) increases BRAFi therapy efficacy in P15056 ( V600E ) melanomas and reduces BRAFi - induced KA and cuSCC frequency . DB08911 also reduced vemurafenib - induced PDV soft agar colonies , but less efficiently than celecoxib . The trametinb / celecoxib combination was more effective than either inhibitor alone . In conclusion , celecoxib suppressed both BRAFi - accelerated skin tumors and soft - agar colonies , warranting its testing as a chemopreventive agent for non - melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi .",
"The preclinical development of regorafenib for the treatment of colorectal cancer . INTRODUCTION : The DB01367 - RAF - MEK - P29323 pathway is one of the best characterized kinase cascades . During the exploration of small molecules that inhibit P04049 kinase , regorafenib ( DB08896 ) was discovered as a multikinase inhibitor which demonstrated anti - cancer , anti - angiogenic , and apoptotic activities in metastatic colorectal cancer . This was not the first multikinase inhibitor discovered for the disease ; indeed , before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012 , sorafenib ( BAY 43 - 9006 ) had already been developed to be the first in the world as a multikinase inhibitor for malignancy . Indeed , the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile , both as a kinase inhibitor as well as in its clinical application . AREAS COVERED : In this drug discovery case history , the authors review the design , discovery , and development of both regorafenib and sorafenib from back in the 1990s . Furthermore , the authors highlight the drug ' s anti - cancer and anti - angiogenic properties as well as its efficacy , safety pharmacology and toxicology based on FDA documents . EXPERT OPINION : In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently , our understanding of drug discovery , the approaches for kinase profiling , and technologies needed for their development are paramount . Indeed , the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics . Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive .",
"Role of P15056 in thyroid oncogenesis . P15056 , a cytoplasmic serine - threonine protein kinase , plays a critical role in cell signaling as an activator within the mitogen - activated protein kinase ( MAPK ) pathway . The most common P15056 mutation is the V600E transversion , which causes constitutive kinase activity . This mutation has been found in a multitude of human cancers , including both papillary thyroid cancer ( PTC ) and papillary - derived anaplastic thyroid cancer ( ATC ) , in which it initiates follicular cell transformation . With such a high frequency of P15056 mutations in PTC ( 44 % ) and PTC - derived ATC ( 24 % ) , research in P15056 ( V600E ) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence . P15056 ( V600E ) in PTC has also provided valuable prognostic information , as its presence has been correlated with more aggressive and iodine - resistant phenotypes . Such findings have initiated research in targeting oncogenic P15056 in cancer therapeutics . Although multiple phase II clinical trials in patients with iodine - refractory metastatic PTC have shown significant efficacy for sorafenib , a first - generation P15056 inhibitor , the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib . Additionally , preclinical and clinical studies investigating combination therapy with agents such as selective ( PLX 4032 ) and potent ( DB08896 and ARQ 736 ) small - molecule P15056 inhibitors and Q96HU1 / extracellular signal - regulated kinase ( P29323 ) kinase inhibitors ( AZD6244 ) hold great promise in the treatment of P15056 ( V600E ) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC .",
"DB08896 in metastatic colorectal cancer . DB08896 is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis ( P17948 , 2 , 3 ; angiopoietin - 1 receptor ) , oncogenesis ( stem cell growth factor receptor ; P07949 ; P15056 including BRAFV600E ) , and tumor microenvironment ( P09619 - β and FGFR ) . Based on data from the Phase III CORRECT study , regorafenib stands as a further option for patient affected by metastatic colorectal cancer who have exhausted previous available therapies . Its multi - targeted effect might explain activity in advanced lines of treatment , when cancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance , but also makes difficult to identify predictive biomarkers . In this article we examine preclinical as well as clinical data of regorafenib in the therapy of metastatic colorectal cancer , challenges for potential markers of efficacy and its role in the treatment algorithm .",
"[ Concept , etiology and epidemiology of primary hyperparathyroidism ] . Primary hyperparathyroidism ( PHPT ) is one of the most frequent endocrinological disorders . In PHPT , there is abnormal regulation of parathyroid hormone ( PTH ) by calcium , which translates into inappropriately high PTH secretion for the level of calcemia . Most patients with PHPT have increased serum PTH levels , with increases in serum calcium , especially ionic calcium . The incidence of PHPT rises with age , the mean age at diagnosis being 55 years . This disorder affects mainly women with a female - to - male ratio of approximately 3 : 1 . Most ( 80 - 85 % ) of cases are produced by chief cell parathyroid adenomas . The factors involved in the genesis of PHPT are largely unknown . Gene mutations affecting oncogenes ( cyclin D1 , P07949 ) or tumor suppressor genes ( O00255 , Q6P1J9 ) are found in a minority of cases . These mutations are especially important in familial forms of PHPT , such as multiple endocrine neoplasia syndrome ( O00255 , MEN2A ) . No mutations affecting the calcium - sensing receptor ( P41180 ) or vitamin D receptor ( P11473 ) gene have been found . In parathyroid adenomas and hyperplasias , there may be abnormal Wnt signalling , with mutations of the coreceptor O75197 gene and beta - catenin accumulation . Expression of the Q9UEF7 protein , which intervenes in serum calcium regulation , is reduced . Low levels of 25 ( OH ) vitamin D frequently coexist , although whether vitamin D deficiency plays a pathogenic role in PHPT is unknown .",
"EV71 induces P35354 expression via c - Src / P09619 / PI3K / Akt / Q8NFH3 / Q8TCB0 MAPK / AP - 1 and NF - kappaB in rat brain astrocytes . Enterovirus 71 ( EV71 ) induces the expression of cyclooxgenase ( P36551 ) - 2 served as a major neurotoxic factor in CNS injury . However , the mechanisms underlying EV71 - initiated intracellular signaling pathways leading to P35354 expression remain unknown . Therefore , we investigated the mechanisms underlying EV71 - induced P35354 expression and prostaglandin E ( 2 ) ( PGE ( 2 ) ) production in rat brain astrocytes ( RBA ) - 1 , determined by Western blotting , RT - PCR , and promoter assay . Here , we reported that EV71 - induced P35354 expression and PGE ( 2 ) production were attenuated by pretreatment with the inhibitors of c - Src ( P50391 ) , P09619 ( AG1296 ) , PI3K ( Wortmannin ) , Q02750 / 2 ( PD98059 ) , NF - kappaB ( helenalin ) , and AP - 1 ( Tanshinone ) and transfection with shRNA or siRNA of c - Src , P09619 , p85 , c - Jun , c - Fos , P27361 , or P28482 . We further observed that EV71 - induced activation of Akt and Q8NFH3 / Q8TCB0 MAPK were mediated via c - Src and P09619 . Pretreatment with P50391 attenuated EV71 - stimulated phosphorylation of Src , P09619 , Akt , and Q8NFH3 / Q8TCB0 MAPK . Inhibition of PI3K by Wortmannin attenuated EV71 - induced Akt and Q8NFH3 / Q8TCB0 MAPK phosphorylation , but had no effect on P09619 phosphorylation , suggesting that P09619 is an upstream and Q8NFH3 / Q8TCB0 MAPK is a downstream component of PI3K / Akt in these responses . EV71 - stimulated NF - kappaB translocation from the cytoplasm to the nucleus , P25963 degradation and NF - kappaB promoter activity were attenuated by pretreatment with helenalin , but not AG1296 , Wortmannin , and PD98059 . EV71 - induced c - Jun mRNA expression was attenuated by pretreatment with PD98059 , AG1296 , or Wortmannin . These results demonstrate that in RBA - 1 cells , EV71 - induced P35354 expression associated with PGE ( 2 ) production is mediated through activation of c - Src / P09619 / PI3K / Akt / Q8NFH3 / Q8TCB0 MAPK to initiate the expression of AP - 1 .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK90___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Management of regorafenib - related toxicities : a review . DB08896 ( Stivarga , DB08896 ; Bayer Pharma AG , Berlin , Germany ) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 ( P35968 ) , P17948 , P35916 , fibroblast growth factor receptor 1 ( P11362 ) , RAF , P10721 , P07949 and P15056 . Its antiangiogenic effect is greater than that of its related drug , sorafenib . DB08896 has been approved by the US Food and Drug Administration ( FDA ) for the treatment of metastatic colorectal cancer ( mCRC ) in patients who have failed treatment with fluoropyrimidine , oxaliplatin and irinotecan based chemotherapy , an anti - P15692 therapy and , if P01116 wild type , an anti - P00533 therapy . The FDA based this approval on data from the CORRECT trial , which showed the efficacy of regorafenib compared with placebo . The most common grade 3 - 4 adverse reactions with the drug are hand foot skin reactions ( HFSR ) , diarrhea , hypertension and fatigue . This review discusses the efficacy data , and the incidence and management of regorafenib ' s toxicities .",
"Critical appraisal of the use of regorafenib in the management of colorectal cancer . The lack of valid clinical management options for patients affected by metastatic colorectal cancer , which has progressed after all approved standard treatments , has lead to research into new active molecules . DB08896 is an oral small - molecule multi kinase inhibitor , binding to several intracellular kinases , with powerful inhibitory activity against vascular endothelial growth factor receptors ( P17948 , P35968 , and P35916 ) , platelet - derived growth factor receptor , fibroblast growth factor receptor 1 , Raf , P35590 - 2 , and the kinases P10721 , P07949 , and P15056 . The antitumor activity of regorafenib has been tested in vitro and in vivo , and inhibition of tumor growth has been observed in several cancer models , particularly colorectal cancer and gastrointestinal stromal tumors . The most frequent adverse events of grade 3 or higher related to regorafenib were hand - foot skin reaction , fatigue , diarrhea , hypertension , and rash or desquamation . Only a few Phase I - II trials , and most recently a Phase III trial in pretreated colorectal cancer , have been carried out to date . Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy . At this point in time , regorafenib is the first small - molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients .",
"Modulation of mitogen - activated protein kinase cascades by differentiation - 1 protein : acquired drug resistance of hormone independent prostate cancer cells . PURPOSE : The inhibitor of differentiation - 1 protein ( Id - 1 ) is over expressed in multidrug resistance prostate cancer cells . We determined the effect of Id - 1 expression and its underlying pathways on the development of multidrug resistance in prostate cancer . MATERIALS AND METHODS : P01008 cells were transfected with the Id - 1 gene or a blank vector . Id - 1 mRNA expression was determined by reverse transcriptase - polymerase chain reaction and Id - 1 protein content was detected by immunoblot and flow cytometry . Cellular cytotoxicity was determined by MTT ( microculture 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ) assay ( Sigma Chemical Co . , St . Louis , Missouri ) . The activation and expression of mitogen - activated protein kinase ( MAPK ) were measured by transactivation assay and Western blotting , respectively . RESULTS : Id - 1 overproduction drove P01008 cells to become resistant to chemotherapeutic agents but did not induce mdr - 1 gene expression . The p38MAPK and c - jun N - terminal kinase ( JNK ) pathways were suppressed , which correlated with increased Id - 1 expression . No significant change in extracellular signal - regulated kinase ( P29323 ) activation was observed in Id - 1 transfectants compared with that of P01008 or vector control . Treatment of Id - 1 expressing cells with p38MAPK and JNK inhibitors resulted in decreased doxorubicin induced apoptosis . In contrast , Id - 1 expressing cells treated with P29323 inhibitor made cells more sensitive to drug induced apoptosis . CONCLUSIONS : Up - regulation of Id - 1 was found in prostate cancer multidrug resistant cells . Sustained P29323 activation , and JNK and p38MAPK inhibition by Id - 1 in cells may confer drug resistance . These changes in MAPKs could be a mechanism for the acquisition of multidrug resistance in prostate cancer .",
"DB08896 ( DB08896 ) : a new oral multikinase inhibitor of angiogenic , stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Angiogenesis , a critical driver of tumor development , is controlled by interconnected signaling pathways . Vascular endothelial growth factor receptor ( VEGFR ) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature . DB08896 ( DB08896 ) , a novel oral multikinase inhibitor , potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays . Furthermore , regorafenib inhibits additional angiogenic kinases ( P17948 / 3 , platelet - derived growth factor receptor - β and fibroblast growth factor receptor 1 ) and the mutant oncogenic kinases P10721 , P07949 and B - RAF . The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast - enhanced magnetic resonance imaging . DB08896 administered once orally at 10 mg / kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts . In a daily ( qd )× 4 dosing study , the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition ( TGI ) . A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd × 5 dosing at 10 and 30 mg / kg . DB08896 exhibited potent dose - dependent TGI in various preclinical human xenograft models in mice , with tumor shrinkages observed in breast MDA - MB - 231 and renal 786 - O carcinoma models . Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki - 67 and phosphorylated extracellular regulated kinases 1 / 2 . These data demonstrate that regorafenib is a well - tolerated , orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies .",
"Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .",
"Transforming growth factor alpha - induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) - alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF - alpha rescues neurons from N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue - type plasminogen activator ( t - PA ) release was shown to potentiate DB01221 - induced excitotoxicity , we observed that TGF - alpha treatment reduced DB01221 - induced increase of t - PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF - alpha induces activation of the extracellular signal - regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF - alpha , by an P29323 - dependent mechanism , stimulates the astrocytic expression of P05121 , a t - PA inhibitor , which mediates the neuroprotective activity of TGF - alpha against DB01221 - mediated excitotoxic neuronal death . Taken together , we indicate that TGF - alpha rescues neurons from DB01221 - induced excitotoxicity in mixed cultures through inhibition of t - PA activity , involving P05121 overexpression by an P29323 - dependent pathway in astrocytes .",
"First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : ___MASK90___ is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S - warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S - warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23 . 4 ± 7 . 94 mg ) compared to 208 patients carrying the CYP29C9 * 1 genotype ( 32 . 2 ± 12 . 65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .",
"Functional and molecular characterization of ex vivo cultured epiretinal membrane cells from human proliferative diabetic retinopathy . Characterization of the cell surface marker phenotype of ex vivo cultured cells growing out of human fibrovascular epiretinal membranes ( fvERMs ) from proliferative diabetic retinopathy ( PDR ) can give insight into their function in immunity , angiogenesis , and retinal detachment . FvERMs from uneventful vitrectomies due to PDR were cultured adherently ex vivo . Surface marker analysis , release of immunity - and angiogenesis - pathway - related factors upon P01375 α activation and measurement of the intracellular calcium dynamics upon mechano - stimulation using fluorescent dye Fura - 2 were all performed . FvERMs formed proliferating cell monolayers when cultured ex vivo , which were negative for endothelial cell markers ( CD31 , P35968 ) , partially positive for hematopoietic - ( P28906 , Q08722 ) and mesenchymal stem cell markers ( CD73 , CD90 / Thy - 1 , and P09619 β ) , and negative for CD105 . CD146 / P43121 and CD166 / Q13740 , previously unreported in cells from fvERMs , were also expressed . Secretion of 11 angiogenesis - related factors ( DPPIV / P27487 , P58294 / P30613 , ET - 1 , P18065 and 3 , P10145 / P10145 , P13500 / P13500 , P14780 , PTX3 / P26022 , P05121 / P05121 , P36955 / P36955 , P01033 , and P07996 - 1 ) were detected upon P01375 α activation of fvERM cells . Mechano - stimulation of these cells induced intracellular calcium propagation representing functional viability and role of these cells in tractional retinal detachment , thus serving as a model for studying tractional forces present in fvERMs in PDR ex vivo .",
"The role of HIV - related chemokine receptors and chemokines in human erythropoiesis in vitro . In order to better define the role of HIV - related chemokines in human erythropoiesis we studied : A ) the expression of chemokine receptors , both on human P28906 (+) cells which include erythroid progenitors and on more mature erythroid cells ; B ) the functionality of these receptors by calcium flux , chemotaxis assay and phosphorylation of mitogen - activated protein kinases ( MAPK ) Q8NFH3 / 44 ( P27361 / P28482 ) and AKT , and finally C ) the influence of chemokines on BFU - E formation . We found that HIV - related chemokine receptor P61073 , but not P51681 , is detectable on human P28906 (+) BFU - E cells . P61073 surface expression decreased during erythroid maturation , although P61073 mRNA was still present in cells isolated from differentiated erythroid colonies . P48061 , a P61073 ligand , induced calcium flux and phosphorylation of MAPK ( Q8NFH3 / 44 ) and AKT in P28906 (+) P10721 (+) bone marrow mononuclear cells which contain BFU - E , as well as chemotactic activity of both human P28906 (+) BFU - E progenitors and erythroid cells isolated from day 2 - 6 BFU - E colonies . Responsiveness to P48061 decreased when the cells differentiated to the point of surface expression of the erythroid - specific marker P02724 . In contrast , the P51681 ligands ( macrophage inflammatory protein - 1alpha [ MIP - 1alpha ] , MIP - 1beta , and RANTES ) did not activate calcium flux , MAPK and AKT phosphorylation or chemotaxis of P28906 (+) P10721 (+) cells or cells isolated from the BFU - E colonies . Interestingly , none of the chemokines tested in this study had any effect on BFU - E colony formation . In conclusion , only P61073 is functional , and its specific ligand P48061 may therefore play an important role in the homing and / or retention of early erythroid precursors in the bone marrow environment .",
"Involvement of extracellular signal - regulated kinase module in HIV - mediated P01730 signals controlling activation of nuclear factor - kappa B and AP - 1 transcription factors . Although the molecular mechanisms by which the HIV - 1 triggers either T cell activation , anergy , or apoptosis remain poorly understood , it is well established that the interaction of HIV - 1 envelope glycoproteins with cell surface P01730 delivers signals to the target cell , resulting in activation of transcription factors such as NF - kappa B and AP - 1 . In this study , we report the first evidence indicating that kinases MEK - 1 ( Q96HU1 kinase / Erk kinase ) and P27361 ( extracellular signal - regulated kinase ) act as intermediates in the cascade of events that regulate NF - kappa B and AP - 1 activation upon HIV - 1 binding to cell surface P01730 . We found that CEM cells transfected with dominant negative forms of MEK - 1 or P27361 do not display NF - kappa B activation after HIV - 1 binding to P01730 . In contrast , NF - kappa B activation was observed in these cells after PMA stimulation . Although the different cell lines studied expressed similar amounts of P01730 and p56 ( lck ) , HIV - 1 replication and HIV - 1 - induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK - 1 or P27361 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK - 1 or wild - type P27361 . In light of recently published data , we propose that a positive signal initiated following oligomerization of P01730 by the virus is likely to involve a recruitment of active forms of p56 ( lck ) , P04049 , MEK - 1 , and P27361 , before AP - 1 and NF - kappa B activation .",
"DB08896 for cancer . INTRODUCTION : DB08896 ( DB08896 ) is a novel , orally active , diphenylurea multikinase inhibitor of P17948 - 3 , c - P10721 , P35590 - 2 , P09619 - β , P11362 , P07949 , RAF - 1 , P15056 and p38 Q96HU1 kinase . AREAS COVERED : This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies . The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile . Current clinical developments , especially in colorectal cancer ( CRC ) and gastrointestinal stromal tumor ( GIST ) , are addressed . Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed . EXPERT OPINION : DB08896 ( DB08896 ) is a novel , orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed . The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets . DB08896 has promising antineoplastic activity in various tumor types . Two large , randomized Phase III pivotal registration studies in patients with GIST and CRC , respectively , already completed enrolment , with final results being awaited . Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing . Moreover , regorafenib has recently been granted Orphan Drug Status for GIST tumors and ' fast track ' status for both GIST and CRC by the FDA .",
"Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .",
"Connexin 43 and P29323 regulate tension - induced signal transduction in human periodontal ligament fibroblasts . Periodontal ligament ( PDL ) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone . Connexin 43 ( P17302 ) , a gap junction protein , is essential for bone homeostasis and regulates bone remodeling . However , the function of P17302 in human PDL fibroblast - regulated bone remodeling has not yet been elucidated . In this study , human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5 % elongation for different durations . We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal - regulated kinase ( P29323 ) in human PDL fibroblasts after loading . We found that mechanical tension increased P17302 , which further upregulated osteogenic ( e . g . , Q13950 , Osterix , and O00300 ) and down - regulated osteoclastogenic ( e . g . , O14788 ) signaling molecules . Suppressing P17302 gene ( Gja1 ) by siRNA inhibited the increase in osteogenesis - related molecules but enhanced O14788 expression . Similar to P17302 , activated P27361 / 2 was also enhanced by mechanical tension and suppressed by P17302 siRNA . Inhibition of P27361 / 2 signaling using PD98059 reduced the tension - regulated increase in osteogenesis - related molecules but enhanced that of osteoclastogenesis - related ones . These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the P17302 - P27361 / 2 signaling pathway ."
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___MASK90___
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MH_train_356
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interacts_with DB01088?
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[
"Inhibitory effect of fluvastatin , an P04035 inhibitor , on the expression of adhesion molecules on human monocyte cell line . The effect of fluvastatin , an P04035 inhibitor , was investigated on the adhesive interaction between U937 cells , the human monocyte cell line , and human umbilical vein endothelial cells ( HUVEC ) , focusing on the expression of adhesion molecules . U937 treated with fluvastatin lowered the capacity for binding to HUVEC . ___MASK94___ at 0 . 1 microM or more inhibited the expression of lymphocyte function associated antigen - 1 ( LFA - 1 ) on U937 and intercellular adhesion molecule - 1 ( P05362 ) on U937 . The expression of P05362 on HUVEC was not inhibited by fluvastatin . The inhibitory effects of fluvastatin on the expression of adhesion molecules on U937 were completely reversed by the addition of mevalonate . Because fluvastatin did not affect the expression of other cell surface markers , P01730 and CD71 , the inhibitory effects of fluvastatin on adhesion molecule expression could not be attributed to the non - specific suppression of the cell . It is conceivable that cellular interaction between monocytes and endothelial cells is inhibited by fluvastatin , mediated via reducing the expression of adhesion molecules , particularly in the side of monocyte .",
"DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . DB05229 sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .",
"Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high - affinity ( KD = 36 +/- 3 nM ) and low - affinity ( KD = 2 . 1 +/- 0 . 8 microM ) prostacyclin ( DB01240 ) - receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [ 3H ] iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5 - 10 - fold increase in the number of both the low - and the high - affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5 - fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 - G2 - adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor .",
"Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole : possible roles of acetylcholine function and neurotrophic factor expression . Increases in dopamine D ( 2 ) receptor sensitivity are known to be common in drug abuse and neurological disorders . Past data from this laboratory have shown that long - term increases in D ( 2 ) sensitivity can be produced by quinpirole treatment ( a D ( 2 )/ D ( 3 ) agonist ) during early development . The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D ( 2 ) sensitivity . Female Sprague - Dawley rats were treated with quinpirole ( 1 mg / kg ) or saline from postnatal day 1 ( PD 1 ) to PD 21 . Beginning in adulthood ( PD 61 ) , rats were treated with nicotine ( 0 . 3 mg / kg free base ) or saline twice daily for 14 consecutive days before behavioural testing commenced . Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls . Deficits on both tasks were completely alleviated by adulthood nicotine treatment . Animals neonatally treated with quinpirole demonstrated a significant 36 % decrease of P28329 in the hippocampus compared to saline controls that was partially eliminated by nicotine . Additionally , neonatal quinpirole produced a significant decrease in hippocampal P01138 content compared to controls , however , nicotine failed to alleviate this decrease in P01138 . The results of this investigation demonstrate that long - term increases in dopamine D ( 2 ) receptor sensitivity produce significant decreases in hippocampal cholinergic and P01138 expression that may result in cognitive impairment . ___MASK77___ alleviates both cognitive and skilled reaching impairments caused by increases in D ( 2 ) sensitivity , but the mechanism through which nicotine is acting is currently unknown .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK94___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK49___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . ___MASK86___ ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"[ Detection of a high - affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high - and a low - affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low - affinity binding sites disappear totally and the specific high - affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto ' s and Riedl ' s thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key - role of DB01240 in thyroid intermediary metabolism .",
"Q01094 : DP - 1 induces p53 and overrides survival factors to trigger apoptosis . The E2F DNA binding activity consists of a heterodimer between E2F and DP family proteins , and these interactions are required for association of E2F proteins with P06400 and the P06400 - related proteins P28749 and Q08999 , which modulate E2F transcriptional activities . Q01094 expression is sufficient to release fibroblasts from G0 and induce entry into S phase , yet it also initiates apoptosis . To investigate the mechanisms of E2F - induced apoptosis , we utilized interleukin - 3 ( P08700 ) - dependent 32D . 3 myeloid cells , a model of hematopoietic progenitor programmed cell death . In the absence of P08700 , Q01094 alone was sufficient to induce apoptosis , and p53 levels were diminished . DP - 1 alone was not sufficient to induce cell cycle progression or alter rates of death following P08700 withdrawal . However , overexpression of both Q01094 and DP - 1 led to the rapid death of cells even in the presence of survival factors . In the presence of P08700 , levels of endogenous wild - type p53 increased in response to Q01094 , and coexpression of DP - 1 further augmented p53 levels . These results provide evidence that E2F is a functional link between the tumor suppressors p53 and P06400 . However , induction of p53 alone was not sufficient to trigger apoptosis , suggesting that the ability of E2F to override survival factors involves additional effectors .",
"HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT - PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF - beta ) , macrophage colony - stimulating factor ( P09603 ) , oncostatin - M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL - 11 , IL - 12 and P05231 receptor ( IL - 6R ) . At the same time the expression of IL - 1 , P60568 , P08700 , P05231 , P29965 and IL - 2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro - and anti - inflammatory and other regulatory cytokines .",
"Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK15___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"The molecular biology of interleukin 6 and its receptor . Functional pleiotropy and redundancy are characteristic features of cytokines . Interleukin 6 ( P05231 ) is a typical example : P05231 induces cellular differentiation or expression of tissue - specific genes ; it is involved in processes such as antibody production in B cells , acute - phase protein synthesis in hepatocytes , megakaryocyte maturation , cytotoxic T cell differentiation , and neural differentiation of PC12 ( pheochromocytoma ) cells . It promotes growth of myeloma / plasmacytoma cells , T cells , keratinocytes and renal mesangial cells , and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines . The P05231 receptor consists of two polypeptide chains , a ligand - binding chain ( IL - 6R ) and a non - ligand - binding , signal - transducing chain ( P40189 ) . Interaction of P05231 with IL - 6R triggers the association of P40189 and IL - 6R , and the signal can be transduced through P40189 . Association of P40189 with IL - 6R is involved in the formation of high affinity binding sites . This two - chain model has been shown to be applicable to receptor systems for several other cytokines , such as granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) , P08700 , P05113 and nerve growth factor ( P01138 ) . The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system .",
"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK49___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .",
"Two types of prostacyclin receptor coupling to stimulation of adenylate cyclase and phosphatidylinositol hydrolysis in a cultured mast cell line , BNu - 2cl3 cells . DB01240 ( DB01240 ) - mediated signal transduction was examined in interleukin 3 ( P08700 ) - dependent BNu - 2cl3 mast cells . DB01088 , a stable DB01240 analogue , induced the accumulation of intracellular DB02527 and IP3 , and an increase in the intracellular Ca2 + concentration . Pretreatment of the cells with a protein kinase C activator , 12 - O - tetradecanoyl phorbol 13 - acetate , suppressed the iloprost - induced IP3 accumulation and Ca2 + mobilization , but inversely potentiated the DB02527 accumulation , suggesting that neither of these signal transduction pathways of iloprosts is the result of a secondary effect of activation of the other . Removal of P08700 from the culture medium reduced the iloprost - induced IP3 accumulation and Ca2 + mobilization , while it had no effect on the iloprost - induced DB02527 accumulation at all . These results taken together suggest that BNu - 2cl3 cells express two types of P43119 ; one couples to stimulation of adenylate cyclase , its expression being independent of P08700 , while the other couples to phosphatidylinositol hydrolysis , its expression being dependent on P08700 .",
"P43119 - induced P40763 phosphorylation in human erythroleukemia cells is mediated via Galpha ( s ) and Galpha ( 16 ) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 via pertussis toxin - insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G ( s ) and G ( q ) proteins for signal transduction and that both G proteins can induce P40763 phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 DB00135 ( 705 ) and DB00133 ( 727 ) phosphorylations by the IP - specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin - dependent protein kinase II and O60674 / 3 . Unlike Galpha ( 16 )- mediated regulation of P40763 in the same cells , cicaprost - induced P40763 DB00135 ( 705 ) phosphorylation was resistant to inhibition of Src and MEK while P40763 DB00133 ( 727 ) phosphorylation distinctly required phosphatidylinositol - 3 kinase . This unique inhibitor - sensitivity pattern of P40763 phosphorylation was reproduced in HEL cells by stimulating the G ( 16 )- coupled C5a receptor in the presence of dibutyryl - DB02527 , suggesting that the change in inhibitor - sensitivity was due to activation of the G ( s ) pathway . This postulation was confirmed by expressing constitutively active Galpha ( 16 ) QL and Galpha ( s ) QL in human embryonic kidney 293 cells and the inhibitor - sensitivity of Galpha ( 16 ) QL - induced P40763 phosphorylations could be converted by the mere presence of Galpha ( s ) QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha ( 16 )- mediated inhibitor - sensitivity upon cicaprost induction in Galpha ( s )- knocked down HEL cells again verified the pivotal role of G ( s ) signal . Taken together , our observations illustrate that co - stimulation of G ( s ) and G ( q ) can result in the fine - tuning of P40763 activation status , and this may provide the basis for cell type - specific responses following activation of hIP .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK86___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK2___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Monocytes can be induced to express lymphatic phenotypes . Although it has been recently shown that monocytes can transdifferentiate into blood vascular endothelial cells which are involved in angiogenesis , little attention has been paid to their potential to transdifferentiate into lymphatic endothelial cells . Therefore , we examined this question in our study . We first stimulated monocytes with either fibronectin ( FN ) , P49767 , P01375 , LPS , or P08700 for 24h . Then we examined the expression of several markers of lymphatic endothelium and found that the monocytes expressed specific lymphatic endothelial markers , Q9Y5Y7 , Q86YL7 , and Prox - 1 , but not common endothelial markers P04275 or P29474 . Next , monocytes were incubated in endothelial growth medium with FN and P49767 for 6d . These monocytes were also found to express Q9Y5Y7 , Q86YL7 and Prox - 1 , but not P04275 or P29474 . Our results indicate that monocytes in vitro can be easily induced to present lymphatic phenotypes in an inflammatory environment .",
"P01730 T cells in murine acquired immunodeficiency syndrome : polyclonal progression to anergy . We have examined the kinetics of changes that occur in the helper T cell subset during murine acquired immunodeficiency syndrome , which occurs after infection with the mix of viruses known as BM5 . We find that there is expansion of the P01730 T cells by 2 wk , 50 % of the P01730 T cells become large as the disease progresses , and the P01730 T cell population is increasingly comprised of cells with a memory / activated phenotype . These effects are apparent by 2 wk postinfection , and the change is nearly complete by 6 - 8 wk . The phenotypic shift is paralleled by the loss of the ability of the P01730 T cells to proliferate or to produce interleukin 2 ( P60568 ) , P08700 , P05112 , and interferon gamma in response to stimulation with mitogens , superantigen , or anti - CD3 . There is no obvious expansion or deletion of P01730 T cells expressing particular V beta genes , as might be expected if a conventional superantigen were driving the changes . The results suggest , however , that the total P01730 population has been driven to anergy by some potent polyclonal stimulus directly associated with viral infection .",
"' VASPFix ' for measurement of P50552 phosphorylation in platelets and for monitoring effects of Q9H244 antagonists . P50552 ( P50552 ) is phosphorylated and dephosphorylated consequent to increases and decreases in cyclic nucleotide levels . Monitoring changes in P50552 phosphorylation is an established method for indirect measurement of cyclic nucleotides . Here we describe the use of an innovative cocktail , VASPFix , which allows sensitive and reproducible measurement of phosphorylated P50552 ( P50552 - P ) in a simple , single - step procedure using cytometric bead technology . Frozen VASPFix - treated samples are stable for at least six months prior to analysis . We successfully used VASPFix to measure P50552 - P in platelets in both platelet - rich plasma and blood in response to compounds that increase ( dibutyryl DB02527 , adenosine , iloprost , PGE1 ) and decrease ( ADP , PGE1 ) DB02527 , and to determine the effects of certain receptor antagonists on the results obtained . The change in P50552 - P brought about by adding ADP to PGE1 - stimulated platelets is a combination of the effect of ADP at the Q9H244 receptor and of PGE1 at both IP and EP3 receptors . For iloprost - stimulated platelets EP3 receptors are not involved . A procedure in which iloprost , ADP and VASPFix were used to determine effectiveness of clopidogrel and prasugrel in patients was compared with an established commercial procedure that uses PGE1 and ADP ; the latter produced higher platelet reactivity values that were the result of PGE1 interacting with platelet EP3 receptors . We conclude that VASPFix can be used both as a research tool and for clinical investigations and provides better specificity for Q9H244 receptor inhibition . The latter confers a distinct advantage over existing methods used to monitor effects of Q9H244 antagonists on platelet function .",
"[ Genetic aspects of occupational chronic obstructive lung disease under exposure to various risk factors ] . The article deals with data on association of SNP rs1828591 of Q96QV1 gene with COLD development under exposure to dust and chemical factors . SNP rs1800470 of TGFbeta1 gene is associated with occupational COLD under exposure to dust and did not show connection with COLD under exposure to chemical aerosols . No association was seen between SNP rs4129267 of IL - 6R gene and SNP rs1051730 of P32297 gene with occupational COLD under exposure to the studied factors . SNP rs1828591 of Q96QV1 gene is associated with occupational COLD development under exposure to dust and chemical factors . Study of association of genotype and phenotypic features of COLD revealed the following trends : \" dust \" COLD patients with genotype AA SNP rs1800470 of TGFbeta1 gene show lower level of P02741 and P01375 , if compared with other genotypes .",
"Identification of in vitro P19526 fate regulators by differential lipid raft clustering . Most hematopoietic stem cells ( P19526 ) in the bone marrow reside in a quiescent state and occasionally enter the cell cycle upon cytokine - induced activation . Although the mechanisms regulating P19526 quiescence and activation remain poorly defined , recent studies have revealed a role of lipid raft clustering ( LRC ) in P19526 activation . Here , we tested the hypothesis that changes in lipid raft distribution could serve as an indicator of the quiescent and activated state of HSCs in response to putative niche signals . A semi - automated image analysis tool was developed to map the presence or absence of lipid raft clusters in live HSCs cultured for just one hour in serum - free medium supplemented with stem cell factor ( P21583 ) . By screening the ability of 19 protein candidates to alter lipid raft dynamics , we identified six factors that induced either a marked decrease ( Wnt5a , Wnt3a and P10451 ) or increase ( P08700 , P05231 and P15692 ) in LRC . Cell cycle kinetics of single HSCs exposed to these factors revealed a correlation of LRC dynamics and proliferation kinetics : factors that decreased LRC slowed down cell cycle kinetics , while factors that increased LRC led to faster and more synchronous cycling . The possibility of identifying , by LRC analysis at very early time points , whether a stem cell is activated and possibly committed upon exposure to a signaling cue of interest could open up new avenues for large - scale screening efforts .",
"DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .",
"[ Thrombocyte prostacyclin receptors in gestational hypertension and pre - eclampsia ] . OBJECTIVE : To determine prostacyclin ( DB01240 ) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome . METHODS : Radioligand binding studies with [ 3H ] - DB01088 were performed to measure receptor capacity ( Bmax ) and affinity ( Kd - 1 ) using platelet membranes from patients with preeclampsia , gestational hypertension or normal pregnancy . RESULTS : P43119 capacity did not differ between the patient groups . In contrast , P43119 affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy . A similar pattern was found in fetal growth ( normal pregnancy > gestational hypertension > preeclampsia ) . Furthermore , the rate of low Apgar scores and acidosis was increased in preeclampsia . CONCLUSIONS : In preeclampsia reduced platelet P43119 affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy , whereas these differences were less pronounced in gestational hypertension . This suggests a role of DB01240 and its receptor in gestational hypertension and in particular in preeclampsia .",
"___MASK77___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"Bresol inhibits phosphodiesterase 4 gene expression and modulates the levels of select mediators of inflammation in human monocytic cells . Bresol - a poly - herbal formulation , has been reported to be effective against bronchial asthma and allergic rhinitis in children . In vivo studies have supported the anti - histaminic and anti - anaphylactic action of bresol . However , the mechanism of action of bresol in modulation of inflammation has not been studied at the cellular and molecular level . The present study was aimed to elucidate the mechanism ( s ) of action of bresol at the cellular and molecular levels , using human monocyte leukemia cells . The effects of bresol on phosphodiesterase 4B ( Q07343 ) gene expression were analyzed using human monocytic U937 leukemia cells . The ability of bresol to stimulate DB02527 formation in these cells , as well as its effects on mediators of inflammation like tumor necrosis factor - α ( TNFα ) , nitric oxide ( NO ) , and cycloxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated U937 cells , were also studied . The results here indicated that bresol exhibited potential anti - inflammatory properties by inhibiting LPS - induced Q07343 gene expression in the cells . Bresol also dose dependently activated DB02527 formation , and inhibited TNFα , NO , as well as P35354 formation in the LPS - stimulated cells . Based upon the results , we concluded that the reported anti - inflammatory activity of bresol might be attributed to its abilities to inhibit Q07343 and thus elevate DB02527 levels in human monocytes . The anti - inflammatory effects of bresol might also be a result of the capacity of bresol to modulate the formation of TNFα , NO , and P35354 in monocytes .",
"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .",
"MicroRNA - 155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting O15524 . MicroRNA ( miR ) - 155 is a critical player in both innate and adaptive immune responses . It can influence P01730 (+) T cell lineage choice . To clarify the role of miR - 155 in P01730 (+) CD25 (+) regulatory T ( Treg ) / T helper ( Th ) 17 cell differentiation and function , as well as the mechanism involved , we performed gain - and loss - of - function analysis by transfection pre - miR - 155 and anti - miR - 155 into purified P01730 (+) T cells . The results showed that miR - 155 positively regulated both Treg and Th17 cell differentiation . It also induced the release of interleukin ( IL ) - 17A by Th17 cells , but not the release of P22301 and transforming growth factor ( TGF ) - β1 by Treg cells . Furthermore , we found that miR - 155 reacted through regulating Janus kinase / signal transducer and activator of transcription ( JAK / P35610 ) rather than TGF - β / mothers against decapentaplegic homolog ( SMAD ) signaling pathway in the process of Treg and Th17 cells differentiation . This may because suppressors of cytokine signaling ( Q9NSE2 ) 1 , the important negative regulator of JAK / P35610 signaling pathway , was the direct target of miR - 155 in this process , but Q15796 and Q99717 were not . Therefore , we demonstrated that miR - 155 enhanced Treg and Th17 cells differentiation and Q16552 production by targeting O15524 .",
"DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .",
"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .",
"P35354 - derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up - regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females .",
"Altered expression of inflammation - related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low - density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44 / 92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up - regulated and 31 down - regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 - α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK74___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .",
"The interaction between P35968 and interleukin - 3 receptor ( IL - 3R ) beta common modulates tumor neovascularization . As vascular endothelial growth factor ( P15692 ) , interleukin - 3 ( P08700 ) , released into the tumor microenvironment stimulates motogenic and mitogenic activity of normal and transformed cells . In the present study , we investigate the effects of P08700 and P15692 on neoplastic vascular growth . Engagement of P08700 receptor beta common ( IL - 3R beta c ) contributes to both P08700 - and P15692 - induced Rac1 activation , cell migration and in vitro tube - like structure formation as shown by the expression of the dominant - negative IL - 3R beta c construct ( Delta455 ) . In normal and transformed endothelial cells ( EC ) as well as in P29320 293 cells expressing P35968 and IL - 3R , P15692 and P08700 treatment induces the formation of a P35968 / IL - 3R beta c complex . Moreover , as shown by the IL - 3R Delta455 mutant or by the kinase dead P35968 , functional receptors are required for this interaction . Consistent with the contribution of IL - 3R beta c in both P08700 - and P15692 - mediated angiogenic signal , a reduced number of vessels inside tumors are found in mice injected with cells expressing the IL - 3R Delta455 mutant . Thus , these findings provide a novel mechanism through which P08700 and P15692 support cell survival and tumor neovascularization .",
"The role of Q8N6T7 in the differentiation of vascular smooth muscle cells in response to cyclic strain . Vascular smooth muscle cells ( VSMCs ) may switch their phenotype between a quiescent contractile phenotype and a synthetic phenotype in response to cyclic strain , and this switch may contribute to hypertension , atherosclerosis , and restenosis . SIRT 6 is a member of the sirtuin family , and plays an important role in different cell processes , including differentiation . We hypothesized that cyclic strain modulates the differentiation of VSMCs via a transforming growth factor - β1 ( TGF - β1 ) - Smad - Q8N6T7 pathway . VSMCs were subjected to cyclic strain using a Flexercell strain unit . It was demonstrated that the strain stimulated the secretion of TGF - β1 into the supernatant of VSMCs . After exposed to the strain , the expressions of contractile phenotype markers , including smooth muscle protein 22 alpha , alpha - actin , and calponin , and phosphorylated Q15796 , phosphorylated Q99717 , Q8N6T7 and c - fos were up - regulated in VSMCs by western blot and immunofluorescence . And the expression of intercellular - adhesion molecule - 1 ( P05362 ) was also increased detected by flow cytometry . The strained - induced up - regulation of Q8N6T7 was blocked by a TGF - β1 neutralizing antibody . Furthermore , the effects of strain on VSMCs were abrogated by Q8N6T7 - specific siRNA transfection via the suppression c - fos and P05362 . These results suggest that Q8N6T7 may play a critical role in the regulation of VSMC differentiation in response to the cyclic strain .",
"P43119 suppresses cardiac fibrosis : role of CREB phosphorylation . Cardiac fibrosis is a consequence of many cardiovascular diseases and contributes to impaired ventricular function . Activation of the prostacyclin receptor ( IP ) protects against cardiac fibrosis , but the molecular mechanisms are not totally understood . Using mouse cardiac fibroblasts , we found that IP activation with cicaprost suppressed expression of collagen I and other target genes of transforming growth factor - beta . This effect of cicaprost was unlikely to be mediated by inhibition of the Q15796 / 3 or mitogen - activated protein kinase ( MAPK ) activities , but was associated with DB02527 elevation and phosphorylation of the transcription factor DB02527 response element binding protein ( CREB ) . Expression of a non - phosphorylated CREB mutant suppressed the inhibitory effect of cicaprost . It appears that phosphorylated CREB binds to and sequestrates the transcription coactivator CBP / p300 from binding to Smad . Inhibition of the intrinsic histone acetyl - transferase activity of CBP / p300 with garcinol significantly suppressed collagen I expression in fibroblasts . Using apolipoprotein E and IP double knockout mouse , we demonstrated that endogenous prostacyclin / IP signaling had an inhibitory effect on angiotensin II - induced cardiac fibrosis under hypercholesterolemic conditions . Taken together , our results suggest that the prostacyclin / IP pathway suppresses cardiac fibrosis , at least partly , by inducing CREB phosphorylation .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK96___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"P43119 stimulation facilitates detection of human platelet P2Y ( 12 ) receptor inhibition by the PFA - 100 system . The rationale for monitoring platelet inhibition by thienopyridines for the identification of patients at risk for future recurrent arterial thrombosis or ischemic events is intensively discussed , as well as which monitoring systems are appropriate , robust and reliable . Flow cytometric measurement of phosphorylated P50552 ( vasodilator - stimulated phosphoprotein ) , expressed as platelet reactivity index ( P13489 ) , is presently \" the gold standard method \" for evaluating P2Y ( 12 ) receptor inhibition . The PFA - 100 system , a commercially available and clinically widely used platelet test system , is based on a different principle , not that of P50552 phosphorylation . The aim of the present study was to compare the two methods and evaluate whether the conventional PFA - 100 collagen / ADP cartridge could be pharmacologically improved to enable its routine clinical use for detection of platelet P2Y ( 12 ) receptor inhibition . The effects of increasing concentrations of the competitive P2Y ( 12 ) receptor antagonist cangrelor ( AR - C69931MX ) and the time - dependent effects of a single oral loading dose of clopidogrel ( 600 mg ) were analysed with human whole blood . P2Y ( 12 ) receptor inhibition was measured by the P50552 / P13489 assay and the PFA - 100 collagen / ADP cartridge system , with and without preincubation with the prostacyclin analog iloprost ( Ilomedin ) . In vitro addition of iloprost ( 0 . 5 nM ) enabled PFA - 100 collagen / ADP cartridge system detection of P2Y ( 12 ) receptor inhibition in whole blood by cangrelor in vitro or by clopidogrel treatment of volunteers . The addition of a prostacyclin analog facilitates PFA - 100 collagen / ADP system detection of P2Y ( 12 ) receptor inhibition , achieving a sensitivity similar to that of the P50552 / P13489 reference method . Future studies should now evaluate whether this modified PFA - 100 system , like the P50552 assay , is a reliable test system for monitoring P2Y ( 12 ) receptor inhibition under clinical conditions .",
"___MASK92___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK92___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells ."
] |
[
"___MASK15___",
"___MASK2___",
"___MASK49___",
"___MASK74___",
"___MASK77___",
"___MASK86___",
"___MASK92___",
"___MASK94___",
"___MASK96___"
] |
___MASK96___
|
MH_train_357
|
interacts_with DB06699?
|
[
"DB06699 . DB06699 is a gonadotropin - releasing hormone ( DB00644 ) receptor antagonist that , in common with P30968 agonists ( e . g . leuprolide , goserelin and triptorelin ) , is indicated for use as an androgen - deprivation therapy in patients with advanced prostate cancer . In 1 - year , randomized , open - label , phase II or III trials in patients with all stages of prostate cancer , subcutaneous degarelix was associated with rapid , profound and sustained suppression of serum testosterone and prostate - specific antigen ( PSA ) , without evidence of testosterone surges or microsurges . In the phase III trial , degarelix ( 240 mg initially followed by 80 mg every 28 days ) was considered to be effective and noninferior to intramuscular leuprolide ( 7 . 5 mg every 28 days ) with regard to inducing and maintaining suppression of serum testosterone to castrate levels ( i . e . < or = 0 . 5 ng / mL ) . DB06699 induced testosterone suppression more rapidly than leuprolide . Median serum testosterone levels of < or = 0 . 5 ng / mL were achieved by day 3 in degarelix recipients , but not until day 28 in leuprolide recipients . PSA suppression was also more rapid with degarelix than with leuprolide , with significant between - group differences in serum PSA levels favouring degarelix at 14 and 28 days . DB06699 treatment for 1 year was generally well tolerated ; the adverse events reported were mostly related to subcutaneous drug administration ( i . e . injection - site reactions ) and hormonal androgen deprivation ( e . g . hot flushes ) .",
"The effect of rivastigmine on the LPS - induced suppression of DB00644 / LH secretion during the follicular phase of the estrous cycle in ewes . This study was designed to determine the effect of a potent subcutaneously injected acetylcholinesterase inhibitor , rivastigmine ( 6mg / animal ) , on the gonadotropin - releasing hormone ( DB00644 ) / luteinizing hormone ( LH ) release during inflammation induced by an intravenous lipopolysaccharide ( LPS ) ( 400ng / kg ) injection in ewes during the follicular phase of the estrous cycle . The results are expressed as the mean values from - 2 to - 0 . 5h before and + 1 to + 3h after treatment . ___MASK42___ decreased the acetylcholinesterase concentration in the blood plasma from 176 . 9 ± 9 . 5 to 99 . 3 ± 15 . 1μmol / min / ml . Endotoxin suppressed LH ( 5 . 4 ± 0 . 6ng / ml ) and DB00644 ( 4 . 6 ± 0 . 4pg / ml ) release ; however , the rivastigmine injection restored the LH concentration ( 7 . 8 ± 0 . 8ng / ml ) to the control value ( 7 . 8 ± 0 . 7ng / ml ) and stimulated DB00644 release ( 7 . 6 ± 0 . 8pg / ml ) compared to the control ( 5 . 9 ± 0 . 4pg / ml ) . Immune stress decreased expression of the DB00644 gene and its receptor ( P30968 ) in the median eminence as well as LHβ and P30968 in the pituitary . In the case of the DB00644 and LHβ genes , the suppressive effect of inflammation was negated by rivastigmine . LPS stimulated cortisol and prolactin release ( 71 . 1 ± 14 . 7 and 217 . 1 ± 8 . 0ng / ml ) compared to the control group ( 9 . 0 ± 5 . 4 and 21 . 3 ± 3 . 5ng / ml ) . ___MASK42___ also showed a moderating effect on cortisol and prolactin secretion ( 43 . 1 ± 13 . 1 and 169 . 7 ± 29 . 5ng / ml ) . The present study shows that LPS - induced decreases in DB00644 and LH can be reduced by the P22303 inhibitor . This action of the P22303 inhibitor could result from the suppression of pro - inflammatory cytokine release and the attenuation of the stress response . However , a direct stimulatory effect of ACh on DB00644 / LH secretion should also be considered .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK27___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .",
"P01308 augments gonadotropin - releasing hormone induction of translation in LbetaT2 cells . The integrated signaling of insulin and gonadotropin - releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function , although the cross - receptor signaling mechanisms are unclear . We demonstrate that the insulin receptor is constitutively localized to non - caveolar lipid raft microdomains in the pituitary gonadotrope cell line LbetaT2 . The localization to rafts is consistent with similar localization of the P30968 . P06213 phosphorylation occurs in raft domains and activates the downstream signaling targets P01308 Receptor Substrate1 and Akt / Protein Kinase B . Although insulin alone does not strongly activate the extracellular signal - regulated kinase second messenger cascade , co - stimulation potentiates the phosphorylation of the extracellular signal - regulated kinase by gonadotropin - releasing hormone . The co - stimulatory effect of insulin and gonadotropin - releasing hormone is also evident in increased activation of cap - dependent translation . In contrast , co - stimulation attenuates Akt / Protein Kinase B activation . Our results show that both gonadotropin - releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades . We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK40___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Synthesis and biological activity of DB00644 antagonists modified at position 3 with 3 -( 2 - methoxy - 5 - pyridyl )- alanine . DB06699 is a potent very long - acting DB00644 antagonist after subcutaneous administration . In this paper , we describe the synthesis of two analogs of degarelix incorporating racemic 3 -( 2 - methoxy - 5 - pyridyl )- alanine ( 2 - OMe - 5Pal , 5 ) at position 3 . The two diastereomers were separated by reverse - phase high - performance liquid chromatography ( RP - HPLC ) and the absolute stereochemistry at position 3 in the peptides was determined by enzymatic digestion with proteinase K . These analogs were tested in vitro for their ability to antagonize the P30968 and in vivo for duration of action in a castrated male rat assay . Analog 7 with D2 - OMe - 5Pal was potent in vitro ( IC50 = 5 . 22 nM ) ; however , analog 8 with Q401N2 - OMe - 5Pal at position 3 in degarelix lost potency as an antagonist of the human P30968 ( IC50 = 36 . 95 nM ) . Both the analogs were found to be short - acting in vivo .",
"Paradoxical effects of kisspeptin : it enhances oocyte in vitro maturation but has an adverse impact on hatched blastocysts during in vitro culture . Kisspeptin ( Kp ) is best known as a multifunctional peptide with roles in reproduction , the cardiovascular system and cancer . In the present study the expression of kisspeptin hierarchy elements ( Q15726 , P01148 and P01229 ) and their receptors ( Q969F8 , P30968 and P22888 , respectively ) in porcine ovary and in cumulus - oocyte complexes ( COCs ) were investigated , as were its effects on the in vitro maturation ( IVM ) of oocytes and their subsequent ability to sustain preimplantation embryo competence after parthenogenetic electrical activation . Kp system elements were expressed and affected IVM of oocytes when maturation medium was supplemented with 10 (- 6 ) M Kp . Oocyte maturation , maternal gene expression ( MOS , O60383 and O95972 ) , blastocyst formation rate , blastocyst hatching and blastocyst total cell count were all significantly increased when oocytes were matured in medium containing Kp compared with the control group ( without Kp ) . A Kp antagonist ( p234 ) at 4 × 10 (- 6 ) M interfered with this hierarchy but did not influence the threshold effect of gonadotrophins on oocyte maturation . DB00094 was critical and permissive to Kp action on COCs by increasing the relative expression of Q969F8 . In contrast , Kp significantly increased apoptosis , the expression of pro - apoptotic gene , Q16611 , and suppressed trophoblast outgrowths from hatched blastocysts cultured on feeder cells . The present study provides the first functional evidence of the Kp hierarchy in porcine COCs and its role in enhancing oocyte maturation and subsequent developmental competence in an autocrine - paracrine manner . However , Kp supplementation may have a harmful impact on cultured hatched blastocysts reflecting systemic or local regulation during the critical early period of embryonic development .",
"Evaluation of degarelix in the management of prostate cancer . Medical castration using gonadotropin - releasing hormone ( DB00644 ) receptor agonists currently provides the mainstay of androgen deprivation therapy for prostate cancer . Although effective , these agents only reduce testosterone levels after a delay of 14 to 21 days ; they also cause an initial surge in testosterone that can stimulate the cancer and lead to exacerbation of symptoms ( \" clinical flare \" ) in patients with advanced disease . Phase III trial data for the recently approved P30968 blocker , degarelix , demonstrated that it is as effective and well tolerated as DB00644 agonists . However , it has a pharmacological profile more closely matching orchiectomy , with an immediate onset of action and faster testosterone and PSA suppression , without a testosterone surge or microsurges following repeated injections . As a consequence , with this DB00644 blocker , there is no risk of clinical flare and no need for concomitant antiandrogen flare protection . DB06699 therefore provides a useful addition to the hormonal armamentarium for prostate cancer and offers a valuable new treatment option for patients with hormone - sensitive advanced disease . Here , we review key preclinical and clinical data for degarelix , and look at patient - focused perspectives in the management of prostate cancer .",
"Expression of type I P01148 receptor and in vivo and in vitro P01148 - I effects in corpora lutea of pseudopregnant rabbits . The expression of type I P01148 receptor ( P30968 - I ) and the direct role of P01148 - I on corpora lutea ( CL ) function were studied in the pseudopregnant rabbit model . Immunohistochemistry evidenced P30968 - I and P01148 - I in luteal cells at early ( day 4 pseudopregnancy ) - , mid ( day 9 ) - , and late ( day 13 ) - luteal stages . Real - time RT - PCR and western blotting revealed P30968 - I mRNA and protein at the three luteal stages . DB06719 in vivo treatment at days 9 and 13 decreased plasma progesterone levels for 48 and 24 h respectively . In in vitro cultured CL , buserelin reduced progesterone secretion , increased prostaglandin F ( 2α ) ( P49763 ( 2α ) ) secretion and cyclo - oxygenase - 2 ( P35354 ) and nitric oxide synthase ( NOS ) activities at days 9 and 13 , and decreased PGE₂ at day 13 . Co - incubation with antagonists for P01148 - I ( antide ) , inositol 1 , 4 , 5 - trisphosphate ( IP₃ , 2 - amino - ethoxydiphenylborate ) , and diacylglycerol ( DAG , 1 - hexadecyl - 2 - acetyl glycerol ) or inhibitors for phospholipase C ( P98160 , compound 48 / 80 ) , and protein kinase C ( PKC , staurosporine ) counteracted the buserelin effects . DB06719 co - incubated with P36551 inhibitor ( acetylsalicylic acid ) increased progesterone and decreased P49763 ( 2α ) and NOS activity at days 9 and 13 , whereas co - incubation with NOS inhibitor ( DB04223 methyl ester ) increased progesterone at the same luteal stages . These results suggest that P30968 - I is constitutively expressed in rabbit CL independently of luteal stage , whereas P01148 - I down - regulates directly CL progesterone production via P49763 ( 2α ) at mid - and late - luteal stages of pseudopregnancy , utilizing its cognate type I receptor with a post - receptorial mechanism that involves P98160 , IP₃ , DAG , PKC , P35354 , and NOS .",
"Interaction between P20292 and P20815 gene variants significantly increases the risk for cerebral infarctions in Chinese . In this study , we investigated associations between susceptibility genes and cerebral infarctions in a Chinese population , and whether gene - gene interactions increase the risk of cerebral infarctions . Overall , 292 patients with cerebral infarctions and 259 healthy control individuals were included . Eight variants in five candidate genes were examined for the risk of stroke , including the SG13S32 ( rs9551963 ) , SG13S42 ( rs4769060 ) , SG13S89 ( rs4769874 ) , and SG13S114 ( rs10507391 ) variants of the P09917 activating protein ( P20292 ) gene , the G860A ( rs751141 ) variant of the soluble epoxide hydrolase ( P34913 ) gene , the A1075C ( rs1057910 ) variant of the P11712 * 2 gene , the C430T ( rs1799853 ) variant of the P11712 * 3 gene , and the A6986G ( rs776746 ) variant of the P20815 gene . Gene - gene interactions were explored using generalized multifactor dimensionality reduction methods . There were no statistically significant differences in the frequencies of the genotypes of the eight candidate genes . The generalized multifactor dimensionality reduction analysis showed a significant gene - gene interaction between SG13S114 and A6986G , with scores of 10 for cross - validation consistency and 9 for the sign test ( P = 0 . 0107 ) . These gene - gene interactions predicted a significantly higher risk of cerebral infarction ( adjusted for age , hypertension , and diabetes mellitus ; odds ratio = 1 . 80495 % , confidence interval : 1 . 180 - 2 . 759 , P = 0 . 006 ) . A two - loci gene interaction confers a significantly higher risk for cerebral infarction . The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases .",
"Improvement of chloride transport defect by gonadotropin - releasing hormone ( DB00644 ) in cystic fibrosis epithelial cells . Cystic fibrosis ( CF ) , the most common autosomal recessive disease in Caucasians , is due to mutations in the P13569 gene . F508del , the most frequent mutation in patients , impairs P13569 protein folding and biosynthesis . The F508del - P13569 protein is retained in the endoplasmic reticulum ( ER ) and its traffic to the plasma membrane is altered . Nevertheless , if it reaches the cell surface , it exhibits a Cl (-) channel function despite a short half - life . Pharmacological treatments may target the F508del - P13569 defect directly by binding to the mutant protein or indirectly by altering cellular proteostasis , and promote its plasma membrane targeting and stability . We previously showed that annexine A5 ( AnxA5 ) directly binds to F508del - P13569 and , when overexpressed , promotes its membrane stability , leading to the restoration of some Cl (-) channel function in cells . Because Gonadotropin - Releasing Hormone ( DB00644 ) increases AnxA5 expression in some cells , we tested it in CF cells . We showed that human epithelial cells express DB00644 - receptors ( P30968 ) and that DB00644 induces an AnxA5 overexpression and an increased Cl (-) channel function in F508del - P13569 cells , due to an increased stability of the protein in the membranes . Beside the numerous physiological implications of the P30968 expression in epithelial cells , we propose that a topical use of DB00644 is a potential treatment in CF .",
"Anandamide regulates the expression of GnRH1 , GnRH2 , and DB00644 - Rs in frog testis . DB00644 ( either GnRH1 or GnRH2 ) exerts a local activity in vertebrate testis , including human testis . Relationships between endocannabinoid ( eCB ) and DB00644 systems in gonads have never been elucidated in any species so far . To reveal a cross - talk between eCBs and DB00644 at testicular level , we characterized the expression of DB00644 ( GnRH1 and GnRH2 ) as well as P30968 ( DB00644 - Q96GN5 , - R2 , and - R3 ) mRNA in the testis of the anuran amphibian Rana esculenta during the annual sexual cycle ; furthermore , the corresponding transcripts were localized inside the testis by in situ hybridization . The possible endogenous production of the eCB , anandamide ( AEA ) , was investigated in testis by analyzing the expression of its biosynthetic enzyme , Nape - pld . Incubations of testis pieces with AEA were carried out in the postreproductive period ( June ) and in February , when a new spermatogenetic wave takes place . In June , AEA treatment significantly decreased GnRH1 and DB00644 - R2 mRNA , stimulated the transcription of GnRH2 and DB00644 - Q96GN5 , and did not affect DB00644 - R3 expression . In February , AEA treatment upregulated GnRH2 and DB00644 - R3 mRNA , downregulated DB00644 - R2 , and did not affect GnRH1 and DB00644 - Q96GN5 expression . These effects were mediated by type 1 cannabinoid receptor ( P21554 ) since they were fully counteracted by SR141716A ( DB06155 ) , a selective P21554 antagonist . In conclusion , eCB system modulates DB00644 activity in frog testis during the annual sexual cycle in a stage - dependent fashion .",
"A new compound heterozygous mutation of the gonadotropin - releasing hormone receptor ( L314X , Q106R ) in a woman with complete hypogonadotropic hypogonadism : chronic estrogen administration amplifies the gonadotropin defect . We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the P30968 ( GnRHR ) gene . A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described . L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO - P04264 cells compared to the wild - type receptor . The disease is transmitted as an autosomal recessive trait , as shown by pedigree analysis . Heterozygous patients with GnRHR mutations had normal pubertal development and fertility . The present study shows an absence of LH and DB00094 response to pulsatile DB00644 administration ( 20 microg / pulse , sc , every 90 min ) . However , DB00644 triggered free alpha - subunit ( FAS ) pulses of small amplitude , demonstrating partial resistance to pharmacological doses of DB00644 . DB00094 , LH , and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of DB00644 . Not only were plasma DB00094 , LH , and FAS concentrations decreased , but FAS responsiveness was reduced . This new case emphasizes the implication of the P30968 mutations in the etiology of idiopathic hypogonadotropic hypogonadism . We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level , dependent on the GnRHR signaling pathway .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK44___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Single - cell transcription site activation predicts chemotherapy response in human colorectal tumors . Candidate gene and pathway approaches , and unbiased gene expression profiling , have identified marker signatures predictive of tumor phenotypes , such as drug sensitivity and invasive or metastatic potential . However , application of such information to evaluation of tumors in the clinic is limited by cell heterogeneity in the tumor . We have developed a novel method of fluorescence in situ hybridization ( Q5TCZ1 ) that can detect transcriptional activation of individual genes at their site in single cells in the interphase nucleus . A major obstacle in the treatment of colorectal cancer is relative insensitivity to the chemotherapeutic agent ___MASK21___ ( ___MASK21___ ) . Here , we have developed a sensitive approach to predict relative sensitivity of colorectal cancer cells to ___MASK21___ , using Q5TCZ1 with probes targeted to nascent mRNAs to measure the number of individual cells with active transcription sites for a panel of candidate genes . These results reveal that the transcriptional status of four key genes , thymidylate synthase ( P04818 ) , Q8WYB5 - related gene X ( Q15014 ) , Bcl2 - antagonist / killer ( Q16611 ) , and ATPase , Cu ( 2 +) transporting beta polypeptide ( P35670 ) , can accurately predict response to ___MASK21___ . As proof of principle , we show that this transcriptional profile is predictive of response to ___MASK21___ in a small number of patient colon tumor tissues . This approach provides a novel ability to identify and characterize unique minor cell populations in the tumor that may exhibit relative resistance to chemotherapy .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK25___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"DB06699 : a novel gonadotropin - releasing hormone blocker for the treatment of prostate cancer . Androgen deprivation therapy with gonadotropin releasing - hormone ( DB00644 ) receptor agonists provides the mainstay of endocrine treatment for advanced prostate cancer . Although effective , DB00644 agonists induce an initial testosterone surge , which can cause painful and potentially dangerous clinical flare . DB06699 is a novel P30968 blocker that provides immediate , profound and sustained testosterone reduction , without an initial surge . In a Phase III trial , degarelix and leuprolide showed similar long - term efficacy in maintaining testosterone levels of 0 . 5 ng / ml or less over 1 year , and induced significantly faster testosterone and prostate - specific antigen suppression . DB06699 was well tolerated ; the most common side effects were mild / moderate injection - site reactions and hot flashes . Findings to date suggest that degarelix may make an important contribution to the treatment of prostate cancer .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"Production of leukotrienes in gonadotropin - releasing hormone - stimulated pituitary cells : potential role in luteinizing hormone release . DB00644 ( DB00644 ) stimulated the formation of two major metabolites of the P09917 pathway , leukotriene ( LT ) B4 and LTC4 , as well as luteinizing hormone ( LH ) release in primary cultures of rat anterior pituitary cells . Several lines of evidence suggested the presence of a DB00644 - dependent pituitary endocrine system in which LTs act as second messengers for LH release : ( i ) DB00644 - dependent LT formation was observed within 1 min and immediately preceded DB00644 - induced LH release , whereas exogenous LTs stimulated LH release at low concentrations ; ( ii ) the dose responses of DB00644 - induced LT production and LH release were similar and both effects required the presence of extracellular Ca2 + ions ; ( iii ) DB00644 - induced LH release was blocked by up to 45 % following the administration of several LT receptor antagonists ; ( iv ) LTE4 action on LH secretion was entirely abolished by LT receptor antagonists ; and ( v ) an activator of protein kinase C acted synergistically with LTE4 to induce LH release . The major source of LT formation in the pituitary cell cultures appeared to be the gonadotrophs , as shown by P30968 desensitization experiments . The results demonstrate the presence of a DB00644 - activatable P09917 pathway in anterior pituitary cells and provide strong support for the hypothesis that LTs play a role in LH release in the DB00644 signaling pathway .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK5___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"[ The efficacy of degarelix on LUTS ( Lower urinary tract symptoms ) relief in patients with prostate cancer ] . Hormonal therapy is one of the treatment options for prostate cancer patients . There are many hormonal treatments modality to block the testosterone effect on prostate cancer cell proliferation . DB06699 is an innovative molecule able to antagonize the P30968 with comparable oncological results to DB00644 agonist , but with less side effects , avoiding the flare up phase , and better efficacy in LUTS relief . These characteristics of degarelix can impact on the clinical decision making to choose a therapy instead of another .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK89___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"[ ___MASK38___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK38___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization ."
] |
[
"___MASK21___",
"___MASK25___",
"___MASK27___",
"___MASK38___",
"___MASK40___",
"___MASK42___",
"___MASK44___",
"___MASK5___",
"___MASK89___"
] |
___MASK25___
|
MH_train_358
|
interacts_with DB00281?
|
[
"Effects of P28335 - receptor expression on cell proliferation control in hamster fibroblasts : serotonin fails to induce a transformed phenotype . 5 - HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells , inducing ligand - dependent focus formation . In order to assess their mitogenic and oncogenic potential in a different cell system , we transfected these receptors into CCL39 hamster fibroblasts , a well - characterized growth factor - dependent cell line . Cell clones expressing functional receptors were isolated and tested for ( a ) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum , ( b ) the response to serotonin alone or in combination with other growth factors , and ( c ) the capacity for anchorage - independent proliferation . In the absence or presence of serotonin , the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar . None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments , but synergy was observed between serotonin and the tyrosine kinase activating growth factors P01133 and FGF . However , the major part of this effect could be abolished by an antagonist of 5 - HT1b receptors , which are endogenous in CCL39 cells . The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha - ras - transfected cells . The fact that 5 - HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like DB01367 , P12931 , or P07333 .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK66___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"___MASK3___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK3___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK3___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK3___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Ventilation - induced increases in P00533 ligand mRNA are not altered by intra - amniotic LPS or ureaplasma in preterm lambs . Chorioamnionitis and mechanical ventilation are associated with bronchopulmonary dysplasia ( BPD ) in preterm infants . Mechanical ventilation at birth activates both inflammatory and acute phase responses . These responses can be partially modulated by previous exposure to intra - amniotic ( IA ) LPS or Ureaplasma parvum ( UP ) . P00533 ( P00533 ) ligands participate in lung development , and angiotensin converting enzyme ( P12821 ) 1 and Q9BYF1 contribute to lung inflammation . We asked whether brief mechanical ventilation at birth altered P00533 and P12821 pathways and if antenatal exposure to IA LPS or UP could modulate these effects . Ewes were exposed to IA injections of UP , LPS or saline multiple days prior to preterm delivery at 85 % gestation . Lambs were either immediately euthanized or mechanically ventilated for 2 to 3 hr . IA UP and LPS cause modest changes in the P00533 ligands amphiregulin ( P15514 ) , epiregulin ( O14944 ) , heparin binding epidermal growth factor ( HB - P01133 ) , and betacellulin ( P35070 ) mRNA expression . Mechanical ventilation greatly increased mRNA expression of P15514 , O14944 , and HB - P01133 , with no additional increases resulting from IA LPS or UP . With ventilation P15514 and O14944 mRNA localized to cells in terminal airspace . P00533 mRNA also increased with mechanical ventilation . IA UP and LPS decreased ACE1 mRNA and increased Q9BYF1 mRNA , resulting in a 4 fold change in the ACE1 / Q9BYF1 ratio . Mechanical ventilation with large tidal volumes increased both ACE1 and Q9BYF1 expression . The alterations seen in P12821 with IA exposures and P00533 pathways with mechanical ventilation may contribute to the development of BPD in preterm infants .",
"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK63___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Involvement of Stat3 in interleukin - 6 - induced IgM production in a human B - cell line . P05231 ( P05231 ) is an important B - cell growth and differentiation factor . P05231 treatment of the human lymphoblastoid cell line , SKW6 . 4 , leads to increased IgM production . We have previously shown that P05231 induces activation of P23458 and O60674 in human B cell lines . A chimeric P05231 receptor , comprised of the intracellular tail of the P05231 receptor subunit P40189 fused to the extracellular domain of the epidermal growth factor ( P01133 ) receptor , was stably transfected into SKW6 . 4 cells . P01133 treatment induced IgM production in cells transfected with an intact P40189 cytoplasmic tail , but not in untransfected cells or cells transfected with a cytoplasmic tail lacking all four signal transducers and activators of transcription ( Stat ) binding sites . Moreover , P01133 treatment induced Stat3 phosphorylation in cells transfected with the intact chimeric P01133 - P40189 receptor along with induction of DNA - mobility shift of a classical interferon - gamma - activated site . To define further the relation between Stat3 activation and enhanced IgM production , we determined the effect of chimeric P40189 on the transcriptional activation of a genetic element linked to immunoglobulin production , namely the immunoglobulin heavy chain enhancer ( IgH - enhancer ) . Parental as well as transfected SKW6 . 4 cells were transiently transfected with an IgH - enhancer - luciferase construct . The transcriptional activity of the IgH - luciferase construct was induced upon ligation of the full - length chimeric receptor but not by truncated P40189 receptors . Moreover , the P40189 - induced activity of this reporter gene was abrogated by Stat3EE , a mutant Stat3 incapable of binding DNA . These results indicate that P05231 - induced B - cell differentiation , as measured by IgM production , may be controlled by Stat3 proteins .",
"___MASK86___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK86___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Selective antitumor activity of ibrutinib in P00533 - mutant non - small cell lung cancer cells . ___MASK13___ , which irreversibly inhibits Q06187 , was evaluated for antitumor activity in a panel of non - small cell lung cancer ( NSCLC ) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor ( P00533 ) gene , including T790M mutant and erlotinib - resistant H1975 cells . ___MASK13___ induced dose - dependent inhibition of phosphor - P00533 at both Y1068 and Y1173 sites , suggesting ibrutinib functions as an P00533 inhibitor . Survival was analyzed by Kaplan - Meier estimation and log - rank test . All statistical tests were two - sided . In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice ( n = 5 per group ) . The mean survival times for solvent - and erlotinib - treated mice were both 17 . 8 days ( 95 % confidence interval [ CI ] = 14 . 3 to 21 . 3 days ) , while the mean survival time for ibrutinib - treated mice was 29 . 8 days ( 95 % CI = 26 . 0 to 33 . 6 days , P = . 008 ) . Our results indicate that ibrutinib could be a candidate drug for treatment of P00533 - mutant NSCLC , including erlotinib - resistant tumors .",
"P05305 activates P25101 receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL . OBJECTIVE : Lipid retention in the vessel wall by glycosaminoglycan ( GAG ) chains on chondroitin / dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells ( VSMC ) have recently been established as an early event in human coronary artery atherosclerosis . GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein ( LDL ) . The aim of this study was to determine if proteoglycans produced by endothelin - 1 treated VSMCs had increased binding to human LDL , to examine the effect of endothelin - 1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway . METHODS AND RESULTS : P05305 stimulated an increase in [( 35 ) S ] sulfate and [( 3 ) H ] glucosamine incorporation into proteoglycans produced by human VSMC . The increase was due to an increase in GAG chain size assessed by SDS - PAGE and size exclusion chromatography . Increased radiolabel incorporation was inhibited by an ET ( A ) but not an ET ( B ) receptor antagonist . P05305 stimulated an increase in the 6 : 4 position sulfation ratio on the disaccharides of the GAG chains , an effect that was blocked by ___MASK61___ . The P01133 receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin - 1 . Inhibition of protein kinase C ( PKC ) with GF109203X or down regulation by PMA pre - treatment attenuated the effect of endothelin - 1 on GAG synthesis . CONCLUSION : These data demonstrate that endothelin - 1 stimulates changes in GAG chain structure that increase binding to LDL . This action of endothelin - 1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction .",
"Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells . Associations of ErbB4 ( Q15303 / Q15303 ) , the fourth member of the P00533 family , with cancer are variable , possibly as a result of structural diversity of this receptor . There are multiple structural isoforms of Q15303 arising by alternative mRNA splicing , and a subset undergo proteolysis that releases membrane - anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription . To compare the differential and common signaling activities of full - length ( FL ) and soluble intracellular isoforms of Q15303 , four JM - a isoforms ( FL and soluble intracellular domain ( ICD ) CYT - 1 and CYT - 2 ) were expressed in isogenic MCF10A cells and their biologic activities were analyzed . Both FL and ICD CYT - 2 promoted cell proliferation and invasion , and CYT - 1 suppressed cell growth . Transcriptional profiling revealed several new and underexplored Q15303 - regulated transcripts , including : proteases / protease inhibitors ( P08254 and P07093 ) , the YAP / Hippo pathway ( P29279 , O00622 , and P09486 ) , the mevalonate / cholesterol pathway ( P04035 , Q01581 , P01130 , and Q9UBM7 ) , and cytokines ( P10145 , P78556 , and P09341 ) . Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses Q15303 . Furthermore , ChIP - seq experiments identified O75689 , P02649 , P09486 , P16949 , and Q05195 as novel molecular targets of Q15303 . These findings clarify the diverse biologic activities of Q15303 isoforms , and reveal new and divergent functions . IMPLICATIONS : ErbB4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer .",
"Nimotuzumab suppresses epithelial - mesenchymal transition and enhances apoptosis in low - dose UV - C treated salivary adenoid cystic carcinoma cell lines in vitro . Salivary adenoid cystic carcinoma ( SACC ) , which is one of the most common malignant tumors of the salivary glands , is associated with a poor long - term outcome . There are currently few therapeutic options for patients with SACC . Recent studies have shown the potential of the application of ultraviolet - C ( UV - C ) irradiation for the treatment of human cancer . In the present study , we investigated the effects of UV - C in the SACC cell lines SACC - 83 and SACC - LM . High - dose UV - C ( 200 J / m ) induced apoptosis and inhibited colony formation significantly . However , low - dose UV - C ( 10 J / m ) , which had little effect on apoptosis and colony formation , increased the ability of migration in SACC cells accompanied by a decrease in P12830 and an increase in vimentin , suggesting the occurrence of epithelial - mesenchymal transition ( EMT ) . Low - dose UV - C ( 10 J / m ) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor ( P00533 ) and Akt ( p - P00533 and p - Akt , respectively ) . Pretreatment with Nimotuzumab , an anti - P00533 monoclonal antibody , reversed the EMT as well as upregulation of p - P00533 / p - Akt induced by UV - C . Moreover , Nimotuzumab enhanced UV - C induced apoptosis and inhibition of colony formation . Our results indicate that EMT exerts a protective effect against apoptosis induced by low - dose UV - C . Thus , the combined application of Nimotuzumab and low - dose UV - C in vitro has an advantageous antitumor effect in SACC compared with the application of UV - C alone .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , ___MASK33___ , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK94___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK94___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor . Local anesthetics suppress proliferation in several cancer cells . The mechanism of the suppression , however , is unknown . Our previous study shows that lidocaine , at the level of tissue concentration under topical or local administration , has a direct inhibitory effect on the activity of epidermal growth factor receptor ( P00533 ) , which is a potential target for antiproliferation in cancer cells . Therefore , we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of P00533 activity . We investigated the effects of lidocaine ( 40 - 4000 microM ) on proliferation of a human tongue cancer cell line , CAL27 , which has a high level of P00533 expression , and also examined the effect of lidocaine on epidermal growth factor ( P01133 ) - stimulated autophosphorylation of P00533 in CAL27 cells . A clinical concentration of lidocaine ( 400 microM ) suppressed both serum - induced and P01133 - induced proliferation of CAL27 cells and inhibited P01133 - stimulated tyrosine kinase activity of P00533 without cytotoxicity . A larger concentration of lidocaine ( 4000 microM ) showed cytotoxicity with an antiproliferative effect . We suggest that the inhibition of P01133 - stimulated P00533 activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells . DB00281 administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells .",
"DB00281 inhibits tyrosine kinase activity of the epidermal growth factor receptor and suppresses proliferation of corneal epithelial cells . BACKGROUND : Although lidocaine is recognized as an excellent topical corneal analgesic , its toxic effect on corneal epithelial cells limits its use during corneal epithelial wound healing . Mechanism of the impairment of corneal reepithelialization with lidocaine , however , has not been evaluated . The authors ' previous study revealed that lidocaine inhibits the activity of tyrosine kinase receptors through the interaction with specific amino acid sequences around autophosphorylation sites , including acidic , basic , and aromatic amino acids . P00533 ( P00533 ) , a tyrosine kinase receptor with an important role in epithelial cell proliferation after corneal wounding , also possesses these amino acids sequences around autophosphorylation sites . The authors hypothesized that lidocaine would suppress tyrosine kinase activity of P00533 and would impair corneal epithelial cell proliferation . METHODS : To investigate the effect of lidocaine ( 4 microM - 40 mM ) on epidermal growth factor ( P01133 ) - stimulated autophosphorylation of P00533 , the authors studied purified P00533 in microtubes . They cultured human corneal epithelial cells ( HCECs ) with P01133 and lidocaine to investigate the effect of lidocaine on cell proliferation and on autophosphorylation of P00533 in HCECs . RESULTS : DB00281 ( > or = 400 microM ) significantly suppressed P01133 - stimulated autophosphorylation of the purified P00533 . In the HCEC study , P01133 alone stimulated cell proliferation and increased autophosphorylation of P00533 in HCECs . DB00281 ( > or = 400 microM ) significantly suppressed both the proliferation of HCECs promoted by P01133 and P01133 - stimulated autophosphorylation of P00533 . CONCLUSION : DB00281 directly inhibits tyrosine kinase activity of P00533 and suppresses the corneal epithelial cell proliferation .",
"___MASK92___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK92___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events ."
] |
[
"___MASK13___",
"___MASK33___",
"___MASK3___",
"___MASK61___",
"___MASK63___",
"___MASK66___",
"___MASK86___",
"___MASK92___",
"___MASK94___"
] |
___MASK61___
|
MH_train_359
|
interacts_with DB01166?
|
[
"Comparison of the micro - and macro - vascular effects of glimepiride and gliclazide in metformin - treated patients with Type 2 diabetes : a double - blind , crossover study . AIMS : To compare the metabolic and vascular effects of two sulphonylureas ( SU ) , gliclazide ( specific for the pancreatic [ Q09428 ] receptor ) and glimepiride ( a nonspecific agent that also binds to vascular and cardiac [ SUR2 ] receptors ) , during chronic administration in metformin - treated patients with Type 2 diabetes ( T2DM ) . METHODS : A randomized , double - blind , crossover study of gliclazide 80 mg P55957 and glimepiride 2 mg OD , each for 4 weeks as add - on therapy to metformin , with a 4 - week washout period . Patients attended four study mornings after first dose and 4 weeks ' SU treatment for measurements of arterial distensibility ( Ax ) , pressor responsiveness to i . v . angiotensin II ( ANGII ) , and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) . RESULTS : Glycaemic responses were similar ( e . g . serum fructosamine was 315 vs 329 micro mol l - 1 after 4 weeks ) , and there was no change in augmentation index during treatment with either SU ( 9 . 1 vs 9 . 8 mmHg after 4 weeks [ 95 % confidence interval - 8 . 1 , 10 . 5 ] ) . Similarly , there were no differences between treatments in pressor responsiveness ( e . g . PD10 [ dose of agonist required to increase mean BP by 10 mmHg ] for ANGII was 1 . 37 vs 1 . 68 ng kg - 1 min - 1 [ - 4 . 3 , 6 . 9 ] ) or cutaneous microvascular vasodilator responses ( peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [ - 82 . 7 , 79 . 1 ] ) . CONCLUSIONS : There is no evidence that Q09428 - specific and nonspecific SUs have differential effects on arterial distensibility , endothelial function or vasodilator mechanisms in metformin - treated patients with T2DM .",
"Phase I and pharmacological study of the broad - spectrum tyrosine kinase inhibitor JNJ - 26483327 in patients with advanced solid tumours . BACKGROUND : JNJ - 26483327 is an oral , potent , multi - targeted tyrosine kinase inhibitor , inhibiting kinases of epidermal growth factor receptor ( P00533 ) - 1 , - 2 and - 4 , rearranged during transfection ( P07949 ) receptor , vascular endothelial growth factor receptor ( VEGFR ) - 3 and Src family ( Lyn , Fyn , Yes ) at low nanomolar concentrations . This phase I , accelerated titration study assessed maximum tolerated dose , safety , pharmacokinetics and pharmacodynamic effects of JNJ - 26483327 . METHODS : Nineteen patients with advanced cancers received JNJ - 26483327 continuous twice daily ( P55957 ) in escalating dose cohorts ranging from 100 to 2100 mg . Pharmacodynamic effects were assessed in paired skin biopsies and blood . RESULTS : JNJ - 26483327 was well tolerated in doses up to 1500 mg P55957 , with target - inhibition - related toxicity such as diarrhoea and skin rash , and other common reported toxicities being nausea , vomiting , anorexia and fatigue . At 2100 mg , two episodes of dose - limiting toxicity were observed , consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue , respectively . Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti - tumour activity in xenograft mouse models . Pharmacodynamic analysis did not show a substantial effect on expression of Ki - 67 , p27 ( kip1 ) , phosphorylated mitogen - activated protein kinase , phosphorylated Akt and P00533 , and serum levels of sVEGFR - 2 , P49767 and O43915 remained unchanged . Stable disease was noted in six patients ( 32 % ) . CONCLUSION : JNJ - 26483327 is well tolerated and shows a predictable pharmacokinetic profile ; the recommended dose for further studies is 1500 mg P55957 .",
"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .",
"Dissociation of LH and DB00094 Responses to P01148 during estrogen therapy of patients with ovarian failure . This study examines the effect of oral estrogen treatment on gonadotropin secretion in three young women with gonadal failure . Each subject was treated with 0 . 1 mg P55957 of ethinyl estradiol for four weeks , and the LH and DB00094 responses to 200 microgram of intravenously administered P01148 were measured basally and weekly during therapy . Significant reduction of basal levels of DB00094 occurred within one week of treatment , with obliteration of P01148 - mediated DB00094 responsiveness within two weeks . By contrast , basal levels of LH were significantly reduced by the end of the second week of treatment , and P01148 - mediated LH levels were sustained for three weeks . In one subject an P01148 test was performed every other day for two weeks after cessation of therapy . Return of DB00094 responsiveness was delayed one week beyond that of LH , which occurred within three days of discontinuation of estrogen . These results indicate that during the early phase of oral estrogen replacement therapy , DB00094 secretion may be selectively blunted ; after discontinuation of treatment , recovery of DB00094 secretion lags behind recovery of LH .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK51___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Bioluminescent imaging study : Q05397 inhibitor , PF - 562 , 271 , preclinical study in PC3M - luc - P13671 local implant and metastasis xenograft models . Focal adhesion kinase ( Q05397 ) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation , as well as motility , making Q05397 a distinctive target in the field of anticancer drug development , especially with regards to metastatic disease .( 1 ) Our objective was to demonstrate tumor growth inhibition by PF - 562 , 271 , a selective inhibitor of Q05397 and Q14289 , or Pyk2 ,( 2 ) in mouse xenograft models , both subcutaneous and metastatic , employing the human prostate cancer cell line PC3M - luc - P13671 , a modified PC3M cell line that expresses luciferase . After 2 weeks of treatment with PF - 562 , 271 , 25 mg / kg PO P55957 5x / wk , the subcutaneous model showed a 62 % tumor growth inhibition compared to control based on tumor measurements ( p < 0 . 05 ) , with a 88 % vs . a 490 % increase in bioluminescent signal for treatment and control respectively ( p < 0 . 05 ) . In the metastasis model , the percent change from baseline , after 18 days of treatment , of the treatment group was 2 , 854 vs . 14 , 190 % for the vehicle ( p < 0 . 01 ) . These results show that PF - 562 , 271 has a potent effect on metastatic prostate cancer growth in vivo .",
"NT - 702 ( parogrelil hydrochloride , DB05505 ) , a novel and potent phosphodiesterase inhibitor , improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental intermittent claudication model . NT - 702 ( parogrelil hydrochloride , DB05505 ) , 4 - bromo - 6 -[ 3 -( 4 - chlorophenyl ) propoxy ]- 5 -[( pyridin - 3 - ylmethyl ) amino ] pyridazin - 3 ( 2H )- one hydrochloride , a novel phosphodiesterase ( PDE ) inhibitor synthesized as a potent vasodilatory and antiplatelet agent , is being developed for the treatment of intermittent claudication ( IC ) in patients with peripheral arterial disease . We assessed the efficacy of NT - 702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo . NT - 702 selectively inhibited PDE3 ( IC ( 50 )= 0 . 179 and 0 . 260 nM for Q14432 and 3B ) more potently than cilostazol ( IC ( 50 )= 231 and 237 nM for Q14432 and 3B ) among recombinant human PDE1 to PDE6 . NT - 702 inhibited in vitro human platelet aggregation induced by various agonists ( IC ( 50 )= 11 to 67 nM ) and phenylephrine - induced rat aortic contraction ( IC ( 50 )= 24 nM ) . Corresponding results for cilostazol were 4 . 1 to 17 microM and 1 . 0 microM , respectively . NT - 702 ( 3 mg / kg or more ) significantly inhibited ex vivo rat platelet aggregation after a single oral dose . For cilostazol , 300 mg / kg was effective . In a rat femoral artery ligation model , NT - 702 at 5 and 10 mg / kg repeated oral doses twice a day ( P55957 ) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2 . 5 mg / kg and more . DB01166 also improved the walking distance and surface temperature at 300 mg / kg P55957 but significant difference was only observed for surface temperature on day 8 . These results suggest that NT - 702 can be expected to have therapeutic advantage for IC .",
"[ ___MASK55___ sodium ( Photofrin - II ) ] . ___MASK55___ sodium ( ___MASK55___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK55___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK12___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK12___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK12___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK12___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK12___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .",
"P50591 - activated stress kinases suppress apoptosis through transcriptional upregulation of Q8WXI8 - 1 . P01375 - related apoptosis - inducing ligand ( P50591 ) is a potentially useful anticancer agent with exquisite selectivity for cancer cells . Unfortunately , many cancers show or acquire resistance to P50591 . In this study we report that P50591 activates a O43318 --> mitogen - activated protein kinase ( MAPK ) kinase 3 ( P46734 ) / P52564 --> p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL - 2 family member Q8WXI8 - 1 . P50591 alone triggered robust formation of the ' death - inducing signaling complex ' ( DISC ) , activation of the initiator caspase - 8 , and truncation of the Q7L3V2 P55957 ( tBID ) . Nevertheless , simultaneous disruption of the p38 MAPK pathway was required to suppress Q8WXI8 - 1 expression , thereby allowing tBID to activate the proapoptotic BCL - 2 family member Q16611 and stimulate mitochondrial outer membrane permeabilization ( MOMP ) . Release of the inhibitor - of - apoptosis ( IAP ) antagonist , Q9NR28 / Q9NR28 , from the intermembrane space was sufficient to promote P50591 - induced apoptosis , whereas release of cytochrome c and activation of the apoptosome was dispensable . Even after MOMP , however , mitochondrial - generated reactive oxygen species ( ROS ) activated a secondary signaling pathway , involving c - Jun N - terminal kinases ( JNKs ) , that similarly upregulated Q8WXI8 - 1 expression and partially rescued some cells from death . Thus , stress kinases activated at distinct steps , before and after mitochondrial injury , mediate P50591 resistance through maintenance of Q8WXI8 - 1 expression .",
"scFv - mediated delivery of truncated P55957 suppresses P04626 - positive osteosarcoma growth and metastasis . Osteosarcoma is the most common primary malignant bone tumor , with high rates of metastasis . Here , we examined the expression of human epidermal growth factor receptor - 2 ( HER - 2 ) in osteosarcoma cell lines with different metastatic potential , finding that the expression was correlated with metastasis of implanted tumors . We then introduced an expression vector encoding the e23sFv - PEA II - Bid O00548 - 60 gene , composed of a P04626 - specific single - chain antibody fused with domain II of Pseudomonas exotoxin A ( PEA ) and the carboxy end of truncated active Bid . We demonstrated that the e23sFv - PEA II - Bid O00548 - 60 molecule selectively recognized and killed P04626 - overexpressing osteosarcoma cells in vitro . Subsequently , we introduced the e23sFv - PEA II - bid O00548 - 60 gene into BALB / c athymic mice bearing P04626 - positive osteosarcomas using i . m . injections of liposome - encapsulated vector . Expression of the e23sFv - PEA II - Bid O00548 - 60 gene suppressed tumor growth , significantly prolonged animal survival and inhibited metastasis , thereby suggesting it may represent a competitive approach to treating P04626 / neu - positive osteosarcoma .",
"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .",
"Modulation of GSK - 3β activity in Venezuelan equine encephalitis virus infection . Alphaviruses , including Venezuelan Equine Encephalitis Virus ( VEEV ) , cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases . Features of the host immune response and tissue - specific responses may contribute to fatal outcomes as well as the development of encephalitis . It has previously been shown that VEEV infection of mice induces transcription of pro - inflammatory cytokines genes ( e . g . , IFN - γ , P05231 , IL - 12 , P35228 and P01375 - α ) within 6 h . GSK - 3β is a host protein that is known to modulate pro - inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer ' s . Hence inhibition of GSK - 3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity . Small molecule GSK - 3β inhibitors and GSK - 3β siRNA experiments indicated that GSK - 3β was important for VEEV replication . Thirty - eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor , with an IC ( 50 ) of ∼ 0 . 5 µM and a CC ( 50 ) of > 100 µM . BIOder was a more potent inhibitor of GSK - 3β than BIO , as demonstrated through in vitro kinase assays from uninfected and infected cells . Size exclusion chromatography experiments demonstrated that GSK - 3β is found in three distinct complexes in VEEV infected cells , whereas GSK - 3β is only present in one complex in uninfected cells . Cells treated with BIOder demonstrated an increase in the anti - apoptotic gene , survivin , and a decrease in the pro - apoptotic gene , P55957 , suggesting that modulation of pro - and anti - apoptotic genes contributes to the protective effect of BIOder treatment . Finally , BIOder partially protected mice from VEEV induced mortality . Our studies demonstrate the utility of GSK - 3β inhibitors for modulating VEEV infection .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK8___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK32___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Beclin 1 knockdown retards re - endothelialization and exacerbates neointimal formation via a crosstalk between autophagy and apoptosis . OBJECTIVE : Endothelial regeneration is an essential process for the prevention of excessive neointimal formation following endothelial denudation . Beclin 1 , a mammalian autophagy gene , is a link between autophagy and apoptosis . We hypothesized that the interference of Beclin 1 can influence re - endothelialization and ultimately affect neointimal formation by regulating autophagy and apoptosis . METHODS : A rat carotid injury model of endothelial denudation was used , and small interfering RNA of Beclin 1 was perivascularly administered . Neointima was evaluated by morphological analysis . P04275 , Beclin 1 , LC3 , autophagic substrate p62 and caspase - 3 levels were detected by immunofluorescence or Western blotting . Terminal deoxynucleotidyl transferase - mediated digoxigenin - dUTP - biotin nick - end labeling assay was performed to evaluate apoptosis . RESULTS : Carotid injury induced an upregulation of Beclin 1 protein which was down regulated by more than 50 % with small RNA interference . Beclin 1 knockdown significantly retarded re - endothelialization 7 days after injury and subsequently augmented neointima by more than 2 folds at 14 and 21 days . Autophagy and apoptosis were detected to reveal the regulatory effect of Beclin 1 . The injury - activated autophagy , shown by the increased levels of punctate LC3 and LC3II as well as decreased p62 expression , was significantly inhibited by Beclin 1 knockdown . Meanwhile , the apoptotic endothelial cell number was increased and caspase - 3 was up - regulated , though the expression of truncated P55957 was not significantly influenced . CONCLUSION : Beclin 1 knockdown exacerbated neointimal formation after rat carotid injury , associated with retarded re - endothelialization due to enhanced apoptosis , while simultaneously prohibiting autophagic activation . The data suggested an essential role of Beclin 1 as a regulator between autophagy and apoptosis in the setting of neointimal formation .",
"___MASK41___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"Hexarelin suppresses high lipid diet and vitamin D3 - induced atherosclerosis in the rat . Growth hormone - releasing peptides ( Q92847 ) and ghrelin are synthetic and natural ligands of growth hormone secretagogue receptor ( Q92847 ) respectively and are shown to exert protective actions on cardiac dysfunction . Because ghrelin has been reported to inhibit proinflammatory responses in human endothelium and Q92847 has been identified in blood vessels , we hypothesized that Q92847 could alleviate the development of atherosclerosis ( As ) . Atherosclearosis was induced by a short period ( 4 days ) of vitamin D ( 3 ) and chronic ( three months ) intragastric feeding of high fat emulsion ( containing 0 . 5 % propylthiouracil ) in adult SD rats . Some As rats received chronic hexarelin ( a variant of Q92847 ) injection ( SC P55957 , 30 days ) and normal rats received placebo as control . Significant atherosclerosis developed in animals fed with the emulsion . Serum total cholesterol and LDL - c increased , and HDL - c and aortic nitric oxide ( NO ) decreased significantly in As group . Hexarelin suppressed the formation of atherosclerotic plaques and neointima , partially reversed serum HDL - c / LDL - c ratio and increased the levels of serum NO and aortic mRNAs of P29474 , Q92847 and P16671 in As rats . Hexarelin also decreased [ ( 3 ) H ] - TdR incorporation in cultured vascular smooth muscle cell ( VSMC ) and calcium sedimentation in aortic wall . Furthermore , foam cell formation induced by ox - LDL was decreased by hexarelin . In conclusion , hexarelin suppresses high lipid diet and vitamin D3 - induced atherosclerosis in rats , possibly through upregulating HDL - c / LDL - c ratio , vascular NO production and downregulating the VSMC proliferation , aortic calcium sedimentation and foam cell formation . These novel anti - atherosclerotic actions of hexarelin suggest that the peptide might have a clinical potential in treating atherosclerosis .",
"___MASK28___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK28___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK28___ is a promising pharmacological tool in the treatment of renal edema .",
"___MASK86___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK86___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK20___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 ."
] |
[
"___MASK12___",
"___MASK20___",
"___MASK28___",
"___MASK32___",
"___MASK41___",
"___MASK51___",
"___MASK55___",
"___MASK86___",
"___MASK8___"
] |
___MASK8___
|
MH_train_360
|
interacts_with DB03615?
|
[
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK75___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK75___ is also being investigated as part of triplet drug regimens . ___MASK75___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"Disulfide - dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum . A protein disulfide isomerase - Q9BQB6 redox enzyme complex appears to be responsible for vitamin P04264 2 , 3 - epoxide reduction . Gamma - carboxylation of vitamin K - dependent proteins is dependent on formation of reduced vitamin P04264 ( Vit . K1H2 ) in the endoplasmic reticulum ( ER ) , where it works as an essential cofactor for gamma - carboxylase in post - translational gamma - carboxylation of vitamin K - dependent proteins . Vit . K1H2 is produced by the warfarin - sensitive enzyme vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) of the vitamin K cycle that has been shown to harbor a thioredoxin - like CXXC center involved in reduction of vitamin P04264 2 , 3 - epoxide ( Vit . K > O ) . However , the cellular system providing electrons to the center is unknown . Here data are presented that demonstrate that reduction is linked to dithiol - dependent oxidative folding of proteins in the ER by protein disulfide isomerase ( P07237 ) . Oxidative folding of reduced RNase is shown to trigger reduction of Vit . K > O and gamma - carboxylation of the synthetic gamma - carboxylase peptide substrate FLEEL . In liver microsomes , reduced RNase - triggered gamma - carboxylation is inhibited by the P07237 inhibitor bacitracin and also by small interfering RNA silencing of P07237 in P29320 293 cells . Immunoprecipitation and two - dimensional SDS - PAGE of microsomal membrane proteins demonstrate the existence of a Q9BQB6 enzyme complex where P07237 and Q9BQB6 appear to be tightly associated subunits . We propose that the P07237 subunit of the complex provides electrons for reduction of the thioredoxin - like CXXC center in Q9BQB6 . We can conclude that the energy required for gamma - carboxylation of proteins is provided by dithiol - dependent oxidative protein folding in the ER and thus is linked to de novo protein synthesis .",
"Leishmania major protein disulfide isomerase as a drug target : enzymatic and functional characterization . Leishmaniasis is a major health problem worldwide and tools available for their control are limited . Effective vaccines are still lacking , drugs are toxic and expensive , and parasites develop resistance to chemotherapy . In this context , new antimicrobials are urgently needed to control the disease in both human and animal . Here , we report the enzymatic and functional characterization of a Leishmania virulence factor , Leishmania major Protein disulfide isomerase ( LmPDI ) that could constitute a potential drug target . LmPDI possesses domain structure organization similar to other P07237 family members ( a , a ' , b , b ' and c domains ) , and it displays the three enzymatic and functional activities specific of P07237 family members : isomerase , reductase and chaperone . These results suggest that LmPDI plays a key role in assisting Leishmania protein folding via its capacity to catalyze formation , breakage , and rearrangement of disulfide bonds in nascent polypeptides . Moreover , DB00626 , a reductase activity inhibitor , and DB03615 , a chaperone activity inhibitor , were tested in LmPDI enzymatic assays and versus Leishmania promastigote in vitro cultures and Leishmania amastigote multiplication inside infected THP - 1 - derived macrophages . DB00626 inhibited both isomerase and reductase activities , while DB03615 had no effect on the chaperone activity . Interestingly , DB00626 blocked in vitro promastigote growth as well as amastigote multiplication inside macrophages with EC ( 50 ) values of 39 μM . These results suggest that LmPDI may constitute an interesting target for the development of new anti - Leishmania drugs .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK72___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK71___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK76___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Transcriptional profiling of erythroid progenitors from G - P04141 mobilized and nonmobilized peripheral blood . PURPOSE : The purpose of this study was to examine the gene expression profile of granulocyte colony stimulating factor ( DB00099 ) - mobilized peripheral blood ( mPB ) - derived progenitors , used in transplantation . METHODS : We correlated gene expression patterns of highly enriched steady - state peripheral blood ( PB ) - and mPB - derived CD71 + cells by microarray and ingenuity pathway analyses , to identify the transcriptional program during in vitro erythroid differentiation . RESULTS : The gene expression was more than doubled in mPB - derived ( 4180 genes ) compared to PB - derived erythroid progenitors ( 1667 genes ) while PB - and mPB - derived erythroid progenitors shared 1534 common genes . Comparative analysis of transcript levels showed differential expression of 54 genes between cultured erythroid progenitors of PB and mPB origin , where we identified common 13 downregulated and 30 upregulated genes . The most significant genes in mPB - derived erythroid progenitors were P07237 , DDIA3 , O15144 and P48201 . Regarding G - P04141 stimulation the Q99062 P32927 ( 1 . 1 - fold ) was linked via P40763 to erythroid - specific P22557 ( 2 . 9 - fold ) and P23769 ( 1 . 3 - fold ) factors , all upregulated in mPB - derived erythroid progenitors , coupled to common upregulated Q9Y266 gene involved in the proliferation of erythroid cells . CONCLUSION : This report provides an extensive transcriptional profile of cultured erythroid progenitors and leads to a better understanding of diversity among the progenitor sources .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK45___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK18___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"___MASK15___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Multi - chaperone complexes regulate the folding of interferon - gamma in the endoplasmic reticulum . The quality control mechanisms directing the folding of cytokines in the endoplasmic reticulum ( ER ) are poorly understood . We have investigated ER chaperone usage by the cytokine interferon - gamma ( P01579 ) . DB00171 - depletion or inhibition of N - glycosylation was found to cause P01579 to accumulate into detergent - insoluble aggregates in the ER . Six chaperones , P14625 , P11021 , P13667 , P07237 , Q9NZU7 / Q15084 and CRT were found to associate with P01579 during its steady state folding . Interaction of the five first chaperones with P01579 was regulated co - ordinately by DB00171 . These chaperones were recently reported to be part of a multi - chaperone complex involved in the folding of complex , multi - subunit proteins . Our data suggest that also proteins with a relatively simple quaternary structure such as cytokines may fold in association with this complex . In addition , we identified calreticulin as the major chaperone interacting with P01579 , and the related class II cytokine interleukin - 10 , during heat - shock in vivo . P01579 was maintained in a folding - competent form by calreticulin during heat - shock and released during subsequent recovery at 37 degrees C . This interaction was observed in both recombinant ( CHO - P03951 ) and natural producer cells ( Jurkat , NK - 92MI ) of P01579 . Since cytokines such as P01579 and P22301 are frequently produced in the course of inflammatory conditions associated with fever , the thermo - protective effect of calreticulin may constitute a previously unrecognized component of the cellular cytokine production machinery , of likely relevance in sustaining cytokine folding and secretion in pathophysiological conditions .",
"The antiangiogenic effects of a vascular endothelial growth factor decoy receptor can be monitored in vivo using contrast - enhanced ultrasound imaging . The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response . We investigated whether the effects of a vascular endothelial growth factor decoy receptor ( DB08885 , Regeneron Pharmaceuticals , Tarrytown , NY ) could be monitored in vivo using contrast - enhanced ultrasonography ( CEUS ) . Twenty nude mice ( in two groups ) were implanted with a human melanoma cell line ( DB - 1 ) . The active group received DB08885 ( 4 × 25 mg / kg over 2 weeks ) , whereas the control group received an inactive protein . An ultrasound contrast agent was injected followed by power Doppler imaging ( P07237 ) and pulse inversion harmonic imaging ( PIHI ; regular and intermittent ) . Specimens were sectioned in the same planes as the images and stained for endothelial cells ( CD31 ) , cyclooxygenase - 2 ( P35354 ) , P15692 , and hypoxia ( Glut1 ) . Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis . Mean tumor volume was smaller in the active group than in the control group ( 656 ± 225 vs 1 , 160 ± 605 mm3 ) . Overall , P07237 and P15692 correlated ( r = . 34 ; p = . 037 ) . Vascularity decreased from control to treated mice with intermittent PIHI , as did the expression of CD31 and P35354 ( p ≤ . 02 ) , whereas P15692 increased ( p = . 05 ) . CEUS appears to allow in vivo monitoring of the antiangiogenic effects of DB08885 in the DB - 1 human melanoma xenograft model .",
"Porous polyimide membranes prepared by wet phase inversion for use in low dielectric applications . A wet phase inversion process of polyamic acid ( PAA ) allowed fabrication of a porous membrane of polyimide ( PI ) with the combination of a low dielectric constant ( 1 . 7 ) and reasonable mechanical properties ( Tensile strain : 8 . 04 % , toughness : 3 . 4 MJ / m3 , tensile stress : 39 . 17 MPa , and young modulus : 1 . 13 GPa ) , with further thermal imidization process of PAA . PAA was simply synthesized from purified pyromellitic dianhydride ( PMDA ) and 4 , 4 - oxydianiline ( ODA ) in two different reaction solvents such as γ - DB04699 ( Q9BVC4 ) and N - methyl - 2 - pyrrolidinone ( NMP ) , which produce Mw / P07237 of 630 , 000 / 1 . 45 and 280 , 000 / 2 . 0 , respectively . The porous PAA membrane was fabricated by the wet phase inversion process based on a solvent / non - solvent system via tailored composition between Q9BVC4 and NMP . The porosity of PI , indicative of a low electric constant , decreased with increasing concentration of Q9BVC4 , which was caused by sponge - like formation . However , due to interplay between the low electric constant ( structural formation ) and the mechanical properties , Q9BVC4 was employed for further exploration , using toluene and acetone vs . DI - water as a coagulation media . Non - solvents influenced determination of the PAA membrane size and porosity . With this approach , insight into the interplay between dielectric properties and mechanical properties will inform a wide range of potential low - k material applications .",
"DB03615 inhibits the chaperone activity of protein disulfide isomerase . In the process of screening of proteins binding to ribostamycin in bovine liver using the affinity column chromatography , we found that ribostamycin inhibited the chaperone activity of protein disulfide isomerase ( P07237 ) , but it did not inhibit the isomerase activity . P07237 was identified by SDS - PAGE , Western blotting , and N - terminal amino acid sequence analysis . A 100 : 1 molar ratio of ribostamycin to P07237 was almost sufficient to completely inhibit the chaperone activity of P07237 . The binding affinity of ribostamycin to purified bovine P07237 was determined by the Biacore system , which gave a K ( D ) value of 3 . 19 x 10 (- 4 ) M . This suggests that ribostamycin binds to region distinct from the CGHC motif of P07237 . This is the first report to describe the inhibitor of the chaperone activity of P07237 .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK23___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Live cell off - target identification of lapatinib using ligand - directed tosyl chemistry . We demonstrate that ligand - directed tosyl ( DB01265 ) chemistry is applicable to off - target identification in live cells . DB01259 ( Lap ) - based DB01265 reagents not only labeled a receptor tyrosine kinase , P04626 , target protein , but also the protein disulfide isomerase ( P07237 ) that should be an off - target protein for Lap .",
"P07237 - mediated ER retention and proteasomal degradation of procollagen I in corneal endothelial cells . Procollagen I in corneal endothelial cells ( CECs ) is intracellularly degraded immediately after its synthesis . In this study , we investigated the mechanism of intracellular degradation of procollagen I by determining the role of protein disulfide isomerase ( P07237 ) in endoplasmic reticulum ( ER ) retention and further determined the degradation pathway of procollagen I in CECs . When association of P07237 to monomeric proalpha chains or the trimeric procollagen I carboxyl propeptides ( PICPs ) was analyzed , immune complex precipitated with anti - PICP antibody contained more P07237 than that precipitated with antibodies to monomeric chains . PICPs were completely colocalized with P07237 . When CECs were transfected with P07237 vector , procollagen I and the recombinant P07237 were colocalized in the ER , whereas CECs transfected with P07237 minus KDEL ( the ER retrieval sequence ) vector demonstrated that the two proteins were localized in the Golgi and were subsequently secreted into the medium . DB03615 ( an inhibitor of the chaperone activity of P07237 ) blocked colocalization of P07237 and procollagen I . Cells treated with chloroquine ( lysosome inhibitor ) did not alter the subcellular localization of procollagen I , because the inhibitor failed to induce the accumulation of procollagen I at Golgi . On the other hand , procollagen I was colocalized with ubiquitin in the cytoplasm , and proteasomal inhibitors further facilitated the colocalization of the two proteins and accumulation of ubiquitinated procollagen I ladders . These results suggest that association of P07237 with procollagen I , whether monomeric or trimeric , leads to ER retention of procollagen I before intracellular degradation via the ubiquitin - proteasome pathway .",
"___MASK25___ block of cloned human T - type voltage - gated calcium channels . ___MASK25___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve .",
"P10599 - 1 and protein disulfide isomerase catalyze the reduction of similar disulfides in HIV gp120 . HIV - 1 enters cells via interaction of the viral glycoprotein gp120 , the host cell surface receptor P01730 and the co - receptors P51681 or P61073 . For entry , gp120 undergoes conformational changes that depend on the reduction of one or more disulfides . Previous studies indicate that protein disulfide isomerase ( P07237 ) , thioredoxin - 1 ( Trx1 ) , and glutaredoxin - 1 ( Grx1 ) catalyze gp120 reduction , but their specific disulfide targets are not known . Here , it was demonstrated that P07237 and Trx1 have similar gp120 disulfide targets as determined by labeling after reduction , but with some pattern differences , including overall stronger labeling with Trx1 than with P07237 . Furthermore , uneven labeling of the residues of a disulfide may reflect altered accessibility by conformational changes upon the reduction process . Since both P07237 and Trx1 may be involved in viral entry , compounds that target the host redox system or the viral gp120 were tested in vitro to investigate whether redox regulation is a target for anti - HIV therapy . Carbohydrate binding agents ( CBAs ) , previously shown to bind gp120 and inhibit HIV entry , were now demonstrated to inhibit gp120 disulfide reduction . DB00995 , an inhibitor of thioredoxin reductase 1 ( TrxR1 ) , also showed inhibitory activity towards HIV infection , although close to its cytotoxic concentration . Our results demonstrate that both the host redox system and the viral surface glycoproteins are of interest for the development of new generations of anti - HIV therapeutics ."
] |
[
"___MASK15___",
"___MASK18___",
"___MASK23___",
"___MASK25___",
"___MASK45___",
"___MASK71___",
"___MASK72___",
"___MASK75___",
"___MASK76___"
] |
___MASK45___
|
MH_train_361
|
interacts_with DB00087?
|
[
"High levels of B cell activating factor during the peritransplantation period are associated with a reduced incidence of acute graft - versus - host disease following myeloablative allogeneic stem cell transplantation . B cell activating factor ( Q9Y275 ) , also known as B cell survival and activation factor , is associated with autoimmune disease and chronic graft - versus - host disease ( cGVHD ) . T cells are known to be modulated by soluble Q9Y275 ( sBAFF ) . Considering the possible association of sBAFF with T cell as well as B cell function , sBAFF during the peritransplantation period may affect the development of acute GVHD ( aGVHD ) . To test this hypothesis , we evaluated 45 patients who had undergone myeloablative ( MA ) allogeneic stem cell transplantation ( P09683 ) for hematologic malignancy . Serum sBAFF levels were measured before conditioning and on day 0 , day + 7 , and day + 14 . Thirty - three of the 45 patients ( cumulative incidence , 73 % ) developed aGVHD between 16 days and 98 days posttransplantation . Repeated - measures analysis of variance revealed significantly lower sBAFF levels during the peritransplantation period in patients with aGVHD than in those without aGVHD ( P =. 001 ) . Receiver operating characteristic curve analysis revealed that sBAFF levels at every time point were available for the prediction of aGVHD development , and that patients with a sBAFF level > 43 pg / mL at each time point ( which could ensure 75 % sensitivity and 73 % - 82 % specificity for the prediction of aGVHD at every time point ) had a significantly lower cumulative incidence of aGVHD . This study is the first to demonstrate that sBAFF level during the peritransplantation period not only may be predictive of aGVHD , but also may have a protective effect against aGVHD in humans . Further investigation is needed to confirm our findings .",
"Intraepithelial CD8 - positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas : relevance of clonal selection of T lymphocytes . BACKGROUND : The aim of this study was to investigate the prognostic effect of tumour - infiltrating lymphocytes ( TILs ) in serous stage III ovarian carcinoma to determine Q15399 clonality and to correlate this to Her2 / neu expression . METHODS : DB03843 - fixed and paraffin - embedded ovarian carcinomas were examined for P11836 - , CD3 - , P01730 - and CD8 - positive lymphocytes ( n = 100 ) , and for Her2 / neu - positive tumour cells ( n = 55 / 100 ) by immunohistochemistry . Clonality analysis was carried out by T - cell receptor gamma ( TCRgamma ) gene rearrangements ( n = 93 / 100 ) . Statistical analyses included experimental and clinico - pathological variables , as well as disease - free ( DFS ) and overall ( OS ) survival . RESULTS : P11836 - positive B lymphocytes were present in 57 . 7 % ( stromal ) / 33 . 0 % ( intraepithelial ) and CD3 - positive T lymphocytes in 99 . 0 % ( stromal ) / 90 . 2 % ( intraepithelial ) of ovarian carcinomas . Intraepithelial CD3 - positive T lymphocytes were correlated with improved DFS in optimally debulked patients ( P = 0 . 0402 ) . Intraepithelial CD8 - positive T lymphocytes were correlated with improved OS in all optimally debulked patients ( P = 0 . 0201 ) and in those undergoing paclitaxel / carboplatin therapy ( P = 0 . 0092 ) . Finally , rarified and clonal TCRgamma gene rearrangements were detected in 37 out of 93 ( 39 . 8 % ) and 15 out of 93 ( 16 . 1 % ) cases , respectively . This was marginally associated with improved DFS ( P = 0 . 0873 ) . Despite a significant correlation of P04626 / neu status and intraepithelial CD8 - positive lymphocytes ( P = 0 . 0264 ) , this was non - directional ( R =- 0 . 257 ; P = 0 . 0626 ) . CONCLUSION : Improved survival of ovarian cancer patients is related to the infiltration , clonal selection and intraepithelial persistence of T lymphocytes .",
"DB00087 in the treatment of chronic lymphocytic lymphoma . DB00087 was the first monoclonal antibody to be humanized , a process which embeds rodent sequence fragments in a human IgG framework . The antibody target is P31358 , an antigen expressed on normal lymphocytes as well as many T - and B - cell neoplasms . It therefore has a potential broad application across a spectrum of B - and T - cell malignancies as well as use as an immunosuppressant drug in , for example , bone marrow transplantation . The original licensing in the USA and Europe was for the treatment of fludarabine - refractory chronic lymphocytic leukemia ( CLL ) . However , recent trials using alemtuzumab as a first - line agent for CLL have shown superior response rates compared with traditional alkylator therapy and this has led to US FDA approval for first - line treatment for CLL . It seems to be particularly useful in patients with CLL who have deletion of the P04637 tumor suppressor gene , a subset of disease that responds poorly to other currently available chemotherapeutics .",
"Post - transplant repopulation of naïve and memory T cells in blood and lymphoid tissue after alemtuzumab - mediated depletion in heart - transplanted cynomolgus monkeys . Repopulation of memory T cells ( Tmem ) in allograft recipients after lymphodepletion is a major barrier to transplant tolerance induction . Ineffective depletion of naïve T cells ( Tn ) and Tmem may predispose to repopulation of Tmem after transplantation . Cynomolgus macaque monkeys given heart allografts were lymphodepleted using DB00087 ( Campath - 1H ; anti - P31358 ) . Peripheral blood ( PB ) and lymph nodes ( LN ) were analyzed for CD95 (-) ( Tn ) and CD95 (+) cells ( Tmem ) , one day , one month and up to three months after DB00087 infusion . P31358 expression , susceptibility to DB00087 cytotoxicity and pro - apoptotic caspase - 3 were evaluated in Tn and Tmem . In vivo , DB00087 induction profoundly depleted lymphocytes in PB ( 99 % reduction ) but exerted a lesser effect in LN ( 70 % reduction ) , with similar depletion of Tn and Tmem subsets . After transplantation , Tmem comprised the majority of lymphocytes in PB and LN . In vitro , LN T cells were more resistant to DB00087 - mediated cytotoxicity than PB lymphocytes . P01730 (+) Tn and Tmem were equally susceptible to DB00087 - mediated cytotoxicity , whereas CD8 (+) Tn were more resistant than CD8 (+) Tmem . However , no significant differences in P31358 expression between lymphocyte subsets in PB and LN were observed . P42574 expression was higher in PB than LN T cells . P01730 (+) and CD8 (+) Tn expressed lower levels of P42574 than Tmem , in both PB and LN . Thus , after DB00087 infusion , residual Tn in secondary lymphoid tissue may predispose to rapid recovery of Tmem in allograft recipients .",
"[ DB00087 , a monoclonal antibody against P31358 : hopes and fears ] . P31358 , an antigen expressed on immune cells including mature T lymphocytes , is thought to be involved in immunomodulatory mechanisms . DB00087 is a humanized monoclonal antibody against P31358 , which causes a marked and long - term decrease in immune cells , especially P01730 - positive T lymphocytes . A few randomized clinical trials have revealed the efficacy of alemtuzumab to be much greater than that of interferon - β in patients with relapsing - remitting multiple sclerosis . However , the development of other autoimmune disorders , including autoimmune thyroid disorders and thrombocytic purpura , because of alemtuzumab application has been considered an obstacle in its widespread use .",
"Immunity 12 years after alemtuzumab in RA : CD5 ⁺ B - cell depletion , thymus - dependent T - cell reconstitution and normal vaccine responses . OBJECTIVES : Lymphocyte depleting therapies have been used to treat refractory autoimmune disease , including RA , but treatment may be associated with long - term lymphopenia . It is unclear whether delayed reconstitution preferentially affects lymphocyte subsets , how this modulates immune challenges and whether thymic function influences the outcome . These questions are now addressed in a detailed analysis of RA patients 12 years after alemtuzumab ( anti - P31358 ) treatment . METHODS : Blood was obtained from 20 RA patients 12 years after alemtuzumab treatment . Lymphocyte subsets were enumerated by flow cytometry . T - cell receptor excision circles ( TRECs ) / ml were determined to quantify thymic function , and serological responses to neoantigens and recall antigens were assessed . RESULTS : RA patients remained lymphopenic 12 years after their first dose of alemtuzumab . P06127 (+) B cells , which may be associated with autoantibody production , were significantly reduced in alemtuzumab - treated patients compared with age - matched disease controls . In addition , naïve and memory P01730 (+) T - cell subsets were present in altered proportions in patients who had received alemtuzumab , with increased effector memory P01730 (+) T cells , and decreased naïve and central memory P01730 (+) T cells . TRECs were detectable in alemtuzumab - treated patients and correlated with P01730 (+) lymphocyte counts . Vaccine responses to neoantigens and recall antigens fell within the normal range for an ageing population . CONCLUSIONS : DB00087 therapy resulted in long - term alterations in lymphocyte subsets . The significance of these changes remains uncertain but patients respond normally to antigenic challenges . Thymic function remains an important determinant of T - cell reconstitution even several years after lymphocytotoxic therapy .",
"The genotype of Q5VY80 ( ULBP6 ) , a ligand for human P26718 ( P26718 ) , markedly influences the clinical outcome of allogeneic stem cell transplantation . P26718 ( P26718 ) is an activating receptor on natural killer ( NK ) and T - cells and binds a diverse panel of polymorphic ligands encoded by the MIC and RAET1 gene families . We studied the clinical importance of retinoic acid early transcript - 1 ( RAET1 ) polymorphism in allogeneic stem cell transplantation ( P09683 ) by determining the frequency of 18 single nucleotide polymorphisms ( SNPs ) and individual RAET1 alleles in 371 patient - donor pairs and relating this to clinical outcome . A strong association was observed between the presence of five SNPs within the patient Q5VY80 ( ULBP6 ) gene and relapse - free survival and overall survival . Two common alleles of Q5VY80 were determined and the presence of the protective Q5VY80 * 02 allele in the patient was associated with a relapse - free survival of 44 % at 8 years compared with just 25 % in patients who lacked a Q5VY80 * 02 allele ( P < 0 · 001 ) . Overall survival at this time was 55 % in those with Q5VY80 * 02 allele compared to 39 % in patients who lacked a Q5VY80 * 02 allele ( P = 0 · 003 ) . These novel findings indicate a critical role for P26718 - Q5VY80 interactions in determining P09683 clinical outcome and show Q5VY80 may have an important influence on regulating the strength of the alloreactive immune response . The data will be of value in guiding the development of future transplant therapy protocols .",
"hsBAFF enhances activity of NK cells by regulation of P01730 (+) T lymphocyte function . B cell activating factor belonging to the P01375 family ( Q9Y275 , also called Q9Y275 , Q9Y275 , THANK , or zTNF4 ) is an important survival factor for B cells , and is able to regulate T cell activation . Recently , we have demonstrated that human soluble Q9Y275 ( hsBAFF ) potently elevates NK cell activity of murine splenic cells in vivo . In this study , we further show that hsBAFF markedly enhanced NK cell activity of in vitro mouse splenic cells . Purified NK cell activities treated with hsBAFF in the presence of P60568 or P01579 , but not with hsBAFF alone were obviously elevated . hsBAFF strongly increased the activity of NK cells co - incubated with mixed T and B lymphocytes or T lymphocytes alone , but not with B lymphocytes alone . We also found that culture supernatants , from mixed T and B lymphocytes or T lymphocytes alone , but not from B lymphocytes alone post - hsBAFF treatment , effectively increased NK cell activity , and noticed that P60568 and P01579 levels significantly increased in the culture supernatants of hsBAFF - treated T lymphocytes . Of importance , we pinpointed that hsBAFF elicited robust population of P01730 (+) T lymphocytes in vitro , and further demonstrated that hsBAFF induced significantly high P60568 and P01579 secretion of P01730 (+) T lymphocytes . These findings indicate that hsBAFF results in the elevation of NK cell activity by regulation of P01730 (+) T lymphocytes contributing to P60568 and P01579 generation .",
"Maturation of dendritic cells by recombinant human P29965 - trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production . Dendritic cells ( DC ) have been shown to be potent inducers of specific cytotoxic T - cell responses both in vivo and in vitro . Furthermore , exposure to cytokines such as tumour necrosis factor ( P01375 ) - alpha or P25942 triggering changes DC phenotype and cytokine production and may enhance the T - cell activating capacity of the DC . We studied DC phenotype and cytokine production as well as the T - cell proliferation and cytotoxic T lympocyte ( CTL ) activation induced by DC generated in vitro . In addition , the effect of exposure to recombinant human P29965 - trimer ( huCD40LT ) on these parameters was investigated . Effective differentiation of monocytes derived from freshly isolated peripheral blood mononuclear cells ( PBMC ) was obtained with granulocyte macrophage - colony stimulating factor ( GM - P04141 ) and interleukin ( IL ) - 4 . The DC expression of human leucocyte antigen ( HLA ) molecules , P33681 , Q01151 , and P42081 was markedly enhanced by exposure to huCD40LT even compared to P01375 exposure . Only a moderate cytokine production was observed initially , while P01375 addition or P25942 triggering , especially , induced enhanced production of P05231 and IL - 12 p40 . Surprisingly , comparable induction of T - cell proliferation by a DC allostimulus or through the presentation of PPD , and influenza M1 - peptide specific CTL activity was obtained with nonmaturated ( Q01151 - ) and maturated ( Q01151 + ) DC . In conclusion , a final maturation of monocyte - derived DC through huCD40LT resulted in a highly homogeneous cell population with enhanced surface marker expression and high production of pro - inflammatory cytokines . In addition , the induction of responses to allo or recall antigens presented by huCD40LT maturated DC was comparable to the responses obtained with the DC maturated through P01375 exposure .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"___MASK49___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .",
"DB11320 enhances TGF - beta1 - mediated suppression of Th2 responses . Susceptibility of T cells to TGF - beta1 produced by regulatory T cells has an important impact on the induction and maintenance of peripheral tolerance and therefore on the development of autoimmunity , cancer , and allergy . DB11320 not only mediates the deleterious effects of allergic reactions , it can also modulate the Th1 / Th2 cell balance . We demonstrate that histamine dose - dependently enhanced TGF - beta1 - mediated suppression and TGF - beta1 responsiveness of P01730 + T cells . This effect was mediated by the histamine 2 receptor ( P25021 ) , as demonstrated by receptor - specific agonists and antagonists . Furthermore , the histamine effect on TGF - beta1 responsiveness was DB02527 / PKA dependent . This pathway is activated by the P25021 , which is preferentially expressed on Th2 cells . Thus a higher additive effect of histamine on TGF - beta1 responsiveness was found in Th2 cells compared with Th1 cells . In fact , findings are confirmed by analysis of cytokine regulation , since activation of the P25021 / DB02527 pathway promoted TGF - beta1 - mediated P05112 inhibition but was ineffective in suppressing P01579 . These results demonstrate that histamine supports TGF - beta1 susceptibility of T cells . Moreover , Th2 cells are more affected by histamine - enhanced TGF - beta1 suppression , which is particularly important for the regulation of allergen - specific T cells in allergic immune responses .",
"Determination of ancestral allele for possible human cancer - associated polymorphisms . To determine ancestral allele in possible cancer - associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 ( alias IL - 1RA ) variable number tandem repeat ( VNTR ) ; P04818 ( previously TS ) VNTR ; AR CAG repeat ; dinucleotide repeats of P22309 , IGF1 , P01579 ( alias P01579 ) , P03372 ( alias P03372 ) , and P00533 ] and 9 single nucleotide polymorphisms ( P03956 - 1607 1G / 2G , P08254 - 1171 5A / 6A , O15527 Ser326Cys , P05091 Gly487Lys , P04637 Arg72Pro , Q9UNQ0 Gln141Lys , P16455 Leu84Phe , P04179 Ala - 9Val , and P42898 Ala222Val ) . No chimpanzee polymorphism corresponded to human P18510 VNTR ; the ancestral allele was a repeat lost in humans . Dinucleotide repeat polymorphisms of IGF1 , P01579 , P03372 , and P00533 were shared by chimpanzees , but the length of repeats tended to be longer in humans than in chimpanzees . This tendency was particularly evident for IGF1 . All of the SNPs tested are human - specific nucleotide changes . The ancestral allele 7A was shown to be lost in P08254 - 1171 5A / 6A . Thus , all of the possible cancer - associated polymorphisms tested have human - specific alleles , and the ancestral allele is lost in three polymorphisms ( P18510 VNTR , P22309 CA repeat , and P08254 - 1171 5A / 6A ) , suggesting a possible involvement of human - specific alleles in cancer susceptibility .",
"Examination of genetic polymorphisms in newborns for signatures of sex - specific prenatal selection . Success rate in human pregnancies is believed to be very low and sex - specific mechanisms may operate in prenatal loss . Assuming a sex - differential in prenatal loss exists , we examined genetic markers in biologically plausible targets in the HLA complex , other immune system - related and iron - regulatory genes in 388 healthy newborns from Wales ( UK ) using one sex as a control group for the other . Genotyping of 333 single nucleotide polymorphisms ( SNPs ) from 107 genes was achieved mainly by TaqMan assays . Twenty - two of autosomal SNPs showed frequency differences between 187 male and 201 female newborns either individually or as part of a haplotype . Of these , six markers ( P28702 rs2076310 , HLA complex haplotype HLA - DQA1 rs1142316 - P01903 rs7192 - P0DMV9 rs1061581 , P22492 rs198844 , P01579 rs2069727 , P26718 rs10772266 and Q15306 heterozygosity ) showed statistically robust differences between male and female newborns and multivariable modeling confirmed their independence . There were fewer males homozygote for combined wildtype genotypes of P15018 rs929271 , P04637 rs1042522 and Q00987 rs2279744 compared with females [ OR = 0 . 3 , 95 % confidence interval ( CI ) = 0 . 1 - 0 . 8 ; P < 0 . 01 ] although these SNPs did not show any association individually . It is unlikely that SNPs have clinical utility as single markers in any trait with complex etiology but polygenic predictive models remain a possibility . If their validity is confirmed in larger studies of different populations and functional mechanisms of these preliminary associations are elucidated , these markers from the HLA complex , P26718 region and cytokines may cumulatively have sufficient predictive value for susceptibility to prenatal selection in each sex .",
"G - P04141 downregulates natural killer cell - mediated cytotoxicity in donors for hematopoietic P09683 . In G - P04141 - mobilized hematopoietic P09683 ( HSCT ) , natural killer ( NK ) cells have a critical role in GVHD and GVL effects . However , regulation of NK cell response to G - P04141 remains unclear . This study assayed G - P04141 effects in both HSCT donors and NK - 92MI cells . The donors who received G - P04141 had significantly decreased NK cell cytotoxicity . Levels of phosphatidylinositol 3 - kinase ( PI3K ) and phosphorylated ( p )- Akt , but not mammalian target of rapamycin ( P42345 ) , were downregulated in NK cells from G - P04141 - injected donors . G - P04141 also decreased cytotoxicity without affecting viability and NF - κB of NK - 92MI cells . PI3K and p - P29323 expression were also decreased in G - P04141 - treated NK - 92MI cells , and their inhibitors , wortmannin and PD98059 , respectively , both enhanced the downregulation of cytotoxicity . These effects were accompanied by decreased expression of a cytotoxicity - related gene , triosephosphate isomerase ( P60174 ) . Wortmannin , but not PD98059 , enhanced the downregulation of P60174 in G - P04141 - treated NK - 92MI cells , indicating a correlation between PI3K and P60174 . We conclude that G - P04141 - impaired NK cell cytotoxicity may accompany PI3K / Akt signaling . The effect is transient and NK cells may recover after G - P04141 clearance , suggesting that G - P04141 - mobilized HSCT may benefit both acute GVHD prevention and late - phase GVL promotion in HSCT recipients .",
"Long - term follow - up of symptomatic patients with lymphoplasmacytic lymphoma / Waldenström macroglobulinemia treated with the anti - P31358 monoclonal antibody alemtuzumab . P31358 is expressed on malignant cells in lymphoplasmacytic lymphoma ( P06858 ) , including IgM - secreting Waldenström macroglobulinemia ( WM ) . We examined the activity of alemtuzumab in 28 symptomatic P06858 ( 27 IgM and 1 IgA ) patients . The median prior number of therapies for these patients was 2 ( range , 0 - 5 ) and 43 % had refractory disease . Patients received alemtuzumab at 30 mg IV 3 times weekly for up to 12 weeks after test dosing , and also received hydrocortisone , acyclovir , and Bactrim or equivalent prophylaxis . Patients had a complete response ( n = 1 ) , a partial response ( n = 9 ) , or a MR ( n = 11 ) for an overall and major response rate of 75 % and 36 % , respectively . Median serum Ig decreased from 3510 to 1460 mg / dL ( P < . 001 at best response ) . With a median follow - up of 64 months , the median time to progression was 14 . 5 months . Hematologic and infectious complications , including CMV reactivation , were more common in previously treated patients and were indirectly associated with 3 deaths . Long - term follow - up revealed late - onset autoimmune thrombocytopenia ( AITP ) in 4 patients at a median of 13 . 6 months after therapy , which contributed to 1 death . DB00087 is an active therapy in patients with P06858 , but short - and long - term toxicities need to be carefully weighed against other available treatment options . Late AITP is a newly recognized complication of alemtuzumab in this patient population . This study is registered at www . clinicaltrials . gov as NCT00142181 .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK54___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"___MASK80___ - mediated cyclooxygenase - 2 expression via epidermal growth factor receptor / Q15717 interaction enhances the aggressiveness of triple - negative breast cancer cells . ___MASK80___ , a dual epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) kinase inhibitor , showed clinical benefits in advanced P04626 - positive breast cancer patients . Because some triple - negative breast cancers ( TNBCs ) frequently overexpress P00533 , the antitumor activity of lapatinib in such diseases was also tested . However , the results showed a worse event - free survival rate . It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells . In this study , our results demonstrated that lapatinib facilitated axillary and lung metastases of triple - negative MDA - MB - 231 breast cancer cells without affecting their viability , leading to worse survival in orthotopic xenograft mice . The lapatinib - increased motility was attributed by the elevation of P00533 through the downregulation of microRNA - 7 and by the subsequent overexpression of cyclooxygenase - 2 ( P35354 ) . Strikingly , independent of its kinase activity , the elevated P00533 at least partly stabilized P35354 expression by enhancing the binding of Q15717 to P35354 mRNA . Our results suggest that lapatinib may increase the migration and invasion of MDA - MB - 231 cells by upregulating P00533 and P35354 through the downregulation of microRNA - 7 , providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib - based treatment . These findings also shed new light on the molecular mechanism of P35354 mRNA stabilization by P00533 in a kinase - independent manner .",
"Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab ( anti - P31358 monoclonal antibody ) in patients with relapsing - remitting multiple sclerosis . DB00087 ( anti - P31358 mAb ) provides long - lasting disease activity suppression in relapsing - remitting multiple sclerosis ( RRMS ) . The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab - induced lymphocyte depletion . The study was performed on blood samples from RRMS patients enrolled in the CARE - MS II clinical trial , which was recently completed and led to the submission of alemtuzumab for U . S . Food and Drug Administration approval as a treatment for RRMS . DB00087 - treated patients exhibited a nearly complete depletion of circulating P01730 (+) lymphocytes at day 7 . During the immunological reconstitution , P01730 (+) CD25 (+) CD127 ( low ) regulatory T cells preferentially expanded within the P01730 (+) lymphocytes , reaching their peak expansion at month 1 . The increase in the percentage of TGF - β1 - , P22301 - , and P05112 - producing P01730 (+) cells reached a maximum at month 3 , whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline . A gradual increase in serum P13232 and P05112 and a decrease in Q16552 , Q96PD4 , Q9HBE4 , Q9GZX6 , and IFN - γ levels were detected following treatment . In vitro studies have demonstrated that P13232 induced an expansion of P01730 (+) CD25 (+) CD127 ( low ) regulatory T cells and a decrease in the percentages of Th17 and Th1 cells . In conclusion , our results indicate that differential reconstitution of T cell subsets and selectively delayed P01730 (+) T cell repopulation following alemtuzumab - induced lymphopenia may contribute to its long - lasting suppression of disease activity .",
"Alternative immunosuppression in patients failing immunosuppression with ATG who are not transplant candidates : Campath ( DB00087 ) . Antithymocyte globulin ( ATG ) - based immunosuppression remains the standard immunosuppressive therapy ( IST ) for aplastic anemia ( AA ) patients lacking a sibling donor ; however , treatment failures are relatively frequent , including about one - quarter to one - third of patients who do not show any response to initial IST , and about half of the initial responders who may experience subsequent relapses or require continuous maintenance IST . For these patients , there is the option of further IST , which may include additional courses of ATG - based IST , or attempts with alternative IST regimens . DB00087 is a monoclonal anti - P31358 Ab , which has been recently investigated as novel IS agent for the treatment of AA patients . Recent data from different groups have clearly demonstrated the biological efficacy of DB00087 in AA patients , ruling out the initial concerns about possible unacceptable infectious risks secondary to its extremely powerful lympholytic effect . Preliminary data demonstrate a remarkable efficacy , especially in the context of relapsed and , to less extent , refractory patients , whereas data in naïve patients are still limited . On the basis of these results , DB00087 - based immunosuppression is a worthy option for AA and other marrow failure patients requiring a second - line IST . Here we describe a consensus regimen that the European Group for Blood and Marrow Transplantation Severe Aplastic Anemia Working Party suggests for AA patients failing initial IST who are not indicated for P09683 .",
"Different cytokine signatures in children with localized and invasive adenovirus infection after stem cell transplantation . HAdV infection is a dangerous complication after pediatric P09683 . In this study , we aimed at determining the cytokine profile in plasma samples in case of HAdV infection after P09683 to gain more knowledge about the HAdV - specific immune response . In this prospective study , 47 pediatric P09683 recipients were included in three yr . By using particle - based Q16674 , 17 different cytokines were analyzed in 41 plasma samples of patients with a localized HAdV infection ( presence of HAdV in feces , urine or throat detected by culture ) and patients with invasive HAdV infection ( HAdV viremia in blood , detected by PCR ) . In patients with invasive HAdV infection , but not in patients with localized HAdV infection , the pro - inflammatory cytokines IL1beta , P05231 , P10145 , IL12 , IFNgamma , TNFalpha , and also Q16552 , MIP1alpha , P13725 , and IP10 were produced . The simultaneous release of the cytokines IL1beta , Q16552 , Q14116 , P13725 , MIP1alpha , and IP10 was related to invasive HAdV infections . We also show that cytokine signatures can be helpful to differentiate invasive HAdV infection from GvHD and EBV infections . In conclusion , after P09683 , children with invasive HAdV infection have a different cytokine profile compared with patients with a localized HAdV infection .",
"The polymorphism IL - 1beta T - 31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto - P09683 . Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma ( MM ) . Therefore , it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients . We investigated 348 MM patients undergoing high - dose melphalan treatment followed by Auto - P09683 and examined the influence of single nucleotide polymorphisms ( SNPs ) in genes involved in the inflammatory response . We found that the polymorphism IL - 1beta T - 31C significantly influenced overall survival ( OS ; P = 0 . 02 ) and that carriers of the variant C - allele had a significantly longer survival than homozygous wild - type allele TT - carriers ( relative risk 0 . 6 ( 95 % CI = 0 . 5 - 0 . 9 ) ; P = 0 . 008 ) . The polymorphisms P05231 G - 174C , P22301 C592A , PPARgamma2 Pro ( 12 ) Ala , P35354 A - 1195G , P35354 T8473C and P19838 ins / del did not influence the OS in this group of patients . Furthermore , homozygous carriers of the variant allele of IL - 1beta T - 31C were at 1 . 37 - fold ( CI = 1 . 05 - 1 . 80 ) increased risk of MM as compared with population - based controls ( P = 0 . 02 ) . Our results indicate that IL - 1beta is involved in the pathogenesis of MM .",
"DB00087 for the prevention and treatment of graft - versus - host disease . DB00087 is a humanized monoclonal antibody against the P31358 antigen , which is expressed on the surface of various hematopoietic cells such as B and T lymphocytes , and has been widely used for preventing acute graft - versus - host disease ( GVHD ) in allogeneic stem cell transplantation ( P09683 ) . Administration of 100 mg alemtuzumab before transplantation has resulted in a low incidence of acute GVHD in HLA - matched and mismatched transplantation from either related or unrelated donors . However , because alemtuzumab could remain in the blood at the lympholytic level 1 - 2 months after transplantation , immune reconstitution was substantially delayed , leading to a high incidence of viral infection and relapse . A dose reduction of alemtuzumab was attempted in a reduced - intensity conditioning setting to facilitate immune reconstitution , and this resulted in earlier immune reconstitution , but the clinical benefits were unclear . The dose of alemtuzumab and the timing of its administration should be optimized to maximize the benefit of acute GVHD suppression and minimize the risk of infection and relapse . Another strategy to facilitate immune reconstitution and augment anti - tumor effects is donor cell infusion of T and NK cells . Although there is accumulating evidence regarding the use of alemtuzumab for acute GVHD prevention , information on the salvage treatment for steroid - refractory acute and chronic GVHD is still limited .",
"The stop transfer sequence of the human UDP - glucuronosyltransferase 1A determines localization to the endoplasmic reticulum by both static retention and retrieval mechanisms . Human UDP - glucuronosyltransferase 1A ( P22309 ) isoforms are endoplasmic reticulum ( ER ) - resident type I membrane proteins responsible for the detoxification of a broad range of toxic phenolic compounds . These proteins contain a C - terminal stop transfer sequence with a transmembrane domain ( TMD ) , which anchors the protein into the membrane , followed by a short cytosolic tail ( CT ) . Here , we investigated the mechanism of ER residency of P22309 mediated by the stop transfer sequence by analysing the subcellular localization and sensitivity to endoglycosidases of chimeric proteins formed by fusion of P22309 stop transfer sequence ( TMD / CT ) with the ectodomain of the plasma membrane P01730 reporter protein . We showed that the stop transfer sequence , when attached to C - terminus of the P01730 ectodomain was able to prevent it from being transported to the cell surface . The protein was retained in the ER indicating that this sequence functions as an ER localization signal . Furthermore , we demonstrated that ER localization conferred by the stop transfer sequence was mediated in part by the KSKTH retrieval signal located on the CT . Interestingly , our data indicated that P22309 TMD alone was sufficient to retain the protein in ER without recycling from Golgi compartment , and brought evidence that organelle localization conferred by P22309 TMD was determined by the length of its hydrophobic core . We conclude that both retrieval mechanism and static retention mediated by the stop transfer sequence contribute to ER residency of P22309 proteins .",
"___MASK41___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK41___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"DB00087 in the treatment of chronic lymphocytic leukemia . DB00087 is a humanized therapeutic monoclonal antibody ( MAb ) that recognizes the P31358 antigen , expressed on normal and neoplastic lymphocytes , monocytes , and natural killer cells . In 2001 , alemtuzumab was approved in the US and Europe to treat B - cell chronic lymphocytic leukemia ( CLL ) that had been treated previously with alkylating agents and was refractory to fludarabine . In heavily pretreated patients this MAb is able to produce response rates of about 40 % , and in symptomatic , previously untreated patients response rates of more than 80 % can be achieved . DB00087 can also be used in patients with CLL as a preparative regimen for stem cell transplantation ( P09683 ) and to prevent graft versus host disease . Moreover its in vivo use before or after P09683 may also potentially result in depletion of residual leukemia cells , especially in the autologous setting . Adverse events associated with alemtuzumab include acute first - dose reaction , hematologic toxicity , and infectious complications . Usually they are predictable , manageable , and acceptable in the context of CLL . However , in a significant percentage of patients , cytomegalovirus reactivation occurs during alemtuzumab therapy , and routine weekly monitoring with the polymerase chain reaction methodology is indicated . Moreover , antiviral and antibacterial prophylaxis is mandatory .",
"Phase II study of trastuzumab in combination with S - 1 plus cisplatin in P04626 - positive gastric cancer ( HERBIS - 1 ) . BACKGROUND : S - 1 , an oral fluoropyrimidine , plus cisplatin ( SP ) is a standard regimen for advanced gastric cancer ( AGC ) in East Asia . To date , no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 ( P04626 ) - positive AGC . METHODS : Patients with P04626 - positive AGC received S - 1 ( 80 - 120 mg per day ) orally on days 1 - 14 , cisplatin ( 60 mg m (- 2 ) ) intravenously on day 1 , and trastuzumab ( course 1 , 8 mg kg (- 1 ) ; course 2 onward , 6 mg kg (- 1 ) ) intravenously on day 1 of a 21 - day cycle . The primary end point was response rate ( RR ) ; secondary end points included overall survival ( OS ) , progression - free survival ( PFS ) , time to treatment failure ( Q15669 ) , and adverse events . RESULTS : A total of 56 patients were enrolled . In the full analysis set of 53 patients , the confirmed RR was 68 % ( 95 % confidence interval ( CI )= 54 - 80 % ) , and the disease control rate was 94 % ( 95 % CI = 84 - 99 % ) . Median OS , PFS , and Q15669 were estimated as 16 . 0 , 7 . 8 , and 5 . 7 months , respectively . Major grade 3 or 4 adverse events included neutropaenia ( 36 % ) , anorexia ( 23 % ) , and anaemia ( 15 % ) . CONCLUSIONS : DB00072 in combination with SP showed promising antitumour activity and manageable toxic effects in patients with P04626 - positive AGC .",
"DB00087 ( anti - P31358 monoclonal antibody ) as single - agent therapy in patients with relapsed / refractory chronic lymphocytic leukaemia ( CLL ) - a single region experience on consecutive patients . DB00087 , a humanized anti - P31358 monoclonal antibody , is used in patients with refractory chronic lymphocytic leukaemia ( CLL ) . We report results in health care with alemtuzumab on consecutive , advanced - stage patients from a well - defined geographical region . Records from 1 , 301 patients ( Stockholm - Cancer - Registry 1991 - 2010 ) identified 56 relapsed / refractory patients treated with alemtuzumab . Median age was 69 years , 88 % had advanced Rai - stage with median 3 prior therapies . One fourth had bulky lymphadenopathy and 73 % were refractory to purine analogues . Median treatment length was 11 . 6 weeks . Median cumulative dose was 930 mg , significantly higher ( p = 0 . 0277 ) for responders . Overall response - rate ( ORR ) was 43 % ; 32 . 5 % , 50 % and 87 . 5 % in the Refractory , Purine analogue relapsed and Relapsed / Other subgroup , respectively . Response rate was significantly associated with subgroup ( p = 0 . 0104 ) . Good performance status ( PS ) was associated with better response rate ( p = 0 . 0227 ) . Median time - to - treatment - failure ( Q15669 ) ( months ) was 7 . 8 months , significantly ( p < 0 . 0001 ) longer for responders ( 13 . 4 ) Major infections occurred in 36 % . Median overall survival was 22 . 5 months ( range 0 . 4 - 74 . 3 ) . Positive predictive factors were good PS ( p < 0 . 0001 ) and fewer previous therapies ( p = 0 . 0038 ) . Twenty percent were retreated with alemtuzumab with an ORR of 54 . 5 % , and a Q15669 of 7 . 1 months . A high cumulative dose / longer duration of therapy and a relatively high response rate was observed compared to previous reports . Optimal patient identification and management may result in avoidance of early discontinuation and possibly better outcomes .",
"[ Post - genome challenges against inflammatory bowel diseases ] . Advancement of genome analysis might give great impact to the treatment of inflammatory bowel diseases ( Q9UKU7 ) . Q9UKU7 patients are treated by sulfadrugs , steroids and anti - immune drugs . For difficult cases , leukocytapheresis , beclomethasone dipropionate , anti - P01375 therapy , anti - LTB4 therapy and other new methods are applied . Developing epoch - making drugs will be achieved by finding new molecular targets . Histologic identification of dysplasia is important in the surveillance of long - standing ulcerative colitis . The molecular diagnosis is required for the distinction of dysplasia from the regenerative inflammatory changes . P04637 immunostaining have been proved useful . Various molecular targets will be taken into discussion as additional procedures . Recent genome analysis have revealed some genetic factors contribute to pathogenesis of Q9UKU7 , which are HLA , P05112 , MUC3 , Q9HC29 locus , IBD2 locus and so on . More information about genes concerning Q9UKU7 will be provided by analyzing dense SNP map using DNA tip . They will open the way to the tailored therapy .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK80___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Chlamydia pneumoniae heat shock protein 60 is associated with apoptotic signaling pathway in human atheromatous plaques of coronary artery disease patients . BACKGROUND : Chlamydia pneumoniae heat shock protein ( HSP ) 60 is known to contribute to the activation of inflammation . In addition , there are contradictory reports on C . pneumoniae and their role in activation of pathways ( apoptotic / antiapoptotic / necrosis ) in coronary artery disease ( CAD ) . Hence , more studies are required to know the actual role of C . pneumoniae in activation of apoptotic / antiapoptotic / necrosis pathways . METHODS AND RESULTS : In this study , two sets of patient groups ( cHSP60 positive and cHSP60 negative ) were included and gene expression was studied by cDNA micro array and real time polymerase chain reaction arrays . Expression of P42574 , 8 , 9 , O15519 , Q07869 - γ , P20142 - 1α , and Gsk - 3b were also evaluated at protein level by immunoblotting . In cHSP60 positive CAD patients significantly higher ( p < 0 . 001 ) mRNA expression was found for P13236 , P02776 , Q07325 , P10145 , P29965 , CD8 , TGFβ1 , TGFβ2 , P02649 , P18146 , P29279 , P04114 , P01130 , P08519 , and P06858 , whereas significantly lower ( p < 0 . 001 ) mRNA expression was detected for P01730 , Q8WWZ1 , P01563 , and P22301 as compared to cHSP60 negative CAD patients . Additionally , at protein level expression of P42574 ( p = 0 . 027 ) , 8 ( p = 0 . 028 ) , and 9 ( p = 0 . 037 ) were higher and O15519 ( p = 0 . 028 ) and Q07869 - γ ( p = 0 . 95 ) expression were comparable in cHSP60 positive CAD patients compared to cHSP60 negative CAD patients . CONCLUSION : Genes / proteins of pre - apoptotic caspase dependent / independent pathways , chemokines , and inflammatory cytokines receptors were significantly up - regulated in human atheromatous plaques of cHSP60 positive CAD patients suggesting an association of cHSP60 with CAD .",
"Antibody - based therapy of non - Hodgkin ' s lymphoma . Monoclonal antibodies ( mAb ) have dramatically advanced our ability to treat non - Hodgkin ' s lymphoma ( Q9NZ71 ) , and there has been a virtual explosion of clinical data regarding their use . DB00073 is a humanized anti - P11836 mAb and has significant single agent activity in follicular lymphoma , and to a lesser extent in mantle - cell and diffuse large B - cell lymphoma ( DLCL ) . DB00073 appears to have synergistic activity with cytotoxic chemotherapy and the combination has recently demonstrated improved rates of complete remission ( CR ) and overall survival in older patients with DLCL . DB00087 ( Campath - 1H ) is a humanized mAb targeting P31358 and has recently been approved in the USA for the treatment of fludarabine - refractory B - cell chronic lymphocytic leukaemia . Impressive activity has also been demonstrated in T - cell prolymphocytic leukaemia and mycosis fungoides . The radioconjugated anti - P11836 mAbs ibritumomab tiuxetan and I131 - tositumomab also have impressive clinical activity in low - grade B - cell Q9NZ71 , and the former has demonstrated superior CR rates to rituximab . Myelosuppression is more significant however , and their place in the treatment algorithm remains to be clearly defined . Other immunotoxins ( e . g . BL22 ) and mAb against alternate targets ( e . g . epratuzumab , humanized anti - P20273 ) are in development .",
"___MASK15___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK15___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK15___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK64___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK52___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"DB00087 in peripheral T - cell malignancies . The humanized monoclonal antibody CAMPATH - 1H ( alemtuzumab ) binds to the P31358 antigen , a glycoprotein that is widely expressed on normal and malignant B - and T - lymphocytes . Over the past 5 years , a number of trials have demonstrated that alemtuzumab has clinical activity in mature T - cell diseases such as T - cell prolymphocytic leukemia ( T - PLL ) and cutaneous T - cell lymphoma ( CTCL ) . In heavily pretreated relapsed / refractory patients alemtuzumab induced responses in more than two thirds of T - PLL and more than 50 % of CTCL patients . Responding patients had improved survival compared to nonresponders . DB00087 is particularly effective in clearing malignant lymphocytes from peripheral blood and bone marrow and may therefore facilitate stem - cell transplantation ( P09683 ) in selected patients . The toxicity profile for the antibody is acceptable ; the major complications are infusional reactions , which generally subside after the first 1 - 2 weeks of therapy , and prolonged lymphopenia associated with reactivation of viruses . These can be minimized by careful monitoring and the use of prophylactic therapy . Future studies will be directed toward : alternative routes ( subcutaneous ) and schedules of administration ; use as first - line therapy ; combination strategies with conventional chemotherapy ; and use of alemtuzumab to purge minimal residual bone - marrow disease prior to P09683 .",
"GVHD after allogeneic haematopoietic P09683 for AML : angiogenesis , vascular endothelial growth factor and P15692 receptor expression in the BM . There is increasing evidence suggesting that both angiogenesis and endothelial injury are involved in GVHD . To study the dynamics of angiogenesis , we examined 26 patients with AML who had undergone allogeneic haematopoietic P09683 . All were in CR and had either acute GVHD ( aGVHD ) or chronic GVHD ( cGVHD ) . We performed immunohistochemical studies of BM microvessel density ( P53602 ) using Abs against vascular - endothelial ( VE ) - cadherin , P28906 and CD105 , and expression of vascular endothelial growth factor ( P15692 ) and its receptors P17948 and P35968 . At the time of diagnosis , the P53602 in AML patients was higher than that in the normal controls , and the P53602 decreased after induction chemotherapy . Patients with aGVHD had a significantly higher P53602 than patients without aGVHD . Conversely , patients with cGVHD did not have a significantly different P53602 . In previous aGVHD , we also found more P15692 + megakaryocytes . XY Q5TCZ1 in sex - mismatched patients showed that the BM blood vessels consisted mainly of recipient endothelial cells . Taken together , these results suggest that new vessel formation and the P15692 / VEGFR system are involved in aGVHD .",
"The potential role of PD0332991 ( ___MASK34___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK34___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"In vivo alemtuzumab enables haploidentical human leukocyte antigen - mismatched hematopoietic stem - cell transplantation without ex vivo graft manipulation . BACKGROUND : DB00087 , a humanized monoclonal antibody directed against human P31358 , has a strong lympholytic effect . This study evaluates the safety of unmanipulated peripheral blood stem - cell transplantation from two or three loci - mismatched related donors using alemtuzumab in vivo . METHODS : A total body irradiation - based regimen was used in young patients , whereas those 50 years or older received fludarabine - based conditioning . DB00087 was added to these regimens by intravenous infusion at 0 . 2 mg / kg per day for 6 days ( days - 8 to - 3 ) . RESULTS : We treated 12 patients with a median age of 49 . 5 years . Eight patients demonstrated active disease , and four patients demonstrated acute leukemia in high - risk remission . All achieved neutrophil engraftment a median of 17 . 5 days after transplantation with complete donor - type chimerism . The cumulative incidence of grades III to IV acute graft - versus - host disease was only 9 % . Infection - related deaths were not observed . CD3 +/ P01730 + and CD3 +/ CD8 + T cells were strongly suppressed within 2 months after transplantation , but recovered on day 90 . Relapse was observed in five of eight patients who underwent transplantation for active disease , whereas none of the three patients who underwent transplantation in first remission had a relapse . CONCLUSIONS : We conclude that in vivo alemtuzumab enables haploidentical hematopoietic stem - cell transplantation without ex vivo graft manipulation .",
"The chromosomal translocation ( 11 ; 14 ) ( p13 ; q11 ) in acute B - Cell lymphocytic leukemia . BACKGROUND : Cytogenetic abnormalities are the most important independent prognostic factors of acute leukemia and imply the potential molecular mechanism of the disease . Translocation ( 11 ; 14 ) ( p13 ; q11 ) has been predominantly found in T - cell acute lymphocytic leukemia ( ALL ) but is rare in B - cell ALL . CASE REPORT : We present the case of a 30 - year - old male patient , who presented with symptomatic anemia , thrombocytopenia and leukocytosis . Bone marrow aspirate smear showed hypercellularity with 90 . 4 % of blast cells , which were negative for peroxidase reaction and partially positive for periodic acid - Schiff reaction . Immunophenotyping analysis was positive for P28906 , HLA - DR , P15144 , P20138 , P15391 , P20273 , cCD79c , and negative for P06729 , CD3 , P09564 , CD8 , CD10 , P11836 , cCD3 . Conventional cytogenetic study by R - banding showed complex chromosome aberrations involving t ( 11 ; 14 )( p13 ; q11 ) with the following karyotype : 46 , XY , t ( 11 ; 14 )( p13 ; q11 )[ 2 ]/ 46 , idem , add2 ( q ? ) [ 2 ]/ 46 , XY , add16 ( p ? ) [ 3 ] / 46 , XY [ 13 ] . Fluorescence in situ hybridization analysis indicated the translocation of chromosomes 11 and 14 , and was negative for P11274 / P00519 fusion . The patient went into complete remission after the first induction chemotherapy ( ALL - IC - BFM 2002 regimen ) , but he relapsed and died after 4 months . CONCLUSIONS : Translocation ( 11 ; 14 ) ( p13 ; q11 ) in B - cell ALL is rare , but it is worth exploring the molecular mechanisms and discovering the prognostic value in more B - cell ALL patients .",
"DB00087 as a bridge to allogeneic P09683 in atypical hemophagocytic lymphohistiocytosis . BACKGROUND : A 39 - year - old woman with no relevant medical or family history was admitted to hospital with episodic fever , which persisted despite antibiotic therapy . Other notable findings at admission were splenomegaly , pancytopenia , hyponatremia , elevated levels of liver enzymes , hyperferritinemia and hypofibrinogenemia . INVESTIGATIONS : Physical examination , laboratory tests , rheumatic marker serology , pathogen detection assays , complete blood counts , measurement of levels of ferritin , fibrinogen , triglycerides and soluble CD25 , natural killer cell functional studies , P14222 mutation analysis , renal biopsy , bone marrow biopsy , CT imaging of the chest and abdomen . DIAGNOSIS : Idiopathic , atypical hemophagocytic lymphohistiocytosis . MANAGEMENT : Initial treatment with antibiotics was followed by immunosuppressive therapy ( including intravenous immunoglobulin , ciclosporin , infliximab , corticosteroids and etoposide ) . Remission was achieved by treatment with the anti - P31358 monoclonal antibody , alemtuzumab , after which allogeneic stem - cell transplantation ( with reduced - intensity conditioning treatment and graft - versus - host disease prophylaxis ) resulted in a definitive cure .",
"___MASK41___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"[ Cutaneous non - tuberculous mycobacterial infection following cord blood stem cell transplantation ] . We describe a 4 - year - old - girl with familial hemophagocytic lymphohistiocytosis ( FHL ) who developed disseminated cutaneous nontuberculous mycobacterial ( Q9P121 ) infection after unrelated cord blood stem cell transplantation ( uCBSCT ) . After transplantation , the patient developed steroid - refractory acute graft - versus - host disease , and was given methylprednisolone , cyclosporin and mycophenolate mofetil . Six months after uCBSCT , cutaneous lesions that looked like insect bites appeared and spread widely over the thighs . Q9P121 infection was diagnosed by skin biopsy although no organism could be identified . DB01017 ( MINO ) and sulfamethoxazole / trimethoprim ( ST ) were administered . However , the cutaneous disease followed a course of remissions and exacerbations . One month after the skin biopsy , mycobacterium chelonae was detected by bacteriological culture of abscess drainage . Ten months after uCBSCT , the cutaneous lesions quickly progressed and the inguinal lymph nodes became enlarged and painful . Then the antibiotics were switched from MINO and ST to amikacin and clarithromycin ( P62158 ) based on the results of mycobacterial susceptibility test . The cutaneous lesions gradually improved after continuous administration of P62158 . Cutaneous Q9P121 infection is rare , but it may occur in immunocompromised patients after P09683 .",
"Therapeutic implications of variable expression of P31358 on clonal cytotoxic T cells in CD8 + large granular lymphocyte leukemia . BACKGROUND : T - cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T - lymphocytes which often results in severe cytopenia . Current treatment options favor chronic immunosuppression . DB00087 , a humanized monoclonal antibody against glycophosphatidylinositol - anchored P31358 , is approved for patients refractory to therapy in other lymphoid malignancies . DESIGN AND METHODS : We retrospectively examined treatment outcomes in 59 patients with CD8 + T - cell large granular lymphocytic leukemia , 41 of whom required therapy . Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy . Flow cytometry was used to monitor expression of glycophosphatidylinositol - anchored P31358 , P08174 , and P13987 as well as to characterize T - cell clonal expansions by T - cell receptor variable beta - chain ( Vbeta ) repertoire . RESULTS : Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient , red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three , resulting in an overall response rate of 50 % ( 4 / 8 patients ) . Clonal large granular lymphocytes exhibited decreased P31358 expression post - therapy in patients refractory to treatment . Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of P31358 - negative cells while a healthy control population had no such P31358 deficiency ( p = 0 . 026 ) . CONCLUSIONS : While alemtuzumab may be highly effective in large granular lymphocytic leukemia , prospective serial monitoring for the presence of P31358 - deficient clonal cytotoxic T - lymphocytes should be a component of clinical trials investigating the efficacy of this drug . P31358 deficiency may explain lack of response to alemtuzumab , and such therapy may confer a survival advantage to glycophosphatidylinositol - negative clonal cytotoxic T - lymphocytes .",
"Current status of antibody therapy in ALL . Despite the significant advances in modern chemotherapy , it remains challenging to treat adult patients with acute lymphoblastic leukaemia ( ALL ) . The relapse rate remains high , and the outcome at the time of relapse is dismal . Antibody - based therapies have demonstrated promising results in this patient group . Variable mechanisms have been applied to target surface antigens ( P11836 [ also termed P11836 ] , P20273 , P31358 and P15391 ) that are commonly expressed on malignant leukaemia cells . In this review , we will focus on the clinical application of such therapies in adult ALL , including the naked antibodies : DB00073 , Ofatumumab , DB04958 and DB00087 ; the immunotoxins : BL22 and Combotox ; the immunoconjugates : inotuzumab and SAR 3419 ; as well as the Bi - specific T cell engaging ( BiTE ) - specific antibody , DB09052 .",
"DB00087 in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation . Despite substantial improvements in early survival after lung transplantation , refractory acute rejection ( RAR ) and bronchiolitis obliterans syndrome ( BOS ) remain major contributors to transplant - related morbidity and mortality . We have utilized alemtuzumab , a humanized anti - P31358 antibody which results in potent lymphocyte depletion , in consecutive patients with RAR ( n = 12 ) or BOS ( n = 10 ) . All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis . DB00087 significantly improved histological rejection scores in RAR . Total rejection grade / biopsy was 1 . 98 +/- 0 . 25 preceding alemtuzumab versus 0 . 33 +/- 0 . 14 posttreatment , p - value < 0 . 0001 ( with a similar number of biopsies / patient per respective time interval ) . Freedom from BOS was observed in 65 % of RAR patients 2 years after alemtuzumab treatment . Although there was no statistically significant change in forced expiratory volume in 1 second ( FEV1 ) before and after alemtuzumab treatment in patients with BOS , a stabilization or improvement in BOS grade occurred in 70 % of patients . Patient survival 2 years after alemtuzumab for BOS was 69 % . Despite a dramatic decline in P01730 counts in alemtuzumab - treated patients , only one patient developed a lethal infection . Thus , we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS .",
"Immunologic effects of an orally available BRAFV600E inhibitor in P15056 wild - type murine models . ___MASK64___ is an orally available small molecule that targets constitutively activated BRAFV600E , an integral part of the MAPK pathway involved in melanomagenesis . We examined the effects of vemurafenib on cytokine production and antitumor response in a P15056 wild - type ( WT ) non - tumor - bearing murine model and a P15056 WT murine insulinoma system to determine its effect on immune function during immunotherapy . We demonstrate no significant effect from vemurafenib on P01730 + and CD8 + T - cell cytokine production or on a T - cell - mediated antitumor response . Our data demonstrate that vemurafenib does not significantly affect P15056 WT targets , suggesting that there may be a role for combining vemurafenib treatment with T - cell - directed immunotherapy .",
"Immunoregulatory and anti - tumor effects of polysaccharopeptide and Astragalus polysaccharides on tumor - bearing mice . The aim of this study was to determine whether polysaccharopeptide ( PSP ) and Astragalus polysaccharides ( APS ) can be combined together as a new complex prescription ( PSP + APS ) for aiding adriamycin ( AMD ) chemotherapy . Ehrlich ' s ascites carcinoma ( EAC ) was used to establish a solid tumor model in Kunming mice . Immunocytochemical and immunohistochemical analysis were employed to detect the immunoregulatory and anti - tumor effects of EAC bearing mice after 30 days of administration with PSP and APS . PSP and PSP + APS could significantly increase the percentage of CD3 (+) and P01730 (+) T - lymphocytes , the ratio of P01730 (+)/ CD8 (+) , and the expression of P60568 / IL - 2R in spleen and Bax in tumor tissue , but led to a diminution of Bcl - 2 and P11802 in tumor tissue compared with those of control group . In addition , PSP + APS could restore the immunological effects against AMD - induced immunosuppression , such as the subset of leukomonocyte , the expression of P60568 / IL - 2R in the spleen , and the thymus index . These findings suggest that the immunomodulatory and anti - cancer effects of this new formula ( PSP + APS ) were better than those of PSP alone , and also could resist immunosuppression induced by AMD .",
"Dedifferentiated chondrosarcoma mimicking a giant cell tumor . Is this low grade dedifferentiated chondrosarcoma ? We report a very rare case of a dedifferentiated chondrosarcoma mimicking a benign giant cell tumor . A 22 - year - old male was admitted to our hospital with a history of mild left wrist pain after a skiing trauma . Radiology revealed an extensive meta - epiphyseal osteolytic lesion in the distal ulna , which appeared to be a giant cell tumor . Histological examination showed a biphasic tumor comprising chondroid and non - chondroid areas with a giant cell - rich lesion resembling a conventional giant cell tumor of the bone . Immunohistochemistry showed no expression of p16 ( INK4a ) , P17948 , P35968 ( P35968 ) , P35916 , cKIT , Q00987 or P11802 . However , high expression of the tyrosine kinases P16234 and P09619 was observed . Molecular analysis showed no amplification of the cMYC gene and no activating mutations in the cKIT ( exons 9 and 11 ) or P16234 ( exon 18 ) genes . He has been on follow - up for ten months , with no evidence of local recurrence or metastatic disease . In summary , this report highlights a very rare case of a dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor bears histologic resemblance to a conventional giant cell tumor of bone . We suggest that this tumor might be categorized in the group of low - grade dedifferentiated chondrosarcomas .",
"Reduced radiosensitivity and increased P25942 expression in cyclophosphamide - resistant subclones established from human cervical squamous cell carcinoma cells . To investigate the interaction between anticancer drug resistance and radioresistance in cervical cancer cells , 3 single cell - derived cyclophosphamide - resistant subclones were established from the drug - and radiosensitive human cervical squamous cell carcinoma cell line ME180 by chronic exposure cultures with 4 - hydroxy - cyclophosphamide followed by limiting dilution . The established cyclophosphamide - resistant subclones were also radio - and multidrug - resistant to 7 other anticancer drugs . Flow cytometric analysis revealed significantly increased levels of P25942 expression on the 3 resistant subclones , whereas no P25942 expression was found on the parent ME180 cells . However , there were no changes in the expression levels of CD29 , CD49a - CD49f or P13987 between the parent cells and resistant subclones . A recombinant human soluble P29965 had no effect on the proliferation of the resistant subclones . Irradiation had no effect on the 4 - hydroxy - cyclophosphamide sensitivity of the parent cells . These results indicate that the established cyclophosphamide - resistant subclones have impaired cell death signals , which are common to both drug - and radiation - induced apoptosis , and cyclophosphamide may not be an adequate drug for use in concurrent chemoradiotherapy . Furthermore , P25942 activation signals may be associated with the multidrug - and radioresistance in these cyclophosphamide - resistant subclones .",
"Lymphocyte depletion and repopulation in peripheral blood and small intestine of cynomolgus monkeys after alemtuzumab treatment . BACKGROUND : DB00087 has been used as an induction agent in organ transplantation over 10 years , but the effect of alemtuzumab on lymphocytes in small intestine was not clear . We investigate lymphocyte depletion and repopulation phenomena both in peripheral blood and small intestine of cynomolgus monkeys , to assess the model using in preclinical transplantation . MATERIALS AND METHODS : Monkeys without P31358 antigen on erythrocytes were selected . Lymphocyte depletion and repopulation was documented by flow cytometry . Sections of ileum were obtained for isolation of intestinal intraepithelial lymphocytes ( IEL ) and lamina propria lymphocytes ( P06858 ) , and also for immunofluorescence examination . RESULTS : Powerful depletion of lymphocytes ( > 80 % ) from blood followed by gradual repopulation was observed . P11836 (+) B cells , CD8 (+) T cells , P01730 (+) T cells returned to pretreatment levels by d 21 , 35 , 56 . IEL , P06858 reduced by 70 % , 72 % on d 9 , recovered to 59 % , 57 % of pretreatment levels by d 35 , and were completed by d 56 . Depletion and repopulation of IEL and P06858 were confirmed by immunofluorescence . CONCLUSIONS : Depletion of lymphocytes in peripheral blood was less powerful and repopulation occurred faster than in patients . The lymphocyte depletion and repopulation occurred in small intestine . This model can be used in preclinical transplantation .",
"DB00087 in allogeneic hematopoetic stem cell transplantation . INTRODUCTION : With the use of reduced - intensity conditioning ( RIC ) , early toxicity of allogeneic stem cell transplantation ( P09683 ) has been much reduced . Graft - versus - host disease ( GvHD ) causes morbidities and mortality . DB00087 is a mAb directed against P31358 . When administered prior to transplant , it leads to T - cell depletion . Incorporation of alemtuzumab in RIC results in low rates of GvHD and treatment - related mortality ( TRM ) in haematological diseases , even in the setting of mismatched - donor transplantation . AREAS COVERED : The use of alemtuzumab for GvHD prophylaxis in P09683 . The benefit of alemtuzumab - based conditioning is partially offset by increased disease relapse due to impaired graft - versus - tumor effect ( GvT ) and by slower immune reconstitution , necessitating special precautions . While GvHD is prevented with alemtuzumab , post - P09683 interventions are often required . Most studies find that alemtuzumab - based conditioning results in decreased chronic GvHD and TRM , but also in decreased progression - free survival . Overall survival after 3 - 5 years is usually equivalent and quality of life may be improved because of a lower incidence of sequelae of chronic GvHD . Many aspects of alemtuzumab treatment are under investigation . EXPERT OPINION : DB00087 reduces GvHD and TRM after P09683 . Use of alemtuzumab requires awareness and strict management of the risk of opportunistic infections and of an increased risk of disease recurrence .",
"Involvement of neutrophils and natural killer cells in the anti - tumor activity of alemtuzumab in xenograft tumor models . DB00087 is a recombinant humanized IgG1 monoclonal antibody directed against P31358 , an antigen expressed on the surface of normal and malignant B and T lymphocytes . DB00087 is approved for the treatment of B - cell chronic lymphocytic leukemia ( B - CLL ) , but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined . To address this issue , the anti - tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models . The density of P31358 target antigen on the surface of tumor cells appeared to correlate with the anti - tumor activity of alemtuzumab . Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti - tumor activity in vivo . Individual inactivation of effector mechanisms in tumor - bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells . Increasing the number of circulating neutrophils by treatment with G - P04141 enhanced the anti - tumor activity of the antibody , thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK14___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK15___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"[ Differentially expressed genes in immunosuppressive and healthy mice after intranasal inoculation of Aspergillus fumigatus ] . OBJECTIVE : To screen out the differential expression genes between the immune suppressive host and healthy host after intranasal inoculation of Aspergillus fumigatus ( A fumigatus ) . METHODS : Six immune suppressive mice and 6 healthy mice were inoculated with A , fumigatus intranasally . Three days after the inoculation the mice were killed and autopsied . The total RNA of the lungs was isolated . Gene chip technology was used to examine the differentially expressed genes . RESULTS : 66 differentially expressed genes were screened out of the 4098 genes . In the experimental group the genes encoding P20273 , P19397 , and 24p3 and the genes related to engulfment and digestion of macrophage or monocytes were up - regulated . The genes encoding surfactant associated protein C , immunoglobulin lambda chain and the genes related to pulmonary metabolism were down - regulated . The genes encoding Q14116 , CD8 , and P10747 were not differentially expressed . CONCLUSION : The up - regulation of P20273 gene may be one of the ways by which the host defense is inhibited . P19397 may take part in the regulation of engulfment of phagocytes . 24p3 protein , an acute stress protein , protects the host from excessive inflammatory response ."
] |
[
"___MASK14___",
"___MASK15___",
"___MASK34___",
"___MASK41___",
"___MASK49___",
"___MASK52___",
"___MASK54___",
"___MASK64___",
"___MASK80___"
] |
___MASK15___
|
MH_train_362
|
interacts_with DB00098?
|
[
"Elevated serum levels of soluble P78423 in patients with microscopic polyangiitis . OBJECTIVES : To test the hypothesis that P78423 contributes to the pathogenesis of microscopic polyangiitis . METHODS : Serum samples from 18 patients with microscopic polyangiitis ( ___MASK48___ ) , who fulfilled the revised criteria of the American College of Rheumatology ( P10323 ) , were collected during both the newly diagnosed , untreated active disease states and inactive disease states . Also serum was from patients with large vessel vasculitis ( LVV ) , including giant cell arteritis ( n = 4 ) and Takayasu arteritis ( n = 3 ) , and from 52 healthy individuals . Soluble ( s ) P78423 levels in serum were measured using an enzyme - linked immunosorbent assay . Disease activity was assessed using Birmingham vasculitis activity scores ( BVAS ) . Expression of P49238 was examined by flow cytometry . RESULTS : Serum sCX3CL1 levels were significantly higher in ___MASK48___ patients than in either LVV group or healthy individuals . The elevated sCX3CL1 levels seen in ___MASK48___ patients correlated positively with BVAS , as well as with CRP levels and P03372 , and similarly increased expression of cell - surface P49238 was seen on peripheral blood P01730 and CD8 T cells from patients with ___MASK48___ . Notably , sCX3CL1 levels and P49238 expression were diminished during clinical remission following treatment . CONCLUSION : Our findings suggest that P78423 may be involved in the pathogenesis of ___MASK48___ , and may serve as a useful serologic marker of disease activity in systemic vasculitis .",
"Induction of bona fide regulatory T cells after liver transplantation - the potential influence of polyclonal antithymocyte globulin . T - cell - depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting . Besides prevention of alloreactivity , treatment with rabbit antithymocyte globulin ( DB00098 ) has been related to the induction of immunoregulatory T cells ( Treg ) in vitro and in vivo . To investigate Treg induced by DB00098 , we prospectively studied the effect of DB00098 induction therapy in liver - transplanted recipients in vivo ( n = 28 ) . Treg induction was further evaluated by means of Treg - specific demethylation region ( TSDR ) analysis within the Q9BZS1 locus . Whereas no induction of P01730 (+) CD25 ( high ) CD127 (-) Treg could be observed by phenotypic analysis , we could demonstrate an induction of TSDR (+) T cells within P01730 (+) T cells exclusively for DB00098 - treated patients in the long - term ( day 540 ) compared with controls ( P = NS ) . Moreover , although in vitro experiments confirm that DB00098 primarily led to a conversion of P01730 (+) CD25 (-) into P01730 (+) CD25 (+) T cells displaying immunosuppressive capacities , these cells can not be classified as bona fide Treg based on their Q9BZS1 demethylation pattern . Consequently , the generation of Treg after DB00098 co - incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined .",
"Differential expression and function of phosphodiesterase 4 ( DB05876 ) subtypes in human primary P01730 + T cells : predominant role of Q08499 . Type 4 phosphodiesterases ( DB05876 ) are critical regulators in TCR signaling by attenuating the negative constraint of DB02527 . In this study , we show that anti - CD3 / P10747 stimulation of human primary P01730 (+) T cells increases the expression of the DB05876 subtypes P27815 , Q07343 , and Q08499 in a specific and time - dependent manner . P27815 and Q08499 mRNAs as well as enzyme activities were up - regulated within 5 days , Q07343 showed a transient up - regulation with highest levels after 24 h . The induction was shown to be independent of different stimulation conditions and was similar in naive and memory T cell subpopulations . To elucidate the functional impact of individual DB05876 subtypes on T cell function , we used DB05876 subtype - specific short - interfering RNAs ( siRNAs ) . Knockdown of either Q07343 or Q08499 inhibited P60568 release 24 h after stimulation ( time point of maximal P60568 concentrations ) to an extent similar to that observed with the panPDE4 inhibitor RP73401 ( piclamilast ) . Substantial amounts of P01579 or P05113 were measured only at later time points . siRNA targeting Q08499 showed a predominant inhibitory effect on these cytokines measured after 72 h . However , the inhibition of all cytokines was most effective when DB05876 siRNAs were applied in combination . Although the effect of DB05876 inhibition on T cell proliferation is small , the Q08499 - targeting siRNA alone was as effective as the panPDE4 inhibitor , whereas P27815 or Q07343 siRNAs had hardly an effect . In summary , individual DB05876 subtypes have overall nonredundant , but complementary , time - dependent roles in propagating various T cell functions and Q08499 is the form likely playing a predominant role .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK12___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK12___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK12___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK12___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK12___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK12___ increased the protein expression of hepatic P05181 and ___MASK12___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK12___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK12___ and RFP - induced hepatotoxicity .",
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"Effect of different induction strategies on effector , regulatory and memory lymphocyte sub - populations in clinical islet transplantation . This prospective study assessed lymphocyte subsets in the peripheral blood of 42 islet allograft recipients using flow cytometry from 2 weeks and up to 2 years post - transplantation . Subjects received daclizumab ( n = 16 ) , DB00098 ( n = 12 ) or alemtuzumab ( n = 14 ) . DB00087 was associated with an early ( within 1 month ) and transient ( up to 6 months ) increase in the frequency of CD3 (+) P01730 (+) Foxp3 (+) T cells , while daclizumab induced a near complete loss of these cells ( P < or = 0 . 001 ) . The frequency of memory P01730 (+) T cells was increased following depleting immunosuppression induction with either DB00098 or alemtuzumab ( P < or = 0 . 05 ) , but remained unchanged while using daclizumab . DB00087 induction resulted in a significant loss of memory B lymphocytes when compared with the other induction groups ( P < or = 0 . 001 ) . While the clinical significance of these findings remains to be fully determined , the observed altered balance between effector , regulatory and memory cells suggests that the immune status of patients will be affected according to the induction strategy chosen .",
"Significance of immune cell function monitoring in renal transplantation after DB00098 induction therapy . Monitoring of immune status in transplant recipients is essential for predicting the risk of rejection or infection . In this study , we assessed the significance of immune cell function in 76 renal allograft recipients after DB00098 induction and initiation of maintenance immunosuppression . Using the Immuknow ( Cylex Inc ) assay , the amount of adenosine triphosphate ( DB00171 ) produced by P01730 + cells in response to phytohemagglutinin ( PHA ) was measured in patients whole blood . In parallel , the frequency and phenotype of P01730 + T cells were determined by flow cytometry . The Immuknow assay yielded paradoxically high DB00171 values during the first 3 months post - transplantation , despite very low P01730 + T cell counts . High DB00171 values were caused by peripheral blood myeloid cells , did not predict rejection , and occurred primarily in transplant recipients who received darbepoietin ( p = 0 . 017 ) . P01730 + T cells displayed predominantly an activated / memory phenotype and comprised a subpopulation of CD25 + Q9BZS1 + cells . Over the first 5 months post - transplantation , mean DB00171 activity gradually decreased , whereas P01730 + T cell counts slowly increased . Low DB00171 values were predictive of infection ( p = 0 . 002 ) . Thus Immuknow results need to be interpreted with caution in patients receiving DB00098 induction therapy . Although low DB00171 levels identify patients at increased risk for infection , high DB00171 values fail to correlate with rejection and do not justify increased immunosuppression .",
"ATG induction in renal transplant recipients : Long - term hazard of severe infection is associated with long - term functional T cell impairment but not the ATG - induced P01730 cell decline . BACKGROUND AND METHODS : We showed previously that DB00098 induction induces a strong decrease of P01730 + T cells together with impaired in vitro P60568 secretion up to 1 year post - transplant . To further characterize long - term immunological effects of ATG induction 2 and 5 years post - transplant , we used sensitive intracellular cytokine analysis in the same prospective study of 84 renal transplant recipients ( ATG , n = 44 ) . RESULTS : A significantly increased frequency of severe infectious disease ( HR = 2 . 0 , p = 0 . 027 ) as well as suppressed T cell functions were found within 2 years after ATG induction but not beyond ( logistic regression ( logreg ) : P01730 cell P22301 responses , p = 0 . 064 ; T cell proliferation , p = 0 . 038 ) . Impaired T cell proliferation at 2 years was associated with occurrence of severe infection ( p = 0 . 017 ) . Importantly , a strong and persistent decrease of P01730 cell counts ( p < 0 . 0005 at 5 years ) was independently associated with ATG induction ( logreg p = 0 . 002 ) but not related to functional P01730 cell impairment ( helper activity / cytokine production ) or an increased risk of infection . CONCLUSIONS : Severe infection up to 2 years after ATG induction was associated with impaired T cell proliferative capacity but not with the profound decline in P01730 cell counts that occurred after ATG induction and persisted up to 5 years .",
"In vivo characterization of rabbit anti - mouse thymocyte globulin : a surrogate for rabbit anti - human thymocyte globulin . BACKGROUND : Polyclonal rabbit anti - human thymocyte globulin ( DB00098 ) is used clinically for immunosuppression in solid organ transplantation ; however , it is difficult to fully characterize the effects of this agent in humans . METHODS : A surrogate rabbit anti - murine thymocyte globulin ( mATG ) was generated analogously to the commercial product DB00098 and in vivo activities were evaluated , including pharmacokinetics , T - cell depletion , dose response and kinetics , depletion / sparing of T - cell subsets or other leukocyte populations , and depletion in different lymphoid organs . RESULTS : Within 1 day , T cells are depleted by mATG in the blood , spleen , lymph node , and bone marrow down to doses of 1 mg / kg . Although mATG binds and depletes thymocytes in vitro , there is no thymocyte depletion in vivo at any dose level , suggesting decreased antibody accessibility to the thymus . After two doses of mATG given 3 days apart , T - cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for P01730 and CD8 T cells , respectively . There is also preferential depletion of naïve T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration . Depletion of natural killer - T cells , natural killer cells , plasma cells , and plasmablasts occurs , but is modest and more transient compared with T cells . B cells , macrophages , dendritic cells , hematopoetic stem cells , and bone marrow stromal cells seem resistant to mATG depletion . CONCLUSIONS : These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of DB00098 .",
"Regulatory T cells in kidney transplant recipients : the effect of induction immunosuppression therapy . BACKGROUND : Regulatory T cells have been suggested to down - regulate the alloimmune response . The aim of this prospective open study was to evaluate the effects of different inductive agents on peripheral blood regulatory T cells in kidney transplant patients and to analyse their association with short - term graft outcome . METHODS : Regulatory and effector T cell numbers in peripheral blood were determined by flow cytometry in 71 prospectively followed kidney transplant recipients at postoperative day 0 , 7 , 14 , 21 , 28 , 60 and 90 . Patients were treated with a calcineurin inhibitor - based triple immunosuppression with polyclonal rabbit anti - thymocyte globulin ( DB00098 , n = 28 ) , basiliximab , the anti - CD25 monoclonal antibody ( n = 18 ) or without induction ( controls , n = 25 ) . Flow cytometry data were correlated to rejection incidence . RESULTS : Compared to controls , P01730 (+) CD25 (+) FoxP3 (+) regulatory T - cell expansion among P01730 (+) T cells was noticed in the DB00098 group at all post - transplant time - points by Day 14 ( P < 0 . 001 ) . A significant decrease in Treg frequency ( P < 0 . 001 ) and concurrently a transient increase of P01730 (+) CD25 ( low /-) FoxP3 (+) population were observed in basiliximab - treated patients 7 - 60 days post - transplantation . Biopsy - proven acute rejection occurred in 16 . 7 % of controls , 10 . 7 % of the DB00098 group and in 11 . 1 % of the basiliximab group . Higher P01730 (+) FoxP3 (+)/ CD8 (+) CD45RA (+) CD62L (-) ratios were observed repeatedly in those patients after basiliximab induction who were rejection free ( P < 0 . 01 ) . CONCLUSIONS : In this study , the DB00098 induction therapy was associated with an expansion of regulatory cells . Sustained high P01730 (+) FoxP3 (+)/ Teff ratios were associated with the absence of rejection after basiliximab induction .",
"Efficacy of combination therapy with amantadine , thymosin alpha 1 and alpha / beta interferon in mice infected with influenza A virus . The aim of this study was to examine the effects of the antiviral drug amantadine ( Q9BXJ7 ) administered in combination with thymosin alpha 1 ( T alpha 1 ) and murine alpha / beta interferon ( IFN ) on mice infected with influenza A PR8 virus . Combined treatment with Q9BXJ7 and T alpha 1 , for 4 days , followed by a single injection of IFN , was initiated 1 h after intranasal viral inoculation . The effectiveness of this new chemoimmunotherapy protocol was seen in the long - term survival of a high percentage of animals and was statistically significant when compared to treatment with single agents in conjunction with chemotherapy or to chemotherapy alone . In addition , chemoimmunotherapy treatment reduces the viral titre in the lungs as well as restoring the immunological parameters tested ( natural killer cell activity ; cytotoxic T - lymphocyte responses ; P01730 +/ CD8 + lymphocyte subsets ) with respect to all other groups . These results suggest the potential use of these immunomodulating agents in combination with an antiviral drug in controlling PR8 influenza virus infection .",
"DB00098 - associated Cd4 + T - cell depletion and infection risk in HIV - infected renal transplant recipients . HIV - infected patients are increasingly referred for kidney transplantation , and may be at an increased risk for rejection . Treatment for rejection frequently includes thymoglobulin . We studied thymoglobulin ' s effect on P01730 + T - cell count , risk of infection and rejection reversal in 20 consecutive HIV - infected kidney recipients . All patients used antiretroviral therapy and opportunistic infection prophylaxis . Maintenance immunosuppression consisted of prednisone , mycophenolate mofetil and cyclosporine . Eleven patients received thymoglobulin ( 7 for rejection and 4 for delayed / slow graft function ) while 9 did not . These two groups were similar in age , gender , race , donor characteristics and immunosuppression . Mean P01730 + T - cell counts remained stable in patients who did not receive thymoglobulin , but became profoundly suppressed in those who did , decreasing from 475 +/- 192 to 9 +/- 10 cells / microL ( p < 0 . 001 ) . Recovery time ranged from 3 weeks to 2 years despite effective HIV suppression . Although opportunistic infections were successfully suppressed , low P01730 + T - cell count was associated with increased risk of serious infections requiring hospitalization . Rejection reversed in 6 of 7 patients receiving thymoglobulin . We conclude that thymoglobulin reverses acute rejection in HIV - infected kidney recipients , but produces profound and long - lasting suppression of the P01730 + T - cell count associated with increased risk of infections requiring hospitalization .",
"Enhanced IgE allergic response to Aspergillus fumigatus in P13569 -/- mice . To gain insight into aberrant cytokine regulation in cystic fibrosis ( CF ) , we compared the phenotypic manifestations of allergen challenge in gut - corrected P13569 - deficient mice with background - matched C57Bl6 ( B6 ) mice . Aspergillus fumigatus ( Af ) antigen was used to mimic allergic bronchopulmonary aspergillosis , a peculiar hyper - IgE syndrome with a high prevalence in CF patients . P13569 -/- , C57BL / 6 and FVB / NJ mice were sensitized with Af antigen by serial intraperitoneal injections . Control mice were mock sensitized with PBS . Challenges were performed by inhalation of Af antigen aerosol . After Af antigen challenge , histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains . However , total serum IgE levels were markedly elevated in CF mice . Sensitized CF mice showed a five - fold greater IgE response to sensitization as compared with B6 - and FVB - sensitized controls . Additional littermate controls to fully normalize for B6 - FVB admixture in the strain background confirmed the role of P13569 mutation in the hyper - IgE syndrome . Cytokine mRNA levels of P05113 and GM - P04141 in the bronchoalveolar lavage ( BAL ) fluid , and BAL cell differentials indicated that P13569 mutation caused a shift from an P05113 - predominant to an P05112 - predominant cytokine profile . This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease .",
"Acute and chronic vascular rejection in nonhuman primate kidney transplantation . A nonhuman primate ( NHP ) study was designed to evaluate in nonlife - supporting kidney allografts the progression from acute rejection with transplant endarteritis ( TXA ) to chronic rejection ( CR ) with sclerosing vasculopathy . Group P55008 ( n = 6 ) received high cyclosporine A ( DB00091 ) immunosuppression and showed neither TXA nor CR during 90 days post - transplantation . Group G2 ( n = 6 ) received suboptimal DB00091 immunosuppression and showed severe TXA with graft loss within 46 days ( median ) . Arterial intimal changes included infiltration of macrophages and T lymphocytes ( CD3 , P01730 , CD8 ) with few myofibroblasts , abundant fibronectin / collagen IV , scant collagens I / III , high rate of cellular proliferation and no C4d accumulation along peritubular capillaries . Group P46379 ( n = 12 ) received suboptimal DB00091 and anti - rejection therapy ( DB00098 + methylprednisolone + DB00091 ) of TXA . Animals developed CR and lost grafts within 65 days ( median ) . As compared to G2 , the arterial intimal changes showed less macrophages and T lymphocytes , an increased number of myofibroblasts , abundant fibronectin / collagen IV and scar collagens I / III , C4d deposition along capillaries in 60 % of animals and transplant glomerulopathy in 80 % of animals . In conclusion , CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts , and progressive deposition of collagens in the intima . Our experimental design appears well suited to study events leading to CR .",
"Atypical acute rejection after hand transplantation . Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse , patchy or focal , and distributed over forearms and dorsum of the hands . This ' classical ' pattern of rejection usually spares the skin of the palm and does not affect the nails . Herein , we report the experience on four cases presenting with an ' atypical ' pattern of rejection that is novel in involving the palmar skin and the nails . All patients were young and exposed to repetitive and persistent mechanical stress of the palm . Characteristic features of rejection included a desquamative rash associated with dry skin , red papules , scaling and lichenification localized to the palm . Skin lesions were associated with nail dystrophy , degeneration , deformation or loss . Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells ( CD3 + , P01730 + and CD8 + ) , with small numbers of B cells ( P11836 + and CD79a + ) and a low number of Forkhead transcription factor 3 ( Q9BZS1 ) - positive cells in one patient . The lesions persisted over weeks to months , responded poorly to steroid treatment and were managed with antithymocyte globulin ( ATG ; DB00098 , Genzyme , Cambridge , MA ) , alemtuzumab and / or intensified maintenance immunosuppression .",
"The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia . Anti - thymocyte globulin ( ATG ) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia . However , there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome . Therefore , in this study , we retrospectively compared the effect of two different DB00098 preparations [ DB00098 ( ATG - G ) and ATG - Fresenius ( ATG - F ) ] on immune recovery and cytomegalovirus infection after transplantation . The conditioning regimen was a combination of fludarabine , cyclophosphamide , and ATG . Low dose total body irradiation was added in alternative donor transplantation . Four patients received ATG - F at 5 mg / kg / day from day - 7 to day - 3 , whereas ATG - G was given at 2 . 5 mg / kg / day from day - 5 to day - 2 in three patients . There was no graft rejection and no grade II - IV acute graft - versus - host disease . All three patients in the ATG - G group developed positive cytomegalovirus antigenemia including two with high - grade antigenemia , whereas two of the four patients in the ATG - F group were persistently negative . Immunological evaluation on day 60 revealed that both P01730 + and CD8 + T - cell recoveries were delayed in the ATG - G group . These findings suggested that ATG - G has a stronger immunosuppressive activity than the ATG - F with a dose ratio of 1 : 2 . 5 .",
"Upregulation of molecules associated with T - regulatory function by thymoglobulin pretreatment of human P01730 + cells . BACKGROUND : This study evaluated the immunologic effects of thymoglobulin in modulating human P01730 + cells . METHODS : Human P01730 + cells were purified from peripheral blood mononuclear cells by negative selection method . P01730 + cells were pretreated with thymoglobulin and incubated for 72 hr . Cells and culture supernatants were collected and studied by real - time quantitative polymerase chain reaction , fluorescence activated cell scanning , multiplex cytokine assay , and mixed lymphocyte reaction ( P08235 ) . RESULTS : DB00098 pretreated P01730 + cells demonstrated up - regulation of gene transcripts for P16410 , OX40 , forkhead box P09131 ( Foxp3 ) , CD25 , P01579 , P22301 , and P60568 as determined by real - time quantitative polymerase chain reaction . Fluorescence - activated cell scanning analysis demonstrated that P01730 + cells , pretreated with thymoglobulin , up - regulated CD25 expression on their surface , and the surface expression of P16410 and OX40 and the expression of intracellular Foxp3 were observed in these P01730 + CD25 + cells . Additionally , P08235 demonstrated that thymoglobulin - pretreated cells partially inhibited proliferation of untreated autologous P01730 + cells in response to allogeneic cells . The high levels of P01579 , P22301 , P60568 , and P05112 were detected by multiplex cytokine assay in supernatants collected from cultures of thymoglobulin - pretreated P01730 + cells . The lymphocyte proliferation of allogeneic P08235 was also partially blocked in the presence of supernatants from cultures of thymoglobulin - pretreated P01730 + cells . CONCLUSIONS : This study demonstrates that the unique effects of thymoglobulin in modulating P01730 + cells may be an important mechanism for its action in inducing immunosuppression and transplant tolerance .",
"Comparative polyclonal antithymocyte globulin and antilymphocyte / antilymphoblast globulin anti - CD antigen analysis by flow cytometry . Polyclonal antithymocyte globulin ( ATG ) / antilymphocyte and antilymphoblast globulins ( ALG ) antibodies have been used successfully in transplantation , aplastic anemia and graft - versus - host disease . Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG / ALG preparations for immunosuppression . Recent reports have indicated clinical dose adjustment based on levels of patient ' s cells expressing various CD antigens . In vitro analysis of individual polyclonal ATG / ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data . Therefore , a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed . Activities found in four lots each of horse ATG ( ATGAM , Upjohn ) , rabbit and horse ATG ( thymoglobulin and lymphoglobulin , Merieux ) , horse ALG ( Minnesota ) , and DB00098 ( Fresenius ) have been compared for P06729 , CD3 , P01730 , P06127 , P09564 , CD8 , CD11a , P05107 , P10747 , P16070 , P08575 , and TCR - alpha / beta antigens . Quantitation is achieved by measuring the concentration of ATG / ALG required to give 50 % inhibition of antigen specific fluorescent - labeled monoclonal antibody relative to buffer controls . The three horse products tested have similar activity to most antigens tested . However , Fresenius DB00098 has the lowest activity for almost all antigens tested whereas the Merieux DB00098 has activities closer to the horse products . This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency .",
"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK61___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK61___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK61___ or Enalapril .",
"Human P01730 (+) CD25 (+) Cells in Combination with P28906 (+) Cells and DB00098 to Prevent Anti - hematopoietic Stem Cell T Cell Alloreactivity . Cotransplantation of human P28906 (+) hematopoietic stem cells ( P19526 ) and P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) could prevent anti - P19526 alloreactivity and reduce the risk of rejection in HLA mismatched transplants . To pursue this hypothesis we cocultured P28906 (+) cells and P01730 (+) CD25 (+) cells immunomagnetically isolated ( Milteny ) from human peripheral blood ( unmanipulated or granulocyte - colony stimulating factor [ DB00099 ] mobilized ) or cord blood . Enriched Tregs obtained from the same source ( autologous ) of P28906 (+) cells showed greater inhibitory effect on T cell alloreactivity than third - party ( allogeneic ) Tregs . The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic P28906 (+) cells and Tregs did not modify the clonogenic activity of P28906 (+) cells in vitro . Cotransplantation of Tregs with P28906 (+) cells at 1 : 1 or 2 : 1 ratios in nonobese diabetic / severe combined immunodeficiency ( NOD / SCID ) mice resulted in normal hematopoietic stem cell engraftment . Incubation with physiologic doses of rabbit antithymocyte globulin ( DB00098 , thymoglobulin ) did not affect the number of Tregs in 6 - day culture . Upon exposure to thymoglobulin Tregs maintained their suppressive activity , increased expression of P32248 , and released multiple cytokines , primarily interleukin ( IL ) 10 . Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with P28906 (+) cells after preparative regimens including thymoglobulin .",
"Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation . Experimental studies have shown that rabbit antithymocyte polyclonal globulin ( ATG ) can expand human P01730 + CD25 ++ Foxp3 + cells ( Tregs ) . We investigated the major biological effects of a self - manufactured rabbit polyclonal anti - rat thymoglobulin ( DB00098 ) in vitro , as well as its effects on different peripheral T - cell subsets . Moreover , we evaluated the allogeneic suppressive capacity of DB00098 - induced Tregs in an experimental rat renal transplant model . Our results show that DB00098 has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T - cell depletion . Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets , directly proportional to the DB00098 dose used , but not of the effector memory T cells , which required significantly higher DB00098 doses . After DB00098 administration , we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats , leading to an increase in the Treg / T effector ratio . Importantly , DB00098 - induced Tregs displayed a strong donor - specific suppressive capacity when assessed in an antigen - specific allogeneic co - culture . All of these results were associated with better renal graft function in rats that received DB00098 . Our study shows that DB00098 has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post - transplant homeostatic proliferation .",
"P00797 - angiotensin system expression in rat bone marrow haematopoietic and stromal cells . The existence of a bone marrow renin - angiotensin system ( DB01367 ) is evidenced by the association of renin , angiotensin converting enzyme ( P12821 ) , and angiotensin ( Ang ) II and its AT ( 1 ) and AT ( 2 ) receptors with both normal and disturbed haematopoiesis . The expression of DB01367 components by rat unfractionated bone marrow cells ( BMC ) , haematopoietic - lineage BMC and cultured marrow stromal cells ( O60682 ) was investigated to determine which specific cell types may contribute to a local bone marrow DB01367 . The mRNAs for angiotensinogen , renin , P12821 , and AT ( 1a ) and AT ( 2 ) receptors were present in BMC and in cultured O60682 ; Q9BYF1 mRNA was detected only in BMC . Two - colour flow fluorocytometry analysis showed immunodetectable angiotensinogen , P12821 , AT ( 1 ) and AT ( 2 ) receptors , and Ang II , as well as binding of Ang II to AT ( 1 ) and AT ( 2 ) receptors , in P01730 (+) , CD11b / c (+) , CD45R (+) and CD90 (+) BMC and cultured O60682 ; renin was found in all cell types with the exception of P01730 (+) BMC . Furthermore , Ang II was detected by radioimmunoassay in O60682 homogenates as well as conditioned culture medium . The presence of Ang II receptors in both haematopoietic - lineage BMC and O60682 , and the de novo synthesis of Ang II by O60682 suggest a potential autocrine - paracrine mechanism for local DB01367 - mediated regulation of haematopoiesis .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK9___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK9___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK9___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK9___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK9___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Low - dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression . Rabbit antithymocyte globulin therapy ( DB00098 ) is a potent lymphocyte - depleting agent commonly used following renal transplantation to reduce the risk of acute rejection . Standard doses ( 7 - 10 mg / kg ) of DB00098 result in profound lymphopenia and predispose patients to infection and malignancy . The effects of lower doses of DB00098 ( LoD - DB00098 , 3 - 5 mg / kg ) on peripheral blood lymphocytes ( PBL ) are as yet unknown . In this prospective clinical trial , PBL subsets were characterized by flow cytometry over 12 months following LoD - DB00098 therapy . All patients were initially treated with standard doses of tacrolimus , mycophenolic acid , and prednisone . At 3 months , patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence . LoD - DB00098 therapy resulted in prolonged suppression of P15391 + B cells , total CD3 + T cells , as well as naïve and memory P01730 + T cell and P01730 / CD25 / Foxp3 + T - regulatory subsets irrespective of chronic immunosuppressive therapy . Selective depletion was only noted in the CD4CD45RA + naïve T - cell subset resulting in an altered memory / naïve P01730 + ratio . LoD - DB00098 failed to deplete CD8 + T cells , which increased their relative contribution to the total CD3 + pool . All other lymphocyte subsets maintained near normal proportions . Thus , LoD - DB00098 therapy may lessen the adverse effects of full dose DB00098 while maintaining overall efficacy .",
"Investigating hypothetical products from noncoding frames ( HyPNoFs ) . Hypothetical Products from Noncoding Frames ( i . e . , HyPNoFs ) are hypothetical , not - coded proteins , translated from alternate reading frames ( i . e . , coding + 1 and coding + 2 ) of cDNAs . HyPNoFs of P01730 , PKC , oncostatin , bcl - 2 proto - oncogene , tumor suppressor p53 , cystic fibrosis transmembrane regulator ( P13569 ) , and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS - Q99884 data bank . Homology searchers carried out revealed that hypothetical products ( i . e . , HyPNoFs ) may share high similarity with real protein products actually coded . Sequence similarity of hypothetical products to real proteins is sometimes very high , suggesting common conformational features , according to the Sander and Schneider cutoff value . This finding supports the hypothesis that eukaryotic DNA , currently considered to be monocistronic , might occasionally have polycistronic regions , carrying different protein messages on overlapping frames . As yet , polycistronic genes have been observed in viral genomes only . The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy , rather than a present feature of the genome in eukaryotes . These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes ' evolution and to investigate structure - function relationships of protein and DNA sequences .",
"SV40 infection associated with rituximab treatment after kidney transplantation in nonhuman primates . BACKGROUND : A regimen consisting of polyclonal anti - T - cell antibody , sirolimus ( Q86TD4 ) , and donor bone marrow ( DBM ) infusion induces robust transplantation tolerance to skin allografts in mice . We investigated the effect of a similar regimen in a nonhuman primate ( NHP ) model . METHODS : Cynomolgus macaques ( Macaca fascicularis ) were transplanted with mismatched kidney allografts . Recipients were treated with 7 doses of antithymocyte globulin ( DB00098 , day 1 to 9 ) , sirolimus , and DBM infusion ( day 14 ) . Anti - P11836 antibody , rituximab , was given on days 0 and 5 . RESULTS : A regimen of DB00098 , 30 days of Q86TD4 , and DBM infusion induced significantly greater prolongation of graft survival with a mean survival time of 88 days compared with the control regimen ( no DBM ) with an mean survival time of 53 days ( P = 0 . 022 ) . Unlike the murine skin allograft model , all grafts were rejected within 111 days . A combination of DB00098 , continuous Q86TD4 , and rituximab caused graft and systemic SV40 infection and failed to achieve further extension of graft survival . C4d deposition was observed in 50 % of recipients as early as 18 days , suggesting antidonor antibody production . A transient , low - to - moderate degrees of multilineage chimerism was observed after DBM infusion . Treatment with DB00098 resulted in profound depletion of P01730 + and CD8 + T cells , whereas addition of rituximab achieved prolonged ( up to 3 months ) depletion of P11836 + B cells . CONCLUSION : The DB00098 , Q86TD4 , and DBM protocol is simple and produces long - term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long - term tolerance .",
"Anti - allergic function and regulatory mechanisms of KR62980 in allergen - induced airway inflammation . The ligand - activated transcription factor , peroxisome proliferator - activated receptor ( Q07869 ) gamma , and its ligands inhibit pro - inflammatory cytokine production by immune cells , thus exerting anti - inflammatory activity . As a non - thiazolidinedione PPARgamma ligand , KR62980 has anti - diabetic and anti - adipogenic activities , but its anti - inflammatory function has yet to be characterized . In this study , we investigated the functions and mechanisms of KR62980 in the activation and differentiation of P01730 + T helper ( Th ) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand , rosiglitazone . KR62980 dose - dependently and significantly suppressed TCR - triggered Th cell proliferation by suppressing P60568 / IL - 2Ralpha - mediated signaling . Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose - dependent manner , whereas P05112 gene expression was specifically suppressed by only KR62980 . In addition , sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c - Maf expression . In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin - induced eosinophil infiltration , allergic cytokine production and collagen deposition in the lung . KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium , concurrent with decreases of allergic Th2 cytokines and Q16552 in the draining lymph node . In conclusion , a novel PPARgamma ligand , KR62980 , suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA - induced airway inflammation , suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis .",
"FoxP3 + , and not CD25 + , T cells increase post - transplant in islet allotransplant recipients following anti - CD25 + DB00098 immunotherapy . Anti - CD25 antibodies are used as an induction therapy in islet allotransplantation for type 1 diabetes . Although previous reports suggested that anti - CD25 treatment may lead to depletion of P01730 + CD25 + regulatory T cells ( Tregs ) and questioned its use in tolerance - promoting protocols for transplantation , the effect of anti - CD25 antibodies on the frequency and function of Tregs remains unclear . We examined the effect of anti - CD25 antibody , daclizumab , in vivo on Tregs in islet allograft recipients enrolled in a single - center study and monitored post - transplant . Our data shows that the reduction in CD25 + Treg cells observed post - transplant is due to masking of CD25 receptor by daclizumab and not due to depletion . In addition , using Treg marker , FoxP3 , we show that anti - CD25 + ATG treatment leads to an increase in FoxP3 + Tregs post - transplant . These data suggest that anti - CD25 - based therapy has beneficial effects on Tregs and combined with ATG may be a promising therapy for autoimmunity and transplantation .",
"Acute cellular rejection . The incidence of acute rejection of the kidney allograft in the world has been around 15 % during the period between 2001 and 2003 . It is clinically defined as an elevation in the level of serum creatinine by more than 0 . 3 mg / dL and is diagnosed by kidney biopsy . On pathologic examination , the interstitium of the allograft is diffusely edematous and infiltrated by P01730 and CD8 lymphocytes . Tubulitis occurs when the lymphocytes and monocytes extend into the walls and lumina of the tubules . Presence of leukocytes determines infection or antibody - mediated rejection . Typically C4d staining is negative . Other causes of acute allograft dysfunction included prerenal factors , interstitial nephritis , infection , acute tubular necrosis , toxicity by drugs , and obstruction in the urinary tract . The primary diagnostic assessments include history , especially adherence to immunosuppressive therapy , physical examination , blood and urine laboratory tests , measurement of the serum levels of the drugs , and ultrasonography . Diagnosis of acute cellular rejection depends on biopsy , P11836 staining for refractory cases , negative C4d staining , presence of markers of activating lymphocyte , and proteomic study . Treatment of acute cellular rejection in kidney transplant recipients include pulse steroid for the first rejection episode . It can be repeated for recurrent or resistant rejection . DB00098 and OKT3 are used as the second line of treatment if graft function is deteriorating . Changing the protocol from cyclosporine to tacrolimus or adding mycophenolate mofetil or sirolimus might be effective . Prognosis depends on number of rejection episodes , the use of potent drugs , time of rejection from transplantation , and response to treatment .",
"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK68___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK68___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK35___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Rapid T cell repopulation after rabbit anti - thymocyte globulin ( DB00098 ) treatment is driven mainly by cytomegalovirus . Rabbit anti - thymocyte globulin ( DB00098 ) induces a long - lasting lymphocytopenia . P01730 (+) T cells remain depleted for up to 2 years , whereas the CD8 (+) T cell compartment is refilled rapidly by highly differentiated P26842 (-) CD45RA (+) CD57 (+) effector - type cells . Because the presence of these highly differentiated CD8 (+) T cells has been associated with cytomegalovirus ( CMV ) infection , we questioned to what extent restoration of CMV T cell immunity contributes to the re - emergence of T cells following DB00098 treatment . We compared T cell repopulation in six CMV - seropositive patients with CMV reactivation ( reactivating CMV (+) ) to that in three CMV (+) patients without reactivation ( non - reactivating CMV (+) ) , and to that in three CMV - seronegative recipients receiving a kidney from a CMV - seronegative donor ( CMV (-/-) ) . All patients received DB00098 because of acute allograft rejection . Total P01730 and CD8 counts , frequency and phenotype of virus - specific CD8 (+) T cells were determined . In reactivating CMV (+) patients , total CD8 (+) T cells reappeared rapidly , whereas in non - reactivating CMV (+) patients they lagged behind . In CMV (-/-) patients , CD8 (+) T cell counts had not yet reached pretransplant levels after 2 years . CMV reactivation was indeed followed by a progressive accumulation of CMV - specific CD8 (+) T cells . During lymphocytopenia following DB00098 treatment , serum interleukin ( IL ) - 7 levels were elevated . Although this was most prominent in the CMV - seronegative patients , it did not result in an advantage in T cell repopulation in these patients . Repopulated CD8 (+) T cells showed increased skewing in their Vβ repertoire in both CMV (-/-) and reactivating CMV - seropositive patients . We conclude that rapid T cell repopulation following DB00098 treatment is driven mainly by CMV .",
"The AP - 1 family member P01100 blocks transcriptional activity of the nuclear receptor steroidogenic factor 1 . Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II ( Ang II ) , which , upon binding to its receptor , activates protein kinase C ( PKC ) within these cells . PKC is a potent inhibitor of the steroidogenic enzyme P05093 . We have demonstrated that , in the ovary , PKC activates expression of P01100 , a member of the AP - 1 family , and increased expression of this gene is linked to P05093 downregulation . However , the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on P05093 expression are not defined . Herein , we demonstrated that Ang II inhibited P05093 through PKC and P27361 / 2 - activated P01100 and that blocking P01100 expression decreased PKC - mediated inhibition . Although P05093 transcription was activated by the nuclear receptor Q13285 , expression of P01100 resulted in a decrease in Q13285 - mediated gene transcription . P01100 physically interacted with the hinge region of Q13285 and modulated its transactivity , thus preventing binding of cofactors such as SRC1 and CBP , which were necessary to fully activate P05093 transcription . Collectively , these results indicate a new regulatory mechanism for Q13285 transcriptional activity that might influence adrenal zone - specific expression of P05093 , a mechanism that can potentially be applied to other steroidogenic tissues .",
"Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1 - polarizing capacity . Inhibitors of DB02527 - specific phosphodiesterase ( PDE ) 4 have been shown to inhibit inflammatory mediator release and T cell proliferation , and are considered candidate therapies for T ( h ) 1 - mediated diseases . However , little is known about how DB05876 inhibitors influence dendritic cells ( DC ) , the cells responsible for the priming of naive T ( h ) cells . Therefore , we investigated the PDE profile of monocyte - derived DC , and whether DB05876 inhibitors modulate DC cytokine production and T cell - polarizing capacity . We mainly found DB02527 - specific DB05876 enzymatic activity in both immature and mature DC . In contrast to monocytes that mainly express Q07343 , we found that P27815 is the predominant DB05876 subtype present in DC . Immature DC showed reduced ability to produce IL - 12p70 and tumor necrosis factor ( P01375 ) - alpha upon lipopolysaccharide or P29965 ( P29965 ) stimulation in the presence of DB05876 inhibitors , whereas cytokine production upon P29965 stimulation of fully mature DC in the presence of DB05876 inhibitors was not affected . Exposure to DB05876 inhibitors for 2 days during DC maturation did not influence T cell - stimulatory capacity or acquisition of a mature phenotype , but increased the expression of the chemokine receptor P61073 . Furthermore , DC matured in the presence of DB05876 inhibitors showed reduced capacity to produce IL - 12p70 and P01375 upon subsequent P29965 stimulation . Using these DB05876 inhibitor - matured DC to stimulate naive T cells resulted in a reduction of P01579 - producing ( T ( h ) 1 ) cells . These findings indicate that DB05876 inhibitors can affect T cell responses by acting at the DC level and may increase our understanding of the therapeutic implication of DB05876 inhibitors for T ( h ) 1 - mediated disorders .",
"The stop transfer sequence of the human UDP - glucuronosyltransferase 1A determines localization to the endoplasmic reticulum by both static retention and retrieval mechanisms . Human UDP - glucuronosyltransferase 1A ( P22309 ) isoforms are endoplasmic reticulum ( ER ) - resident type I membrane proteins responsible for the detoxification of a broad range of toxic phenolic compounds . These proteins contain a C - terminal stop transfer sequence with a transmembrane domain ( TMD ) , which anchors the protein into the membrane , followed by a short cytosolic tail ( CT ) . Here , we investigated the mechanism of ER residency of P22309 mediated by the stop transfer sequence by analysing the subcellular localization and sensitivity to endoglycosidases of chimeric proteins formed by fusion of P22309 stop transfer sequence ( TMD / CT ) with the ectodomain of the plasma membrane P01730 reporter protein . We showed that the stop transfer sequence , when attached to C - terminus of the P01730 ectodomain was able to prevent it from being transported to the cell surface . The protein was retained in the ER indicating that this sequence functions as an ER localization signal . Furthermore , we demonstrated that ER localization conferred by the stop transfer sequence was mediated in part by the KSKTH retrieval signal located on the CT . Interestingly , our data indicated that P22309 TMD alone was sufficient to retain the protein in ER without recycling from Golgi compartment , and brought evidence that organelle localization conferred by P22309 TMD was determined by the length of its hydrophobic core . We conclude that both retrieval mechanism and static retention mediated by the stop transfer sequence contribute to ER residency of P22309 proteins .",
"Rabbit anti T - lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells , while hematopoetic stem cells are apoptosis resistant . Polyclonal anti - T - lymphocyte globulins ( ATG ) are used in allogeneic stem cell transplantation ( P09683 ) for the prophylaxis of graft versus host disease ( GVHD ) by in vivo T cell depletion . In this study we investigated the complement independent induction of apoptosis by DB00098 in peripheral blood mononuclear cell ( PBMNC ) compartments and hematopoetic stem cells ( P19526 ) . We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells . We found ATG to induce apoptosis in T - lymphocytes ( P01730 (+) , CD8 + ) , B - lymphocytes ( P11836 + ) , natural killer ( NK ) - cells ( CD56 (+) ) , and monocytes ( P08571 (+) ) . P19526 , in contrast , were apoptosis resistant and could be growth stimulated by low - dose ATG in the presence of bystander cells . The human leukemia cell lines Jurkat , Daudi , DG - 75 ( lymphoblastic ) , and K562 , HL - 60 , KG1 , and U937 ( myeloblastic ) underwent ATG - induced apoptosis , whereas the NK - cell line YT was resistant . Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia , 9 of 10 patients with chronic lymphocytic leukemia , and 4 of 8 patients with acute myeloblastic leukemia underwent ATG - induced apoptosis . We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis . ATG might support engraftment . Finally , antileukemic activity of ATG could positively influence the transplantation outcome .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK100___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Kinetics of homeostatic proliferation and thymopoiesis after DB00098 induction therapy in kidney transplant patients . BACKGROUND : Lymphocyte - depleting therapy is associated with long - lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies . The mechanisms of T - cell repopulation and their posttransplantation kinetics are not fully understood . METHODS : We studied thymopoiesis by CD31 (+) naïve T cells ( recent thymic emigrants ) and homeostatic proliferation by Ki - 67 (+) T cells in rabbit antithymocyte globulin ( DB00098 ) - treated patients the first 6 months after transplantation . Patients receiving basiliximab or no induction therapy served as controls . RESULTS : At 6 months after transplantation , T - cell numbers were lower than before transplantation in DB00098 - treated patients , whereas T - cell numbers remained stable in both control groups . In this time period , thymopoiesis was similar between the three treatment groups ; CD8 (+) T cells showed the highest percentage of recent thymic emigrants . At month 1 , percentages of Ki - 67 (+) naïve and memory P01730 (+) and CD8 (+) T cells were the highest in DB00098 - treated patients , but these percentages declined in the months thereafter . When CD31 was used to distinguish between cytokine - and antigen - driven proliferation in naïve T cells , we found evidence for cytokine - dependent proliferation . Cytokine - dependent proliferation was also shown by in vivo increased percentages of phosphorylated P42229 and high expression levels of the interleukin - 7 receptor - α and interleukin - 15 receptor - α by T cells . CONCLUSION : These findings demonstrate that , in the first month after DB00098 therapy , cytokine - induced homeostatic proliferation is involved in T - cell repopulation of both naïve and memory T cells . At later time points , the contribution of homeostatic proliferation diminished , which explains the observed incomplete T - cell recovery .",
"P29972 and Q92482 , psoriasin , and nitric oxide synthases 1 - 3 are inflammatory mediators in erythema toxicum neonatorum . Erythema toxicum neonatorum is a common , inflammatory skin reaction in healthy newborn infants characterized by an accumulation of activated immune cells in the lesions . Its etiology and physiologic significance are still unclear . The purpose of this study was to extend the search for possible inflammatory mediators of the rash . We performed immunohistochemistry on punch biopsy cryosections from lesions of four , 1 - day - old infants and from four matched controls without rash , using antibodies against the water channel proteins aquaporin - 1 ( P29972 ) and aquaporin - 3 ( Q92482 ) , psoriasin , and the nitric oxide synthase ( NOS ) enzymes , neuronal NOS ( P29475 ) , inducible NOS ( P35228 ) , and endothelial NOS ( P29474 ) . All sections from the lesions showed a dense , nodular cellular infiltrate located near the hair follicle . The vessels in the dermis showed a high incidence of P29972 and P29474 . Strong staining for P29972 , Q92482 , and psoriasin , as well as P29475 , P35228 , and P29474 were seen in the entire epidermal layer . The infiltrate in the dermis contained numerous cells expressing P29972 , Q92482 , P29475 , P35228 , and P29474 . Double immunofluorescence staining showed that Q92482 was located in CD1a - expressing Langerhans cells and other dendritic cells in the dermis , as well as in P08571 - expressing macrophages , CD15 - expressing neutrophils , and EG2 - expressing eosinophils surrounding the hair follicle . Our findings show that P29972 and Q92482 , psoriasin , and NOSs are involved in the activation of the skin immune system at birth .",
"Antithymocyte globulins suppress dendritic cell function by multiple mechanisms . BACKGROUND : The polyclonal rabbit antithymocyte and anti - T - cell immunoglobulins ( ATGs ) DB00098 ( TG ) and DB05320 ( ATG - F ) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation . Although immunosuppressive mechanisms of ATGs on T cells are well studied , less is known about their impact on dendritic cells ( DCs ) . METHODS : Effects of TG and ATG - F on immune functions and signaling pathways of human monocyte - derived DCs were determined by flow cytometry , enzyme - linked immunosorbent assay , Western blot , apoptosis assays , endocytosis assays , and T cell stimulation assays . RESULTS : TG and ATG - F bind rapidly and with high affinity to CD11c , P33681 , P42081 , P25942 , P16671 , P28907 , CD206 , and human leukocyte antigen - DR on DCs . TG and , to a lesser extent , ATG - F induce apoptosis in immature and mature DCs . Macropinocytotic and receptor - mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG - F due to their binding of the C - type lectins CD206 and Q9NNX6 . TG and ATG - F induce activation of the mitogen - activated protein kinases P27361 / 2 and p38 that contributes to the induction of apoptosis . TG and ATG - F also induce cytoplasmic - nuclear translocation of the NF - kappaB / Rel transcription factors RelB , RelA , p50 , and p52 . Production of interleukin - 12p70 in mature DCs is suppressed by TG and ATG - F . TG and ATG - F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells . CONCLUSIONS : ATGs interfere with basic DC functions , suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation .",
"Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion . BACKGROUND : Polyclonal antithymocyte globulins ( ATGs ) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells . However , nondepleting mechanisms may also be important mediators of graft survival . In the present study , 14 lots of thymoglobulin ( DB00098 ) were analyzed and compared for nondepletive immunomodulatory activities in vitro . METHODS : Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces P01730 + CD25 ( high ) Foxp3 + regulatory T cells , which were evaluated for consistent ability to suppress T - cell activation in mixed lymphocyte reactions . The consistency of P06729 , CD3 , CD11a , and P08575 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells . A transwell chemotaxis assay was established and used to evaluate ATG - mediated inhibition of stromal cell - derived factor ( SDF ) - 1alpha - driven Jurkat T - cell migration . RESULTS : Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities , which were consistent from batch to batch . All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T - cell surface antigens . In addition , these studies provide the first demonstration that thymoglobulin effectively inhibits P61073 / SDF - 1alpha - driven T - cell chemotaxis . CONCLUSIONS : This novel , systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival .",
"Immune reconstitution following rabbit antithymocyte globulin . Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome . The effects of depleting agents on T - cell subsets and subsequent T - cell reconstitution are incompletely defined . We used flow cytometry to examine the effects of rabbit antithymocyte globulin ( DB00098 ) on the peripheral T - cell repertoire of pediatric and adult renal transplant recipients . We found that while DB00098 effectively depleted CD45RA + P26842 + naïve and CD45RO + P26842 + central memory P01730 + T cells , it had little effect on CD45RO + P26842 - P01730 + effector memory or CD45RA + CD31 - , CD45RO + P26842 + and CD45RO + P26842 - CD8 + T cell subsets . When we performed a kinetic analysis of CD31 + recent thymic emigrants and CD45RA +/ RO + T cells , we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution . We additionally examined the impact of DB00098 on peripheral P01730 + Foxp3 + T cells . We found that in adults , administration of DB00098 - induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype , while P01730 + Foxp3 + T cells of thymic origin predominated in children , providing the first evidence that DB00098 induces Treg in vivo . Collectively our data indicate that DB00098 alters the balance of regulatory to memory effector T cells posttransplant , providing an explanation for how it positively impacts transplant outcome .",
"Effect of acetazolamide on aquaporin - 1 and fluid flow in cultured choroid plexus . ___MASK8___ ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill - defined . The drug reversibly inhibits aquaporin - 4 ( P55087 ) , the most ubiquitous \" water pore \" in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures . CP tissue culture from 10 - day Sprague - Dawley rats and a TRCSF - B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT - PCR ) were performed . Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels . Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently .",
"A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients . PURPOSE : Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin ( DB00098 , DB00098 (®) ) to the hematopoietic cell transplant ( HCT ) conditioning regimen of IV fludarabine monophosphate ( fludarabine ) and targeted intravenous ( IV ) busulfan ( fludarabine /( T ) busulfan ) . Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients . METHODS : We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan , specifically busulfan concentration at steady state , and fludarabine , specifically F - ara - A area under the curve ( AUC ) and fludarabine triphosphate ( F - ara - DB00171 ) intracellular accumulation and concentration in separate P01730 (+) and CD8 (+) T - lymphocyte populations . RESULTS : Acute and chronic graft versus host disease ( GvHD ) occurred in 11 patients and one patient , respectively . Four patients died before day + 100 of non - relapse causes , which met the protocol stopping guidelines . The cumulative incidence of relapse was 25 % at 3 year post - HCT . Interpatient variability in the busulfan - and fludarabine - relevant pharmacologic biomarkers was 2 . 1 - to 2 . 5 - fold . F - ara - A AUC and accumulated F - ara - DB00171 in CD8 (+) cells had the highest hazard ratio for non - relapse mortality and overall survival , respectively . However , neither achieved statistical significance . CONCLUSIONS : The low rates of GvHD , particularly in its chronic form , were encouraging , and further biomarker studies are warranted to optimize the fludarabine /( T ) busulfan / DB00098 conditioning regimen .",
"Altered balance between effector T cells and Q9BZS1 + Q9UKS7 + regulatory T cells after thymoglobulin induction in kidney transplant recipients . This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients . Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation . DB00098 induction led to an immediate and significant decrease of all T cells and NK cells , but not B cells or monocytes . CD8 (+) T cells recovered to near pretransplant level by 4 weeks post - transplant . P01730 (+) T cells remained at less than 30 % of pretransplant level for the entire study period of 78 weeks . Both P01730 (+) and CD8 (+) T cells showed reduced cytokine production after recovery . Deletion of P01730 (+) Q9BZS1 (+) Q9UKS7 (+) regulatory T cells ( Tregs ) was less profound than that of P01730 (+) Q9BZS1 (-) cells , thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin - treated patients . In contrast , the percentages of Tregs and their expression of Q9BZS1 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56 % of the pretransplant level . Thus , thymoglobulin - induced deletion of T cells led to significant and long - lasting alterations of the T - cell compartment characterized by a preservation of Tregs and long - lasting reduction in P01730 (+) , and potentially pathogenic , T cells .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"Preferential increase in memory and regulatory subsets during T - lymphocyte immune reconstitution after DB00098 induction therapy with maintenance sirolimus vs cyclosporine . BACKGROUND : DB00877 maintenance therapy with DB00098 induction is a promising regimen that may preserve renal function . Data are lacking , however , about the immunologic effects of combined DB00098 - sirolimus . METHODS : In a 12 - month , prospective , randomised , open - label , single - centre pilot study , de novo deceased - donor kidney transplant patients were randomised to receive cyclosporine or sirolimus , with DB00098 induction , mycophenolate mofetil and corticosteroids . Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution . RESULTS : Nineteen patients were recruited ( sirolimus 9 , cyclosporine 10 ) . Reconstitution of the P01730 (+) T - lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1 , but CD8 (+) reconstitution did not differ significantly between groups . The proportion of naïve P01730 (+) T - lymphocytes showed an initial decrease with sirolimus versus cyclosporine . Naïve CD8 (+) T - lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3 , but remained unchanged with sirolimus . Memory P01730 (+) T - lymphocytes occurred more frequently in sirolimus - versus cyclosporine - treated patients during year 1 . The proportion of memory CD8 (+) T - lymphocytes decreased at months 1 and 3 compared to baseline in the DB00091 arm , but did not change in the sirolimus cohort . By month 12 , the proportion of both naïve and memory P01730 (+) and CD8 (+) T - lymphocytes had become similar with sirolimus or cyclosporine . There were fewer naïve B - lymphocytes in the sirolimus cohort and more P15391 (-) IgD (+/-) P26842 (+) memory B - lymphocytes . CONCLUSIONS : In this small population , homeostatic reconstitution after DB00098 induction showed disproportionately high recovery of memory T - lymphocyte subsets during sirolimus therapy , which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation .",
"DB09280 - ___MASK34___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Effect of thymoglobulin induction on HIV - infected renal transplant recipients : differences between HIV - positive and HIV - negative patients . The best immunosuppressive regimen in HIV - infected renal transplant recipients has not been established . DB00098 has been associated with an increased risk of serious bacterial infections in HIV - negative patients and , for this reason , there is some concern over its use in the HIV - infected population . We describe three consecutive HIV - infected renal transplant recipients who received thymoglobulin as induction therapy , and we compared their progress with a cohort of 23 HIV - negative recipients . Median follow - up was 24 and 11 months , respectively . Nadir lymphocytopenia was observed at 1 week in both groups , and their absolute lymphocyte count recovery was similar . An early and deep ( < 30 cells / mm ( 3 ) ) P01730 (+) T cell lymphocytopenia was seen in two of the three HIV - infected patients . No opportunistic infections were diagnosed in HIV - positive patients . One HIV - positive patient had a bacterial infection and five HIV - negative patients had one or more bacterial infections . DB00098 was safe in our three HIV - infected renal transplant recipients . Until those data are confirmed in larger studies , close monitoring is recommended during the thymoglobulin - induced P01730 (+) T cell lymphocytopenia period .",
"Ex vivo expansion of human Tregs by DB00098 is dependent on intact P40763 - signaling in CD4 ⁺ T cells and requires the presence of monocytes . The addition of low , nondepleting doses of rabbit antithymocyte globulin ( ATG ) to human peripheral blood mononuclear cells has been shown to expand functional P01730 (+) CD25 (+) FoxP3 (+) regulatory T cells ( Tregs ) in vitro . This report is the first to elucidate the exact cellular mechanisms of ATG - mediated Treg expansion . P01730 (+) T cells require monocytes , but not other antigen presenting cell subsets , to be present in coculture to expand Tregs . However , T cells do not require direct cell - cell contact with monocytes , suggesting the importance of soluble factors . Moreover , ATG initially \" reprograms \" P01730 (+) T cells , but not monocytes , and induces P40763 and P42229 signaling in P01730 (+) cells . These reprogrammed P01730 (+) T cells subsequently secrete GM - P04141 and P22301 only in case of intact P40763 signaling , which in turn promote the generation of tolerogenic P08571 (+) CD11c (+) dendritic cells characterized by enhanced P22301 and decreased IL - 12 production . Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM - P04141 and Bcl - 2 , but not TGF - β , in peripheral blood mononuclear cells . These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram P01730 (+) T cells in a P40763 - dependent but TGF - β - independent manner , leading to the generation of monocyte - derived dendritic cells with a tolerogenic cytokine profile .",
"Th 1 cytokine production by peripheral blood mononuclear cells in X - linked adrenoleukodystrophy . Cerebral adrenoleukodystrophy ( P33897 ) and adrenomyeloneuropathy ( Q9BXJ7 ) are the two most frequent clinical phenotypes of the same genetic defect leading to the accumulation of very long chain fatty acids ( VLCFA ) . Previous studies have suggested that inflammatory cytokines may play a role in the cerebral demyelination and in phenotype expression of the disease . We analyzed cytokine production by stimulated peripheral blood mononuclear cells ( PBMC ) from 17 patients ( four asymptomatic subjects , eight Q9BXJ7 and five P33897 ) . Our results show that lipopolysaccarides ( LPS ) stimulated PBMC from both symptomatic and asymptomatic patients have an increased production of IL - 12 and TNFalpha compared to controls , while after phitoemoagglutinin ( PHA ) stimulation we observed a decreased production of P05231 and P22301 . These data indicate that , following an immunological stimulus , PBMC from patients have an increased production of cytokines typical of a Th1 cell response which is able to promote the inflammatory process . This characteristic profile of cytokine production could be related to the biochemical defect and could have a role in central nervous system ( CNS ) pathogenesis .",
"Risk factors for impaired P01730 + T - cell reconstitution following rabbit antithymocyte globulin treatment in kidney transplantation . To describe long - term P01730 + T - cell reconstitution after rabbit antithymocyte globulin ( DB00098 ) treatment and identify predictive factors following kidney transplantation . A single - center retrospective study analyzed lymphocyte subsets in DB00098 - treated kidney transplant recipients ( 1986 - 2009 ) . 589 patients were analyzed ( maximum follow - up 21 years ) . A comparator group ( n = 298 ) received an anti - P60568 receptor monoclonal antibody . P01730 + T - cell lymphopenia ( < 200 / mm3 ) was present in 48 . 5 % , 9 . 2 % , 6 . 7 % , 2 . 0 % , and 0 % of patients at one , three , five , 10 , and 20 years post - transplant , respectively . P01730 + T - cell count increased during the first 10 years but remained below the pretransplant count even after 20 years . At 1 , 3 , and 6 months post - transplant , mean P01730 + T - cell count was significantly lower in patients with P01730 + T - cell lymphopenia at 12 months versus patients without lymphopenia . On multivariate analyses , significant independent predictors for long - term impaired P01730 T - cell reconstitution were recipient age , pretransplant P01730 + T - cell count , 12 - month P01730 + T - cell count , and tacrolimus or DB00688 therapy . Recipient age > 40 years was identified as a cutoff point . P01730 + T - cell reconstitution following DB00098 treatment remains impaired even after 21 years . Most risk factors for long - term impaired P01730 + T - cell reconstitution may be evaluated pretransplant or are modifiable post - transplant .",
"Rabbit anti - rat thymocyte immunoglobulin preserves renal function during ischemia / reperfusion injury in rat kidney transplantation . Ischemia / reperfusion ( I / R ) injury is an important cause of renal graft dysfunction in humans . Increases in cold and warm ischemia times lead to a higher risk of early post - transplant complications including delayed graft function and acute rejection . Moreover , prolonged cold ischemia is a predictor of long - term kidney graft loss . The protective effect of rabbit anti - rat thymocyte immunoglobulin ( DB00098 ) was evaluated in a rat model of I / R injury following syngeneic kidney transplantation . Serum creatinine concentration was evaluated at 16 h and 24 h post - transplant . Animals were sacrificed 24 h post - transplant for evaluation of histology , infiltrating leukocytes , nitrotyrosine staining , and apoptosis . DB00098 was effective in preventing renal function impairment , tissue damage and tubular apoptosis associated with I / R only when was given 2 h before transplantation but not at the time of reperfusion . Pretransplant DB00098 treatment of recipient animals effectively reduced the amount of macrophages , P01730 (+) , CD8 (+) T cells and LFA - 1 (+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme - B expression within ischemic kidney . On the other hand , granulocyte infiltration and oxidative stress were not modified by DB00098 . If these results will be translated into the clinical setting , pretransplant administration of Thymoglobuline (®) could offer the additional advantage over peri - transplant administration of limiting I / R - mediated kidney graft damage .",
"___MASK8___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK8___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Murine antithymocyte globulin T - cell depletion is mediated predominantly by macrophages , but the Fas / P48023 pathway selectively targets regulatory T cells . BACKGROUND : DB00098 is a T - cell - depleting polyclonal rabbit anti - human thymocyte antibody used clinically for immunosuppression in solid organ and hematopoietic stem - cell transplantation . By using a surrogate rabbit anti - mouse thymocyte globulin ( mATG ) , we previously demonstrated that murine regulatory and memory T cells are preferentially spared from mATG depletion in vivo . The current studies were designed to determine whether different effector mechanisms are involved in differential depletion of T - cell subsets by mATG . METHODS : Complement - dependent cytotoxicity , antibody - dependent cellular cytotoxicity ( ADCC ) , and apoptotic mechanisms of depletion by mATG were evaluated in vitro and in vivo . RESULTS : In vitro , there was evidence of differential susceptibility of T - cell subsets by different effector mechanisms where naïve and P01730 effector memory T cells show reduced susceptibility to apoptosis , whereas regulatory T cells are less susceptible to mATG - mediated complement - dependent cytotoxicity and ADCC . However , mATG treatment of mice depleted of ADCC effector cell types ( neutrophils , natural killer cells , or macrophages ) or deficient in complement P01031 or Fas demonstrated that mATG depletion of all T - cell subsets is mediated primarily by macrophages and that the role of neutrophils , natural killer cells , and complement is minimal in vivo . Interestingly , the Fas / P48023 pathway does play a role in regulatory T - cell depletion , which is likely a result of increased basal expression of Fas on these cells . CONCLUSIONS : These data suggest that macrophages deplete most T cells by mATG in mice , but regulatory T cells are also uniquely susceptible to mATG - mediated Fas - dependent depletion .",
"Potential immunomodulatory role of P01282 in the implantation sites of prediabetic nonobese diabetic mice . Among several factors known to modulate embryo implantation and survival , uterine quiescence and neovascularization , maternal immunotolerance through the Th1 / Th2 cytokine balance towards a Th2 profile , local regulatory T - cell ( Treg ) activation , and high levels of progesterone were assigned a prominent role . Vasoactive intestinal peptide ( P01282 ) is a neuroimmunopeptide that has anti - inflammatory effects , promotes Th2 cytokines and P01730 (+) CD25 (+) Q9BZS1 (+) Treg activation , and stimulates exocrine secretion , smooth muscle relaxation , and vasodilatation favoring uterus quiescence . The goal of the present work was to explore the participation of P01282 in the implantation sites of normal and pregnant prediabetic nonobese diabetic ( NOD ) females , a mouse strain that spontaneously develops an autoimmune exocrinopathy similar to Sjögren ' s syndrome . Our results indicate a reduction in litter size from the third parturition onwards in the NOD female lifespan with increased resorption rates . Progesterone systemic levels were significantly decreased in pregnant NOD mice compared with BALB / c mice , although the allogeneic response to progesterone by spleen cells was not impaired . P01282 receptors , Vipr1 and Vipr2 ( Vpac1 and Vpac2 ) , were expressed at the implantation sites and P01282 induced leukemia inhibitory factor ( P15018 ) and Treg marker expression in both strains ; however , a reduced Vip expression was found in NOD implantation sites . We conclude that the reduced birth rate at 16 - week - old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of P01282 at the sites of implantation , which acts as a local inducer of pro - implantatory P15018 and Treg activation .",
"Rabbit ATG but not horse ATG promotes expansion of functional P01730 + CD25highFOXP3 + regulatory T cells in vitro . Regulatory T cells ( Treg ) play important roles in suppressing immune responses and maintaining tolerance . Rabbit antithymocyte globulin ( DB00098 ) and horse ATG ( hATG ) are widely used in the treatment of immune - mediated syndromes , but their effects on Treg are unknown . We show here that in vitro culture of normal human peripheral blood mononuclear cells ( PBMCs ) with a low - dose DB00098 resulted in marked expansion of functional Treg by converting P01730 + CD25 - T cells to P01730 + CD25 + T cells . hATG did not expand but rather decreased Treg . Immuno - blot showed increased expression of Q9BZS1 and Q13469 in P01730 + CD25 - and P01730 + CD25 + T cells exposed to DB00098 . PBMCs treated with DB00098 displayed increased interleukin - 10 in culture supernatants than those treated with hATG . Furthermore , DB00098 and hATG showed differences in their potential to stimulate P01730 + T cells as examined using different activation markers . Microarray revealed that DB00098 induced markedly different gene - expression patterns in PBMCs , compared with hATG - treated or untreated PBMCs . Our findings indicate that DB00098 expanded Treg , probably through transcriptional regulation by enhanced Q13469 expression , in turn conferring P01730 + CD25 - T cell Q9BZS1 expression and regulatory activity . The therapeutic effects of DB00098 may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function .",
"The effect of rabbit antithymocyte globulin on human DB05914 . Mesenchymal stem cells ( MSCs ) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation . In transplantation , administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials . Therefore , it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation . We aimed to analyze the effect of rabbit antithymocyte globulin ( DB00098 ) MSCs . MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of DB00098 ( DB00098 (®) , Genzyme ; 0 . 5 - 100 μg / ml ) . Binding of DB00098 , effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested . DB00098 binds dose - dependently to MSCs . This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs . In contrast to nontreated MSCs , DB00098 preexposed MSCs were susceptible to be lysed by cytokine - activated CD8 (+) cytotoxic cells and NKT cells . The capacity of MSCs to suppress the proliferation of anti - CD3 / P10747 activated P01730 and CD8 T cells were reduced by the presence of DB00098 in the culture . DB00098 reduces the viability and antiproliferative capacity of MSCs in a dose - dependent manner and converts them into targets for CD8 T cells and NKT cell lysis .",
"___MASK8___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .",
"Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .",
"ATG - induced expression of Q9BZS1 in human P01730 (+) T cells in vitro is associated with T - cell activation and not the induction of Q9BZS1 (+) T regulatory cells . Several recent reports have suggested that in vitro exposure of P01730 (+) T cells to rabbit antithymocyte globulin ( DB00098 ) , which is commonly used to prevent and treat graft - versus - host disease and allograft rejection , is an effective method to induce P01730 (+) CD25 (+) Q9BZS1 (+) T regulatory cells ( Tregs ) . We and others , however , have shown that Q9BZS1 is also expressed in activated T cells . We therefore investigated whether the induction of Q9BZS1 expression by DB00098 resulted in a stable population of suppressive Tregs . We found that exposure of peripheral blood mononuclear cells ( PBMCs ) or conventional T cells to DB00098 resulted in induction of transient rather than stable expression of CD25 and Q9BZS1 . Furthermore , DB00098 - treated T effector cells acquired neither an immunosuppressive profile of cytokine production nor suppressive capacity , even at the time of maximal Q9BZS1 expression . These findings indicate that the notion that DB00098 can be used to induce Tregs in vitro for cellular therapy in vivo should be re - evaluated .",
"Prolonged lymphocyte depletion by single - dose rabbit anti - thymocyte globulin and alemtuzumab in kidney transplantation . Although antibody induction has gained in popularity , two agents are rarely combined . We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody / combination : alemtuzumab ( C1H ) , DB00098 ( DB00098 ) , daclizumab ( Dac ) , DB00098 + C1H , and DB00098 + Dac . P01730 + T - cells were suppressed by C1H and DB00098 + C1H , as well as by DB00098 and DB00098 + Dac but to a lesser extent . The effect lasted for 3 years at around 40 % of baseline values . CD8 + T - cells showed a similar trend but had a more rapid recovery to baseline . P15391 + B - cells were effectively suppressed for 2 months by C1H and DB00098 + C1H , and abruptly returned to baseline afterwards ; suppression by DB00098 ( 7 doses ) was modest but lasted longer . A higher proportion of CD56 + CD16 + Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type . Low CD25 + T - cells by 5 - dose Dac returned to baseline around 6 months , whereas DB00098 + C1H and DB00098 + Dac showed persistent effect . P01730 + CD25hi T - cells were suppressed by both DB00098 + C1H and DB00098 + Dac , but the initial proportion of P01730 + CD25hi T - cells among P01730 + T - cells and P01730 + CD25hi / P01730 + CD25lo ratio were significantly higher in DB00098 + C1H . Overall , with extensive and persistent lymphocyte suppression by a simple administration of agents , single - dose DB00098 + C1H induction can be an alternative in renal transplantation .",
"___MASK61___ improves endothelial function in db / db mice : role of angiotensin II type 1 receptors and oxidative stress . BACKGROUND AND PURPOSE : P04035 inhibitors , statins , with lipid - reducing properties combat against atherosclerosis and diabetes . The favourable modulation of endothelial function may play a significant role in this effect . The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes - associated endothelial dysfunction . EXPERIMENTAL APPROACH : Twelve - week - old db / db diabetic mice were treated with rosuvastatin at 20 mg · kg ⁻ ¹ · day ⁻ ¹ p . o . for 6 weeks . Isometric force was measured in isolated aortae and renal arteries . Protein expressions including angiotensin II type 1 receptor ( AT₁R ) , Q9NPH5 , O75935 ( phox ) , p67 ( phox ) , Rac - 1 , nitrotyrosine , phospho - P27361 / 2 and phospho - p38 were determined by Western blotting , while reactive oxygen species ( ROS ) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay . KEY RESULTS : ___MASK61___ treatment of db / db mice reversed the impaired ACh - induced endothelium - dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db / db mouse renal arteries and aortae . ___MASK61___ reduced the elevated expressions of AT₁R , O75935 ( phox ) and p67 ( phox ) , Q9NPH5 , Rac1 , nitrotyrosine and phosphorylation of P27361 / 2 and p38 MAPK and inhibited ROS production in aortae from db / db mice . CONCLUSIONS AND IMPLICATIONS : The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability , which is probably achieved by its inhibition of ROS production from the AT₁R - NAD ( P ) H oxidase cascade .",
"Selective targeting of the repressive transcription factors P25490 and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 (+) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ). cMyc and P25490 are two transcription factors that are recruited as part of well - described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 , Q92769 , O15379 , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( DB02546 ) enhanced the increase in LTR transcription in cells that were depleted of P25490 . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency ."
] |
[
"___MASK100___",
"___MASK12___",
"___MASK34___",
"___MASK35___",
"___MASK48___",
"___MASK61___",
"___MASK68___",
"___MASK8___",
"___MASK9___"
] |
___MASK100___
|
MH_train_363
|
interacts_with DB04845?
|
[
"P51955 mediates P00352 - dependent drug resistance in multiple myeloma . We reported previously that increased expression of aldehyde dehydrogenase 1 ( P00352 ) in multiple myeloma ( MM ) is a marker of tumor - initiating cells ( TICs ) that is further associated with chromosomal instability ( Q96GD0 ) . Here we demonstrate that member A1 of the P00352 family of proteins , P00352 , is most abundantly expressed in myeloma . Enforced expression of P00352 in myeloma cells led to increased clonogenicity , tumor formation in mice , and resistance to myeloma drugs in vitro and in vivo . The mechanism underlying these phenotypes included the P00352 - dependent activation of drug - efflux pump , P08183 , and survival proteins , AKT and P10415 . Over expression of P00352 in myeloma cells led to increased mRNA and protein levels of NIMA - related kinase 2 ( P51955 ) , whereas shRNA - mediated knock down of P51955 decreased drug efflux pump activity and drug resistance . The activation of P51955 in myeloma cells relied on the P00352 - dependent generation of the retinoid X receptor α ( RXRα ) ligand , 9 - cis retinoic acid ( 9CRA ) - not the retinoic acid receptor α ( RARα ) ligand , all - trans retinoic acid ( ___MASK22___ ) . These findings implicate the P00352 - RXRα - P51955 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of P00352 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma .",
"___MASK75___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .",
"Comparative proteomic analysis of paclitaxel sensitive A2780 epithelial ovarian cancer cell line and its resistant counterpart A2780TC1 by 2D - DIGE : the role of P30101 . Epithelial ovarian cancer is the leading cause of gynecological cancer mortality . Despite good response to surgery and initial chemotherapy , chemoresistance occurrence represents a major obstacle to a successful therapy . To better understand biological mechanisms at the basis of paclitaxel resistance , a comparative proteomic approach based on DIGE coupled with mass spectrometry ( MALDI - TOF and LC - MS / MS ) was applied to the human epithelial ovarian cancer cell lines A2780 and its paclitaxel resistant counterpart A2780TC1 . Most of the differentially expressed proteins between the two cell lines belong to the class of stress response ( 29 % ) , metabolism ( 21 % ) , and cell cycle and apoptosis ( 17 % ) . We focused on proteins which were most strongly modulated by paclitaxel resistance and in particular on the disulphide isomerase P30101 , which may represent a chemoresistance biomarker . P30101 was found to interact with class III beta - tubulin ( Q13509 ) , involved in paclitaxel resistance in ovarian and other cancers . Moreover , we demonstrated a novel localization of this protein in cytoskeleton and described that P30101 / Q13509 interaction occurs also in the nuclear compartment and in association with a multimeric complex formed by nucleolin , nucleophosmin , hnRNPK , and mortalin . Our data suggest that P30101 plays an important role in chemoresistance mechanisms in ovarian cancer by modulating the attachment of microtubules to chromosomes following paclitaxel treatment through its interaction with Q13509 .",
"Lack of expression of Q13509 characterizes both P10415 - positive and P10415 - negative follicular lymphoma . Follicular lymphoma is characterized by aberrant P10415 expression , a feature that is exploited for diagnostic purposes . However , a certain percentage of follicular lymphomas might be P10415 - negative by immunohistochemistry , increasing the difficulties in differentiating them from follicular hyperplasia . The expression of Q13509 has been recently reported as negative in a small series of follicular lymphomas . We have therefore tested a larger series , including 61 P10415 - positive and 25 P10415 - negative cases , and compared them with 61 reactive lymphoid tissues . First , a subjective score of Q13509 staining was applied , showing that it was consistently positive in reactive germinal centers , while most follicular lymphomas were negative ; in fact , only 10 / 61 ( 16 % ) P10415 - positive and 1 / 25 ( 4 % ) P10415 - negative cases showed a positive staining for Q13509 , while 58 / 61 ( 95 % ) of tissues with follicular hyperplasia were positive . The application of a standardized scoring system to a large number of follicles , based on virtual slides , demonstrated that reactive lymphoid tissues had a significantly higher number of Q13509 - positive follicles both compared with P10415 - positive cases and to P10415 - negative cases . Our data support the use of Q13509 staining in differentiating follicular lymphoma , including P10415 - negative cases , from follicular hyperplasia .",
"P11021 / P11021 / P11021 / Dna K is a universal therapeutic target for human disease . The chaperone P11021 / Dna K is conserved throughout evolution down to prokaryotes . The P11021 inhibitor OSU - 03012 ( AR - 12 ) interacted with sildenafil ( Viagra ) or tadalafil ( ___MASK8___ ) to rapidly reduce P11021 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes . Similar data with the drug combination were obtained for : HSP70 , HSP90 , P14625 , P30101 , HSP27 , P25685 and HSP60 . OSU - 03012 / sildenafil treatment killed brain cancer stem cells and decreased the expression of : O15118 and TIM1 ; P11279 ; and NTCP1 , receptors for Ebola / Marburg / Hepatitis A , Lassa fever , and Hepatitis B viruses , respectively . Pre - treatment with OSU - 03012 / sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce . Similar data were obtained using Chikungunya , Mumps , Measles , Rubella , RSV , CMV , and Influenza viruses . OSU - 03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E . coli and clinical isolate multi - drug resistant N . gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Q9UIJ5 A expression . The O76074 inhibitors sildenafil or tadalafil enhanced OSU - 03012 killing in N . gonorrhoeae and MRSE and low marginally toxic doses of OSU - 03012 could restore bacterial sensitivity in N . gonorrhoeae to multiple antibiotics . Thus , Dna K and bacterial phosphodiesterases are novel antibiotic targets , and inhibition of P11021 is of therapeutic utility for cancer and also for bacterial and viral infections .",
"Biomarker analysis of neoadjuvant doxorubicin / cyclophosphamide followed by ixabepilone or Paclitaxel in early - stage breast cancer . PURPOSE : Predictive biomarkers offer the potential to improve the benefit : risk ratio of a therapeutic agent . DB04845 achieves comparable pathologic complete response ( pCR ) rates to other active drugs in the neoadjuvant setting . This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent . EXPERIMENTAL DESIGN : Women with untreated , histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin / cyclophosphamide , followed by 1 : 1 randomization to ixabepilone ( n = 148 ) or paclitaxel ( n = 147 ) . Rates of pCR were compared between treatment arms based on predefined biomarker sets : Q13509 , Q9Y6A5 , and CAPG gene expression , a 20 - and 26 - gene expression model , P08183 protein expression , and other potential markers of sensitivity . βIII - tubulin protein expression is reported separately but is referred to here for completeness . All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy . Gene expression profiling data were used for molecular subtyping . RESULTS : There was no significant difference in the rate of pCR in both treatment arms in βIII - tubulin - positive patients . Higher pCR rates were observed among βIII - tubulin - positive patients than in βIII - tubulin - negative patients . Furthermore , no correlation was evident between Q13509 , Q9Y6A5 , and CAPG gene expression , P08183 protein expression , multi - gene expression models , and the efficacy of ixabepilone or paclitaxel , even within the estrogen receptor - negative subset . CONCLUSION : These results indicate that βIII - tubulin protein and mRNA expression , P08183 protein expression , Q9Y6A5 and CAPG gene expression , and multigene expression models ( 20 - and 26 - gene ) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early - stage breast cancer .",
"DB09130 metabolism and oxidative stress in chronic inflammatory and cholestatic liver diseases in dogs . Inherited defects of copper metabolism resulting in hepatic copper accumulation and oxidative - stress might cause breed - associated forms of hepatitis . Biliary excretion is the major elimination route of copper , therefore increased hepatic copper concentrations could also be caused by cholestasis . The aim of this study was to find criteria to determine whether copper - accumulation is primary or occurs secondary to hepatitis . Liver samples of Bedlington Terriers with copper toxicosis ( CT ) , breeds with non - copper - associated chronic extrahepatic cholestasis ( EC ) or chronic hepatitis ( CH ) , and healthy dogs were used . DB09130 metabolism was analyzed by means of histochemical staining ( copper concentration ) and quantitative reverse transcriptase polymerase chain reaction ( Q - PCR ) on copper excretion / storage ( O00244 , Q14061 , Q04656 , P35670 , CP , P04731 , Q8N668 , P98170 ) . Oxidative stress was measured by determining DB00143 / GSSG ratios and gene - expression ( P00441 , CAT , GSHS , P07203 , O14618 , p27KIP , Bcl - 2 ) . Results revealed 5 + copper in CT , but no or 1 - 2 + copper in EC and CH . Most gene products for copper metabolism remained at concentrations similar to healthy dogs . Three clear exceptions were observed in CT : 3 - fold mRNA increase of Q04656 and P98170 and complete absence of MURRI . The only quantitative differences between the diseased and the control groups were in oxidative stress , evidenced by reductions in all DB00143 / GSSG ratios . We conclude that 3 + or higher histochemical detection of copper indicates a primary copper storage disease . The expression profile of copper - associated genes can be used as a reference for future studies on copper - associated diseases . All 3 diseases have reduced protection against oxidative stress , opening a rationale to use antioxidants as possible therapy .",
"Chronic crude garlic - feeding modified adult male rat testicular markers : mechanisms of action . BACKGROUND : Garlic or Allium sativum ( As ) shows therapeutic effects such as reduction of blood pressure or hypercholesterolemia but side - effects on reproductive functions remain poorly investigated . Because of garlic ' s chemical complexity , the processing methods and yield in preparations differ in efficacy and safety . In this context , we clarify the mechanisms of action of crushed crude garlic on testicular markers . METHODS : During one month of treatment , 24 male rats were fed 5 % , 10 % and 15 % crude garlic . RESULTS : We showed that crude garlic - feeding induced apoptosis in testicular germ cells ( spermatocytes and spermatids ) . This cell death process was characterized by increased levels of active P42574 but not P55212 . Expression of the caspase inhibitors Q13489 and Q13490 was increased at all doses of As while expression of P98170 and O15392 was unchanged . Moreover , expression of the IAP inhibitor Q9NR28 was increased at doses 10 % and 15 % of As . The germ cell death process induced by As might be related to a decrease in testosterone production because of the reduced expression of steroidogenic enzymes ( Star , Cyp11a , Hsd3b5 and Hsd17b ) . Evaluation of Sertoli markers showed that Q13509 and P09210 expression was unchanged . In contrast , P03971 , RHOX5 and P46527 expression was decreased while P43694 expression was increased . CONCLUSION : In summary , we showed that feeding with crude garlic inhibited Leydig steroidogenic enzyme expression and Sertoli cell markers . These alterations might induce apoptosis in testicular germ cells .",
"Cloning of chick cellular retinol - binding protein , type II and comparison to that of some mammals : expression of the gene at different developmental stages , and possible involvement of RXRs and Q07869 . We cloned chick cellular retinol - binding protein , type two ( P09455 II ) cDNA and compared it with those of some mammals . The deduced amino acid sequence showed that chick P09455 II was one amino acid greater in size than those of mammals , and the nucleotide sequence of chick P09455 II shared 72 % - 75 % similarity with those of mammals . RNA blot hybridization analysis showed that P09455 II transcript of 0 . 7 kb was first detected in the duodenum of day - 18 embryonic chick , and exhibited a rapid increase during 24 hr around the hatching . Northern blot hybridization also revealed that the transcripts of two types of retinoid X receptors ( RXR alpha and RXR gamma ) and peroxisome proliferator - activated receptor ( Q07869 ) were expressed in the chick duodenum at hatching . The organ culture of day 16 embryonic chick duodenum showed that the addition of 9 - cis retinoic acid in the medium caused a significant increase in P09455 II mRNA levels . In addition , arachidonic acid , from which putative ligands for Q07869 were supposed to be generated , was accumulated around hatching in the duodenum . The results may suggest that the abrupt increase of the P09455 II gene expression in the chick duodenum around hatching may be related with RXRs and / or Q07869 .",
"OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood - Brain Barrier : Implications for Anti - Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose - regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . ___MASK10___ ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem - like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP70 and HSP90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF2α - P18848 - P35638 signaling and was blocked by P11021 over - expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over - expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK55___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Microdeletions involving chromosomes 12 and 22 associated with syndromic Duane retraction syndrome . BACKGROUND : Duane retraction syndrome ( Q9H307 ) is the most common of the congenital cranial dysinnervation disorders ( CCDDs ) . CCDDs can be monogenic or chromosomal in origin . Identification of the genetic cause ( s ) in patients and families with Q9H307 facilitates definitive diagnosis and provides insights into these developmental errors . MATERIALS AND METHODS : This study described a young girl with Q9H307 on the left and several additional developmental abnormalities . Clinical examination including neuroimaging , sequencing of candidate genes associated with Q9H307 , and array comparative genomic hybridization ( array CGH ) were performed . RESULTS : The proband had unilateral Q9H307 type 3 on the left with somewhat low - set ears , mild motor delay with normal intelligence , and an asymmetric neck without a palpable right sternocleidomastoid muscle . Spine X - rays revealed a Klippel - Feil syndrome ( KFS ) and an Q9BWK5 showed a webbed neck . She also had spina bifida at Q99618 - T1 and a submucosal cleft palate . The parents of the proband were related with no other family member affected similarly . Sequencing of Q9UJQ4 , P15882 , P49639 , and Q13509 did not show any mutation . Array CGH revealed de novo deletions of 21 Kb on chromosome 12q24 . 31 and 11 Kb on chromosome 22q13 . 31 , each encompassing only one gene , ring finger protein 34 , E3 ubiquitin protein ligase ( Q969K3 ) and peroxisome proliferator - activated receptor alpha ( Q07869 ) respectively . CONCLUSIONS : This patient presents an unusual phenotype associated with a unique combination of two chromosomal microdeletions .",
"___MASK99___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK99___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK99___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK99___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK99___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"Individualized treatment of NSCLC : from research to clinical practice . The exact clinical significance of P00533 mutation status in NSCLC at the time of initial diagnosis remains disputable . The gene expression module in NSCLC for chemotherapy outcome prediction needs to be developed . We analyzed 56 patients with NSCLC received chemotherapy either with ( n = 20 ) or without P00533 - TKIs ( n = 36 ) between 2008 and 2012 in China . P00533 mutation test and gene expression profiling were performed in samples obtained before medication treatment by liquidchip platform . Significant association ( P = 0 . 028 ) was seen between P00533 mutation status before first - line chemotherapy and P00533 - TKIs treatment outcomes , which even can be found from the status before second - or third - line treatment . A14 - gene expression profiling had been studied . Patients with low mRNA expression of P07992 or P04818 preferred higher DCR to cisplatin and pemetrexed than those with high expression ( P = 0 . 39 and P = 0 . 11 ) . Highly co - expression of Q13509 and P16949 gene has associated with the resistance to antimicrotubule drugs ( P = 0 . 03 ) . Our data suggest the P00533 mutations status , even at the time of initial diagnosis , is predictive of outcomes of TKIs treatment after chemotherapy . The mRNA expression profiling investigated in this study has a predictive value in NSCLC treatment , but further research with expanded samples is still required .",
"Immunohistochemical study of P04626 and Q13509 proteins in extramammary Paget disease . Metastatic extramammary Paget disease ( EMPD ) is a potentially fatal malignancy for which effective chemotherapy and good biomarkers are desirable for management . We investigated the status of human epidermal growth factor receptor ( P04626 ) and neuronal β - tubulin isotype ( class III β - tubulin ; Q13509 ) , whose overexpression is a factor involved in resistance of tumor cells to taxane derivatives ) in 32 patients with EMPD . P04626 status was evaluated by immunohistochemistry followed by fluorescence in situ hybridization , and Q13509 status was evaluated by immunohistochemistry . On the basis of the US Food and Drug Administration - approved criteria , 20 ( 63 % ) of the 32 EMPD tumors were found to overexpress P04626 . Positive immunoreactivity for Q13509 was observed in 7 ( 22 % ) of the 32 patients . Although some clinicopathologic variables ( nodule formation , depth of tumor cells , presence of lymph node metastasis , and serum carcinoembryonic antigen level ) were significantly associated with disease outcome ( P < 0 . 05 ) , P04626 gain or aberrant Q13509 expression showed no significant correlation . However , the higher incidence of P04626 gain and the relatively lower incidence of aberrant Q13509 expression suggested that P04626 - targeted immunotherapy combined with taxane derivatives is warranted for metastatic EMPD , and that P04626 and Q13509 status might be a good biomarker for determining the most appropriate therapeutic modality .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK51___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK51___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK51___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK51___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK51___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK51___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK51___ .",
"Global transcriptome analysis of formalin - fixed prostate cancer specimens identifies biomarkers of disease recurrence . Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease . In an effort to identify biomarkers of recurrence , we performed global RNA sequencing on 106 formalin - fixed , paraffin - embedded prostatectomy samples from 100 patients at three independent sites , defining a 24 - gene signature panel . The 24 genes in this panel function in cell - cycle progression , angiogenesis , hypoxia , apoptosis , PI3K signaling , steroid metabolism , translation , chromatin modification , and transcription . Sixteen genes have been associated with cancer , with five specifically associated with prostate cancer ( P78543 , P17936 , Q96EB6 , P50539 , and P14324 ) . Validation was performed on an independent publicly available dataset of 140 patients , where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence . Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors , including several genes involved in the epithelial - to - mesenchymal transition and developmental pathways . Overall , this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer .",
"___MASK86___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK86___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK91___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance ."
] |
[
"___MASK10___",
"___MASK22___",
"___MASK51___",
"___MASK55___",
"___MASK75___",
"___MASK86___",
"___MASK8___",
"___MASK91___",
"___MASK99___"
] |
___MASK86___
|
MH_train_364
|
interacts_with DB09074?
|
[
"Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .",
"PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma . BACKGROUND : Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma ( GBM ) . We show that targeting PARP by the small molecule inhibitors , DB09074 ( AZD - 2281 ) or PJ34 , reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo . METHODS : The sensitizing effects of PARP inhibition on P50591 - mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines , low - passage neurospheres and astrocytes in vitro . Molecular analyses included western blots and gene silencing . In vivo , effects on tumor growth were examined in a murine subcutaneous xenograft model . RESULTS : The combination treatment of PARP inhibitors and P50591 led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single - agent treatment . Mechanistically , pharmacological PARP inhibition elicited a nuclear stress response with up - regulation of down - stream DNA - stress response proteins , e . g . , CCAAT enhancer binding protein ( C / EBP ) homology protein ( P35638 ) . Furthermore , DB09074 and PJ34 increased protein levels of DR5 in a concentration and time - dependent manner . In turn , siRNA - mediated suppression of DR5 mitigated the effects of P50591 / PARP inhibitor - mediated apoptosis . In addition , suppression of P09874 levels enhanced P50591 - mediated apoptosis in malignant glioma cells . Treatment of human astrocytes with the combination of P50591 / PARP inhibitors did not cause toxicity . Finally , the combination treatment of P50591 and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone . CONCLUSIONS : PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Comparative antiproliferative effects of iniparib and olaparib on a panel of triple - negative and non - triple - negative breast cancer cell lines . PARP inhibitors , both as monotherapy and in combination with cytotoxic drugs , are currently undergoing clinical trials in several different cancer types . In this investigation , we compared the antiproliferative activity of two PARP / putative PARP inhibitors , i . e . , olaparib and iniparib , in a panel of 14 breast cancer cell lines ( seven tripe - negative and seven non - triple - negative ) . In almost all cell lines investigated , olaparib was a more potent inhibitor of cell growth than iniparib . Inhibition by both drugs was cell line - dependent and independent of the molecular subtype status of the cells , i . e . , whether cells were triple - negative or non - triple negative . Although the primary target of PARP inhibitors is P09874 , no significant association was found between baseline levels of P09874 activity and inhibition with either agent . Similarly , no significant correlation was evident between sensitivity and levels of P06493 , P38398 or miR - 182 . Combined addition of olaparib and either the P06493 inhibitor , RO - 3306 or a pan HER inhibitor ( neratinib , afatinib ) resulted in superior growth inhibition to that obtained with olaparib alone . We conclude that olaparib , in contrast to iniparib , is a strong inhibitor of breast cancer cell growth and may have efficacy in breast cancer irrespective of its molecular subtype , i . e . , whether P04626 - positive , estrogen receptor ( ER ) - positive or triple - negative . DB09074 , in combination with a selective P06493 inhibitor or a pan HER inhibitor , is a potential new approach for treating breast cancer .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK74___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK74___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK74___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK74___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK74___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK74___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK74___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK74___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK74___ in the treatment of changes in hypervigilance following severe stress .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK46___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK51___ ( ___MASK51___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK51___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK51___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK56___ ) in castrated male and female mice subjected to ___MASK56___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK56___ in mice CPs .",
"PARP inhibition sensitizes childhood high grade glioma , medulloblastoma and ependymoma to radiation . Poly ADP - ribose polymerase ( PARP ) is a protein involved in single strand break repair . Recently , PARP inhibitors have shown considerable promise in the treatment of several cancers , both in monotherapy and in combination with cytotoxic agents . Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways . In addition , PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents , including radiotherapy . Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor DB09074 in childhood medulloblastoma , ependymoma and high grade glioma ( HGG ) . Increased P09874 expression was observed in medulloblastoma , ependymoma and HGG , as compared to non - neoplastic brain tissue . Pediatric high grade glioma , medulloblastoma and ependymoma gene expression profiling revealed that high P09874 expression is associated with poor prognosis . Cell growth inhibition assays with DB09074 resulted in differential sensitivity , with IC50 values ranging from 1 . 4 to 8 . 4 µM , irrespective of tumor type and P09874 protein expression . Sensitization to radiation was observed in medulloblastoma , ependymoma and HGG cell lines with subcytotoxic concentrations of DB09074 , which coincided with persistence of double strand breaks . Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome .",
"Differential effects of poly ( ADP - ribose ) polymerase inhibition on DNA break repair in human cells are revealed with Epstein - Barr virus . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors can generate synthetic lethality in cancer cells defective in homologous recombination . However , the mechanism ( s ) by which they affect DNA repair has not been established . Here we directly determined the effects of PARP inhibition and P09874 depletion on the repair of ionizing radiation - induced single - and double - strand breaks ( SSBs and DSBs ) in human lymphoid cell lines . To do this , we developed an in vivo repair assay based on large endogenous Epstein - Barr virus ( EBV ) circular episomes . The EBV break assay provides the opportunity to assess quantitatively and simultaneously the induction and repair of SSBs and DSBs in human cells . Repair was efficient in P55008 and G2 cells and was not dependent on functional p53 . shRNA - mediated knockdown of P09874 demonstrated that the P09874 protein was not essential for P05455 repair . Among 10 widely used PARP inhibitors , none affected DSB repair , although an inhibitor of DNA - dependent protein kinase was highly effective at reducing DSB repair . Only DB09074 and Iniparib , which are in clinical cancer therapy trials , as well as 4 - AN inhibited P05455 repair . However , a decrease in P09874 expression reversed the ability of Iniparib to reduce P05455 repair . Because Iniparib disrupts P09874 - DNA binding , the mechanism of inhibition does not appear to involve trapping PARP at SSBs .",
"Poly ( ADP - ribose ) binds to specific domains in DNA damage checkpoint proteins . Poly ( ADP - ribose ) is formed in possibly all multicellular organisms by a familiy of poly ( ADP - ribose ) polymerases ( PARPs ) . P09874 , the best understood and until recently the only known member of this family , is a DNA damage signal protein catalyzing its automodification with multiple , variably sized ADP - ribose polymers that may contain up to 200 residues and several branching points . Through these polymers , P09874 can interact noncovalently with other proteins and alter their functions . Here we report the discovery of a poly ( ADP - ribose )- binding sequence motif in several important DNA damage checkpoint proteins . The 20 - amino acid motif contains two conserved regions : ( i ) a cluster rich in basic amino acids and ( ii ) a pattern of hydrophobic amino acids interspersed with basic residues . Using a combination of alanine scanning , polymer blot analysis , and photoaffinity labeling , we have identified poly ( ADP - ribose )- binding sites in the following proteins : p53 , P38936 ( CIP1 / P38936 ) , xeroderma pigmentosum group A complementing protein , P52701 , P49916 , P18887 , DNA polymerase epsilon , DNA - PK ( CS ) , P12956 , NF - kappaB , inducible nitric - oxide synthase , caspase - activated DNase , and telomerase . The poly ( ADP - ribose )- binding motif was found to overlap with five important functional domains responsible for ( i ) protein - protein interactions , ( ii ) DNA binding , ( iii ) nuclear localization , ( iv ) nuclear export , and ( v ) protein degradation . Thus , PARPs may target specific signal network proteins via poly ( ADP - ribose ) and regulate their domain functions .",
"A Phase I , dose - finding and pharmacokinetic study of olaparib ( AZD2281 ) in Japanese patients with advanced solid tumors . DB09074 ( AZD2281 ) is an orally active Poly ( ADP - ribose ) polymerase ( PARP ) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with P38398 / 2 mutations in Western ( USA and European ) studies . This Phase I dose - finding study evaluated the tolerability , pharmacokinetics , PARP inhibitory activity , and antitumor activity of olaparib in Japanese patients with solid tumors . DB09074 was administered as a single - dose on day 1 , followed by twice - daily dosing for 28 days from 48 h after a single dose . Doses were escalated from 100 mg b . i . d . in successive cohorts , up to a maximum of 400 mg b . i . d . The present study enrolled 12 patients ( n = 3 , 3 , and 6 in 100 , 200 and 400 - mg b . i . d . levels , respectively ) . The most common adverse events were nausea , increased blood creatinine , decreased hematocrit , leukopenia and lymphopenia ; dose - limiting toxicities were not observed up to and including the 400 - mg b . i . d . dose level . Following twice - daily dosing , olaparib showed no marked increase in exposure at steady state over that expected from the single - dose pharmacokinetics . P09874 inhibition was observed from the 100 - mg b . i . d . dose level in peripheral blood mononuclear cells from 6 h post - dose on day 1 during the multiple - dosing period . A patient with metastatic breast cancer ( 100 mg b . i . d . ) had a partial response for 13 months and four patients ( two each in the 200 and 400 - mg b . i . d . levels ) had stable disease > 8 weeks . DB09074 was well tolerated up to the 400 - mg b . i . d . dose in Japanese patients with solid tumors . Preliminary evidence of antitumor activity was observed .",
"Inhibition of P09874 - dependent end - joining contributes to DB09074 - mediated radiosensitization in tumor cells . Poly - ADP - ribose - polymerase inhibitors ( PARPi ) are considered to be optimal tools for specifically enhancing radiosensitivity . This effect has been shown to be replication - dependent and more profound in HR - deficient tumors . Here , we present a new mode of PARPi - mediated radiosensitization which was observed in four out of six HR - proficient tumor cell lines ( responders ) investigated , but not in normal cells . This effect is replication - independent , as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin . We showed that responders are radiosensitized by DB09074 because their DSB - repair is switched to P09874 - dependent end - joining ( P09874 - EJ ) , as evident by ( i ) the significant increase in the number of residual γ P16104 foci following irradiation with 3Gy and treatment with DB09074 , ( ii ) the enhanced enrichment of P09874 at the chromatin after 3Gy and ( iii ) the inhibition of end - joining activity measured by a specific reporter substrate upon DB09074 treatment . This is the first study which directly demonstrates the switch to P09874 - EJ in tumor cells and its contribution to the response to DB09074 as a radiosensitizer , findings which could widen the scope of application of PARPi in tumor therapy .",
"7 - Azaindole - 1 - carboxamides as a new class of P09874 inhibitors . 7 - Azaindole - 1 - carboxamides were designed as a new class of P09874 inhibitors . The compounds displayed a variable pattern of target inhibition profile that , in part , paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects . A selected compound ( 1l ; ST7710AA1 ) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp . In antitumor activity studies against the P20591 human breast carcinoma growth in nude mice , the compound exhibited an effect similar to that of DB09074 in terms of tumor volume inhibition when used at a lower dose than the reference compound . Treatment was well tolerated , as no deaths or significant weight losses were observed among the treated animals .",
"Prepubertal octylphenol exposure up - regulate P38398 expression , down - regulate ERalpha expression and reduce rat mammary tumorigenesis . BACKGROUND : Endogenous estrogens play an important role in the development of breast cancer . Octylphenol ( OP ) and genistein ( GEN ) are estrogen - like chemicals . Prepubertal estradiol and genistein exposure can up - regulate P38398 mRNA in mammary gland and reduce futuer breast cancer risk . In the present study , the effects of prepubertal exposure to high - dose OP and GEN on mammary carcinogenesis and the association with the expression of P38398 and ERalpha were investigated . METHODS : Prepubertal female Sprague - Dawley rats were exposed to 20 , 40 , 80mg / kg OP daily from postnatal day ( P01160 ) 22 - 28 , subsequently , the rats were given a single dose of 100mg / kg 7 , 12 - dimethylbenz [ a ] anthracene ( DMBA ) on PND42 to induce mammary tumor . RESULTS : The incidence of DMBA - induced mammary tumors significantly decreased when rats were treated with 40mg / kg OP . P38398 mRNA and protein expression were found up - regulated and ERalpha expression was down - regulated in the mammary tumor when rats were exposed to 40mg / kg octylphenol . CONCLUSION : Exposure 40mg / kg octylphenol can reduce later breast cancer risk in prepubertal Sprague - Dawley rats , the protective effect of OP is associated with persistent up - regulation of P38398 and down - regulation of ERalpha in the mammary tumor .",
"P10275 controls P00533 and P04626 gene expression at different levels in prostate cancer cell lines . P00533 or P04626 contributes to prostate cancer ( PCa ) progression by activating the androgen receptor ( AR ) in hormone - poor conditions . Here , we investigated the mechanisms by which androgens regulate P00533 and P04626 expression in PCa cells . In steroid - depleted medium ( SDM ) , P00533 protein was less abundant in androgen - sensitive LNCaP than in androgen ablation - resistant 22Rv1 cells , whereas transcript levels were similar . ___MASK56___ ( ___MASK56___ ) treatment increased both P00533 mRNA and protein levels and stimulated RNA polymerase II recruitment to the P00533 gene promoter , whereas it decreased P04626 transcript and protein levels in LNCaP cells . ___MASK56___ altered neither P00533 or P04626 levels nor the abundance of prostate - specific antigen ( PSA ) , TMEPA1 , or O15393 mRNAs in 22Rv1 cells , which express the full - length and a shorter AR isoform deleted from the COOH - terminal domain ( ARDeltaCTD ) . The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full - length or both AR isoforms . Silencing of both isoforms strongly reduced PSA , TMEPA1 , and O15393 transcript levels . Inhibition of both AR isoforms did not affect P00533 and P04626 transcript levels but decreased P00533 and increased P04626 protein levels . Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARDeltaCTD . A further decrease was obtained with PKI166 , an P00533 / P04626 kinase inhibitor . Overall , we showed that ARDeltaCTD is responsible for constitutive P00533 expression and P04626 repression in 22Rv1 cells and that ARDeltaCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth .",
"7 , 12 - Dimethylbenz [ a ] anthracene exposure induces the DNA repair response in neonatal rat ovaries . 7 , 12 - Dimethylbenz [ a ] anthracene ( DMBA ) destroys ovarian follicles at all stages of development . This study investigated DMBA - induced DNA double strand break ( DSB ) formation with subsequent activation of the ovarian DNA repair response in models of pre - antral or pre - ovulatory follicle loss . Postnatal day ( P01160 ) 4 Fisher 344 ( F344 ) rat ovaries were cultured for 4 days followed by single exposures of vehicle control ( 1 % DB01093 ) or DMBA ( 12 . 5 nM or 75 nM ) and maintained in culture for 4 or 8 days . Alternately , PND4 F344 rat ovaries were exposed to 1 μM DMBA at the start of culture for 2 days . Total RNA or protein was isolated , followed by qPCR or Western blotting to quantify mRNA or protein level , respectively . γ P16104 and phosphorylated Q13315 were localized and quantified using immunofluorescence staining . DMBA exposure increased caspase 3 and γ P16104 protein . Additionally , DMBA ( 12 . 5 nM and 1 μM ) increased levels of mRNA encoding Atm , Xrcc6 , Brca1 and Rad51 . In contrast , Parp1 mRNA was decreased on d4 and increased on d8 of DMBA exposure , while P09874 protein increased after 8 days of DMBA exposure . Total Q13315 increased in a concentration - dependent temporal pattern ( 75 nM d4 ; 12 . 5 nM d8 ) , while pATM was localized in large primary and secondary follicles and increased after 8 days of 75 nM DMBA exposure compared to both control and 12 . 5 nM DMBA . These findings support that , despite some concentration effects , DMBA induces ovarian DNA damage and that DNA repair mechanisms are induced as a potential mechanism to prevent follicle loss .",
"[ Moclobemide ( ___MASK11___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Effect of interferon - gamma and P01375 on P15941 mucin expression in ovarian carcinoma cell lines . In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment , a study was designed to investigate whether the biological response modifiers interferon - gamma ( P01579 ) and tumour necrosis factor - alpha ( P01375 ) could effect the expression of an epitope on the tumour associated P15941 epithelial mucin . Four ovarian carcinoma cell lines showing high ( OAW42 and GG ) and low ( JAM and PE01 ) basal expression of P15941 were treated with 10 - 1000 U / mL of P01579 or P01375 for one or five days . Changes in P15941 expression in cells exposed to P01579 or P01375 were monitored using an ELISA technique with the monoclonal antibody O43633 which reacts with a core protein epitope on the P15941 mucin , and then corrected for the number of viable cells present . P01375 had little effect on P15941 expression , but one or five days exposure to P01579 significantly increased P15941 expression ( p < 0 . 01 ) in all cell lines including the two cell lines that initially showed little or no expression .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .",
"Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK100___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK100___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"___MASK51___ shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the Q9UBN7 - Hsp90 chaperone axis . Mutant p53 ( mutp53 ) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival , identifying mutp53 as a potentially significant clinical target . However , exploration of effective small molecule therapies targeting mutp53 has barely begun . Mutp53 hyperstabilization , a hallmark of p53 mutation , is cancer cell - specific and due to massive upregulation of the HSP90 chaperone machinery during malignant transformation . We recently showed that stable complex formation between HSP90 and its mutp53 client inhibits E3 ligases Q00987 and Q9UNE7 , causing mutp53 stabilization . Histone deacetylase ( HDAC ) inhibitors ( HDACi ) are a new class of promising anti - cancer drugs , hyperacetylating histone and non - histone targets . Currently , suberoylanilide hydroxamic acid ( ___MASK51___ ) is the only FDA - approved HDACi . We show that ___MASK51___ exhibits preferential cytotoxicity for mutant , rather than wild - type and null p53 human cancer cells . Loss / gain - of - function experiments revealed that although able to exert multiple cellular effects , ___MASK51___ ' s cytotoxicity is caused to a significant degree by its ability to strongly destabilize mutp53 at the level of protein degradation . The underlying mechanism is ___MASK51___ ' s inhibition of Q9UBN7 , an essential positive regulator of HSP90 . This releases mutp53 and enables its Q00987 - and Q9UNE7 - mediated degradation . ___MASK51___ also strongly chemosensitizes mutp53 cancer cells for chemotherapy due to its ability to degrade mutp53 . This identifies a novel action of ___MASK51___ with the prospect of ___MASK51___ becoming a centerpiece in mutp53 - specific anticancer strategies .",
"An improved effect size for single - case research : nonoverlap of all pairs . Nonoverlap of All Pairs ( Q8WYA6 ) , an index of data overlap between phases in single - case research , is demonstrated and field tested with 200 published AB contrasts . Q8WYA6 is a novel application of an established effect size known in various forms as Area Under the Curve ( AUC ) , the Common Language Effect Size ( CL ) , the Probability of Superiority ( PS ) , the Dominance Statistic ( DS ) , Mann - Whitney ' s U , and Sommers D , among others . Q8WYA6 was compared with 3 other non - overlap - based indices : P01160 ( percent of nonoverlapping data ) , P15941 ( percent of data points exceeding the median ) , and PAND ( percent of all nonoverlapping data ) , as well as Pearson ' s R ( 2 ) . Five questions were addressed about Q8WYA6 : ( a ) typical Q8WYA6 values , ( b ) its ability to discriminate among typical single - case research results , ( c ) its power and precision ( confidence interval width ) , ( d ) its correlation with the established effect size index , R ( 2 ) , and ( e ) its relationship with visual judgments . Results were positive , the new index equaling or outperforming the other overlap indices on most criteria .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometrium . This study investigated the hypothesis that different types of recurrent miscarriage history are associated with different markers of endometrial receptivity . A secondary objective was to compare the distribution in endometrial epithelium of a group of cell surface components with roles in cell adhesion . Of 54 women who had an implantation window endometrial biopsy , 17 had idiopathic recurrent fetal loss , 17 had idiopathic recurrent loss of empty gestation sacs , 10 had recurrent implantation failure and 10 had two or more normal pregnancies . Immunohistochemistry and HSCORE was used with frozen sections for integrins ( alpha1beta1 , alpha4beta1 , alpha ( v ) beta3 ) , and P15941 ( O43633 ) and paraffin sections for osteopontin and P15941 ( BC3 ) . Epithelial beta1 integrins were located primarily in the basolateral membrane compartment . Consistently greater expression of alpha4beta1 , alpha1beta1 and alpha ( v ) beta3 was seen in the luminal epithelium and greater expression of alpha4beta1 and alpha1beta1 in the glandular epithelium of women with recurrent fetal loss when compared with those with recurrent loss of empty gestation sacs . There were no significant differences in the expression of osteopontin or P15941 between groups . Different endometrial integrin distribution was found in women suffering different types of recurrent pregnancy loss . It is postulated that impairment of the implantation barrier contributes to recurrent fetal loss .",
"P10275 expression in breast cancer patients tested for P38398 and P51587 mutations . AIM : To assess the expression of receptors for androgen ( AR ) , oestrogen ( ER ) and progesterone ( PR ) as well as human epidermal growth factor receptor type 2 ( Her - 2 / neu ) status of breast carcinomas in breast cancer susceptibility gene ( BRCA ) P38398 / 2 mutation carriers and P38398 / 2 negative tested women . METHODS : One hundred and thirty - five breast cancers in women tested for P38398 / 2 mutations . Screening for P38398 and P51587 mutations was performed by direct sequencing of all P38398 and P51587 exons as well as the surrounding intronic sequences . Additionally , BRCA genes were analysed with multiplex ligation - dependent probe amplification . Consecutive paraffin sections were examined immunohistochemically for AR , ER , PR and Her - 2 / neu . RESULTS : Of the 135 tumours , 43 ( 32 % ) were P38398 - related , 18 ( 13 % ) were P51587 - related and 74 ( 55 % ) were P38398 / 2 - negative . Seventy - two per cent of the P38398 - related , 22 % of the P51587 - related and 12 % of the P38398 / 2 - negative tumours were triple ( ER , PR , Her2neu ) - negative . Eighty - four per cent of P38398 mutated cancers were high - grade ( P46379 ) tumours . ARs were expressed in 30 % ( 13 of 43 ) of P38398 - related , in 78 % ( 14 of 18 ) in P51587 - related tumours and in 76 % ( 56 of 74 ) in P38398 / 2 negative tumours . Twenty - one per cent of ER - negative P38398 - related tumours expressed androgen receptors . CONCLUSION : Approximately one in five P38398 mutated breast cancers negative for ER and PR express androgen receptors . Modulation of AR might open a new avenue for treating these high - risk cancers .",
"P10275 accelerates premature senescence of human dermal papilla cells in association with DNA damage . The dermal papilla , located in the hair follicle , expresses androgen receptor and plays an important role in hair growth . Androgen / P10275 actions have been implicated in the pathogenesis of androgenetic alopecia , but the exact mechanism is not well known . Recent studies suggest that balding dermal papilla cells exhibit premature senescence , upregulation of p16 ( INK4a ) , and nuclear expression of DNA damage markers . To investigate whether androgen / AR signaling influences the premature senescence of dermal papilla cells , we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients . Exposure of androgen induced premature senescence in dermal papilla cells from non - balding frontal and transitional zone of balding scalp follicles but not in beard follicles . Overexpression of the AR promoted androgen - induced premature senescence in association with p16 ( INK4a ) upregulation , whereas knockdown of the androgen receptor diminished the effects of androgen . An analysis of γ - P16104 expression in response to androgen / androgen receptor signaling suggested that DNA damage contributes to androgen / androgen receptor - accelerated premature senescence . These results define androgen / androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen / androgen receptor - mediated DNA damage - p16 ( INK4a ) axis is a potential therapeutic target in the treatment of androgenetic alopecia .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK12___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK12___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2 / M arrest and γ - P16104 foci formation in colorectal cancer . BACKGROUND : Poly ( ADP - ribose ) polymerase 1 ( P09874 ) has an important role in homologous recombination repair . The purpose of this study was to investigate the effect of P09874 inhibitor on oxaliplatin treatment for colorectal cancer ( CRC ) . METHODS : A cell counting kit - 8 assay was used to determine the sensitivity of CRC cells to olaparib and / or oxaliplatin . The gene and protein expressions of P09874 and the gamma histone variant P16104 ( γ P16104 ) were measured by real - time quantitative polymerase chain reaction and western blotting , respectively . The γ P16104 foci formation assay was used to investigate the influence of treatments on cells . Flow cytometry was used to examine the changes in cell cycle distribution . Finally , we investigated the combination of olaparib and oxaliplatin in the CRC tumor model . RESULTS : DB09074 changed the expression of γ P16104 and P09874 , and increased the sensitivity of CRC cells to oxaliplatin . The γ P16104 foci assay showed that olaparib did not induce double - strand breaks ( DSBs ) alone , but it enhanced the induction of DSBs by oxaliplatin . The flow cytometry results showed that cells exposed to combination treatment had more G2 / M - phase cells than control . Additionally , tumor xenograft studies suggested that combined treatment inhibited the growth of CRC . CONCLUSION : CRC cells are sensitized to combined treatment with olaparib and oxaliplatin , and this could be a promising strategy for clinical chemotherapy in CRC .",
"Reactive oxygen species - dependent P01375 converting enzyme activation through stimulation of P41595 and alpha1D autoreceptors in neuronal cells . A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non - neuronal factors . By taking advantage of a neuroectodermal cell line ( 1C11 ) endowed with the capacity to differentiate into serotonergic ( 1C115 - HT ) or noradrenergic ( 1C11NE ) neurons , we identified serotonin ( 5 - hydroxytryptamine , 5 - HT ) - and norepinephrine ( NE ) - dependent signaling cascades possibly involved in neuronal functions . First , we establish that P41595 receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species ( ROS ) synthesis through NADPH oxidase activation in 1C115 - HT and 1C11NE cells . This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context . Second , our data identify P78536 ( P01375 - Converting Enzyme ) , a member of a disintegrin and metalloproteinase ( ADAM ) family , as a downstream target of the P41595 and 1D receptor - NADPH oxidase signaling pathways . Upon P41595 or 1D receptor stimulation , ROS fully govern P01375 - shedding in the surrounding milieu of 1C115 - HT or 1C11NE cells . Third , P41595 and 1Dreceptor couplings to the NADPH oxidase - P78536 cascade are strictly restricted to 1C11 - derived progenies that have implemented a complete serotonergic or noradrenergic phenotype . Overall , these observations suggest that P41595 and 1D autoreceptors may play a role in the maintenance of neuron - and neurotransmitter - associated functions . Eventually , our study may have implications regarding the origin of oxidative stress as well as up - regulated expression of proinflammatory cytokines in neurodegenerative disorders , which may relate to the deviation of normal signaling pathways .",
"Chronic myeloid leukemic cells trigger poly ( ADP - ribose ) polymerase - dependent inactivation and cell death in lymphocytes . NK cells and T cells are commonly dysfunctional in CML , and their status may determine the course of disease . We aimed to define the molecular mechanisms of leukemia - induced immunosuppression with focus on the role of ROS and the P09874 pathway of cell death . Malignant granulocytes from patients with P11274 - P00519 - positive CML expressed the oxygen radical - producing enzyme NOX , produced large amounts of ROS , and triggered extensive cell death in NK cells . Inhibition of P09874 maintained NK cell viability in cocultures with suppressive leukemic cells . Under conditions of oxidative stress , P09874 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells , in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells . Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Bcr / Abl interferes with the Fanconi anemia / BRCA pathway : implications in the chromosomal instability of chronic myeloid leukemia cells . Chronic myeloid leukemia ( CML ) is a malignant clonal disorder of the hematopoietic system caused by the expression of the P11274 / P00519 fusion oncogene . Although it is well known that CML cells are genetically unstable , the mechanisms accounting for this genomic instability are still poorly understood . Because the Fanconi anemia ( FA ) pathway is believed to control several mechanisms of DNA repair , we investigated whether this pathway was disrupted in CML cells . Our data show that CML cells have a defective capacity to generate Q9BXW9 nuclear foci , either in dividing cells or after DNA damage . Similarly , human cord blood P28906 (+) cells transduced with P11274 / P00519 retroviral vectors showed impaired Q9BXW9 foci formation , whereas Q9BXW9 monoubiquitination in these cells was unaffected . Soon after the transduction of P28906 (+) cells with P11274 / P00519 retroviral vectors a high proportion of cells with supernumerary centrosomes was observed . Similarly , P11274 / P00519 induced a high proportion of chromosomal abnormalities , while mediated a cell survival advantage after exposure to DNA cross - linking agents . Significantly , both the impaired formation of Q9BXW9 nuclear foci , and also the predisposition of P11274 / P00519 cells to develop centrosomal and chromosomal aberrations were reverted by the ectopic expression of P38398 . Taken together , our data show for the first time a disruption of the FA / BRCA pathway in P11274 / P00519 cells , suggesting that this defective pathway should play an important role in the genomic instability of CML by the co - occurrence of centrosomal amplification and DNA repair deficiencies .",
"Development and validation of a high - performance liquid chromatography - tandem mass spectrometry assay quantifying olaparib in human plasma . DB09074 is an inhibitor of poly ADP ribose polymerase 1 ( P09874 ) . Phase I and II trials showed promising results of olaparib against tumours in BRCA mutation carriers . Currently an increasing number of clinical trials with olaparib in combination with other compounds or radiotherapy are conducted . To support these clinical trials an LC - MS / MS method was developed and validated for the quantification of olaparib in human plasma . Human plasma samples were collected in the clinic and stored at nominally - 20 ° C . DB09074 was isolated from plasma by liquid - liquid extraction , separated on a C18 column with gradient elution and analyzed with triple quadrupole mass spectrometry in positive ion mode . A deuterated isotope was used as internal standard for the quantification . The assay , ranging from 10 to 5000ng / mL , was linear with correlation coefficients ( r ( 2 ) ) of 0 . 9994 or better . The assay was accurate and precise , with inter - assay and intra - assay accuracies within ± 7 . 6 % of nominal and inter - assay and intra - assay precision ≤ 9 . 3 % at the lower limit of quantification and ≤ 5 . 7 % at the other concentration levels tested . All results were within the acceptance criteria of the US FDA and the latest P15941 guidelines for method validation . A quantitative method was developed and validated for the quantification of olaparib in human plasma . The method could successfully be applied for the pharmacokinetic quantification of olaparib in cancer patients treated with olaparib .",
"Cooperative interactions between androgen receptor ( AR ) and heat - shock protein 27 facilitate AR transcriptional activity . P10275 ( AR ) transactivation is known to enhance prostate cancer cell survival . However , the precise effectors by which the prosurvival effects of androgen and AR drive prostate cancer progression are poorly defined . Here , we identify a novel feed - forward loop involving cooperative interactions between ligand - activated AR and heat - shock protein 27 ( Hsp27 ) phospho - activation that enhance AR stability , shuttling , and transcriptional activity , thereby increasing prostate cancer cell survival . Androgen - bound AR induces rapid Hsp27 phosphorylation on DB00133 ( 78 ) and DB00133 ( 82 ) residues in an AR - and p38 kinase - dependent manner . After this androgen - induced , non - nuclear phospho - activation , Hsp27 displaces Hsp90 from a complex with AR to chaperone AR into the nucleus and interact with its response elements to enhance its genomic activity . Inhibition of Hsp27 phosphorylation , or knockdown using the antisense drug DB06094 , shifted the association of AR with Hsp90 to Q00987 , increased proteasome - mediated AR degradation , decreased AR transcriptional activity , and increased prostate cancer LNCaP cell apoptotic rates . DB06094 treatment of mice bearing LNCaP xenografts transfected with an androgen - regulated , probasin - luciferase reporter construct resulted in decreased bioluminescence and serum PSA levels as pharmacodynamic readouts of AR activity , as well as AR , Hsp27 , and Hsp90 protein levels in LNCaP tumor tissue . These data identify novel nongenomic mechanisms involving androgen , AR , and Hsp27 activation that cooperatively interact to regulate the genomic activity of AR and justify further investigation of Hsp27 knockdown as an AR disrupting therapeutic strategy in prostate cancer .",
"P38398 , P09874 and γ P16104 in acute myeloid leukemia : Role as biomarkers of response to the PARP inhibitor olaparib . DB09074 ( AZD - 2281 , Ku - 0059436 ) is an orally bioavailable and well - tolerated poly ( ADP - ribose ) polymerase ( PARP ) inhibitor currently under investigation in patients with solid tumors . To study the clinical potential of olaparib as a single - agent for the treatment of acute myeloid leukemia ( AML ) patients , we analyzed the in vitro sensitivity of AML cell lines and primary blasts . Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples ( 88 % ) and tested cell lines . At these concentrations , olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and P28906 - enriched peripheral blood cells obtained from healthy donors . Most primary AML analyzed were characterized by low P38398 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib . Noteworthy , while P09874 over - expression was detected in blasts not responsive to olaparib , phosphorylation of the histone P16104 ( γ P16104 ) was associated with drug sensitivity . As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion . The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and / or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy .",
"P02649 and Alzheimer disease : a major gene with semi - dominant inheritance . P02649 ( P02649 ) dependent lifetime risks ( LTRs ) for Alzheimer Disease ( AD ) are currently not accurately known and odds ratios alone are insufficient to assess these risks . We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester ( USA ) incidence data . At the age of 85 the LTR of AD without reference to P02649 genotype was 11 % in males and 14 % in females . At the same age , this risk ranged from 51 % for APOE44 male carriers to 60 % for APOE44 female carriers , and from 23 % for APOE34 male carriers to 30 % for APOE34 female carriers , consistent with semi - dominant inheritance of a moderately penetrant gene . Using PAQUID ( France ) incidence data , estimates were globally similar except that at age 85 the LTRs reached 68 and 35 % for P02649 44 and P02649 34 female carriers , respectively . These risks are more similar to those of major genes in Mendelian diseases , such as P38398 in breast cancer , than those of low - risk common alleles identified by recent GWAS in complex diseases . In addition , stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late - onset but for early - onset AD as well . Together , these results urge a reappraisal of the impact of P02649 in Alzheimer disease .",
"Whole - exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment . Whole - exome sequencing of individuals with mild cognitive impairment , combined with genotype imputation , was used to identify coding variants other than the apolipoprotein E ( P02649 ) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design . Matched unrelated P02649 ε3 homozygous male Caucasian participants from the Alzheimer ' s Disease Neuroimaging Initiative ( ADNI ) were selected at the extremes of the 2 - year longitudinal change distribution of hippocampal volume ( eight subjects with rapid rates of atrophy and eight with slow / stable rates of atrophy ) . We identified 57 non - synonymous single nucleotide variants ( SNVs ) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group , but not in any of the 8 subjects in the slow atrophy group . Among these SNVs , the variants that accounted for the greatest group difference and were predicted in silico as ' probably damaging ' missense variants were rs9610775 ( Q9BWT7 ) and rs1136410 ( P09874 ) . To further investigate and extend the exome findings in a larger sample , we conducted quantitative trait analysis including whole - brain search in the remaining ADNI P02649 ε3 / ε3 group ( N = 315 ) . Genetic variation within P09874 and Q9BWT7 was associated with rate of hippocampal neurodegeneration in P02649 ε3 / ε3 . Meta - analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in P02649 ε3 / ε3 individuals ( N = 923 ) . Larger sequencing studies and longitudinal follow - up are needed for confirmation . The combination of next - generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK40___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"DB09074 , P09874 inhibitor in ovarian cancer . INTRODUCTION : Ovarian cancer is the most important cause of gynecological cancer - related mortality . Conventional treatments for advanced or recurrent disease offer limited results in terms of long - term responses and survival . Researches have recently focused on target therapies , which represent a new , promising , therapeutic approach , able to maximizing tumor kill and minimizing toxicity . The family of polyadenosine diphosphate - ribose polymerase ( PARP ) inhibitors is currently one of the most hopeful and investigated alternatives . AREAS COVERED : Preclinical and clinical studies of DB09074 , the most investigated PARP inhibitor in ovarian cancer , are analyzed and discussed . Data were obtained by searching for all English peer - reviewed articles on Medline , on Cochrane Database and all on - going Phase I and II studies registered on National Cancer Institute Clinical Trials ; also any related abstracts recently presented on DB09074 at major international congresses will be included . EXPERT OPINION : Bad prognosis and drug resistance usually affect ovarian cancer . Recent trends toward the knowledge of molecular - specific pathways have produced new target drugs . PARP inhibition mediated by DB09074 in P38398 ( breast cancer 1 ) and P51587 ( breast cancer 2 ) - mutated and in sporadic ovarian cancer represents a promising field of investigation . Further studies are needed to confirm initial exciting results .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK40___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"O15519 is involved in tumor progression of peripheral T - cell lymphoma and targeted by histone deacetylase inhibitors . BACKGROUND : Peripheral T - cell lymphomas ( PTCLs ) are often aggressive tumors and resistant to conventional chemotherapy . Dysregulation of extrinsic apoptosis plays an important role on tumor cell sensitivity to chemotherapeutic agents . Cellular Q14790 inhibitory protein ( O15519 ) is a key regulator of extrinsic apoptotic pathway . METHODS : O15519 expression was assessed by real - time PCR and compared according to clinical parameters in patients with PTCLs . The relation of O15519 to tumor cell apoptosis mediated by histone deacetylases inhibitors ( HDACIs ) and the possible mechanism were examined in T - lymphoma cell lines and in a murine xenograft model . RESULTS : O15519 was overexpressed and associated with decreased tumor P50591 / DR5 expression , elevated serum lactate dehydrogenase level and high - risk International Prognostic Index of the patients . In vitro , molecular silencing of O15519 by specific small - interfering RNA increased P50591 / DR5 expression , enhanced T - lymphoma cell apoptosis and sensitized cells to chemotherapeutic agents . However , HDACIs valproic acid ( DB00313 ) and suberoylanilide hydroxamic acid ( ___MASK51___ ) could downregulate O15519 expression and triggered extrinsic apoptosis of T - lymphoma cells , through inhibiting NF - κB signaling and interrupting P50 interaction with O15519 promoter . As Class I HDACIs , both DB00313 and ___MASK51___ inhibited Q13547 , resulting in P50 inactivation and O15519 downregulation . In vivo , oral DB00313 treatment significantly retarded tumor growth and induced in situ apoptosis , consistent with inhibition of Q13547 / P50 / O15519 axis and increase of P50591 / DR5 expression . CONCLUSIONS : O15519 overexpression in PTCLs protected tumor cells from extrinsic apoptosis and contributed to tumor progression . Although linking to chemoresistance , O15519 indicated tumor cell sensitivity to HDACIs , providing a potential biomarker of targeting apoptosis in treating PTCLs .",
"P11274 / P00519 activates mdm2 mRNA translation via the La antigen . In a P11274 / P00519 - expressing myeloid precursor cell line , p53 levels were markedly downmodulated . Expression of Q00987 , the negative regulator of p53 , was upregulated in a tyrosine kinase - dependent manner in growth factor - independent P11274 / P00519 - expressing cells , and in accelerated phase and blast crisis CML samples . Increased Q00987 expression was associated with enhanced mdm2 mRNA translation , which required the interaction of the La antigen with mdm2 5 ' UTR . Expression of Q00987 correlated with that of La and was suppressed by La siRNAs and by a dominant negative La mutant , which also enhanced the susceptibility to drug - induced apoptosis of P11274 / P00519 - transformed cells . By contrast , La overexpression led to increased Q00987 levels and enhanced resistance to apoptosis . Thus , La - dependent activation of mdm2 translation might represent an important molecular mechanism involved in P11274 / P00519 leukemogenesis .",
"The C - terminal region of Rad52 is essential for Rad52 nuclear and nucleolar localization , and accumulation at DNA damage sites immediately after irradiation . Rad52 plays essential roles in homologous recombination ( HR ) and repair of DNA double - strand breaks ( DSBs ) in Saccharomyces cerevisiae . However , in vertebrates , knockouts of the Rad52 gene show no hypersensitivity to agents that induce DSBs . Rad52 localizes in the nucleus and forms foci at a late stage following irradiation . P12956 and P13010 , which play an essential role in nonhomologous DNA - end - joining ( NHEJ ) , are essential for the accumulation of other core NHEJ factors , e . g . , Q13426 , and a HR - related factor , e . g . , P38398 . Here , we show that the subcellular localization of EYFP - Rad52 ( 1 - 418 ) changes dynamically during the cell cycle . In addition , EYFP - Rad52 ( 1 - 418 ) accumulates rapidly at microirradiated sites and colocalizes with the DSB sensor protein P13010 . Moreover , the accumulation of EYFP - Rad52 ( 1 - 418 ) at DSB sites is independent of the core NHEJ factors , i . e . , P13010 and Q13426 . Furthermore , we observed that EYFP - Rad52 ( 1 - 418 ) localizes in nucleoli in CHO - P04264 cells and Q13426 - deficient cells , but not in P13010 - deficient cells . We also found that Rad52 nuclear localization , nucleolar localization , and accumulation at DSB sites are dependent on eight amino acids ( 411 - 418 ) at the end of the C - terminal region of Rad52 ( Rad52 CTR ) . Furthermore , basic amino acids on Rad52 CTR are highly conserved among mammalian , avian , and fish homologues , suggesting that Rad52 CTR is important for the regulation and function of Rad52 in vertebrates . These findings also suggest that the mechanism underlying the regulation of subcellular localization of Rad52 is important for the physiological function of Rad52 not only at a late stage following irradiation , but also at an early stage .",
"PARP inhibitor , olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice . We have previously shown that P09874 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury . DB09074 is a potent new generation PARP inhibitor that has been approved for human testing . The present work was designed to evaluate its beneficial potential against LPS - induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice . Administration of olaparib at different doses , 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg / kg b . wt . reduced the total number of inflammatory cells particularly neutrophils in the lungs . This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially . DB09074 provided strong protection against LPS - mediated secondary kidney injury as reflected by restoration of serum levels of urea , creatinine , and uric acid toward normal . The drug restored the LPS - mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and DB00143 levels . Finally , RT - PCR data revealed that olaparib downregulates the LPS - induced expression of NF - κB - dependent genes namely P01375 - α , IL - 1β , and P19320 in the lungs without altering the expression of total p65NF - κB . Overall , the data suggest that olaparib has a strong potential to protect against LPS - induced lung injury and associated dysfunctioning of kidney in mice . Given the fact that olaparib is approved by FDA for human testing , our findings can pave the way for testing of the drug on humans inflicted with acute lung injury .",
"Poly ( ADP - ribose ) polymerase - 1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation : a potential specific effect on P05113 . We recently used a murine model of allergic airway inflammation to show that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays an important role in the pathogenesis of asthma - related lung inflammation . In this study , we show that P09874 inhibition , by a novel inhibitor ( TIQ - A ) or by gene deletion , prevented eosinophilic infiltration into the airways of OVA - challenged mice . Such impairment of eosinophil recruitment appeared to take place after IgE production . OVA challenge of wild - type mice resulted in a significant increase in P05112 , P05113 , P22301 , P35225 , and GM - P04141 secretions . Although P05112 production was moderately affected in OVA - challenged P09874 (-/-) mice , the production of P05113 , P22301 , P35225 , and GM - P04141 was completely inhibited in ex vivo OVA - challenged lung cells derived from these animals . A single TIQ - A injection before OVA challenge in wild - type mice mimicked the latter effects . The marked effect P09874 inhibition exerted on mucus production corroborated the effects observed on the Th2 response . Although P09874 inhibition by gene knockout increased the production of the Th1 cytokines P60568 and IL - 12 , the inhibition by TIQ - A exerted no effect on these two cytokines . The failure of lung cells derived from OVA - challenged P09874 (-/-) mice to synthesize GM - P04141 , a key cytokine in eosinophil recruitment , was reestablished by replenishment of P05113 . Furthermore , intranasal administration of P05113 restored the impairment of eosinophil recruitment and mucus production in OVA - challenged P09874 (-/-) mice . The replenishment of either P05112 or IgE , however , did not result in such phenotype reversals . Altogether , these results suggest that P09874 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to P05113 production .",
"Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK51___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK51___ . Tubacin in combination with ___MASK51___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK51___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK51___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK95___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Type I interferon as a powerful adjuvant for monocyte - derived dendritic cell development and activity in vitro and in Hu - PBL - SCID mice . Type I interferons ( IFNs ) are cytokines exhibiting antiviral and antitumor effects , including multiple activities on immune cells . However , the importance of these cytokines in the early events leading to the generation of an immune response is still unclear . Here , we have investigated the effects of type I IFNs on freshly isolated granulocyte / macrophage colony - stimulating factor ( GM - P04141 ) - treated human monocytes in terms of dendritic cell ( DC ) differentiation and activity in vitro and in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes ( hu - PBL - SCID ) mice . Type I IFNs induced a surprisingly rapid maturation of monocytes into short - lived tumor necrosis factor ( P01375 ) - related apoptosis - inducing ligand ( P50591 ) - expressing DCs endowed with potent functional activities , superior with respect to the interleukin ( IL ) - 4 / GM - P04141 treatment , as shown by FACS ( ( R ) ) analyses , mixed leukocyte reaction assays with allogeneic PBLs , and lymphocyte proliferation responses to HIV - 1 - pulsed autologous DCs . Type I IFN induced P40933 production and strongly promoted a T helper cell type 1 response . Notably , injection of IFN - treated HIV - 1 - pulsed DCs in SCID mice reconstituted with autologous PBLs resulted in the generation of a potent primary immune response , as evaluated by the detection of human antibodies to various HIV - 1 antigens . These results provide a rationale for using type I IFNs as vaccine adjuvants and support the concept that a natural alliance between these cytokines and monocytes / DCs represents an important early mechanism for connecting innate and adaptive immunity .",
"Cytokines and P11274 - P00519 mediate suppression of P50591 - induced apoptosis through inhibition of forkhead FOXO3a transcription factor . Cytokine - provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl - 2 family members . Here we show that in hematopoietic cells , cytokines also regulate death receptor - mediated pathways . We demonstrate that hematopoietic cytokines such as P08700 and erythropoietin in normal cells , as well as P11274 - P00519 oncoprotein in transformed cells , inhibit transcription of tumor necrosis factor - related apoptosis - inducing ligand ( P50591 ) . Using small interfering RNAs , we show that the inhibition of P50591 function is sufficient to partially rescue cytokine - deprived cells from apoptosis . Finally , we demonstrate that cytokine and P11274 - P00519 suppression of P50591 transcription is mediated through phosphorylation and inhibition of the forkhead FOXO3a transcription factor . P11274 - P00519 - induced inhibition of P50591 transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia .",
"Novel targeted therapeutics : inhibitors of Q00987 , Q9UM73 and PARP . We reviewed preclinical data and clinical development of Q00987 ( murine double minute 2 ) , Q9UM73 ( anaplastic lymphoma kinase ) and PARP ( poly [ ADP - ribose ] polymerase ) inhibitors . Q00987 binds to p53 , and promotes degradation of p53 through ubiquitin - proteasome degradation . JNJ - 26854165 and RO5045337 are 2 small - molecule inhibitors of Q00987 in clinical development . Q9UM73 is a transmembrane protein and a member of the insulin receptor tyrosine kinases . Q9HC35 - Q9UM73 fusion gene is identified in approximately 3 - 13 % of non - small cell lung cancer ( NSCLC ) . Early - phase clinical studies with DB08865 , an Q9UM73 inhibitor , in NSCLC harboring Q9HC35 - Q9UM73 have demonstrated promising activity with high response rate and prolonged progression - free survival . PARPs are a family of nuclear enzymes that regulates the repair of DNA single - strand breaks through the base excision repair pathway . Randomized phase II study has shown adding P09874 inhibitor BSI - 201 to cytotoxic chemotherapy improves clinical outcome in patients with triple - negative breast cancer . DB09074 , another oral small - molecule PARP inhibitor , demonstrated encouraging single - agent activity in patients with advanced breast or ovarian cancer . There are 5 other PARP inhibitors currently under active clinical investigation .",
"Long - term safety and anti - tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast , ovarian or fallopian tube cancer . BACKGROUND : DB09074 ( AZD2281 ) , a P09874 / 2 inhibitor , has been extensively investigated in clinical trials . However , limited clinical data are available about its long - term safety and anti - tumour activity . METHODS : Patients had first participated in a phase I study of olaparib combined with carboplatin and / or paclitaxel . They continued with olaparib monotherapy in their best interest if they failed to tolerate the combination due to the treatment - related adverse events ( TRAEs ) . Safety data were collected by physical examination and regular laboratory evaluations . Disease evaluations were performed by CT scan . RESULTS : At data cutoff , 21 patients were included ; 10 with breast , 9 with ovarian and 2 with fallopian tube cancer of whom 16 patients had a BRCA mutation ( 13 P38398 ; 3 P51587 ) . TRAEs were mostly haematological and most prominent shortly after switching from combination to monotherapy , probably due to carry - over effects of chemotherapy . Over time , both severity and frequency of TRAEs decreased . Responses to olaparib were durable with a median treatment duration of 52 ( range 7 - 183 ) weeks . In total , nine ( 43 % ) patients were still on study at data cutoff . CONCLUSION : Continued long - term daily olaparib was found to be safe and tolerable . Encouragingly , patients who showed a favourable response on earlier combination therapy maintained this response on olaparib monotherapy .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK56___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK56___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .",
"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .",
"Inhibition of poly ( ADP - ribose ) polymerase interferes with Trypanosoma cruzi infection and proliferation of the parasite . Poly ( ADP - ribosylation ) is a post - translational covalent modification of proteins catalyzed by a family of enzymes termed poly ( ADP - ribose ) polymerases ( PARPs ) . In the human genome , 17 different genes have been identified that encode members of the PARP superfamily . Poly ( ADP - ribose ) metabolism plays a role in a wide range of biological processes . In Trypanosoma cruzi , PARP enzyme appears to play a role in DNA repair mechanisms and may also be involved in controlling the different phases of cell growth . Here we describe the identification of potent inhibitors for T . cruzi PARP with a fluorescence - based activity assay . The inhibitors were also tested on T . cruzi epimastigotes , showing that they reduced ADP - ribose polymer formation in vivo . Notably , the identified inhibitors are able to reduce the growth rate of T . cruzi epimastigotes . The best inhibitor , DB09074 , is effective at nanomolar concentrations , making it an efficient chemical tool for chacterization of ADP - ribose metabolism in T . cruzi . PARP inhibition also decreases drastically the amount of amastigotes but interestingly has no effect on the amount of trypomastigotes in the cell culture . Knocking down human P09874 decreases both the amount of amastigotes and trypomastigotes in cell culture , indicating that the effect would be mainly due to inhibition of human P09874 . The result suggests that the inhibition of PARP could be a potential way to interfere with T . cruzi infection ."
] |
[
"___MASK100___",
"___MASK11___",
"___MASK12___",
"___MASK40___",
"___MASK46___",
"___MASK51___",
"___MASK56___",
"___MASK74___",
"___MASK95___"
] |
___MASK12___
|
MH_train_365
|
interacts_with DB00242?
|
[
"Ribonucleotide reductase M1 gene promoter activity , polymorphisms , population frequencies , and clinical relevance . P23921 is a gene crucial for determination of the tumor phenotype . It encodes the regulatory subunit of ribonucleotide reductase , and it is a molecular target of gemcitabine . In addition , P23921 induces P60484 expression and inhibits cell migration , invasion , and metastasis formation . In patients with resected lung cancers , increased levels of P23921 are highly associated with long survival . In contrast , patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if P23921 expression is high presumably because of decreased efficacy of chemotherapy . We analyzed the P23921 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for P23921 expression . Two single nucleotide polymorphisms , RR37 and RR524 , were discovered . These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations . Promoter allelotypes were highly associated with overall ( P = 0 . 06 ) and disease - free ( P = 0 . 03 ) patient survival . The allelotype with the highest predicted activity was associated with the best patient outcome . However , we did not find an association between allelotype and tumoral P23921 expression . This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression . We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the P23921 promoter are required to fully elucidate factors controlling P23921 expression .",
"Q8WZ71 and Q8WUP2 as novel marker genes of cisplatin sensitivity in non - small cell lung cancer cells . Even after development of molecular targeting therapies , platinum - based chemotherapy is still a standard care for treatment of locally advanced non - small cell lung cancer ( NSCLC ) . So far , critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined . We here attempted to identify novel biomarker genes for cisplatin ( DB00515 ) for a tailored therapy . Initial screening to explorer association of IC ( 50 ) values of DB00515 obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real - time RT - PCR provided 6 candidate genes , namely , Q8TB37 , Q96H12 , P17014 , Q8WZ71 , P49841 , and Q8WUP2 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells . These 6 genes together with 5 reported biomarkers , i . e . , P09211 , P07992 , P38398 , P42345 , and P23921 , were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells : only Q8WUP2 and Q8WZ71 genes showed positive associations with statistical significances ( P = . 016 and . 026 , respectively ) . The biological significance of these genes was explored by in vitro experiments : Knockdown experiments in PC - 9 / DB00515 cells revealed that the reduced expression of Q8WZ71 significantly decreased the chemo - resistance against DB00515 ( P < . 0001 ) , while 2 transformants of PC - 6 cells stably over - expressing Q8WUP2 resulted in an enhanced resistance to DB00515 ( P = . 004 and P = . 001 ) . Furthermore , a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of Q8WZ71 and Q8WUP2 ( R ( 2 ) = 0 . 755 , P = . 0018 ) . Q8WZ71 and Q8WUP2 may be powerful predictive biomarkers for DB00515 therapy in NSCLC .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK45___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"___MASK51___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Association of cytidine deaminase and xeroderma pigmentosum group D polymorphisms with response , toxicity , and survival in cisplatin / gemcitabine - treated advanced non - small cell lung cancer patients . BACKGROUND : Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non - small cell lung cancer ( NSCLC ) . Genetic variations in drug metabolism may affect the clinical response , toxicity , and prognosis of NSCLC patients treated with cisplatin / gemcitabine - based therapy . PATIENTS AND METHODS : We evaluated seven single - nucleotide polymorphisms of six genes P32320 Lys27Gln ( A / C ) ; P32320 C435T ; P07992 C118T ; O43542 Thr241Met ( C / T ) ; P18074 Lys751Gln ( A / C ) ; P04637 Arg72Pro ( G / C ) , and P23921 C524T in 192 chemotherapy - naive patients with advanced NSCLC treated with cisplatin / gemcitabine - based regimen by TaqMan probe - based assays with 7300 Real - Time PCR System , using genomic DNA extracted from blood samples . RESULTS : The P32320 435 T / T genotype was significantly associated with better response ( p = 0 . 03 ) . The P32320 435 C / T genotype was associated with a significantly increased risk of nonhematological toxicity of grade ≥ 3 ( p = 0 . 02 ) after adjusting for performance status , age , and type of treatment regimen . In the multivariate Cox model , the P18074 751 C / C genotype was a significant prognostic factor of longer progression - free survival ( p = 0 . 006 ) . CONCLUSION : Our data suggest polymorphic variations of drug metabolic gene were associated with response and toxicity of cisplatin / gemcitabine - based therapy and progression - free survival of patients with advanced NSCLC .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK15___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Expression of the human concentrative nucleotide transporter 1 ( O00337 ) gene correlates with clinical response in patients affected by Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) undergoing a combination treatment with 2 - chloro - 2 '- deoxyadenosine ( DB00242 ) and DB00073 . PURPOSE : Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration , metabolism and targeting . In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 ( O00337 ) - deficient cells display resistance . EXPERIMENTAL DESIGN : We applied real - time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter ( hENT1 , O00337 ) , deoxycytidine and deoxyguanosine kinase ( P27707 , Q16854 ) , 5 '- nucleotidase ( 5 '- NT ) , ribonucleotide reductase catalytic and regulatory ( P23921 , P31350 ) subunits in bone marrow cells from 32 patients with Waldenström ' s Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) who received 2CdA - based chemotherapy . Responses to chemotherapy , were then correlated to the expression of these markers . RESULTS : All 32 patients enrolled expressed lower levels of O00337 as compared to healthy donors . In univariate analysis , lower expression level of O00337 ( p = 0 . 0021 ) and P31350 ( p = 0 . 02 ) correlated with response to chemotherapy . In particular , patients with low levels of O00337 achieved inferior clinical response . No significant correlation between these genes expression and age , stage of disease was found . This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA - based therapy .",
"___MASK54___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK54___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK40___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"Thrombin - inducible platelet adhesion and regulation of the platelet seven - transmembrane thrombin receptor - 1 ( P25116 ) : effects of unfractionated heparin and lepirudin . ___MASK98___ may induce platelet activation and even heparin - induced thrombocytopenia . DB00001 has been approved for HIT treatment . We speculated that lepirudin inhibits platelet function under high shear and the platelet thrombin receptor P25116 better than heparin . Thrombin - inducible platelet adherence under high shear conditions and the expression of P25116 were studied after samples from healthy donors were exposed in vitro to increasing concentrations of unfractionated heparin or lepirudin . Compared to baseline and to lepirudin , heparin induced platelet P16109 expression ( p = 0 . 04 ) . Platelet adherence increased slightly in the presence of lepirudin , but not heparin ( p = 0 . 04 ) . Thrombin - inducible platelet aggregate formation and consecutive adherence under high shear conditions was inhibited by both anticoagulants ( p = 0 . 004 ) . Further , heparin and lepirudin inhibited thrombin - inducible cleavage and internalization of P25116 at a dosage of 1 . 0 U / ml and 1 . 6 microg / ml , respectively ( p = 0 . 004 ) . Thus , heparin and lepirudin inhibit thrombin - inducible platelet activation in vitro to a similar extent .",
"Plasmodium falciparum : cytoadherence of malaria - infected erythrocytes to human brain capillary and umbilical vein endothelial cells -- a comparative study of adhesive ligands . The cytoadherence of Plasmodium falciparum - infected erythrocytes ( FCR - 3 line ) to human brain capillary endothelial cells ( HBEC ) , Q9UBR5 amelanotic melanoma cells , and human umbilical vein endothelial cells ( HUVEC ) was studied . The adhesion of infected red cells was HBEC > amelanotic melanoma > HUVEC . The presence or absence of the adhesive ligands P05362 ( CD54 or intercellular adhesion molecule 1 ) , P13598 , and P16671 ( = glycoprotein IV ) was determined for each of these cells by indirect immunofluorescence using the monoclonal antibodies P23921 / 1 , 6D5 , and OKM 5 / OKM 8 , respectively . It appeared that a major ligand for the FCR - 3 line of P . falciparum with amelanotic melanoma cells and HBECs was P16671 . Binding to HUVECs was very low , presumably due to their lack of expression of P16671 . HBECs , because of their ease of in vitro propagation , long - term maintenance of cytoadherent properties , and their high degree of adhesiveness , will be useful for in vitro studies of adherence .",
"Cytokine regulation of intercellular adhesion molecule - 1 ( P05362 ) expression on human glioblastoma cells . Intercellular adhesion molecule - 1 ( P05362 ) has recently been identified as one of the ligands for lymphocyte function - associated antigen - 1 ( LFA - 1 ) . Immunohistochemical staining of frozen tissue sections using the P05362 antibody P23921 / 1 demonstrated significant levels of P05362 expression on human glioblastoma cells and on intratumoural vascular endothelial cells . P05362 was weakly expressed or absent from low grade gliomas and absent from normal and fetal brain . P05362 expression was similar to that of MHC class II . HLA - DR antigens . Glioblastoma cell lines constitutively expressed P05362 to a minimal or moderate extent . Surface antigen expression of P05362 and P05362 - specific mRNA could be significantly increased by incubating glioblastoma cells with interleukin - 1 beta ( P01584 ) , tumour necrosis factor - alpha ( P01375 ) , and interferon - gamma ( P01579 ) . P60568 , P05112 , P05231 and transforming growth factor beta 2 ( TGF - beta 2 ) had no significant effect on surface antigen expression . Significant enhancement of P05362 expression was obtained using P01375 and P01584 at 1 - 10 U / ml and at 500 U / ml of P01579 . Induction of P05362 specific mRNA was observed 4 h after cytokine treatment and decreased by 24 h . Surface antigen expression of P05362 increased for up to 48 h after treatment .",
"Delineation of gastric cancer subtypes by co - regulated expression of receptor tyrosine kinases and chemosensitivity genes . Chemotherapy plays a key role in improving disease - free survival and overall survival of gastric cancer ( GC ) ; however , response rates are variable and a non - negligible proportion of patients undergo toxic and costly chemotherapeutic regimens without a survival benefit . Several studies have shown the existence of GC subtypes which may predict survival and respond differently to chemotherapy . It is also known that the expression level of chemotherapy - related and target therapy - related genes correlates with response to specific antitumor drugs . Nevertheless , these genes have not been considered jointly to define GC subtypes . In this study , we evaluated seven genes known to influence chemotherapeutic response ( P07992 , P38398 , P23921 , Q13509 , P16949 , P04818 and P11388 ) and five receptor tyrosine kinases ( RTKs ) ( P00533 , P04626 , P09619 , P17948 and P35968 ) . We demonstrate significant heterogeneity of gene expression among GC patients and identified four GC subtypes using the expression profiles of eight genes in two co - regulation groups : chemosensitivity ( P38398 , P16949 , P04818 and P11388 ) and RTKs ( P00533 , P09619 , P17948 and P35968 ) . The results are of immediate translational value regarding GC diagnostics and therapeutics , as many of these genes are curently widely used in relevant clinical testing .",
"___MASK79___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Statins exhibit anticancer effects through modifications of the pAkt signaling pathway . Statins are cholesterol lowering drugs that exhibit antitumor effects in several in vitro and in vivo models , and epidemiological studies indicate that statins prevent cancer . However , the molecular mechanism underlying the effects of statins still needs to be elucidated . We previously demonstrated that single doses of different statins rapidly affect Akt signaling via the purinergic receptor Q99572 . In particular , statins down - regulated nuclear pAkt . Here , we report that long - term treatment of A549 cells with high concentrations of statins ( 15 - 75 µM ) selects cell sub - populations exhibiting altered P2X receptor expression , signs of increased P60484 activity , enhanced Q6ZVD8 , decreased PI3K p110β and inhibited downstream pAkt signaling . Furthermore , the nuclear accumulation of pAkt in response to insulin was inhibited in selected cells . Statin - selected cells displayed reduced proliferation rate and were more vulnerable to etoposide - and 5 - fluorouracil - elicited cytotoxic effects . The stability of a selected phenotype ( 50 µM ) was tested for three weeks in the absence of statins . This resulted in a reversal of some , but not all alterations . Importantly , the truncated nuclear insulin response was retained . We conclude that long - term treatment with high doses of statins selects cells exhibiting stable alterations in insulin - Akt signaling and which are vulnerable to DNA damage . Our studies strengthen the hypothesis that an altered Akt signaling has a role in chemopreventive effects of statins .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK4___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK4___ is also being investigated as part of triplet drug regimens . ___MASK4___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"P23921 domain of the splicing oncoprotein Q07955 is required for Q02750 - MAPK - P29323 activation and cellular transformation . Alternative splicing regulators have emerged as new players in cancer development , modulating the activities of many tumor suppressors and oncogenes and regulating the signaling pathways . However , little is known about the mechanisms by which these oncogenic splicing factors lead to cellular transformation . We have shown previously that the splicing factor serine and arginine splicing factor 1 ( Q07955 ; Q07955 / ASF ) is a proto - oncogene , which is amplified in breast cancer and transforms immortal cells when overexpressed . In this study , we performed a structure - function analysis of Q07955 and found that the RNA recognition motif 1 ( P23921 ) domain is required for its oncogenic activity . Deletion of P23921 eliminated the splicing activity of Q07955 on some of its endogenous targets . Moreover , we found that Q07955 elevates the expression of B - Raf and activates the mitogen - activated protein kinase kinase ( MEK ) extracellular signal - regulated kinase ( P29323 ) pathway and that P23921 is required for this activation as well . B - Raf - MEK - P29323 activation by Q07955 contributes to transformation as pharmacological inhibition of Q02750 inhibits Q07955 - mediated transformation . In conclusion , P23921 of Q07955 is both required ( and when tethered to the RS domain ) also sufficient to activate the Raf - MEK - P29323 pathway and to promote cellular transformation .",
"Intraretinal lipid transport is dependent on high density lipoprotein - like particles and class B scavenger receptors . PURPOSE : In our companion paper we demonstrated that circulating lipoproteins enter the retina via the retinal pigment epithelium ( Q96AT9 ) and possibly Müller cells . In order to understand how these lipids are transported within the retina , expression and localization of the main proteins known to be involved in systemic lipid transport was determined . METHODS : Expression of O95477 , apoA1 ( the major HDL protein ) , Q8WTV0 , SR - Q15878 , P16671 , lecithin : cholesterol acyltransferase ( P04180 ) , and cholesteryl ester transfer protein ( P11597 ) was determined by reverse transcriptase polymerase chain reaction ( RT - PCR ) and immunoblots . Localization was determined by immunohistochemistry using fresh monkey vibrotome sections and imaged by confocal microscopy . RESULTS : O95477 and apoA1 were localized to the ganglion cell layer , retinal pigment epithelium ( Q96AT9 ) , and rod photoreceptor inner segments . ApoA1 was also observed associated with rod photoreceptor outer segments , presumably localized to the interphotoreceptor matrix ( IPM ) . The scavenger receptors Q8WTV0 and SR - Q15878 localized mainly to the ganglion cell layer and photoreceptor outer segments ; in the latter they appear to be associated with microtubules . P04180 and P11597 localized mainly to the IPM . CONCLUSIONS : The presence and specific localization of these well - known lipid transport proteins suggest that the retina employs an internal lipid transport mechanism that involves processing and maturation of HDL - like particles .",
"P25116 14 - amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P16109 - dependent mechanism . Thrombin cleaves its receptor at arginine - 41 , resulting in the generation of a new receptor NH2 - terminus with the sequence SFLLRNPNDKYEPF . This peptide ( TRP - 14 ) may signal a variety of thrombin ' s responses . We examined the effects of TRP - 14 in inducing endothelial cell hyperadhesivity and neutrophil ( PMN ) adhesion to endothelial cell monolayers . Human umbilical vein endothelial cells ( HUVECs ) challenged with TRP - 14 ( 10 (- 4 ) to 10 (- 5 ) M ) produced concentration - dependent increases in endothelial adhesivity to PMN . In contrast , position 1 to 2 inverted peptide ( FSLLRNPNDKYEPF ) did not induce the response . The adhesion response was transient ; that is , PMN adhesion increased within 15 minutes and decreased by 75 minutes after TRP - 14 challenge of HUVECs . The transient endothelial adhesiveness paralleled the time course of P16109 expression . TRP - 14 - induced release of P16109 from intracellular stores may be a critical determinant of the response since treatment of endothelial cells with anti - P16109 monoclonal antibody ( mAb ) P55008 prevented the increase in PMN adhesion . Control nonneutralizing anti - P16109 mAb P28222 and mAb P23921 / 1 directed against intercellular adhesion molecule - 1 ( P05362 ) on HUVECs were ineffective . The results indicate that the \" tethered ligand \" of the thrombin receptor created by the proteolytic action of thrombin on its receptor ( i . e . , TRP - 14 ) signals increased endothelial adhesiveness by a P16109 - dependent mechanism . Thrombin - induced PMN adhesion may involve formation of a new NH2 - terminus of the endothelial thrombin receptor with the sequence SFLLRNPNDKYEPF followed by activation of endothelial second messenger pathways and the transient expression of P16109 .",
"___MASK82___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK82___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK82___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK82___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"P10275 - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti - tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR - target genes , mediating androgen - induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas ."
] |
[
"___MASK15___",
"___MASK40___",
"___MASK45___",
"___MASK4___",
"___MASK51___",
"___MASK54___",
"___MASK79___",
"___MASK82___",
"___MASK98___"
] |
___MASK4___
|
MH_train_366
|
interacts_with DB00126?
|
[
"Prolyl - 4 - hydroxylase domain protein 2 controls NF - κB / p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus . Prolyl - 4 - hydroxylase ( P20941 ) proteins are key in sensing tissue hypoxia . In nucleus pulposus ( NP ) cells , our previous work demonstrated that P20941 isoforms have a differential contribution in controlling hypoxia - inducible factor ( HIF ) - α degradation and activity . Recently we have shown that a regulatory relationship exists between Q9H6Z9 and inflammatory cytokines in NP cells . With respect to Q9GZT9 , the most abundant P20941 isoform in NP cells , very little is known concerning its function and regulation under inflammatory conditions that characterize intervertebral disc degeneration . Here , we show that Q9GZT9 is a potent regulator of the catabolic activities of P01375 - α ; silencing of Q9GZT9 significantly decreased P01375 - α - induced expression of catabolic markers including P31431 , P08254 , P45452 , and Q9UNA0 , as well as several inflammatory cytokines and chemokines , while partially restoring aggrecan and collagen II expression . Use of NF - κB reporters with ShPHD2 , SiHIF - 1α , as well as p65 (-/-) , Q9GZT9 (-/-) , and Q9H6Z9 (-/-) cells , shows that Q9GZT9 serves as a co - activator of NF - κB / p65 signaling in Q9BYW2 - independent fashion . Immunoprecipitation of endogenous and exogenously expressed tagged proteins , as well as fluorescence microscopy , indicates that following P01375 - α treatment , Q9GZT9 interacts and co - localizes with p65 . Conversely , loss of function experiments using lentivirally delivered Sh - p65 , Sh - IKKβ , and NF - κB inhibitor confirmed that cytokine - dependent Q9GZT9 expression in NP cells requires NF - κB signaling . These findings clearly demonstrate that Q9GZT9 forms a regulatory circuit with P01375 - α via NF - κB and thereby plays an important role in enhancing activity of this cytokine . We propose that during disc degeneration Q9GZT9 may offer a therapeutic target to mitigate the deleterious actions of P01375 - α , a key proinflammatory cytokine .",
"Silencing of HIF prolyl - hydroxylase 2 gene in the renal medulla attenuates salt - sensitive hypertension in Dahl S rats . BACKGROUND : In response to high salt intake , transcription factor hypoxia - inducible factor ( HIF ) 1α activates many antihypertensive genes , such as heme oxygenase 1 ( P09601 ) 1 and cyclooxygenase 2 ( P35354 ) in the renal medulla , which is an important molecular adaptation to promote extra sodium excretion . We recently showed that high salt inhibited the expression of HIF prolyl - hydroxylase 2 ( Q9GZT9 ) , an enzyme that promotes the degradation of HIF - 1α , thereby upregulating HIF - 1α , and that high salt - induced inhibition in Q9GZT9 and subsequent activation of HIF - 1α in the renal medulla was blunted in Dahl salt - sensitive hypertensive rats . This study tested the hypothesis that silencing the Q9GZT9 gene to increase HIF - 1α levels in the renal medulla attenuates salt - sensitive hypertension in Dahl S rats . METHODS : Q9GZT9 short hairpin RNA ( shRNA ) plasmids were transfected into the renal medulla in uninephrectomized Dahl S rats . Renal function and blood pressure were then measured . RESULTS : Q9GZT9 shRNA reduced Q9GZT9 levels by > 60 % and significantly increased HIF - 1α protein levels and the expression of HIF - 1α target genes P09601 and P35354 by > 3 - fold in the renal medulla . Functionally , pressure natriuresis was remarkably enhanced , urinary sodium excretion was doubled after acute intravenous sodium loading , and chronic high salt - induced sodium retention was remarkably decreased , and as a result , salt - sensitive hypertension was significantly attenuated in Q9GZT9 shRNA rats compared with control rats . CONCLUSIONS : Impaired Q9GZT9 response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats , and inhibition of Q9GZT9 in the renal medulla could be a therapeutic approach for salt - sensitive hypertension .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK2___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK66___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Hypoxia - inducible factor 1 is activated by dysregulated cyclin E during mammary epithelial morphogenesis . Increased cyclin E expression has been identified in human tumors of diverse histologies , and in studies of primary breast cancers , high cyclin E is associated with poor prognosis . We have studied dysregulated cyclin E in epithelial tissues using organotypic cultures of human mammary epithelial cells and a murine model . We unexpectedly discovered that dysregulated cyclin E impairs normal acinar morphogenesis in vitro , and this is associated with the induction of P38936 ( Cip1 ) , p27 ( Kip1 ) , and cellular senescence . P12004 E - induced morphogenesis arrest is dependent upon hypoxia - inducible factor 1α ( HIF - 1α ) , which itself is induced by high cyclin E both in cultured mammary acini and in mammary epithelial tissues in a mouse model of deregulated cyclin E expression . We next determined that E2F activity directly regulates and is required for induction of Q16665 by cyclin E . Additionally , we found that cyclin E deregulation in mammary acini decreases , in an E2F - independent manner , expression of the Q9GZT9 prolyl hydroxylase that regulates HIF - 1α degradation within the P40337 ubiquitin ligase pathway . Together , our findings reveal a direct link between cyclin E and Q9BYW2 activities in mammary epithelial cells and implicate Q9BYW2 as a mediator of proliferation - independent phenotypes associated with high cyclin E expression in some human breast cancers .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK26___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases , c - kit and P09619 , in the rat testis . Imatinib mesylate ( Glivec , ___MASK58___ ; Novartis ) , a small - molecular analog of DB00171 that potently inhibits the tyrosine kinase activities of Bcr - Abl , P16234 , P09619 , c - Fms , DB00125 and c - kit , is one of the novel molecularly targeted agents being introduced into cancer therapy . P21583 ( P21583 ) / c - kit and platelet - derived growth factor ( PDGF ) signaling pathways regulate postnatal formation of the pools of spermatogonial stem cells and Leydig cells in the rat testis . The effect of short postnatal imatinib exposure on fertility of the male rats and offspring of these animals were investigated . Imatinib significantly reduced the litter size sired by the treated animals and led to permanently slightly elevated serum levels of the gonadotropins . Testicular morphology and mRNA levels of ligands and receptors involved in stem cell factor / c - kit and PDGF signaling returned to control levels , and the offsprings were born healthy . Our findings indicate that treatment of cancer with certain molecularly targeted drugs may have latent effects on testicular development by inhibiting specific physiological signaling pathways .",
"The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK7___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK7___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK7___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK7___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK7___ .",
"___MASK41___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK41___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"Immunohistochemical analysis in ethinylestradiol - treated breast cancers after prior long - term estrogen - deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER - positive patients become resistant to hormone therapy after long - term hormone treatment . ___MASK95___ ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well - known breast cancer - related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down - regulated ER and up - regulated PgR while nuclear and cytosolic AR were oppositely down - and up - regulated , respectively . Cytosolic staining of P38398 was significantly up - regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non - responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non - genomic pathway and this may be reflected in their sensitivity to EE2 treatment .",
"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .",
"Beta - cell alpha - ketoglutarate hydroxylases may acutely participate in insulin secretion . The presence of Fe ( II ) alpha - ketoglutarate hydroxylases in rat and human pancreatic islets and P01308 - 1 832 / 13 cells was demonstrated with the reverse transcriptase polymerase chain reaction ( Q96KS0 , 2 , and 3 ; lysyl hydroxylases 1 , 2 , and 3 ; and phytanoyl - coenzyme A hydroxylase were seen ) and / or immunoblotting ( high levels of proline hydroxylase P4Halpha1 , Q9GZT9 , and PHD4 and low levels of Q9GZT9 and Q9H6Z9 in human islets , and high levels of Q9GZT9 in rat islets and P01308 - 1 cells were seen ) . Prolyl hydroxylase enzyme activity in P01308 - 1 832 / 13 cells was purified with polyproline affinity chromatography . Inhibitors of alpha - ketoglutarate hydroxylases lowered glucose - induced and leucine - plus - glutamine - induced insulin release in rat pancreatic islets , suggesting that there may be acute unknown effects of alpha - ketoglutarate hydroxylases in insulin secretion . It is possible that an increase in mitochondrially generated alpha - ketoglutarate derived from insulin secretagogue carbon and translocated to the cytosol may be part of the signal for insulin secretion .",
"Deficiency of the oxygen sensor Q96KS0 augments liver regeneration after partial hepatectomy . PURPOSE : Liver regeneration after partial hepatectomy ( PH ) occurs in conditions of reduced oxygen supply . HIF prolyl hydroxylase enzymes ( Q96KS0 , Q9GZT9 , and Q9H6Z9 ) are oxygen sensors involved in adaptive response to hypoxia . Specific functions of these P20941 enzymes in liver regeneration have , however , remained enigmatic . Here , we investigated the significance of Q96KS0 in liver regeneration following hepatectomy . METHODS : Liver regeneration was studied in Q96KS0 - deficient ( Q96KS0 (-/-) ) and wild type ( WT ) mice subjected to 80 % hepatectomy . For in vitro analyses , hepatocytes were isolated from Q96KS0 (-/-) and WT livers . Cell cycle progression was studied via FACS - based analysis of nuclear DNA profile . Transcription factor binding assays , qRT - PCR , and immunoblotting were applied to study the relevance of Q96KS0 downstream effectors during liver regeneration . RESULTS : Liver regeneration was significantly enhanced in Q96KS0 (-/-) mice compared to WT littermates . This effect was due to enhanced proliferation rather than to hypertrophy of liver cells . Cell cycle progression was significantly enhanced , and transcriptional activity of the cell cycle regulator c - Myc was increased in Q96KS0 - deficient hepatocytes . These changes coincided with increased expression of cyclin D2 , a cell cycle - promoting c - Myc target , and decreased expression of the cell cycle - delaying c - Myc target P38936 . CONCLUSIONS : Loss of Q96KS0 enhances liver regeneration by boosting hepatocyte proliferation in a c - Myc - dependent fashion . Q96KS0 might , therefore , represent a potential target to facilitate liver regeneration after surgical resection .",
"Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK82___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .",
"Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation . AIMS : Studies have shown that some of statin ' s pleiotropic effects were achieved by either promotion or inhibition of angiogenesis , depending on the underlying disease . This study tested the hypothesis that the angiogenic potential of simvastatin is related to the microenvironmental conditions . MAIN METHODS : Human umbilical vein endothelial cells ( HUVEC ) were studied after exposure to hypoxia or the inflammatory factors tumor necrosis factor ( P01375 ) - alpha , with or without co - incubation with simvastatin ( 1 micromol / L ) and mevalonate . HUVEC angiogenesis was evaluated by tube formation , migration , and proliferation assays . Hypoxia inducible factor ( HIF ) - 1alpha , vascular endothelial growth factor ( P15692 ) , Akt , endothelium nitric oxide synthase ( e - NOS ) , and oxidative stress were evaluated . KEY FINDINGS : HUVEC angiogenesis increased during hypoxia ( tube length 14 . 7 +/- 0 . 5 vs . 7 . 8 +/- 0 . 6 mm , p < 0 . 05 ) and further enhanced by simvastatin ( 19 . 3 +/- 1 . 1 mm , p < 0 . 05 vs . hypoxia alone ) , which downregulated the expression of the Q9BYW2 inhibitor Q9GZT9 and upregulated HIF - 1alpha , P15692 , and Akt , without changing oxidative stress or P29474 . Incubation with P01375 promoted HUVEC angiogenesis ( 7 . 4 +/- 0 . 2 vs . 6 . 5 +/- 0 . 2 mm , p < 0 . 05 ) with increased oxidative stress . However , simvastatin inhibited this promotion ( 2 . 5 +/- 0 . 3 mm , p < 0 . 001 vs . P01375 alone ) by decreasing oxidative stress , P15692 , Akt , and P29474 . SIGNIFICANCE : We conclude that at the same dosage , simvastatin can either promote or inhibit angiogenesis , possibly by activating upstream regulators of HIF - 1alpha in hypoxia , but conversely interfering with angiogenic signaling downstream to inflammation . These opposing angiogenic effects should be considered in the therapeutic strategies with statins .",
"Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .",
"DB00126 is dispensable for oxygen sensing in vivo . Prolyl - 4 - hydroxylation is necessary for proper structural assembly of collagens and oxygen - dependent protein stability of hypoxia - inducible transcription factors ( HIFs ) . In vitro function of HIF prolyl - 4 - hydroxylase domain ( P20941 ) enzymes requires oxygen and 2 - oxoglutarate as cosubstrates with iron ( II ) and vitamin C serving as cofactors . Although vitamin C deficiency is known to cause the collagen - disassembly disease scurvy , it is unclear whether cellular oxygen sensing is similarly affected . Here , we report that vitamin C - deprived Gulo (-/-) knockout mice show normal HIF - dependent gene expression . The systemic response of Gulo (-/-) animals to inspiratory hypoxia , as measured by plasma erythropoietin levels , was similar to that of animals supplemented with vitamin C . Hypoxic HIF induction was also essentially normal under serum - and vitamin C - free cell - culture conditions , suggesting that vitamin C is not required for oxygen sensing in vivo . Glutathione was found to fully substitute for vitamin C requirement of all 3 P20941 isoforms in vitro . Consistently , glutathione also reduced HIF - 1α protein levels , transactivation activity , and endogenous target gene expression in cells exposed to CoCl ( 2 ) . A Cys201Ser mutation in Q9GZT9 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro , suggesting that this surface - accessible Q9GZT9 cysteine residue is a target of antioxidative protection by vitamin C and glutathione .",
"P38398 tumours correlate with a HIF - 1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression . BACKGROUND : There are limited data regarding the hypoxia pathway in familial breast cancers . We therefore performed a study of hypoxic factors in P38398 , P51587 and BRCAX breast cancers . METHODS : Immunoperoxidase staining for HIF - 1alpha , Q96KS0 , Q9GZT9 , Q9H6Z9 , P15692 and FIH was carried out in 125 ( 38 P38398 , 33 P51587 and 54 BRCAX ) breast carcinomas . These were correlated with clinicopathological parameters and the intrinsic breast cancer phenotypes . RESULTS : P38398 tumours correlated with positivity for HIF - 1alpha ( P = 0 . 008 ) and negativity for Q9H6Z9 ( P = 0 . 037 ) . HIF - 1alpha positivity ( P = 0 . 001 ) , Q9H6Z9 negativity ( P = 0 . 037 ) and nuclear FIH negativity ( P = 0 . 011 ) was associated with basal phenotype . HIF - 1alpha expression correlated with high tumour grade ( P = 0 . 009 ) , negative oestrogen receptor ( ER ) status ( P = 0 . 001 ) and the absence of lymph node metastasis ( P = 0 . 028 ) . Nuclear FIH expression and Q9H6Z9 correlated with positive ER expression ( P = 0 . 024 and P = 0 . 035 , respectively ) . P38398 cancers with positive HIF - 1alpha or cytoplasmic FIH had a significantly shorter relapse - free survival ( P = 0 . 007 and P = 0 . 049 , respectively ) . CONCLUSIONS : The aggressive nature of P38398 and basal - type tumours may be partly explained by an enhanced hypoxic drive and hypoxia driven ER degradation because of suppressed P20941 and aberrantly located FIH expression . This may have important implications , as these tumours may respond to compounds directed against HIF - 1alpha or its downstream targets .",
"Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK67___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Gene expression profiling of parkinsonian substantia nigra pars compacta ; alterations in ubiquitin - proteasome , heat shock protein , iron and oxidative stress regulated proteins , cell adhesion / cellular matrix and vesicle trafficking genes . Gene expression profiling of human substantia nigra pars compacta ( SNpc ) from Parkinson ' s disease ( PD ) patients , was examined employing high density microarrays . We identified alterations in the expression of 137 genes , with 68 down regulated and 69 up regulated . The down regulated genes belong to signal transduction , protein degradation ( e . g . ubiquitin - proteasome subunits ) , dopaminergic transmission / metabolism , ion transport , protein modification / phosphorylation and energy pathways / glycolysis functional classes . Up - regulated genes , clustered mainly in biological processes involving cell adhesion / cytoskeleton , extracellular matrix components , cell cycle , protein modification / phosphorylation , protein metabolism , transcription and inflammation / stress ( e . g . key iron and oxygen sensor Q9GZT9 ) . One major finding in the present study is the particular decreased expression of P63208 , a member of the P21583 ( E3 ) ligase complex specifically in the substantia nigra ( SN ) of sporadic parkinsonian patients , which may lead to a wide impairment in the function of an entire repertoire of proteins subjected to regulatory ubiquitination . These findings reveal novel players in the neurodegenerative scenario and provide potential targets for the development of novel drug compounds .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange ."
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___MASK95___
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MH_train_367
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interacts_with DB08904?
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"DB08904 in the treatment of Crohn ' s disease . INTRODUCTION : The introduction of antibodies directed against tumour necrosis factor ( anti - P01375 ) has dramatically changed the concept of treating patients with Crohn ' s disease ( CD ) . Unfortunately , the long - term efficacy of anti - P01375 agents may be hampered by immunogenicity . The availability of more anti - P01375 agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti - P01375 . In this review , the authors will focus on the efficacy of certolizumab pegol ( CZP ) . AREAS COVERED : A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD . The authors first focused on the mechanism of action of CZP . Second , they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure . Next , they explored the influence of previous anti - P01375 exposure and baseline P02741 levels . Finally , they analysed the safety data on CZP , including the development of antibodies against CZP and the use of CZP during pregnancy . EXPERT OPINION : Based on the provided literature , CZP could be a good alternative in patients with moderate - to - severe CD failing another anti - P01375 agent . More data are required to conclude on its impact on the long - term outcome of CD .",
"Profile of certolizumab and its potential in the treatment of psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic inflammatory arthropathy associated with psoriasis ( PsO ) . PsA could be considered an enthesal disease because of the link between mechanical stress ( entheses ) and immunologically active tissue ( synovium ) . Evidence of efficacy of anti - tumor necrosis factor alpha ( P01375 - α ) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment . DB08904 ( CZP ) is a polyethylene glycolylated ( PEGylated ) Fab ' fragment of a humanized monoclonal antibody that binds and neutralizes human P01375 - α . The PEG moiety of the Fab fragment , markedly increases the half - life of CZP and confers to the drug a unique structure that differs from the other anti - P01375 - α agents tested for the treatment of Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , axial spondyloarthritis , nonradiographic spondyloarthritis , PsO , and PsA . In contrast to other anti - P01375 - α agents , CZP did not mediate increased levels of apoptosis , suggesting that these mechanisms are not essential for the anti - P01375 - α efficacy in Crohn ' s disease . As CZP , infliximab , and adalimumab , but not etanercept , almost completely inhibited lipopolysaccharide - induced interleukin - 1 beta release from monocytes , this cytokine - production inhibition may be relevant for drug efficacy . Due to these characteristics , it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO , with a safety profile similar to rheumatoid arthritis . This drug can be considered as a valid treatment in patients affected by PsA . The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA .",
"P01375 as a therapeutic target in inflammatory diseases , ischemia - reperfusion injury and trauma . P01375 - alpha ( P01375 ) is a central regulator of inflammation , and P01375 antagonists may be effective in treating inflammatory disorders in which P01375 plays an important pathogenetic role . Recombinant or modified proteins are an emerging class of therapeutic agents . To date , several recombinant or modified proteins which acts as P01375 antagonists have been disclosed . In particular , antibodies that bind to and neutralise P01375 have been sought as a means to inhibit P01375 activity . Inhibition of P01375 has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis , psoriatic arthritis , and ankylosing spondylitis , inflammatory bowel disease . Additionally , the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research . The currently available therapies include a soluble p75 P01375 receptor : Fc construct , etanercept , a chimeric monoclonal antibody , infliximab , and a fully human monoclonal antibody , adalimumab . DB08904 is a novel P01375 inhibitor which is an antigen - binding domain of a humanized P01375 antibody coupled to polyethylene glycol ( PEG ) to increase half - life , and thus is Fc - domain - free . In this review , we discuss briefly the present understanding of P01375 - mediated biology and the current therapies in clinical use , and focus on some of the new therapeutic approaches with small - molecule inhibitors . Moreover , we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs , as P01375 activity inhibitories , especially in therapies of several inflammatory diseases within the nervous system .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK53___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"DB08904 for the treatment of psoriatic arthritis . DB08904 ( CZP ) is a P01375 - α inhibitor approved for the treatment of psoriatic arthritis in 38 countries , including many European countries and the USA . It is a pegylated humanized anti - P01375 - α antigen - binding fragment , administered subcutaneously . As other P01375 - α antibodies , CZP binds to and neutralizes both soluble and membrane P01375 - α . In contrast to whole antibodies and etanercept , CZP does not activate antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity , as it does not have an Fc piece . CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate - to - severe plaque psoriasis . In a Phase III study of CZP in 409 psoriatic arthritis patients , CZP treatment resulted in improvements in peripheral arthritis , as well as dactylitis , enthesitis , nail disease and quality of life . The safety profile of CZP appears to be similar to that of other P01375 - α inhibitor .",
"Efficacy and safety of certolizumab pegol in rheumatoid arthritis : meeting rheumatologists ' requirements in routine clinical practice . DB08904 , a pegylated Fab ' anti - tumour necrosis factor ( P01375 ) - α agent , has shown efficacy in patients with rheumatoid arthritis ( RA ) unresponsive to previous treatment . In key randomised controlled trials involving patients with moderate to severe RA and an inadequate response to methotrexate or one or more disease - modifying antirheumatic drug ( DMARD ) , the efficacy of certolizumab pegol , as monotherapy or with methotrexate , was similar to that reported in other anti - P01375 clinical studies , with 60 % or fewer of patients achieving American College of Rheumatology 20 % improvement in RA . Rapid clinical response was also seen , with significant differences evident at week 1 , and efficacy maintained at study end and in open - label extensions . Adding certolizumab pegol to non - biological DMARDs is efficacious in other RA populations . In the CERTAIN study , certolizumab increased remission rates , prevented disease worsening and improved work productivity and daily activity in patients with low to moderate RA . In the REALISTIC study , rapid and consistent clinical responses were observed in a diverse group of anti - P01375 - eligible RA patients representing those seen in clinical practice . In the RAPID studies , rapid and sustained reduction in RA signs and symptoms , inhibition of structural joint damage progression , and improved physical function were seen with certolizumab pegol plus methotrexate versus methotrexate alone in RA patients with an incomplete response to methotrexate . DB08904 was generally well - tolerated in clinical trials , although long - term observational data are not yet available . Current data suggest that certolizumab pegol suits a ' treat to target ' approach , providing rapid and sustained improvements in RA signs and symptoms , and beneficial effects on workplace and home productivity in patients with RA .",
"DB08904 : a review of its use in the management of rheumatoid arthritis . DB08904 ( Cimzia (®) ) is a recombinant , polyethylene glycolylated , antigen - binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor ( P01375 ) - α . The drug is indicated for subcutaneous use every 2 or 4 weeks ( q2w or q4w ) for the treatment of adults with moderate to severe active rheumatoid arthritis ( RA ) . The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed , placebo - controlled trials . In four pivotal studies of ≤ 52 weeks duration , patients with moderate to severe disease receiving recommended dosages of certolizumab pegol ( 200 mg q2w or 400 mg q4w ) , either as monotherapy ( after failing prior disease - modifying anti - rheumatic drug [ DMARD ] therapy ) or in combination with methotrexate ( after responding inadequately to methotrexate alone ) , experienced rapid clinical improvement , with some combination trials also demonstrating inhibition of radiographic progression . The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈ 5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w . Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity , as well as more clinically representative patient populations . The tolerability profile of certolizumab pegol was acceptable , with infections / infestations the most common adverse events . Thus , certolizumab pegol is an effective option for the management of active RA in adults , although additional long - term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs , particularly other anti - P01375 agents .",
"DB08904 in rheumatoid arthritis : current update . INTRODUCTION : The development of P01375 - α inhibitors ( P01375 - is ) represents a major advancement in the treatment of rheumatoid arthritis ( RA ) . Currently , there are five agents licensed for moderate - to - severely active RA . DB08904 ( CZP ) is a novel PEGylated , constant fragment - free P01375 - i therapy , which is the focus of this review . AREAS COVERED : Data from Phase III randomised controlled trials in terms of clinical efficacy , radiographic progression , patient - reported outcomes and safety profile are reviewed . These include long - term data from open - label extension studies . EXPERT OPINION : The advantages of CZP include rapid reduction of disease activity , low rates of injection - site reaction and may be safe for use in pregnancy . The long - term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti - rheumatic drugs ( DMARDs ) , in moderate - to - severely active RA , comparable to other P01375 - is . Notably , prolonged CZP exposure is not associated with increased risk of severe infection compared to general population , contrasting with preliminary analysis of short - term data . Over the next few years , evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD - naïve patients , biomarkers and the development and licensing of P01375 - i biosimilars .",
"Prefilled certolizumab pegol ( Cimzia (®) ) syringes for self - use in the treatment of rheumatoid arthritis . A new anti - tumor necrosis factor alpha ( P01375 - α ) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis ( RA ) . DB08904 ( Cimzia (®) ) is a humanized Fab ' antibody fragment against P01375 - α with a polyethylene glycol tail that prevents complement - dependent and antibody - dependent cell - mediated cytotoxicity or apoptosis . Four randomized clinical trials have been published so far . Reported results are similar to those published in previous studies with other P01375 - α inhibitors , with ACR20 , ACR50 , and ACR70 responses of around 60 % , 40 % , and 20 % , respectively , when combined with methotrexate and slightly lower when used as monotherapy . Safety was shown to be similar to that seen with P01375 - α blockers and some cases of tuberculosis were seen in the trials , stressing the importance of a complete screening in these patients . Although we still need effectiveness and safety data in larger numbers of patients and longer follow - up , this new P01375 inhibitor is a welcome addition to our current armamentarium for the treatment of RA .",
"Current directions of biologic therapies in inflammatory bowel disease . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . A greater understanding of their pathophysiology has led to new therapies that target specific molecules of the inflammatory cascade . Three anti - tumor necrosis factor ( P01375 ) monoclonal antibodies have been developed . DB00065 and adalimumab can induce clinical response and sustained remission in CD . DB00065 is also effective in UC . DB08904 gives good short - term results but long - term efficacy has yet to be determined in other clinical trials . Therapies that target leucocyte trafficking ( anti - integrins ) have also been developed and are associated with good clinical response in CD . DB00108 ( anti - α4 integrin antibody ) is associated with important side effects and is not used anymore in gastroenterology in Europe but is still used in the USA . DB09033 ( MLN0002 ) , an anti - α4β7 integrin antibody , has a good efficacy and safety profile . Monoclonal antibodies targeting other cytokines are also under development . For example , ustekinumab ( CNTO 1275 ) inhibits interleukins 12 and 23 . It is associated with a good clinical response in CD .",
"The efficacy and safety of certolizumab pegol ( CZP ) in the treatment of active rheumatoid arthritis ( RA ) : a meta - analysis from nine randomized controlled trials . OBJECTIVE : DB08904 ( CZP ) is a novel anti - P01375 agent that is used for patients with moderate to severe active rheumatoid arthritis ( RA ) . However , the efficacy of CZP in RA remains controversial . Thus , we performed this meta - analysis to assess the efficacy and safety of CZP in the treatment of RA patients . METHODS : Eligible studies were randomized controlled trials ( RCTs ) that evaluated the efficacy and safe of CZP in the patients with active RA . The primary outcome was American College of Rheumatology 20 % ( ACR20 ) , and secondary outcome were ACR50 , ACR70 , disease activity , patient - reported outcomes ( PROs ) , and adverse events . A fixed - effect model or random - effect model was used to pool the estimates , depending on the absence or presence of heterogeneity among the included studies . RESULTS : Nine RCTs with a total of 5228 patients were included in this meta - analysis , and all of the patients were administered CZP or placebo . The pooled results showed that CZP significantly improved the ACR20 , ACR50 , ACR70 response rates , and physical function . CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints - Erythrocyte sedimentation rate , arthritis pain , and fatigue . Patients who received CZP treatment did not have a higher incidence of treatment - related adverse events , no matter in any intensity . CONCLUSIONS : CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms , and improved physical function as compared with the placebo . More large - scale RCTs are needed to evaluate the long - term efficacy and safety of CZP in the treatment of active RA .",
"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .",
"[ DB08904 ] . DB08904 is a new anti - P01375 drug formed by the Fab ' fragment of a humanized mouse monoclonal antibody bound to two molecules of polyethylene glycol . DB08904 recognizes and binds to human P01375 - α , both in its soluble and membrane bound form , and has shown clinical efficacy in controlled trials for the treatment of RA and Crohns ' disease . In this review we summarize the structural characteristics and clinical efficacy data , as well as safety data of this anti - P01375 agent in patients with RA .",
"Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK24___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .",
"New concepts in anti - tumor necrosis factor therapy for inflammatory bowel disease . Crohn ' s disease is a T helper type 1 response immune disease characterized by increased production of interleukin - 12 tumor necrosis factor - a ( P01375 ) , and interferon - g . Clinical trials have demonstrated that inhibition of P01375 is effective for the treatment of Crohn ' s disease . Adverse events reported in patients treated with anti - P01375 agents include immunogenicity , acute infusion reactions , delayed hypersensitivity - type reactions , autoimmune diseases including drug - induced lupus and demyelination , and infection . This article reviews new concepts in the treatment of Crohn ' s disease and ulcerative colitis with a variety of anti - P01375 biologic therapies : infliximab , adalimumab , DB08904 , CDP571 , etanercept , and onercept .",
"Targeting nanomedicines in the treatment of Crohn ' s disease : focus on certolizumab pegol ( DB08904 ) . A variety of targets for therapeutic intervention are based upon advances in understanding of the immunopathogenesis of Crohn ' s disease . Crohn ' s disease is initiated by an innate immune response , which eventuates in a T - cell driven process , characterized by a T - helper cell 1 type cytokine profile . Several new treatments now focus on suppressing T - cell differentiation or T - cell inflammation . Since inflammatory bowel disease ( Q9UKU7 ) represents a state of dysregulated inflammation , drugs that augment the anti - inflammatory response have the potential to downregulate inflammation and thereby hopefully modify the disease . Tumour necrosis factor ( P01375 ) is a major target of research and clinical investigation . P01375 has proinflammatory effects in the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade . DB08904 ( DB08904 ) is a PEGylated , Fab ' fragment of a humanized anti - P01375 monoclonal antibody . PEGylation increases the half - life , reduces the requirement for frequent dosing , and possibly reduces antigenicity as well . Certolizumab has been shown in Phase III trials to achieve and maintain clinical response and remission in Crohn ' s disease patients . It improves the quality of life . DB08904 will be indicated for moderately to severely active Crohn ' s disease , but it is not yet licensed in Europe or the US . It is not possible to construct an algorithm for treatment , but when compared with infliximab the two principal advantages are likely to be lower immunogenicity ( as shown by anti - drug antibodies , absence of infusion reactions , and low rate of antinuclear antibodies ) , and a subcutaneous route of administration . These two factors may be sufficient to promote it up the pecking order of anti - P01375 agents .",
"How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn ' s disease . The chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , infliximab , is an effective therapy for Crohn ' s disease . However , the formation of human anti - chimeric antibodies to infliximab ( immunogenicity ) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions . The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment DB08904 are biologic therapies against P01375 that might be effective for Crohn ' s disease and less immunogenic than infliximab . Other potential alternatives to infliximab for Crohn ' s disease include the humanized anti - adhesion molecule antibodies natalizumab and DB05802 , the humanized anti - interleukin 12 antibody ABT - 874 , the humanized anti - interferon g antibody fontolizumab , the humanized anti - interleukin 6 receptor antibody DB06273 , and human recombinant granulocyte macrophage colony stimulating factor ( sargramostim ) . Some , or all , of these therapies will likely represent important treatments for Crohn ' s disease in the future .",
"Meta - analysis : the efficacy and safety of certolizumab pegol in Crohn ' s disease . BACKGROUND : DB08904 is the third anti - P01375 agent approved by the Food and Drug Administration of the United States . AIM : To provide a comprehensive up - to - date review of the efficacy and safety of certolizumab in Crohn ' s disease ( CD ) . METHODS : Electronic databases , including PubMed , EMBASE , the Cochrane library and the Science Citation Index , were searched to retrieve relevant trials . In addition , meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies . RESULTS : Three trials , enrolling a total of 1040 patients , are included in the meta - analysis to evaluate the short - term efficacy of certolizumab , which is effective for rapid induction and long - term maintenance of clinical response or remission and can improve quality of life in patients with Crohn ' s disease . Certolizumab is also effective for patients who have lost response to infliximab . However , its efficacy in infliximab - exposed patients is probably less than in infliximab - naive patients . Re - induction with certolizumab in patients who have flared on maintenance therapy can rescue a significant proportion of patients . There is no significant association between the efficacy of certolizumab and the baseline P02741 level . In comparison with placebo , certolizumab does not increase the risk of serious adverse events . CONCLUSIONS : Certolizumab is effective and safe in treating Crohn ' s disease . Further studies are still required to assess its full safety profile .",
"Anti - P01375 therapy in Crohn ' s disease . Anti - tumour necrosis factor ( P01375 ) strategies , the most studied of biological therapies , include chimeric monoclonal ( infliximab ) , humanized monoclonal ( CDP571 and the PEGylated DB08904 ) and fully human monoclonal ( adalimumab ) antibodies , p75 fusion protein ( etanercept ) , p55 soluble receptor ( onercept ) and small molecules such as MAPkinase inhibitors . The principal use of infliximab is in treating active Crohn ' s disease patients not responding to or intolerant of conventional therapies . DB00065 is steroid sparing . The development of antibodies against infliximab is associated with an increased risk of infusion reactions , and a reduced duration of response to treatment , and concomitant immunosuppressive therapy reduces the immunogenic response . The demonstration of the efficacy of maintenance therapy every 8 weeks with infliximab in the randomised , controlled , ACCENT I trial opened up the strategy for regular maintenance . In patients who have failed therapy with cortocosteroids and immunosuppressive therapy and are poor surgical candidates , and patients with fistulizing disease , where infliximab therapy is chosen , regular maintenance therapy with infliximab is likely to be required . On the other hand , patients with severely active , steroid - refractory disease in whom immunosuppressive therapy and infliximab are initiated together , may respond adequately and be continued on long - term immunosuppressive therapy alone . In ulcerative colitis the role of infliximab remains uncertain .",
"DB08904 for the treatment of Crohn ' s disease . In this article we provide a contemporary overview of available clinical data on certolizumab pegol , a pegylated anti - tumor necrosis factor ( P01375 ) alpha agent that comprises a uniquely small protein , and its emerging role as a therapy for Crohn ' s disease ( CD ) . The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD . DB08904 is an effective and well - tolerated therapy both in patients who have already received biologics and in patients who are anti - P01375 naïve . Benefits of therapy include a stable dosing regimen , which allows for rapid induction of a clinical response followed by long - term maintenance of response and remission under one fixed dose . Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD , and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression . Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients .",
"DB08904 in Crohn ' s disease . DB08904 is a humanized Fab ' fragment monoclonal antibody to tumor necrosis factor alpha ( P01375 ) . PEGylation increases its half - life , and it is administered subcutaneously to treat immune - mediated inflammatory diseases such as Crohn ' s disease and rheumatoid arthritis . DB08904 improves quality of life and reduces clinical disease activity . Inflammatory markers such as P02741 ( CRP ) also decrease after administration of certolizumab pegol . The dose for induction of remission is 400 mg subcutaneously at weeks 0 , 2 and 4 . The dose for maintenance of remission is 400 mg sc given every four weeks . The safety profile is comparable with other anti - P01375 agents , and the major adverse events are related to infections . This article reviews the published data regarding the efficacy and safety of certolizumab pegol .",
"P01375 polymorphisms as a potential modifier gene in the cystic fibrosis . Modifier genes , as the P01375 - α gene , can modulate the cystic fibrosis ( CF ) severity . Thus , - 238G > A and - 308G > A polymorphisms of P01375 - α gene were analyzed as modifiers of CF . In this context , the present study enrolled 49 CF patients ( diagnosis performed by sweat test and complete P13569 screening ) . The - 238G > A polymorphism analysis was performed by Q9ULH0 - PCR , and - 308G > A , by PCR - RFLP . In our data , the - 238G > A polymorphism was not associated with clinical variability . The AA genotype for - 308G > A polymorphism was a risk factor for early gastrointestinal symptoms ( OR = 5 . 98 , 95 % CI = 1 . 06 - 49 . 68 ) and protection for the first Pseudomonas aeruginosa ( OR = 0 . 05 , 95 % CI = 0 . 0003 - 0 . 007 ) . For the first P . aeruginosa , GA genotype was a risk factor ( OR = 10 . 2 , 95 % CI = 1 . 86 - 84 . 09 ) ; for the same genotype , the diagnosis was made in minor time than the AA genotype ( p = 0 . 031 ) . Considering the - 308G > A polymorphism alleles , the G allele was a risk factor for early pulmonary symptoms ( OR = 3 . 81 , 95 % CI = 1 . 13 - 12 . 97 ) and P . aeruginosa ( OR = 66 . 77 , 95 % CI = 15 . 18 - 482 . 7 ) ; however , the same allele showed better transcutaneous oxygen saturation ( OR = 9 . 24 , 95 % CI = 1 . 53 - 206 . 1 ) . The A allele was a protective factor for early pulmonary symptoms ( OR = 12 . 26 , 95 % CI = 0 . 08 - 0 . 89 ) and P . aeruginosa ( OR = 12 . 15 , 95 % CI = 0002 - 0007 ) , however , the same allele was a risk factor for worst transcutaneous oxygen saturation ( OR = 7 . 01 , 95 % CI = 1 . 14 - 157 . 4 ) . As conclusion , the - 308G > A polymorphism of the P01375 - α gene was associated with the CF severity .",
"The PRECiSE 2 trial of certolizumab pegol , a new PEGylated anti - P01375 agent , in the treatment of Crohn ' s disease : An interview with David A Schwartz , 13 June 2007 . DB08904 ( CDP 870 ) is a new anti - tumor necrosis factor ( P01375 ) therapy currently in development for the treatment of Crohn ' s disease , rheumatoid arthritis , and psoriasis . DB08904 is the first PEGylated biologic anti - P01375 agent and has a high binding affinity for P01375 . Dr . Schwartz was an investigator of the PRECiSE ( PEGylated Antibody Fragment Evaluation in Crohn ' s Disease Safety and Efficacy ) 2 trial of certolizumab pegol in patients with Crohn ' s disease .",
"Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn ' s disease . INTRODUCTION : P01375 - α antagonists have transformed the treatment of patients with Crohn ' s disease ( CD ) . DB08904 ( CZP ) is the third P01375 - α antagonist to be approved for use in the United States but is not currently approved in Europe . AREAS COVERED : This review evaluates the pharmacokinetics , pharmacodynamics and efficacy of CZP in CD . Safety , immunogenicity and its use in pregnancy have also been assessed . A literature search was conducted using Pub Med ( 2004 - 2014 ) for the terms ' Crohn ' s disease ' and ' certolizumab pegol ' or ' certolizumab ' or ' cimzia ' . Additional studies were identified from other sources including citation . EXPERT OPINION : As a Fab ' fragment , CZP is effective in binding P01375 - α , but does not cause Fc - mediated effects . PEGylation has improved its pharmacokinetic profile and allowed for an increased half - life of 2 weeks . Benefit for inducing response ( an improvement in symptoms ) and maintenance of remission has been shown . However , the benefit is less clear for the more stringent end - points of inducing remission and mucosal healing . There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection - site reactions , reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK31___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"DB08904 in axial spondyloarthritis . The axial spondyloarthritis ( SpA ) classification criteria cover both patients with ankylosing spondylitis and non - radiographic axial SpA . After failure of NSAIDs P01375 - α - inhibitors ( P01375 - blockers ) can be given to patients with active axial SpA . Until recently , the P01375 - blockers infliximab , adalimumab , etanercept and DB06674 are labeled for the treatment of active ankylosing spondylitis while for active nr - axSpA only adalimumab has been approved in Europe . The P01375 - blocker certolizumab pegol has recently been evaluated in the RAPID - axSpA trial which is the first placebo - controlled randomized - controlled trial in the entire group of axial SpA . An elevated P02741 and / or evidence of bone marrow edema on Q9BWK5 of the sacroiliac joints were required for inclusion in RAPID - axSpA , and patients could have been preexposed to P01375 - blockers . The interesting data of this important trial in the context of the emerging therapeutic field of non - radiographic axial SpA therapy is discussed in this review .",
"17 ___MASK90___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .",
"Strategies for targeting tumour necrosis factor in Q9UKU7 . Tumour necrosis factor ( P01375 ) plays an important role in mediating the inflammation of inflammatory bowel disease , in particular , Crohn ' s disease . Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse / human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP571 , the human soluble P01375 p55 receptor onercept , the human monoclonal antibody D2E7 ( adalimumab ) , the anti - P01375 human antibody Fab ' fragment - polyethelene glycol ( PEG ) conjugate DB08904 , and the small molecules thalidomide and CNI - 1493 ( Q96HU1 - kinase inhibitor ) . DB00065 is effective for treating active Crohn ' s disease , maintaining remission , closing fistulas , maintaining fistula closure , and treating ankylosing spondylitis . DB00065 is also being investigated for the treatment of ulcerative colitis . Side - effects occurring in patients treated with infliximab include human anti - chimeric antibodies , infusion reactions , delayed hypersensitivity reactions , formation of autoantibodies , and , in rare circumstances , drug - induced lupus and serious infections , including tuberculosis . CDP571 is effective for treating active Crohn ' s disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side - effects occurring in patients treated with CDP571 include anti - idiotype antibodies , infusion reactions and the formation of autoantibodies . A controlled trial of etanercept in patients with Crohn ' s disease was negative . Pilot studies with onercept , thalidomide , and CNI - 1493 have suggested benefit for Crohn ' s disease . There are no published data on the efficacy of adalimumab ( D2E7 ) or DB08904 for either Crohn ' s disease or ulcerative colitis . Anti - tumour necrosis factor therapies are effective for the treatment of Crohn ' s disease and are being investigated for ulcerative colitis .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"DB08904 -- what role does this new P01375 inhibitor have in the treatment of RA ? The efficacy and safety of a new tumor necrosis factor inhibitor , certolizumab pegol , in active rheumatoid arthritis has now been assessed in three phase III , multicenter , randomized , double - blind , placebo - controlled clinical trials . This commentary focuses on the paper by Keystone et al . , in which patients were followed for the longest duration . This study , which compared two doses of subcutaneous certolizumab pegol with placebo in patients with active RA receiving methotrexate , showed no advantage of 400 mg over 200 mg certolizumab pegol over 52 weeks , after induction with 400 mg . The nature of the patients enrolled in this study , trial design and possible safety issues are discussed , as is whether this trial can teach us anything about tumor necrosis factor inhibitors in general . On the basis of the results from this study , certolizumab pegol does not represent a major addition to our armamentarium , but because of the slightly different mechanism of action and structure of this drug , and the apparently acceptable therapeutic effects over one year , it is , nevertheless , welcome .",
"DB08904 attenuates the pro - inflammatory state in endothelial cells in a manner that is atheroprotective . OBJECTIVES : Rheumatoid arthritis ( RA ) is associated with accelerated atherosclerosis and premature cardiovascular death . Anti - P01375 therapy is thought to reduce clinical cardiovascular disease risk and improve vascular function in RA patients . However , the specific effects of P01375 inhibitors on endothelial cell function are largely unknown . Our aim was to explore the effects of certolizumab pegol ( CZP ) on P01375 - activated human aortic endothelial cells ( HAoECs ) . METHODS : HAoECs were cultured in vitro and exposed to i ) P01375 alone , ii ) P01375 plus CZP , or iii ) neither agent . Microarray analysis and quantitative polymerase chain reaction were used to analyse gene expression . Activation of NF - κB was investigated using immunocytochemistry , high content analysis and western blotting . Flow cytometry was performed to detect microparticle release from HAoECs . RESULTS : P01375 alone had strong effects on endothelial gene expression , while P01375 and CZP together produced a global gene expression pattern similar to untreated controls . In particular , genes for P16581 , P19320 and P05362 were significantly up - regulated by P01375 treatment . Notably , the P01375 / CZP cocktail prevented the up - regulation of these genes . P01375 - induced nuclear translocation of NF - κB was abolished by treatment with CZP . In addition the increased production of endothelial microparticles in P01375 - activated HAoECs was prevented by treatment with CZP . CONCLUSIONS : We have found at cellular level , that a clinically available P01375 inhibitor , CZP i ) reduces adhesion molecule expression ; ii ) prevents P01375 - induced activation of the NF - κB pathway and iii ) prevents the production of microparticles by activated endothelial cells . This could be central to the prevention of inflammatory environments underlying these conditions .",
"A review and expert opinion of the use of certolizumab for Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic , idiopathic , inflammatory bowel disease with no known cure . In those patients with moderate to severe disease , the result is often a clinically debilitating condition . In the last decade , one of the most significant developments in therapy has been a class of biological agents that neutralize TNFa . DB08904 ( CZP ) is the most recently FDA approved anti - P01375 agent for the induction and maintenance of moderate to severely active Crohn ' s disease . AREAS COVERED : The currently available evidence regarding the use of CZP in CD , the expected efficacy and possible adverse events associated with this population . EXPERT OPINION : CZP is a TNFa inhibitor that is a safe and effective agent for treatment of CD . It has several unique features which make it useful in patients with moderate to severe disease .",
"Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .",
"DB08904 for the treatment of Crohn ' s disease . DB08904 is a polyethylene glycolated FAb ' fragment of a humanized anti - P01375 monoclonal antibody . This pegylated molecule binds with circulating P01375 and forms an inactive complex that is then eliminated from the body . The drug has been shown to be better than placebo in the treatment of Crohn ' s disease and maintaining a clinical response in adult patients with moderate - to - severe active disease who have had an inadequate response to conventional therapy , and the treatment of adults with moderately to severely active rheumatoid arthritis . Comparative trials with an active control group are lacking . The most common adverse reactions include abdominal pain , diarrhea , injection site reactions and infection . All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy , patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy , and the initiation of therapy should be avoided if the patient has an active infection . Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia . Therapy should be discontinued if the patient develops a serious infection during therapy .",
"DB08904 compared to natalizumab in patients with moderate to severe Crohn ' s disease : results of a decision analysis . INTRODUCTION : A significant proportion of patients with Crohn ' s disease ( CD ) lose response to antibodies directed against tumor necrosis factor α ( P01375 ) . Prior P01375 - antagonist failure is associated with lower rates of response to subsequent P01375 - antagonist therapy . In patients failing two anti - P01375 agents , a choice exists between using a third - anti - P01375 therapy or natalizumab ( NAT ) , an α - 4 integrin inhibitor . A cost - effectiveness analysis comparing these competing strategies has not been performed . METHODS : A decision analytic model was constructed to compare the performance of certolizumab pegol ( CZP ) versus NAT in patients with moderate to severe CD . Previously published estimates of efficacy of third - line anti - P01375 therapy and NAT were used to inform the model . Costs were expressed in 2010 US dollars . A 1 - year time frame was used for the analysis . RESULTS : In the base case estimate , use of NAT was only marginally more effective [ 0 . 71 vs . 0 . 70 quality adjusted life - years ( QALYs ) ] than CZP but was expensive with an incremental cost - effectiveness ratio ( Q03060 ) of $ 381 , 678 per QALY gained . For CZP 2 months response rate of at least 24 % , NAT had an Q03060 above the willingness - to - pay ( WTP ) threshold . The model was sensitive to the costs of both therapies ; for all CZP costs below $ 2 , 300 per dose , NAT had higher Q03060 than the WTP threshold . Substituting adalimumab for CZP resulted in similar Q03060 estimates and thresholds for NAT use . CONCLUSIONS : In patients with moderate to severe CD failing two P01375 - antagonists , using a third P01375 - antagonist therapy appears to be a cost - effective strategy without significantly compromising treatment efficacy .",
"Desmopressin ( ___MASK37___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK37___ ) also has strong vasodilatory effects . ___MASK37___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK37___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK37___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK37___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK37___ - induced vasodilation .",
"P01375 and its inhibitors in cancer . P01375 ( P01375 ) - alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro - inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti - tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long - term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use .",
"The cytotoxic effects of certolizumab pegol and DB06674 mediated by transmembrane tumor necrosis factor α . BACKGROUND : Anti - tumor necrosis factor α ( anti - P01375 - α ) agents have been successfully applied for the treatment of rheumatoid arthritis , Crohn ' s disease , and other chronic inflammatory diseases . Not only the neutralization of soluble P01375 - α but also the effect on transmembrane P01375 - α is important mechanisms of action of anti - P01375 - α agents . This study investigated the cytotoxic effects of new anti - P01375 - α agents , certolizumab pegol and DB06674 , which are mediated by transmembrane P01375 - α . METHODS : Transmembrane P01375 - α - expressing Jurkat T cells that did not express P01375 receptors were used . The binding ability of each anti - P01375 - α agent to transmembrane P01375 - α , antibody - dependent cell - mediated cytotoxicity , complement - dependent cytotoxicity , and the apoptotic effect were examined . RESULTS : DB08904 and DB06674 bound to transmembrane P01375 - α . Golimumab induced antibody - dependent cell - mediated cytotoxicity and complement - dependent cytotoxicity , which was comparable to infliximab and adalimumab . However , certolizumab pegol did not induce antibody - dependent cell - mediated cytotoxicity or complement - dependent cytotoxicity . DB08904 directly induced nonapoptotic cell death in transmembrane P01375 - α - expressing cells . Golimumab induced a weaker apoptotic effect than infliximab and adalimumab . CONCLUSIONS : The cytotoxic effects of anti - P01375 - α agents on P01375 - α - expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases . The direct cytotoxic effect of certolizumab pegol on P01375 - α - producing cells may contribute to its clinical efficacy in Crohn ' s disease . Golimumab may be less effective for granulomatous diseases .",
"Engineering the response to vascular injury : divergent effects of deregulated Q01094 expression on vascular smooth muscle cells and endothelial cells result in endothelial recovery and inhibition of neointimal growth . P01375 - alpha ( P01375 ) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells ( ECs ) , thereby delaying reendothelialization . Prior studies have shown that direct antagonism of P01375 , using a systemically administered soluble receptor , can enhance endothelial recovery and reduce neointimal thickening . These studies have also shown that downregulation of the transcription factor Q01094 was a key mechanism of P01375 ' s effect on ECs . We now show that Ad - Q01094 overexpression at sites of balloon injury accelerates functional endothelial recovery , consistent with the prior in vitro findings . Moreover these studies also reveal divergent effects of P01375 and overexpression of Q01094 on ECs versus VSMCs . P01375 exposure of VSMCs had no affect on proliferation or apoptosis , in contrast to the effect seen in ECs . In Ad - Q01094 - transduced VSMCs , however , P01375 - induced marked apoptosis in contrast to the survival effect seen in ECs . Finally , these studies suggest that differential activation of NF - kappaB may play a key role in mediating these opposing effects . Nuclear translocation and transcriptional activity of NF - kappaB was markedly attenuated in Ad - Q01094 - transduced VSMCs , whereas it remained active in similarly treated ECs when the cells were exposed to P01375 . These studies reveal that overexpression of Ad - Q01094 primes VSMCs to P01375 - induced apoptosis . Furthermore , Q01094 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF - kappaB activation . The divergent responses of VSMCs and ECs to Q01094 overexpression provide unique therapeutic possibilities : simultaneously targeting the cell cycle of two different cell types , within same tissue microenvironment resulting in opposite and biologically complimentary effects .",
"Infectious complications of tumor necrosis factor blockade . PURPOSE OF REVIEW : Our understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs were first introduced . This review summarizes recent data regarding infection risk , examines potential structure - function relationships that may account for the differences , and discusses their implications with regard to tuberculosis prevention and management . RECENT FINDINGS : Recent prospective studies have confirmed the risk of tuberculosis reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 . Screening and initiation of treatment for latent tuberculosis ( TB ) infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . However , alternative strategies to prevent TB because of new transmission may be required as these therapies become available worldwide . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening because of recovery of P01375 - dependent inflammation . Recent case reports suggest reinstitution of P01375 blockade may be safe and effective adjunctive treatment in such cases , but prospective studies are needed to confirm these observations . SUMMARY : P01375 blockers have transformed treatment of several chronic inflammatory conditions . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infection diseases .",
"[ Biologic therapies in chronic inflammatory bowel diseases ] . Crohn ' s disease and ulcerative colitis are chronic inflammatory bowel diseases which can be difficult to control with conventional therapies . Thanks to a better knowledge of their physiopathology , new therapies aimed at specific targets of the inflammatory cascade were developed . Three monoclonal anti - P01375 antibodies were produced . DB00065 and adalimumab , currently widely used , can induce sustained remission in Crohn ' s disease . DB00065 is also efficacious in UC . DB08904 provides good short term results ; its long term efficacy , however , remains to be assessed by further clinical trials . Therapies targeting leucocyte trafficking ( anti - integrine ) have also been provided and are associated with good clinical responses in Crohn ' s disease . DB00108 ( anti - alpha4 ) is responsible for significant side effects and is no longer in use in gasrtoenterology in Europe whereas MLN02 ( anti - alpha417 ) has a good profile in terms of efficacy and safety . Monoclonal anti bodies targeting other cytokines are under development , mainly ustekinumab which inhibits IL12 and IL23 . Ustekinumab generates favourable clinical responses in Crohn ' s disease . The development of biologic therapies in inflammatory bowel disease has dramatically altered the course and management of these disorders .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK84___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"DB09280 - ___MASK52___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Randomised clinical trial : improvement in health outcomes with certolizumab pegol in patients with active Crohn ' s disease with prior loss of response to infliximab . BACKGROUND : Crohn ' s disease ( CD ) is associated with impaired health - related quality of life ( HRQoL ) . DB08904 , administered either every 2 weeks ( q2w ) or q4w , maintains efficacy in patients previously failing on the anti - P01375 agent infliximab ( WELCOME study ) . AIM : To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study . METHODS : Patients with loss of response to infliximab received open - label certolizumab pegol induction and were randomised to receive double - blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24 , with a final evaluation at week 26 . Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment : CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively . RESULTS : Baseline HRQoL burden was representative of moderately to severely active CD . HRQoL , daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26 . Treatment benefits to HRQoL , daily activity and work productivity were similar between the certolizumab pegol q2w vs . q4w groups . CONCLUSIONS : DB08904 therapy results in meaningful improvements in work productivity , daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab ( ClinicalTrials . gov number : NCT00308581 ) .",
"Optimizing anti - tumor necrosis factor strategies in inflammatory bowel disease . The introduction of infliximab , a mouse / human chimeric monoclonal antibody to tumor necrosis factor ( P01375 ) , is an important advance in the treatment of Crohn ' s disease . DB00065 is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease . The development of human antichimeric antibodies ( HACAs ) has led to infusion reactions and loss of efficacy in patients treated with infliximab . Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three - dose regimen at 0 , 2 , and 6 weeks followed by systematic maintenance dosing every 8 weeks ; concomitant immunosuppressive therapy with azathioprine , 6 - mercaptopurine , or methotrexate ; and premedication with intravenous corticosteroids . Humanized or fully human anti - P01375 biotechnologic agents , including CDP571 , DB08904 , etanercept , adalimumab , and onercept , are theoretically less immunogenic than the chimeric antibody infliximab . DB00005 is not effective for Crohn ' s disease . CDP571 is not effective in unselected patients with active Crohn ' s disease , but it may be effective in patients with elevated P02741 . The efficacy of DB08904 , adalimumab , and onercept is under investigation . The different mechanisms of action of these anti - P01375 agents may account for their variable efficacy . Their benefits , however , must be considered in the context of their risks , including infusion reaction ; delayed hypersensitivity - like reaction ; new onset of autoimmunity , with rare cases of drug - induced lupus and new - onset demyelination ; and the potential for rare but serious infections .",
"[ Treatment of patients with destructive arthritis with certolizumab pegol ] . DB08904 is a new anti - P01375 inhibitor which has been approved for the treatment of rheumatoid arthritis since October 2009 . Due to the modification of the antibody fragment by the adherence of polyethylene glycol ( PEG ) a sufficient distribution in inflammatory tissue was found in animal experiments . In two individual case reports a remission of therapy refractive arthritis was achieved by administration of certolizumab pegol .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK33___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK33___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"DB08904 : an evidence - based review of its place in the treatment of Crohn ' s disease . INTRODUCTION : Crohn ' s disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing / remitting course with transmural inflammation of potentially any section of the digestive tract . DB08904 ( CZP ) is a pegylated Fc - free Fab ' fragment of a humanized anti - P01375 - alfa monoclonal antibody that is in development for clinical use in CD . AIMS : To review the available data with CZP in CD , to investigate its possible place in therapy . EVIDENCE REVIEW : Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD , and to improve quality of life compared with placebo . Further studies with CZP are also ongoing . PLACE IN THERAPY : Although only suggested by currently available studies , successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti - P01375 treatment in CD . The impact on clinical management or on resources can not be estimated until the results from all phase III clinical trials are available and the price is determined .",
"Recommendations for the treatment of Crohn ' s disease with tumor necrosis factor antagonists : an expert consensus report . BACKGROUND : Symptom relief is the traditional treatment goal in Crohn ' s disease ( CD ) . New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor ( P01375 ) antagonists . DB00065 and adalimumab are approved as second - line treatments for severe , active CD . DB08904 is approved only in the U . S . and Switzerland as second - line treatment for moderate - to - severe , active CD . Data from trials of infliximab suggest that high - risk patients and patients with active inflammation ( CRP elevation and / or ileocolonic ulcers ) may benefit from earlier use of this drug . METHODS : A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of P01375 antagonists . At the time of this survey , infliximab was the only P01375 antagonist approved for the treatment of CD in Europe , Canada , and Australia . An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated . RESULTS : The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals , and form a rationale for using P01375 antagonists in CD patients . Control of inflammation and induction of mucosal healing were considered essential for bowel preservation . Consensus areas : 1 ) mucosal healing is predictive of improved long - term disease course and increases the likelihood of steroid - free remission ; 2 ) infliximab induces sustained mucosal healing , promotes bowel preservation , and reduces hospitalizations and surgeries ; 3 ) benefits of infliximab in relation to mucosal healing , bowel preservation , and clinical remission increase when therapy is initiated earlier . CONCLUSIONS : Treatment with P01375 antagonists helps preserve the bowel in CD patients .",
"DB08904 : a new biologic targeting rheumatoid arthritis . The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis . This is mostly due to targeted biologic agents that have changed the outcome of this disease . DB08904 ( Cimzia (®) , UCB Inc . , GA , USA ) , which targets P01375 - α with a different mechanism of action than widely used biologics , was initially investigated for Crohn ' s disease but has now been shown to be effective for rheumatoid arthritis . There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis ; two with combination methotrexate and one with monotherapy . This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease - modifying antirheumatic drugs and other biologic agents . Treatment recommendations are beyond the scope of this review ; however , with many options available , there will be annotations on current trends in the care of this chronic disease .",
"The use of P01375 blocking agents in rheumatoid arthritis : an update . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are , at present , three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate : 2 monoclonal antibodies , infliximab and adalimumab , and a fusion protein with p75 receptors , etanercept . These three agents have proved to be effective and safe in large placebo - controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease , improving quality of life and in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs were described serious adverse events , particularly infections such as tuberculosis , especially with infliximab . The risk for malignancies under P01375 antagonists , especially lymphoma , remains controversial . Specific recommendations are given by international experts for selecting and monitoring RA patients with P01375 antagonists . Other drugs targeting P01375 such as PEGylated molecules ( DB08904 or certolizumab ) are in development . These new biological therapies blocking P01375 undoubtedly constitute a considerable advancement in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .",
"Pulmonary infectious complications of tumor necrosis factor blockade . The understanding of the infection risks posed by tumor necrosis factor ( P01375 ) antagonists has continued to evolve in the 10 years since these drugs first were introduced . Recent prospective studies have confirmed the risk of tuberculosis ( TB ) reactivation posed by P01375 antibodies to be several fold greater than soluble P01375 receptor . DB08904 , a monovalent anti - P01375 Fab ' fragment , appears to share this risk , despite its lack of Fc and its inability to cross - link transmembrane P01375 or activate complement . Two - step ( boosted ) tuberculin skin test screening and initiation of treatment for latent TB infection can greatly reduce the TB risk of anti - P01375 treatment in western countries . Current recommendations for withdrawal of anti - P01375 therapy when TB is diagnosed place patients at risk for paradoxical worsening due to recovery of P01375 - dependent inflammation . Further research is needed to determine how best to prevent and manage their infectious complications and to determine their potential adjunctive therapeutic role in chronic infectious diseases .",
"Treatment of Crohn ' s disease with certolizumab pegol . Biologic therapies have revolutionized the treatment of Crohn ' s disease ( CD ) . Targeting P01375 with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD . Intravenous use of infliximab , a chimeric monoclonal antibody to P01375 is , however , limited by the occurrence of adverse events , infusion reactions , infectious complications , aggravation of heart failure , the occurrence of neurological demyelinating conditions and induction of rare malignancies . The incremental development of next - generation P01375 antibodies and binding proteins through antibody - engineering techniques has followed , with the aim of producing efficacious drugs that are less expensive to produce , have a convenient route of administration and have fewer side effects . DB08904 ( DB08904 , Cimzia ) is an engineered humanized anti - P01375 antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol . Clinical studies have demonstrated efficacy in the treatment of moderate - to - severe active CD . Reported adverse events in the clinical trial program have been largely of mild - to - moderate severity , and occurred at similar frequencies in the active - treatment and placebo groups . DB08904 will be a useful addition to the armamentarium of biologic agents that can be used for the long - term treatment of CD .",
"The use of P01375 blocking agents in rheumatoid arthritis : an overview . P01375 has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis ( RA ) . The overexpression of P01375 in RA synovium , the data from in vitro synovial cell cultures with the use of anti - P01375 antibody and the results from P01375 blockade in animal models of arthritis argued for the importance of this cytokine in RA . Drugs targeting P01375 have been developed to neutralise the deleterious effects of this inflammatory cytokine . There are currently three drugs available in the treatment of RA patients with active disease , which was refractory to conventional treatments including methotrexate , infliximab ( a chimeric mouse / human monoclonal antibody ) , etanercept ( a fusion protein combining 2 p75 P01375 receptors with a Fc fragment of human IgG ( 1 ) ) and adalimumab ( a fully human monoclonal antibody ) . These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage . With the long - term surveillance of these drugs serious adverse events were described , particularly intracellular organism infections such as tuberculosis . Other drugs targeting P01375 are in development and include monoclonal antibody ( CDP571 ) , pegylated molecules ( DB08904 and PEG - r - Hu - sTNF - RI ) or soluble p55 P01375 receptor construct ( lenercept ) . These new biological therapies blocking P01375 undoubtedly constitute a considerable advance in the management of RA , but careful evaluation at the initiation of the treatment and long - term surveillance of the patients receiving such drugs remains necessary .",
"___MASK66___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK66___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"DB08904 and rheumatoid arthritis . Just another P01375 alpha antagonist , no therapeutic advantage . No comparison with other P01375 alpha antagonists ; possible bleeding risk .",
"The clinical efficacy and safety of certolizumab pegol in rheumatoid arthritis . IMPORTANCE OF THE FIELD : The treatment of rheumatoid arthritis has changed dramatically over the past 25 years , first with the introduction of methotrexate and then the introduction of biologic therapy . These agents have provided patients with multiple treatment options to try to achieve disease remission . Unfortunately , no one single agent is fully effective in every patient ; different patients respond to different therapies , even those with the same mechanism of action , in different ways . Another medication , such as certolizumab pegol , is a welcome addition to our treatment armamentarium of rheumatoid arthritis . AREAS COVERED IN THIS REVIEW : The basis of this review is all the peer - reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years . WHAT THE READER WILL GAIN : This review should enable the reader to fully understand the benefit : risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis . TAKE HOME MESSAGE : DB08904 is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved P01375 inhibitors .",
"DB08904 for the treatment of rheumatoid arthritis . INTRODUCTION : Improved understanding of the pathogenesis of rheumatoid arthritis ( RA ) , and subsequent development of targeted therapies , have greatly advanced the management of this chronic inflammatory disease . The aim of treatment is a state of clinical remission . DB08904 ( CZP ) is a novel pegylated P01375 alpha inhibitor ( TNFi ) therapy and is the focus of this review . AREAS COVERED : CZP is different from other TNFi as it contains a polyethylene glycol ( PEG ) moiety , and lacks the constant fragment ( Fc ) of immunoglobulin ; therefore it does not activate complement . In this review in addition to clinical efficacy of CZP , effects on radiographic and patient - reported outcomes , are discussed . Adverse event data from clinical trials and extension studies are also reviewed . EXPERT OPINION : The addition of novel TNFi therapies to treat RA is welcomed . As well as displaying clinical efficacy , there is evidence to suggest that CZP has unique characteristics , including reduced transfer across the placenta and reduced frequency of injection site reactions . Furthermore , randomised controlled trials ( RCTs ) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA .",
"Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .",
"Bacterial translocation in cirrhotic rats stimulates P29474 - derived NO production and impairs mesenteric vascular contractility . DB00435 ( NO ) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis . Bacteria , potent activators of NO and P01375 synthesis , are found in the mesenteric lymph nodes ( MLNs ) of ascitic cirrhotic rats . Here , we investigated the impact of bacterial translocation ( BT ) to MLNs on P01375 production , vascular NO release , and contractility in the mesenteric vasculature of ascitic cirrhotic rats . Vascular response to the alpha - adrenoagonist methoxamine , which is diminished in the superior mesenteric arterial beds of cirrhotic rats , is further blunted in the presence of BT . BT promoted vascular NO release in cirrhotic rats , an effect that depended on pressure - induced shear stress and was blocked by the NO inhibitor N ( omega )- nitro - L - arginine . Removing the endothelium had the same effect . Endothelial NO synthase ( P29474 ) , but not the inducible isoform ( P35228 ) , was present in mesenteric vasculature of cirrhotic rats with and without BT , and its expression was enhanced compared with controls . P01375 was induced in MLNs by BT and accumulated in parallel in the serum . This P01375 production was associated with elevated levels of tetrahydrobiopterin ( BH ( 4 ) ) , a P01375 - stimulated cofactor and enhancer of P29474 - derived NO biosynthesis and NOS activity in mesenteric vasculature . These findings establish a link between BT to MLNs and increased P01375 production and elevated BH ( 4 ) levels enhancing P29474 - derived NO overproduction , further impairing contractility in the cirrhotic mesenteric vasculature .",
"Pegylation of biological molecules and potential benefits : pharmacological properties of certolizumab pegol . PEGylation of biological proteins , defined as the covalent conjugation of proteins with polyethylene glycol ( PEG ) , leads to a number of biopharmaceutical improvements , including increased half - life , increased solubility and reduced aggregation , and reduced immunogenicity . Since their introduction in 1990 , PEGylated proteins have significantly improved the management of various chronic diseases , including rheumatoid arthritis ( RA ) and Crohn ' s disease . DB08904 is the only PEGylated anti - tumour necrosis factor ( P01375 ) - α agent . It is a PEGylated , humanised , antigen - binding fragment of an anti - P01375 monoclonal antibody . Unlike other anti - P01375 agents , it has no crystallisable fragment ( Fc ) domain . Because of its novel structure , certolizumab pegol may have a different mechanism of action to the other anti - P01375 agents , and also has different pharmacodynamic properties , which could possibly translate to a different safety profile . Pharmacodynamic studies have shown that certolizumab pegol binds to P01375 with a higher affinity than adalimumab and infliximab . DB08904 is also more potent at neutralising soluble P01375 - mediated signalling than adalimumab and infliximab , and has similar or lesser potency to etanercept . DB08904 does not cause detrimental in vitro effects such as degranulation , loss of cell integrity , apoptosis , complement - dependent cytotoxicity and antibody - dependent cell - mediated cytotoxicity . DB08904 may also penetrate more effectively into inflamed arthritic tissue than other anti - P01375 agents , and is not actively transported across the placenta during pregnancy . Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics . The pharmacokinetics of certolizumab pegol in patients with RA and Crohn ' s disease were consistent with pharmacokinetics in healthy volunteers ."
] |
[
"___MASK24___",
"___MASK31___",
"___MASK33___",
"___MASK37___",
"___MASK52___",
"___MASK53___",
"___MASK66___",
"___MASK84___",
"___MASK90___"
] |
___MASK31___
|
MH_train_368
|
interacts_with DB00082?
|
[
"Automated 22 - kD growth hormone - specific assay without interference from DB00082 . BACKGROUND : Large variability exists among different growth hormone ( GH ) assays owing to differences in calibration , antibody specificity , isoform recognition , and interference from GH binding protein ( P30043 ) . The P10912 antagonist DB00082 presents a new challenge because DB00082 interferes with many GH assays . A recent consensus conference established criteria for standardization and evaluation of GH assays . Following consensus recommendations , we developed a new GH assay on an automated analyzer ( P22304 - iSYS , Immunodiagnostic Systems ) . METHODS : A monoclonal antibody not cross - reacting with DB00082 was combined with a monoclonal antibody specific for 22 - kD GH . Isoform specificity and interference from P30043 was tested and compared to that seen in 2 existing automated GH assays ( Siemens Immulite , Diasorin Liaison ) . We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments . Using the iSYS assay , we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during DB00082 treatment . RESULTS : Analytical and functional sensitivities were 0 . 01 μg / L and 0 . 04 μg / L , with a dynamic range from 0 . 04 to 100 μg / L . Intraassay CVs were 2 % - 4 % , whereas interassay CVs were 5 % - 7 % at GH concentrations between 1 . 7 and 27 . 5 μg / L . The assay was specific for 22 - kD GH and not affected by P30043 . The presence of DB00082 , which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison , had no impact on the iSYS GH assay . CONCLUSIONS : The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH .",
"DB00082 treatment in a 4 - year - old girl with neurofibromatosis type 1 . BACKGROUND / AIMS : Growth hormone ( GH ) excess in childhood is a rare disorder . Current treatment options such as somatostatin analogues , pituitary surgery or irradiation can have serious side effects . Recently , a P10912 antagonist , pegvisomant , was introduced for the treatment of adults with acromegaly . We wanted to investigate whether pegvisomant was effective in a child with octreotide - resistant GH excess . CASE : A 4 - year - old girl with neurofibromatosis type 1 and GH excess associated with optic glioma received pegvisomant injections ( 10 mg subcutaneously ) with increasing intervals from daily to every 4th day . RESULTS : P05019 and P17936 decreased from + 6 . 9 and 4 . 6 standard deviation scores ( SDS ) , respectively , to within normal range . Height velocity dropped from 12 . 4 SDS to mean - 0 . 7 SDS ( range : - 5 . 0 to 5 . 0 ) and height SDS decreased from + 1 . 3 to + 0 . 6 ( target height : + 0 . 2 ) . Random non - fasting serum GH values were mean 5 . 0 mlU / l ( range : 1 . 6 - 9 . 5 ) . There was no change in fasting blood glucose ( 4 . 6 - 4 . 7 mmol / l ) or glycosylated haemoglobin ( 5 . 5 % ) and no subjective or biochemical side effects . Repeated tests of thyroid , adrenal and gonadal function showed no alterations during the treatment period . Intracranial tumours remained unchanged in size and visual impairment did not deteriorate . CONCLUSION : DB00082 normalized P05019 and P17936 levels . Growth velocity was normalized after initial catch - down growth , and it remains to be seen whether this result can be maintained during long - term treatment .",
"P10912 antagonists . Growth hormone ( GH ) has profound effects on vertebrate growth and cellular differentiation in diverse tissue types . Sexually dimorphic levels of circulating GH vary during development and throughout the lifespan . The synthesis and secretion of GH by the pituitary gland are precisely controlled . Abnormal levels are pathological ; hyposecretion in children results in dwarfism while hypersecretion results in acromegaly . This review provides an overview of GH and the GH / insulin - like growth factor ( DB01277 ) axis and highlights a P10912 antagonist ( i . e . Somavert ( R ) , pegvisomant ) . This antagonist competes with endogenous GH for the receptor and results in suppression of serum insulin - like growth factor ( DB01277 ) . DB00082 is important for the treatment of acromegaly and may have therapeutic implications for certain types of cancer and end organ damage due to diabetes .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"A comparison of the effects of pegvisomant and octreotide on glucose , insulin , gastrin , cholecystokinin , and pancreatic polypeptide responses to oral glucose and a standard mixed meal . Standard medical therapy for patients with acromegaly includes somatostatin analogs . Owing to the widespread expression of somatostatin receptors , these may be associated with unwanted effects , such as altered glucose tolerance and impaired gut hormone release . DB00082 is a novel pegylated GH analog that competes with wild - type GH for GH - receptor binding sites but contains a position 120 , amino acid substitution that prevents functional P10912 dimerization , a known prerequisite for GH signal transduction and generation of P05019 . We have studied the short - term effects of these two therapies ( pegvisomant 20 mg / d for 7 d and octreotide 50 microg thrice daily for 7 d ) on glucose tolerance and stimulated gut hormone release in six healthy male volunteers in an open - label , random - order , cross - over study . Subjects were assessed at baseline ( oral glucose tolerance test and standard mixed meal ) and on d 6 and 7 of each therapy with a minimum washout of 2 wk between treatments . Area under the curve and peak responses were analyzed using one - way repeated - measures Q9UNW9 ( on ranks where appropriate ) . DB00082 had no effect on glucose tolerance or stimulated gut hormone response during an oral glucose tolerance test and a standard meal . In contrast , octreotide significantly increased fasting plasma glucose , lowered fasting plasma insulin , and led to deterioration in glucose tolerance ; three subjects developed impaired glucose tolerance and one diabetes mellitus by World Health Organization criteria . DB00104 significantly impaired stimulated release of cholecystokinin , gastrin , insulin , and pancreatic polypeptide . In conclusion , pegvisomant , unlike octreotide , is not associated with deterioration in glucose tolerance and impairment of stimulated gut hormone release in normal males .",
"Cyclooxygenases in rat Leydig cells : effects of luteinizing hormone and aging . Previous studies suggested that increased Leydig cell cyclooxygenase ( P36551 ) 2 expression may be involved in the reduced testosterone production that characterizes aged Leydig cells . Our objective herein was to further elucidate the relationships among LH stimulation , Leydig cell P35354 and P23219 expression , aging , and testosterone production . Incubation of Leydig cells from young or aged rats with LH or dibutyryl DB02527 resulted in increases in both intracellular P35354 protein expression and testosterone production . P23219 expression did not respond to LH or dibutyryl DB02527 . Incubation of adult cells with a protein kinase A inhibitor suppressed the stimulatory effects of LH on P35354 and testosterone production . Short - term incubation of Leydig cells with TGF - alpha or IL - 1beta also increased P35354 protein levels ; P05019 had no effect . In vivo , LH also was found to stimulate both P35354 and testosterone , but not P23219 . As reported previously , P35354 expression was greater in old than in young cells , and old Leydig cells responded to inhibition of P35354 in vitro with increased testosterone production . However , the effects of the P35354 inhibitors were not restricted to old cells ; young Leydig cells also responded to P35354 inhibition with increased testosterone production . This and the observation that the incubation of young or old cells with LH resulted in increased P35354 and testosterone production in both cases suggests that the relationship between P35354 and testosterone production is not unique to aged Leydig cells . Moreover , the close correlation between increases in P35354 and testosterone in LH - stimulated young and aged Leydig cells is difficult to reconcile with the contention that the increased expression of P35354 in aged cells is responsible for age - related suppression of Leydig cell testosterone production .",
"The challenges of reliance on insulin - like growth factor I in monitoring disease activity in patients with acromegaly . Serum insulin - like growth factor I ( P05019 ) is an important marker of disease activity in patients with acromegaly , and epidemiological data indicate control of circulating P05019 in patients with acromegaly restores life expectancy to normal . Improvements in the quality of , and access to , P05019 assays has encouraged monitoring of acromegaly with P05019 , although circulating growth hormone ( GH ) and P05019 values provide different information , so ideally both should be monitored . However , the introduction of the P10912 antagonist pegvisomant poses new challenges . DB00082 binds with high affinity to GH receptors , thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive . This leaves P05019 as the principal marker of disease activity . It is conceptually possible to induce a state of functional GH deficiency ( GHD ) with pegvisomant with P05019 values within the normal range . With the goal of minimizing the risk of over - treatment and GHD , we have provided preliminary guidance on the target range for P05019 in patients receiving pegvisomant based on the gender - and decade - based percentile ranges for P05019 of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database ( KIMS ) .",
"Novel use of endogenous GH - measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant . OBJECTIVE : The P10912 antagonist pegvisomant is increasingly used as therapy in acromegaly . Pituitary surgery might be indicated on pegvisomant treatment , due to side effects , adenoma growth or intention to cure after primary treatment . This study was initiated to clarify if , and when , GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross - react with pegvisomant . METHODS : This study was designed as a prospective study in 2006 with the German Pituitary Working Group . Only 2 cases with potentially resectable adenomas from the German DB00082 Observational Study ( GPOS ) had been operated . Now with a post - operative follow - up of more than 5 years in these 2 cases , the usefulness of immediate pre - operative GH measurement shortly after pegvisomant treatment was evaluated . RESULTS : In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal , of the GH secreting adenomas respectively . Conventional GH assays showed no effect . GH half - life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient . Endogenous GH - levels declined to less than 1 ng / ml in the days after surgery in the patient with long - term cure . CONCLUSION : Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation . Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post - operative monitoring of GH levels .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK51___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Insights from growth hormone receptor blockade . DB00082 is a genetically manipulated growth hormone ( GH ) that disables signal transduction through the P10912 and thus functions as a P10912 antagonist . In a series of studies of the metabolic effects of GH in healthy male individuals , pegvisomant has been used to create a model of acute GH deficiency but without the typical alterations in body composition . This review summarizes studies of the effects of P10912 blockade and fasting , either alone or in combination , on determinants of GH release . Based on these and other data we present a model to explain the somatotroph hyperactivity of fasting",
"The metastatic cascade is reflected in the transcriptome of metastatic canine mammary carcinomas . Proliferation , dedifferentiation and loss of cell - cell contacts are amongst the first steps of the metastatic cascade . The complex molecular pathways and gene expression changes associated with these events in canine mammary tumors are still largely undetermined . In this study , the transcriptome of 13 lymph node positive canine mammary carcinomas and corresponding non - neoplastic mammary glands were compared to identify the molecular pathways associated with metastatic progression . Differential gene expression was analyzed using gene set enrichment and pathway analysis and compared with gene expression data from human breast cancer . Metastatic canine carcinomas had 1312 significantly differentially expressed genes compared to normal mammary glands . This expression profile included a significant up - regulation of cell division and matrix invasion genes ( MMP , P05121 , P35625 ) . In contrast , genes associated with epithelial differentiation ( P01133 , P00533 , P52564 , P35610 5 ) , cell adhesion ( O00501 , Q9UBT7 , P15941 , P16284 ) and angiogenesis ( ANGPT 2 , O95841 - 4 , O43915 , P35590 ) were mostly down - regulated . Tumors had a significant decrease in membrane receptors and pathway gene expression ( P00533 , P11362 , P10912 , P09619 , TGFBR , P35590 ) indicating a tendency towards independence from these proliferative stimuli . A number of the identified deregulated pathways overlapped with gene expression profiles of human breast cancer . Gene expression profiling of metastatic carcinomas , therefore , identified molecular pathways and functional gene families that are deregulated during malignant progression in canine mammary tumors .",
"Optimizing control of acromegaly : integrating a growth hormone receptor antagonist into the treatment algorithm . Acromegaly is associated with significant morbidities and a 2 - to 3 - fold increase in mortality because of the excessive metabolic action of GH and P05019 , a marker of GH output . Reductions in morbidity correspond with decreases in P05019 , and mortality is lowered following normalization of P05019 or GH levels . Therefore , this has become an important end point . Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy , in particular , the place of pegvisomant , a P10912 antagonist . Treatment goals include normalizing biochemical markers , controlling tumor mass , preserving pituitary function , and relieving signs and symptoms . Surgery reduces tumor volume and is considered first - line therapy . Radiation reduces tumor volume and GH and P05019 levels , but the onset of action is slow and hypopituitarism typically develops . Therefore , pharmacotherapy is often used following surgery or as first - line therapy for nonresectable tumors . Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH - prolactin - cosecreting tumors but will not achieve hormone normalization in most patients . Somatostatin analogs effectively suppress GH and P05019 in most patients , but intolerance ( e . g . diarrhea , cramping , gallstones ) can occur . DB00082 , the newest therapeutic option , blocks GH action at peripheral receptors , normalizes P05019 levels , reduces signs and symptoms , and corrects metabolic defects . DB00082 does not appear to affect tumor size and has few adverse effects . DB00082 is the most effective drug treatment for acromegaly in normalizing P05019 and producing a clinical response ; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs .",
"Increased P05231 levels in pituitary - deficient patients are independently related to their carotid intima - media thickness . OBJECTIVE : Increased cardiovascular morbidity and mortality has been observed in patients with pituitary deficiency and untreated growth hormone deficiency ( GHD ) . We investigated peripheral inflammatory and fibrinolytic markers and their associations with arterial intima - media thickness ( IMT ) in GHD . DESIGN : Cross - sectional study . PATIENTS : Thirty - four patients with GHD , but without cardiovascular disease , were compared to healthy controls matched for age , sex , body mass index ( BMI ) and smoking habits . MEASUREMENTS : IMT of the common carotid artery , P02741 ( CRP ) , interleukin - 6 ( P05231 ) , fibrinogen , plasminogen activator inhibitor - 1 ( P05121 ) activity and tissue plasminogen activator antigen ( tPA - ag ) were measured . RESULTS : Median P05231 concentrations were increased by 208 % and 248 % in GHD patients compared to BMI - matched and nonobese controls , respectively . Median CRP and tPA - ag levels were increased by 237 % and 167 % in patients compared to nonobese controls , but not significantly different compared to BMI - matched controls . Plasma levels of fibrinogen and P05121 activity did not differ between groups . Age , low - density lipoprotein ( LDL ) cholesterol , tPA - ag and P05231 were positively correlated , and P05019 was negatively correlated to IMT in the patient group , but only age and P05231 were independently related to IMT . CONCLUSIONS : P05231 concentrations were increased in GHD patients compared to controls and independently related to IMT in patients . This finding may help to explain the variance in IMT and the increased vascular morbidity and mortality in hypopituitary patients with GHD .",
"Lessons from 6 years of P10912 antagonist therapy for acromegaly . DB00082 is a P10912 antagonist and a new agent for the medical management of acromegaly . The clinical efficacy and safety of pegvisomant in the treatment of active acromegaly were demonstrated in a 12 - week , placebo - controlled trial of 112 patients . After a washout period , patients were randomized to a fixed dose of pegvisomant ( 10 , 15 or 20 mg / day ) or placebo given by sc injection . Serum P05019 levels were within the normal age - adjusted reference range in 54 , 81 and 89 % of patients in the 10 - , 15 - and 20 - mg / day groups , respectively . The decrease in serum P05019 levels was accompanied by considerable improvement in the signs and symptoms of active acromegaly . This efficacy profile was maintained in a long - term continuation trial , with normalization of serum P05019 at 12 months occurring in 97 % of patients . DB00082 has been well tolerated with an adverse event profile similar to placebo . Two patients had elevations in liver function tests that resolved after discontinuing treatment with pegvisomant . During treatment with pegvisomant , liver function tests should be monitored on a regular basis . Two patients had an increase in pituitary tumor volume during pegvisomant therapy ; however , the relationship to pegvisomant therapy was not clear . In 131 patients treated for at least 6 months , there was no increase in mean tumor volume , regardless of whether they underwent previous radiotherapy . DB00082 is an effective new treatment for the management of patients with acromegaly . Longer - term data are needed to confirm the safety profile that has been demonstrated in studies up to 18 months .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK42___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK53___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"P21554 regulates P29323 and GSK - 3β - dependent glucocorticoid inhibition of osteoblast differentiation in murine MC3T3 - E1 cells . Supraphysiological glucocorticoid administration accelerates loss of survival and differentiation in osteoblastic cells , thereby increasing the risks of osteopenic or osteonecrotic disorders . Neuroendocrine component type 1 cannabinoid receptor ( P21554 ) is found to regulate bone mass . This study characterized the biological role of P21554 in glucocorticoid - induced suppression of osteoblast differentiation . Murine MC3T3 - E1 osteoblasts were incubated under osteogenic conditions in the presence or absence of 1 μM glucocorticoid , RNA interference , P21554 antagonist AM251 , and agonist WIN55212 - 2 . Cell survival was detected by formazan synthesis and TUNEL staining . Osteoblast differentiation was quantified by mineralized matrix accumulation and expression of the osteogenic factors Runx2 and osteocalcin . Expression of signaling molecules was assessed by immunoblotting . Glucocorticoid increased P21554 expression in association with decreased osteocalcin expression and mineralized nodule deposition . P21554 RNA interference and AM251 attenuated the deleterious actions of glucocorticoid treatment on survival and osteogenic activities , whereas activating P21554 by WIN55212 - 2 impaired osteoblast differentiation . P21554 signaling regulated JNK , P29323 , GSK - 3β , and Akt activation as well as Runx2 and P05019 expression . Inhibition of GSK - 3β by the kinase - inactive GSK - 3β mutant or activation of P29323 by the active MEK - 1 mutant abrogated glucocorticoid - induced inhibition of osteoblast differentiation . Glucocorticoid - induced P21554 expression occurred via glucocorticoid receptor - dependent transcriptional and translational regulation . Gain of Runx2 function and loss of P28562 action attenuated glucocorticoid - induced enhancement of P21554 expression . Taken together , P21554 regulation of P29323 and GSK - 3β - dependent pathways participates in glucocorticoid inhibition of Runx2 signaling and osteoblast differentiation . Runx2 reciprocally regulates glucocorticoid - induced promotion of P21554 signaling . Our findings provide new insights into the role of the neuroendocrine component P21554 in glucocorticoid - induced osteoblast dysfunction .",
"A pegylated growth hormone receptor antagonist , pegvisomant , does not enter the brain in humans . BACKGROUND : GH receptors exist in the hippocampus , cerebral cortex , and hypothalamus , possibly influencing mood , cortical blood flow , and neuronal growth and mediating negative feedback . RATIONALE : DB00082 is a recombinant mutated GH molecule with high affinity , but little or no activating capability , for the P10912 . It is used clinically as a GH antagonist . HYPOTHESIS : Systemic pegvisomant enters brain interstitial fluid via putative choroid - plexus GH receptors , thereby allowing for antagonism of central actions of GH . SUBJECTS AND LOCATION : Six adults requiring a cerebrospinal fluid ( P04141 ) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center . METHODS : Direct assays were conducted of serum and P04141 pegvisomant concentrations 18 - 24 h after sc injection of pegvisomant ( 20 mg ) . OUTCOMES : Median ( range ) concentrations of pegvisomant in serum were 215 ( 74 - 539 ) microg / liter and in P04141 0 . 035 ( 0 . 010 - 0 . 28 ) microg / liter ( P = 0 . 016 ) . P04141 drug levels were indistinguishable from assay threshold . Corresponding GH values were 0 . 29 ( 0 . 010 - 1 . 3 ) in serum and 0 . 075 microg / liter ( 0 . 01 - 0 . 13 ) in P04141 . The geometric mean ratios of serum / P04141 pegvisomant and GH concentrations were 5116 : 1 and 3 . 5 : 1 , respectively , thus defining a more than 1400 - fold difference between mutated and natural GH . CONCLUSIONS : Based upon P04141 measurements , a pegylated GH - receptor antagonist does not cross the human blood - brain barrier , thereby sparing inhibition of central nervous system GH actions . Thus , the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood - brain barrier , such as via the median eminence and / or via suppression of P05019 concentrations .",
"Cytokine responses of intestinal epithelial - like Caco - 2 cells to non - pathogenic and opportunistic pathogenic yeasts in the presence of butyric acid . Candida albicans , Saccharomyces cerevisiae and their cell wall components , zymosan and glucan , have been shown to stimulate interleukin - 8 ( P10145 / CXCL - 8 ) production by intestinal epithelial cell - like Caco - 2 cells pre - cultured with 10 mM butyric acid . We examined in this study whether these yeasts also altered the production of other cytokines and cyclooxygenases ( COXs ) by Caco - 2 cells . Culturing Caco - 2 cells with 10 mM butyric acid and 15 % FBS for 4 days enhanced the basal levels of mRNA encoding P05231 , P10145 , Q14116 , monocyte chemoattractant protein ( MCP ) - 1 , stem cell factor , transforming growth factor ( TGF ) - beta1 , TGF - beta3 , tumor necrosis factor ( P01375 ) - alpha , P23219 , and P35354 , but not of granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) and TGF - beta2 . The inclusion of live S . cerevisiae or C . albicans further enhanced the production of P10145 , but not of the other cytokines and COXs . The non - pathogenic yeasts , C . kefyr , C . utilis , C . versatilis , Kluyveromyces lactis , K . marxianus , Schizosaccharomyces pombe and Zygosaccharomyces rouxii , used for the production of fermented foods and probiotics , and the opportunistic pathogens , C . glabrata , C . krusei , C . parapsilosis and C . tropicalis , isolated from human tissue samples also enhanced P10145 secretion by Caco - 2 cells .",
"Management of acromegaly : is there a role for primary medical therapy ? Acromegaly is a chronic , debilitating disease caused by chronic growth hormone ( GH ) hypersecretion which results in chronic medical comorbidities , poor quality of life and high mortality rates . Successful treatment can improve clinical signs and symptoms and normalize mortality rates . Over 95 % of acromegaly is caused by a somatotroph adenoma of the pituitary , and the first - line treatment is generally transsphenoidal surgery , which can be curative in 50 - 60 % of patients . Nonetheless , high rates of persistent acromegaly following surgery and the limited efficacy of radiation therapy necessitate chronic medical treatment for many patients . Somatostatin analogues have become the preferred first - line medical therapy for many practitioners , as they achieve better biochemical and direct tumor control than the dopamine agonists , and long - acting preparations make once monthly administration possible . Cabergoline , a dopamine agonist , offers a lower - cost option and may be effective in patients with a pituitary tumor that co - secretes GH and prolactin . DB00082 is a P10912 antagonist that produces exceptional biochemical response rates but lacks any direct effects on the tumor , which may limit its effectiveness as life - long monotherapy . Combinations of these three drug classes have not been rigorously studied , and preliminary trials do not suggest improved clinical outcomes . While medical treatment options for acromegaly have significantly improved over the last 30 years , limitations remain , and a multi - specialty team approach is necessary for the effective long - term management of patients with acromegaly .",
"DB00082 : a growth hormone receptor antagonist for the treatment of acromegaly . P10912 ( P10912 ) dimerization is a prerequisite to the generation of growth hormone ( GH ) action . DB00082 is a P10912 antagonist that has been designed to bind to the P10912 at the cell surface and hence block this process . Initial studies suggest that pegvisomant is a highly effective antagonist of GH action in patients with acromegaly . The blockade of GH action , rather than the inhibition of pituitary GH secretion , represents a novel concept in the medical management of acromegaly . In this review , the design , efficacy , challenges and future role of pegvisomant are discussed .",
"Age - and sex - associated plasma proteomic changes in growth hormone receptor gene - disrupted mice . P10912 gene - disrupted ( P10912 -/- ) mice are dwarf , insulin sensitive , and long lived despite being obese . In order to identify characteristics associated with their increased longevity , we studied age - related plasma proteomic changes in these mice . Male and female P10912 -/- mice and their littermate controls were followed longitudinally at 8 , 16 , and 24 months of ages for plasma proteomic analysis . Relative to control littermates , P10912 -/- mice had increased levels of apolipoprotein A - 4 and retinol - binding protein - 4 and decreased levels of apolipoprotein E , haptoglobin , and mannose - binding protein - C . Female P10912 -/- mice showed decreased inflammatory cytokines including interleukin - 1β and monocyte chemotactic protein - 1 . Additionally , sex differences were found in specific isoforms of apolipoprotein E , P02753 - 4 , haptoglobin , albumin , and hemoglobin subunit beta . In conclusion , we find plasma proteomic changes in P10912 -/- mice that favor a longer life span as well as sex differences indicative of an improved health span in female mice .",
"Growth hormone and glucose metabolism : the model of the GH - receptor antagonists . DB00082 is a GH analogue that includes a single amino acid substitution at position 120 that generates the P10912 antagonist . Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half - life and reduce the immunogenicity of the molecule . In acromegalics , pegvisomant is the most effective treatment for normalizing the P05019 , and pegvisomant significantly improves insulin sensitivity in patients suffering from acromegaly . However , there are simply no data available that might support a role for pegvisomant treatment in disorders in which glucose metabolism is disturbed and in which reducing GH action would be theoretically beneficial .",
"DB00082 treatment in gigantism caused by a growth hormone - secreting giant pituitary adenoma . BACKGROUND : Gigantism is rare with the majority of cases caused by a growth hormone ( GH ) - secreting pituitary adenoma . Treatment options for GH - secreting pituitary adenomas have been widened with the availability of long - acting dopamine agonists , depot preparations of somatostatin analogues , and recently the P10912 antagonist pegvisomant . CASE REPORT : A 23 - year - old male patient presented with continuous increase in height during the past 6 years due to a GH - secreting giant pituitary adenoma . Because of major intracranial extension and failure of octreotide treatment to shrink the tumour , the tumour was partially resected by a trans - frontal surgical approach . At immunohistochemistry , the tumour showed a marked expression of GH and a sparsely focal expression of prolactin . Somatostatin receptors ( sst ) 1 - 5 were not detected . Tumour tissue weakly expressed dopamine receptor type 2 . The Gs alpha subunit was intact . Conversion from somatostatin analogue to pegvisomant normalized insulin - like - growth - factor - I ( P05019 ) levels and markedly improved glucose tolerance . CONCLUSION : DB00082 is a potent treatment option in patients with pituitary gigantism . In patients who do not respond to somatostatin analogues , knowledge of the P61278 receptor status may shorten the time to initiation of pegvisomant treatment .",
"Evaluation of the role of keratan sulphate as a molecular marker to monitor cartilage metabolism in horses . The role of keratan sulphate ( KS ) as a metabolic marker of cartilage was evaluated using an in vitro model of equine articular cartilage . Articular cartilage was harvested from clinically healthy 6 - month - old foals ( n = 3 ) . Chondrocytes were centrifuged and cultured as pellets . Chondrocyte pellets were stimulated by insulin - like growth factor - I alpha ( P05019 alpha ) or interleukin - 1 alpha ( P01583 ) for 2 weeks . The concentrations of sulphated glycosaminoglycans ( GAG ) and KS in the culture media were measured by a 1 , 9 - dimethyl - methylene blue ( DMMB ) colorimetric assay and an inhibition enzyme - linked immunosorbent assay using a 1 / 20 / 5D4 antibody , respectively . The concentration of GAG was significantly increased both in the media of pellets stimulated by P05019 alpha and in those stimulated by P01583 . KS concentration was significantly increased in those stimulated by P01583 , while no significant change was found in those stimulated by P05019 alpha . A high correlation between GAG and KS concentrations was found in the media of pellets stimulated by P01583 ( r = 0 . 84 ) , but not in those stimulated by P05019 alpha ( r = 0 . 59 ) . The results suggest that the concentration of KS reacting to 1 / 20 / 5D4 mirrors the GAG concentration during the stage of cartilage catabolism , but not during the cartilage anabolic stage . The KS concentration in biological fluids could therefore be a useful marker to understand further the cartilage catabolic process . It may also represent some aspects of the cartilage anabolic process .",
"Evaluation of growth hormone ( GH ) action in mice : discovery of P10912 antagonists and clinical indications . The discovery of a growth hormone receptor antagonist ( GHA ) was initially established via expression of mutated GH genes in transgenic mice . Following this discovery , development of the compound resulted in a drug termed pegvisomant , which has been approved for use in patients with acromegaly . DB00082 treatment in a dose dependent manner results in normalization of DB01277 levels in most patients . Thus , it is a very efficacious and safe drug . Since the GH / DB01277 axis has been implicated in the progression of several types of cancers , many have suggested the use of pegvisomant as an anti - cancer therapeutic . In this manuscript , we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions . Additionally , we will describe experiments in which the GHA was discovered , review results of pegvisomant ' s preclinical and clinical trials , and provide data suggesting pegvisomant ' s therapeutic value in selected types of cancer .",
"P00747 activator system : implications for mammary cell growth and involution . Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin . The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner . Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution ( the declining phase of lactation ) . Treatment with bST prevented the increase in plasmin during gradual involution , indicating that bST interferes with conversion of plasminogen to plasmin . Concentrations of plasminogen activator in mammary tissue are high after cessation of milking . These results reinforce the association of the plasmin - plasminogen system with gradual involution postlactation . Recently , a role has been proposed for plasminogen activator in cell proliferation in several cellular systems . P01308 and P05019 increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells . In contrast , phorbol myristate acetate , which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells , stimulated proliferation of myoepithelial cells , but not epithelial cells . Thus , expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells .",
"Long - term treatment of acromegalic patients resistant to somatostatin analogues with the P10912 antagonist pegvisomant : its efficacy in relation to gender and previous radiotherapy . CONTEXT : DB00082 is an effective treatment for somatostatin analogue - resistant acromegaly , but the determinants defining the response to this treatment are largely unknown . OBJECTIVE : To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients ( e . g . serum IGF1 at least 1 . 25 x upper normal limit ) in a clinical setting and the factors conditioning this response . DESIGN AND SETTING : A retrospective cross - sectional study performed in six Spanish University hospitals from 2004 to 2007 . Patients Forty - four acromegalic patients ( 61 . 4 % female , mean age : 49 +/- 14 ) , 95 % of whom had undergone pituitary surgery and 61 % having received pituitary radiotherapy . The mean follow - up was 22 . 7 +/- 11 . 2 months . Main outcome measures IGF1 levels reflected treatment efficacy , and the influence of gender , age , weight , previous radiotherapy and duration of treatment was assessed . RESULTS : IGF1 normalisation was achieved in 84 % of the patients . Male gender ( P < 0 . 05 ) , previous irradiation ( P < 0 . 05 ) and the treatment duration ( r = 0 . 364 , P < 0 . 02 ) were associated with a better response to pegvisomant therapy . There was a significant decrease in HbA1c ( P < 0 . 001 ) and in the mean insulin dose ( P < 0 . 01 ) in acromegalic diabetic patients . Although 25 % of patients experienced mild adverse events , pegvisomant was only withdrawn in four patients due to side effects ( two cases of tumour growth , one liver dysfunction and one headache ) . CONCLUSIONS : Long - term pegvisomant is a very effective therapy in resistant acromegaly . Male gender and prior radiotherapy influence the therapeutic response rate .",
"DB00082 : current and potential novel therapeutic applications . BACKGROUND : DB00082 is a genetically engineered molecule , which exhibits specific growth hormone ( GH ) antagonism by directly interacting with the P10912 . It is currently licensed for the treatment of acromegaly where surgery and medical therapy with somatostatin analogues have failed . OBJECTIVE : To delineate the role of pegvisomant in the treatment of acromegaly and its novel application in other areas of clinical medicine where suppression of GH action may be of therapeutic benefit . METHODS : A literature review from PubMed - and EMBASE - listed publications and the web - sites of licensing organisations for medicinal products . CONCLUSION : DB00082 is currently used as a second line therapy in the management of acromegaly . It is highly effective in suppressing the metabolic effects of elevated GH levels when used alone or in combination with somatostatin analogues . However , its long term efficacy and safety for this indication has yet to be established . Preliminary data indicate that pegvisomant may have a role in management of type 1 diabetes with beneficial effects on insulin sensitivity and in preventing the progression of microvascular complications . Additional roles as an adjunct to cancer chemotherapy regimens and for the diagnosis of GH deficiency have been proposed , but have yet to be confirmed .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK36___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK68___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"[ P10912 antagonist in the treatment of acromegaly ] . Exploration of construction , function and interaction of human growth hormone and growth hormone receptor in details resulted in the innovation of the new growth hormone receptor antagonist , pegvisomant . DB00082 with different mechanism of action extended the tools of medical management of acromegaly . Importance of the novel treatment modality is high . In one hand the necessity of the strict control of growth hormone / insulin - like growth factor - I axis has been proven regarding the mortality of the disease . On the other hand , despite the use of all current modes of treatment ( surgery , radiotherapy , dopamine agonists , somatostatin analogs ) , a significant cohort of patients with acromegaly remains inadequately controlled . DB00082 has been registered in 2004 . Since 2006 , it has been used in Hungary for the treatment of acromegaly in patients who have had an inadequate response to surgery and / or radiation therapy and / or other medical therapies , or for whom these therapies are not appropriate . Clinical use of pegvisomant in the treatment of acromegaly is effective , well tolerated , and safe , based on international Acrostudy database . In order to improve the efficacy of therapy clinical trials started with pegvisomant and somatostatin analog combination treatment . Evidence of several further effects of the growth hormone / insulin - like growth factor - I axis suggests other potential uses of growth hormone receptor antagonists .",
"Experience with pegvisomant in the treatment of acromegaly . Established modalities of therapy for acromegaly ( surgical adenomectomy , external beam pituitary irradiation , oral dopamine agonists , and injectable somatostatin analogues ) have as their common goal the lowering of circulating growth hormone ( GH ) levels , with a consequent reduction in serum insulin - like growth factor I ( P05019 ) . DB00082 is a P10912 antagonist that inhibits P10912 dimerization and has a powerful ability to lower serum P05019 levels in patients with active acromegaly . Currently available data suggest that pegvisomant is an effective treatment for acromegaly that is safe , well tolerated , and not associated with expansion of residual pituitary tumour over the time period studied .",
"Successful treatment of resistant acromegaly with a growth hormone receptor antagonist . BACKGROUND / OBJECTIVE : DB00082 is a pegylated analogue of human GH and functions as a potent P10912 antagonist . This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity can not be satisfactorily controlled by conventional therapy . We have documented the clinical details of seven patients with residual active acromegaly after surgery and / or radiation therapy successfully treated with pegvisomant . PATIENTS / METHODS : Seven patients ( four male , mean age 47 years , range 34 - 67 years ) who participated in two separate clinical trials of pegvisomant have completed 2 years ( four patients ) or 1 year ( three patients ) of treatment . All had active acromegaly ( mean serum GH level > 5 mU / l ; serum P05019 elevated for age ) that could not be controlled with standard medical therapy ( dopamine agonist and / or a somatostatin analogue ) following appropriate primary treatment with surgery and / or radiotherapy . RESULTS : On a median dose of 20 mg / day ( range 15 - 40 ) pegvisomant , serum P05019 fell from a mean of 920 +/- 351 ng / ml ( s . d . ) to 258 +/- 91 ng / ml and was normalised in all seven patients . These changes were associated with improvements in soft tissue enlargement and general well being . Treatment was well tolerated and no change in pituitary tumour size was evident on Q9BWK5 scans performed every 6 months . CONCLUSIONS : Treatment with pegvisomant is safe and efficacy is maintained after 2 years . Serum P05019 may be normalised in patients who are refractory to conventional therapy .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"The effects of recombinant human GH on promoting tumor growth depend on the expression of P10912 in vivo . Cancer - related malnutrition is a mortal threat to gastric carcinoma patients . However , conventional nutrition treatment is not effective for recovery . Recombinant human GH ( rhGH ) is widely accepted clinically to treat severe malnutrition caused by non - malignant diseases , but not approved to treat malignant diseases due to the safety concern . To explore the safety of rhGH on gastric cancer , we assessed the effect of rhGH on two tumor - bearing mice models in vivo established by human gastric adenoma cell lines of SGC - 7901 and MKN - 45 . P15692 expression in tumor tissues was detected using immunohistochemistry . The expression of P10912 ( Ghr ) , Jak - 2 , Stat3 , Vegf , Hif - 1α , Fgf , and Mmp - 2 was measured by RT - PCR and protein expression of P40763 , phosphorylated P40763 , P15692 , HIF - 1α , and P08253 was measured by western blotting . The immunocytochemistry results showed that the P10912 expression of SGC - 7901 was strongly positive ( P10912 (+++) ) , while P10912 expression of MKN - 45 was regarded as negative ( P10912 (-) ) . After 14 days of rhGH treatment in SGC - 7901 ( P10912 (+++) ) tumor - bearing mice , we found that the tumor growth was significantly increased , and the expressions of downstream factors and P15692 were increased . However , in MKN - 45 ( P10912 (-) ) tumor - bearing mice , tumor growth was not significantly increased by rhGH , but tumor - free body weight was increased especially in high - dose rhGH - treated group ( P < 0 . 05 ) . These findings suggest that the level of P10912 expression is a key target that influences the effectiveness of rhGH on promoting the growth of gastric cancer and angiogenesis . rhGH may promote the activation of tumor angiogenesis factors through the Jak - 2 - P40763 pathway .",
"Additional metabolic effects of adding P10912 antagonist to long - acting somatostatin analog in patients with active acromegaly . OBJECTIVE : Somatostatin analogs , dopamine agonists and GH - receptor antagonist -- pegvisomant are used in medical therapy of acromegaly . Since pegvisomant has not antitumor effect , the combination of pegvisomant and somatostatin analog could be an attractive option . Aim of study was to assess the effects of pegvisomant and octreotide P10586 treatment on GH and DB01277 levels , and glucose tolerance in acromegaly , and to assess efficacy and tolerability of rapid ( after 7 days ) pegvisomant dose titration . MATERIAL AND METHODS : Six patients ( 4 men , 2 women ) aged 47 . 5 years ( median ) with active acromegaly , after neurosurgery failed , resistant to maximal doses of octreotide , received daily 10 - 20 mg pegvisomant throughout 2 weeks . They were given octreotide P10586 30 mg monthly for at least 6 months before pegvisomant therapy . Clinical symptoms , GH , DB01277 , fasting glucose and insulin levels were measured on the 0 , 8th and 15th day of pegvisomant therapy . On the 8th day pegvisomant dose was titrated based on serum DB01277 level . RESULTS : DB01277 levels reduced from 739 at the beginning to 418 ng / ml ( medians ) on the 15th day of treatment and normalized in one patient . These changes were associated with improvement of glucose metabolism . One diabetic patient could even stop insulin therapy . CONCLUSIONS : DB00082 is an attractive adjuvant therapy for controlling acromegaly . DB00082 improves insulin sensitivity as well as glucose tolerance . The P10912 antagonist is good option for patients with active acromegaly coexistent with disturbances of glucose metabolism , especially with diabetes mellitus . Rapid pegvisomant dose increasing to efficient or maximal is well tolerated and effective .",
"DB00082 in the treatment of acromegaly . Epidemiological studies have highlighted the need for tight control of growth hormone ( GH ) and insulin - like growth factor I ( P05019 ) in patients with acromegaly . Studies highlighting the events involved in P10912 signaling have allowed the development of a pegylated P10912 antagonist ( pegvisomant ) for use in humans , which has been designed to outcompete GH for the P10912 , but which contains a position 120 amino acid substitution that prevents recruitment of a second P10912 . This process of receptor dimerisation is crucial for signal transduction and P05019 generation . Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date , as this therapy is capable of normalising serum P05019 in up to 97 % of patients when doses of 40 mg per day are used . This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date .",
"[ P10912 antagonists : potential indications ] . DB00082 is a mutated human growth hormone molecule , which binds to the growth hormone receptor . This binding , however , does not lead to signal transduction . Therefore , in high concentrations pegvisomant acts as a growth hormone receptor antagonist . In a short term study ( 3 months ) pegvisomant was shown to be an effective treatment for acromegaly . On theoretical grounds decreasing the biological effects of growth hormone in patients with diabetes mellitus could have a favourable impact on the severity of the secondary complications associated with this disease . Animal models for diabetic retino - and nephropathy are in accordance with this concept . Human data are lacking but clinical studies investigating the effect of pegvisomant in diabetes mellitus are in preparation . Growth hormone , either directly or via its downstream effector insulin - like growth factor - I ( P05019 ) has been implicated as an important factor in the growth of malignant tumours . Animal studies in which human colon and breast cancer models were used showed that pegvisomant can powerfully decrease tumour growth . Studies in cancer patients have not yet started .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK89___ and Tissue P00747 Activator in Occluded Arteries .",
"The place of pegvisomant in the management of acromegaly . Conventional treatments for acromegaly include surgery , radiotherapy , dopamine agonists and somatostatin ( P52788 ) analogues , which effect disease control by lowering circulating growth hormone ( GH ) . Due to variability in tumour characteristics , combinations of these treatment modalities leave a significant number of patients with sub - optimal serum GH and insulin - like growth factor - I ( P05019 ) levels , which have been linked to increased morbidity and mortality . The P10912 antagonist pegvisomant is a genetically engineered analogue of GH that prevents functional dimerisation of the growth hormone receptor ( P10912 ) ; a process that is critical to GH action at the cellular level . A crucial amino acid substitution at DB00145 ( 120 ) to DB00125 ( 120 ) within the third alpha helix of the antagonist prevents functional P10912 dimerisation . DB00082 represents a novel treatment for acromegaly as , unlike existing treatment modalities , the effectiveness of pegvisomant is independent of pituitary tumour characteristics . Initial clinical studies in patients with active acromegaly have demonstrated serum P05019 normalisation in over 90 % of patients receiving 20 mg per day , such that , in terms of serum P05019 normalisation , pegvisomant now represents the most effective medical treatment for acromegaly . Although there are limited long - term data on the use of pegvisomant and questions regarding pituitary tumour growth and altered liver function remain , this therapy offers the prospect of serum P05019 normalisation in the vast majority of patients with active acromegaly .",
"The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF - 7 breast cancer xenograft growth . Mammary gland development is dependent upon the growth hormone ( GH ) / insulin - like growth factor - I ( P05019 ) axis , this same axis has also been implicated in breast cancer progression . In this study we investigated the effect of a GH antagonist , pegvisomant ( Somavert , Pfizer ) , on normal mammary gland development and breast cancer xenograft growth . Intraperitoneal administration of pegvisomant resulted in a 60 % suppression of hepatic P05019 mRNA levels and upto a 70 - 80 % reduction of serum P05019 levels . DB00082 administration to virgin female mice caused a significant delay of mammary ductal outgrowth that was associated with a decrease in the number of terminal end buds and reduced branching and complexity of the gland . This effect of pegvisomant was mediated by a complete inhibition of both GH and IGF - IR - mediated signaling within the gland . In breast cancer xenograft studies , pegvisomant caused shrinkage of MCF - 7 xenografts , with an initial 30 % reduction in tumor volume , which was associated with a 2 - fold reduction in proliferation and a 2 - fold induction of apoptosis . Long - term growth inhibition of MCF - 7 xenografts was noted . In contrast , pegvisomant had no effect on MDA - 231 or MDA - 435 xenografts , consistent with primary growth of these xenografts being unresponsive to P05019 both in vitro and in vivo . In MCF - 7 xenografts that regressed , pegvisomant had only minor effects upon P10912 and IGF - IR signaling . This data supports previous studies indicating a role for GH / IGF in mammary gland development , and suggests that pegvisomant maybe useful for the prevention and / or treatment of estrogen receptor positive breast cancer .",
"DB00082 Pfizer / Sensus . Pfizer ( formerly Pharmacia ) , in collaboration with its wholly owned subsidiary Sensus , has developed and launched pegvisomant , a pegylated , genetically modified human growth hormone ( hGH ) , for the treatment of acromegaly . DB00082 , in contrast to classical somatostatin analogs which lower hGH synthesis , exerts its anti - hGH action by preventing P10912 activation . This drug is now available in the US and Europe for the treatment of acromegaly .",
"Secretory proteins and growth factors of the baboon ( Papio anubis ) uterus : potential roles in pregnancy . The primate endometrium undergoes distinct morphological changes during the menstrual cycle . These alterations are regulated by the steroid hormones , estrogen and progesterone . Several lines of evidence suggest that some of these hormonally induced changes may be modulated by growth factors . Our studies have focused on characterizing the secretory activity of the uterine endometrium associated with these hormonally regulated morphological changes during the menstrual cycle and pregnancy in the baboon . Additionally , we have also attempted to study the regulation of specific growth factors and their receptors . In this review we present evidence to indicate that growth factor receptors for insulin - like growth factor - I ( P05019 ) and epidermal growth factor ( P01133 ) , and secretory proteins , insulin - like growth factor binding protein - 1 ( P08833 ) and retinol binding protein ( P02753 ) , which are present in the glandular epithelium during the menstrual cycle , undergo cell - specific changes in gene expression at the implantation site during pregnancy . We postulate that these alterations in growth factor receptor and secretory protein expression are conceptus modulated and may play important regulatory roles during trophoblast invasion and decidualization .",
"[ Pro - inflammatory cytokines P01584 and P01375 reduce growth hormone receptor mRNA concentration in cultivated rat hepatocytes after stimulation with growth hormone ] . Critical illness is associated with catabolism caused by the alteration of several hormonal systems . Low levels of insulin - like growth factor I ( P05019 ) in critical illness are observed despite increased or normal levels of growth hormone ( GH ) . The mechanisms for this apparent GH resistance have not been elucidated . Since proinflammatory cytokines mediate many of the acute responses in critical illness , we evaluated the effects of P01584 and P01375 on growth hormone receptor -( P10912 -) mRNA in cultured rat hepatocytes . Diminished P10912 - mRNA concentrations in response to cytokine stimulation indicate that low P05019 levels in the beginning of severe illness , may at least be partially a cause of P10912 synthesis suppression by proinflammatory cytokines .",
"Effects of cannabis use on human brain structure in psychosis : a systematic review combining in vivo structural neuroimaging and post mortem studies . It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms . We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis . Studies with schizophrenia ( SCZ ) and first episode psychosis ( FEP ) patients as well as individuals at genetic ( P10912 ) or clinical high risk for psychosis ( Q9ULH0 ) were included . We identified 15 structural magnetic resonance imaging ( Q9BWK5 ) ( 12 cross sectional / 3 longitudinal ) and 4 post mortem studies . The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients , 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls . We found evidence for consistent brain structural abnormalities in cannabinoid 1 ( P21554 ) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum . As these effects have not consistently been reported in studies examining nonpsychotic and healthy samples , psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure .",
"The use of a P10912 antagonist in patients with acromegaly resistant to somatostatin analogs . DB00082 , a P10912 antagonist , is a new pharmaceutical approach to acromegaly . It enables P05019 levels to return in the age - and sex - reference range in approximately 90 % of patients . This new approach is particularly beneficial in those patients who do not experience control of hormone hypersecretion after surgery and / or medical treatment with somatostatin analogs . In our preliminary experience , out of 16 patients unsuccessfully operated on by transsphenoidal surgery and resistant to 40 - mg octreotide - P10586 or 120 - mg lanreotide for at least 6 months , 13 normalized their P05019 levels within 6 months from treatment beginning . Normalization of P05019 levels was accompanied by a significant decrease of ring size . We did not observe any increase of tumor remnant in this short period of treatment . In two cases we observed a significant increase of liver transaminases levels . In conclusion , more than 80 % of patients with acromegaly unsuccessfully treated by surgery or currently available somatostatin analogs can achieve normal P05019 levels after short - term treatment with pegvisomant .",
"___MASK85___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Lipodystrophy in patients with acromegaly receiving pegvisomant . CONTEXT : DB00082 , a P10912 antagonist , suppresses serum P05019 levels into the normal range in more than 95 % of patients with acromegaly . Documented side effects in the initial registration studies included headache , injection - site reactions , flu - like syndrome , and reversible elevation of hepatic enzymes . OBJECTIVE : We report seven patients with acromegaly treated with pegvisomant who developed lipodystrophy at the site of injection ( anterior abdominal wall , thigh , buttock , and upper arm ) . This side effect resulted in discontinuation of pegvisomant in four patients , with subsequent regression of lipohypertrophy . SUBJECTS : Six female and one male patient with acromegaly , aged 24 - 59 yr , are reported . All patients had undergone prior transsphenoidal surgery , and four received subsequent radiotherapy . Four patients had been treated with maximal doses of somatostatin analogs with partial suppression of P05019 levels before initiation of pegvisomant therapy . DB00082 suppressed P05019 levels into the normal range in five of seven subjects , before discontinuation of the drug . Two of seven patients received pegvisomant as first - line medical therapy , without prior somatostatin analog treatment , and one received combination therapy with a long - acting somatostatin analog and weekly pegvisomant injections . One patient experienced an erythematous superficial injection - site reaction that responded to application of steroid cream before the onset of lipohypertrophy . CONCLUSIONS : We report seven patients with acromegaly who developed lipohypertrophy at the pegvisomant injection site . DB00082 was discontinued due to dissatisfaction with lipohypertrophy by four patients . Lipohypertrophy regressed in all patients when the medication was discontinued . Lipohypertrophy recurred when two patients were rechallenged with pegvisomant . Patients receiving pegvisomant should undergo frequent examination of injection sites for lipohypertrophy .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK30___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Cancer and the potential place for growth hormone receptor antagonist therapy . DB00082 is a recombinant protein , structurally similar to natural human growth hormone ( GH ) , which is capable of binding to the P10912 as a competitive antagonist . As well as being evaluated for the treatment of acromegaly , pegvisomant is being investigated as a possible antineoplastic agent , initially in mice . So far , in vitro efficacy against meningioma and in vivo efficacy against colon and breast cancer cell lines have been examined .",
"Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant . CONTEXT : Treatment of pituitary gigantism is complex and the results are usually unsatisfactory . OBJECTIVE : The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a P10912 antagonist , pegvisomant . DESIGN : This was a descriptive case series of up to 3 . 5 yr duration . SETTING : The study was conducted at a university hospital . PATIENTS : Patients included three children ( one female , two males ) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery , somatostatin analog , and dopamine agonist . INTERVENTION : The intervention was administration of pegvisomant . MAIN OUTCOME MEASURES : Plasma P05019 and growth velocity were measured . RESULTS : In all three children , pegvisomant rapidly decreased plasma P05019 concentrations . Growth velocity declined to subnormal or normal values . Statural growth fell into lower growth percentiles and acromegalic features resolved . Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog . CONCLUSIONS : DB00082 may be an effective modality for the therapy of pituitary gigantism in children . Titration of the dose is necessary for optimal efficacy , and regular surveillance of tumor size is mandatory .",
"P10912 blocker administration and muscle - tendon collagen synthesis in humans . CONTEXT : The growth hormone ( GH ) / insulin - like growth factor - I ( P05019 ) axis stimulates collagen synthesis in tendon and skeletal muscle , but no studies have investigated the effect of reducing P05019 on collagen synthesis in healthy humans . OBJECTIVE : We hypothesised , that a GH blockade would decrease P05019 and collagen synthesis in the connective tissue of skeletal muscle and tendon . DESIGN : The study was randomised and double blinded . PARTICIPANTS : 20 healthy young males completed the study . INTERVENTION : The participants were randomised to 2 weeks of P10912 blocker supplementation ( pegvisomant , 5 mg / day , n = 9 ) or placebo ( n = 11 ) . MAIN OUTCOME MEASURES : Serum levels of GH , P05019 and P17936 ( P17936 ) were measured before and after pegvisomant / placebo supplementation . Fractional synthesis rates ( FSR ) for collagen and myofibrillar protein were determined with stable isotopes in tendon and muscle , and mRNA for collagen ( P02452 and P02461 ) as well as P05019 isoforms ( Ea and Ec ) were measured in skeletal muscle . RESULTS : DB00082 decreased serum P05019 by 20 % ( p < 0 . 01 ) and serum P17936 by 10 % ( p < 0 . 05 ) . DB00082 supplementation had no effect on collagen synthesis in tendon and skeletal muscle , nor was muscle myofibrillar protein synthesis affected . Similarly , pegvisomant supplementation had no effect on mRNA expression of P05019 and collagen in skeletal muscle . CONCLUSION : P10912 blocker administration in healthy humans resulted in a moderate decrease in serum P05019 . Collagen synthesis in tendon and skeletal muscle , as well as skeletal muscle P05019 and collagen mRNA expression , was unaffected by P10912 blocker supplementation .",
"Management of endocrine disease : GH excess : diagnosis and medical therapy . Acromegaly is predominantly caused by a pituitary adenoma , which secretes an excess of GH resulting in increased IGF1 levels . Most of the GH assays used currently measure only the levels of the 22 kDa form of GH . In theory , the diagnostic sensitivity may be lower compared with the previous assays , which have used polyclonal antibodies . Many GH - secreting adenomas are plurihormonal and may co - secrete prolactin , DB00024 and α - subunit . Hyperprolactinaemia is found in 30 - 40 % of patients with acromegaly , and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent . Although trans - sphenoidal surgery of a GH - secreting adenoma remains the first treatment at most centres , the role of somatostatin analogues , octreotide long - acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate . Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly , GH and IGF1 levels may be discordant , especially during somatostatin analogue therapy . This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range . DB06663 , a new somatostatin analogue , may be more efficacious in some patients , but the drug has not yet been registered for acromegaly . Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels . DB00082 , the P10912 antagonist , is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue . Dopamine - D2 - agonists may be effective as monotherapy in a few patients , but it may prove necessary to apply combination therapy involving a somatostatin analogue and / or pegvisomant .",
"Role of medical therapy in the management of acromegaly . Medical therapy plays an important role in the management of patients with acromegaly and is commonly used adjunctively after surgical resection of the pituitary tumor . Generally , surgery alone provides a 50 to 70 % rate of cure ; however , the outcome depends on the experience and ability of the surgeon and the characteristics of the tumor . The role of postsurgical medical therapy is to achieve long - term biochemical control of the growth hormone ( GH ) / insulin - like growth factor I ( P05019 ) axis . In some patients , medical therapies may be implemented sooner as primary or preoperative therapy . Somatostatin analogs have been the mainstay of medical therapy for acromegaly . The somatostatin analog octreotide produces normalization of P05019 in approximately 50 % of patients but is associated with gastrointestinal adverse effects , including the development of gallstones . DB00104 requires thrice - daily subcutaneous administration . Long - acting formulations of somatostatin analogs ( octreotide P10586 , lanreotide ) are at least as effective and as well tolerated as short - acting octreotide . Unfortunately , some patients are suboptimally responsive to or become intolerant of these agents . DB00082 belongs to a new class of agents known as GH - receptor antagonists . This novel agent competitively binds to the P10912 , blocking P05019 production . DB00082 is highly effective in achieving normal P05019 concentrations and in reducing signs and symptoms of acromegaly , even in patients resistant to previous treatments . DB00082 has been proved safe and well tolerated and has no effect on gallbladder motility . GH levels remain elevated . Transient elevations in liver enzyme levels require monitoring but rarely necessitate termination of therapy . Normalizing P05019 concentrations with pegvisomant also may have a beneficial effect on carbohydrate metabolism and cardiovascular risk .",
"DB00082 , a growth hormone - specific antagonist , undergoes cellular internalization . GH binding to a receptor ( P10912 ) dimer triggers signaling and internalization of the receptor / ligand complex . DB00082 is a specific GH antagonist developed for the treatment of acromegaly , and the basic molecule is GH with an amino acid substitution that blocks the conformational change necessary to generate functional P10912 dimerization required for signal transduction . DB00082 has additional polyethylene glycol moieties to prolong its half - life in the circulation and improve clinical efficacy through reduced renal clearance . DB00082 has a long plasma half - life , and its mode of clearance has not been established . We have studied pegvisomant internalization and demonstrate that despite its size and prolonged plasma half - life , it is internalized by cells expressing the P10912 . As pegvisomant does not activate intracellular signal transduction systems , our results support the concept that the conformational changes required for P10912 signaling are not essential for the intracellular trafficking of the ligand and establish one potential contributing mechanism for pegvisomant clearance .",
"___MASK17___ : kinetic and dynamic profile in the treatment of pain . ___MASK17___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK17___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK17___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK17___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Essential role of growth hormone in ischemia - induced retinal neovascularization . Retinal neovascularization is the major cause of untreatable blindness . The role of growth hormone ( GH ) in ischemia - associated retinal neovascularization was studied in transgenic mice expressing a GH antagonist gene and in normal mice given an inhibitor of GH secretion ( MK678 ) . Retinal neovascularization was inhibited in these mice in inverse proportion to serum levels of GH and a downstream effector , insulin - like growth factor - I ( P05019 ) . Inhibition was reversed with exogenous P05019 administration . GH inhibition did not diminish hypoxia - stimulated retinal vascular endothelial growth factor ( P15692 ) or P15692 receptor expression . These data suggest that systemic inhibition of GH or P05019 , or both , may have therapeutic potential in preventing some forms of retinopathy .",
"Reflex apnoea response and inflammatory mediators in infants with respiratory tract infection . The reflex apnoea response to water stimulation was evaluated in infants with respiratory syncytial virus ( RSV ) infection and compared to the response in non - infected infants who had sustained an apparent life - threatening event ( O96006 ) or were siblings of infants who had died of sudden infant death syndrome ( P22304 ) . RSV - infected infants had a significantly ( p < 0 . 05 ) reinforced reflex apnoea response compared with non - infected infants . There was a significant negative correlation between the concentration of interleukin 1 beta ( IL - I beta ) in pharyngeal secretions and the duration of apnoea ( p < 0 . 01 ) . Increased clinical severity was , however , associated with high ( > 5 . 000 pg ml - 1 ) concentrations of P01584 . There was no correlation between apnoea and interleukin 6 . These findings may be relevant for the understanding of why apnoea may be the presenting symptom of RSV infection , and offer an explanation of why a proportion of P22304 cases has a history of mild respiratory tract symptoms prior to death .",
"P01308 - like growth factor - I treatment of children with Laron syndrome ( primary growth hormone insensitivity ) . Laron syndrome ( LS , congenital primary GH insensitivity ) is caused by deletions or mutations in the P10912 gene , resulting in an inability to generate insulin - like growth factor - I ( P05019 ) . If untreated , the deficiency of P05019 results in severe dwarfism , as well as skeletal and muscular underdevelopment . The only treatment is the daily administration of recombinant P05019 . This review summarizes the present experience by several groups worldwide . The main conclusions are : A . The one or two injections regimen result in the same growth velocity ; B . The growth velocity obtained with P05019 administration is smaller than that observed with hGH in children with congenital isolated GH deficiency ; C . Overdosage of P05019 causes a series of adverse effects which can be avoided by carefully monitoring the serum P05019 and GH levels .",
"P35354 [ corrected ] activation by endotoxin mediates the decrease in IGF1 , but not in P17936 , [ corrected ] gene expression in the liver . The aim of this work was to analyse the role of cyclooxygenase - 2 ( Ptgs2 ) in endotoxin - induced decrease in Igf1 and Igf binding protein - 3 ( Igfbp3 ) . For this purpose , male Wistar rats were injected with lipolysaccharide ( LPS ) and / or the Ptgs2 inhibitor meloxicam . LPS induced a significant decrease ( P < 0 . 01 ) in serum concentrations of Igf1 and Igfbp3 and their mRNAs in the liver . Meloxicam administration prevented the inhibitory effect of LPS injection on serum Igf1 and its liver mRNA . By contrast , meloxicam administration was unable to modify the inhibitory effect of LPS on Igfbp3 . LPS injection also induced a decrease in P10912 ( Ghr ) mRNA in the liver , and meloxicam attenuated this effect . In order to elucidate a direct action of the Ptgs2 inhibitor on the liver cells , the effect of LPS and / or meloxicam was studied in primary cultures of hepatocytes with non - parenchymal cells . LPS decreased Igf1 and Ghr but not Igfbp3 gene expression in liver cells in culture . Meloxicam administration attenuated the inhibitory effect of LPS on Igf1 mRNA , whereas it did not modify the decrease in Ghr mRNA after LPS . The effect of meloxicam on the LPS response does not seem to be mediated by changes in nitric oxide or tumour necrosis factor ( Tnf ) production , since meloxicam did not modify the stimulatory effect of LPS on nitric oxide or Tnfalpha gene expression both in vivo and in vitro . All these data suggest that LPS - induced Ptgs2 activation decreases Igf1 gene expression in liver cells ."
] |
[
"___MASK17___",
"___MASK30___",
"___MASK36___",
"___MASK42___",
"___MASK51___",
"___MASK53___",
"___MASK68___",
"___MASK85___",
"___MASK89___"
] |
___MASK30___
|
MH_train_369
|
interacts_with DB00480?
|
[
"Dentascan - is the investment worth the hype ? ? ? BACKGROUND : Open Bone Measurement ( OBM ) and Bone Sounding ( BS ) are most reliable but invasive clinical methods for Alveolar Bone Level ( P00519 ) assessment , causing discomfort to the patient . Routinely , IOPAs & OPGs are the commonest radiographic techniques used , which tend to underestimate bone loss and obscure buccal / lingual defects . Novel technique like dentascan ( CBCT ) eliminates this limitation by giving images in 3 planes - sagittal , coronal and axial . AIM : To compare & correlate non - invasive 3D radiographic technique of Dentascan with BS & OBM , and IOPA and O00300 , in assessing the P00519 . SETTINGS AND DESIGN : Cross - sectional diagnostic study . MATERIAL AND METHODS : Two hundred and five sites were subjected to clinical and radiographic diagnostic techniques . Relative distance between the alveolar bone crest and reference wire was measured . All the measurements were compared and tested against the OBM . STATISTICAL ANALYSIS : Student ' s t - test , Q9UNW9 , Pearson correlation coefficient . RESULTS : There is statistically significant difference between dentascan and OBM , only BS showed agreement with OBM ( p < 0 . 05 ) . Dentascan weakly correlated with OBM & BS lingually . Rest all techniques showed statistically significant difference between them ( p = 0 . 00 ) . CONCLUSION : Within the limitations of this study , only BS seems to be comparable with OBM with no superior result of Dentascan over the conventional techniques , except for lingual measurements .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK44___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK44___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK44___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK44___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK44___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"___MASK56___ , an endothelin receptor antagonist , ameliorates collagen - induced arthritis : the role of P01375 - α in the induction of endothelin system genes . OBJECTIVE : Endothelins ( ETs ) are involved in several inflammatory events . The present study investigated the efficacy of ___MASK56___ , a dual P25101 / ETB receptor antagonist , in collagen - induced arthritis ( CIA ) in mice . TREATMENT : CIA was induced in DBA / 1J mice . Arthritic mice were treated with ___MASK56___ ( 100 mg / kg ) once a day , starting from the day when arthritis was clinically detectable . METHODS : CIA progression was assessed by measurements of visual clinical score , paw swelling and hypernociception . Histological changes , neutrophil infiltration and pro - inflammatory cytokines were evaluated in the joints . Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology . PreproET - 1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells ( PBMCs ) was evaluated by real - time PCR . The differences were evaluated by one - way Q9UNW9 or Student ' s t test . RESULTS : Oral treatment with ___MASK56___ markedly ameliorated the clinical aspects of CIA ( visual clinical score , paw swelling and hyperalgesia ) . ___MASK56___ treatment also reduced joint damage , leukocyte infiltration and pro - inflammatory cytokine levels ( IL - 1β , TNFα and Q16552 ) in the joint tissues . Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after ___MASK56___ treatment . PreproET mRNA expression increased in PBMCs from rheumatoid arthritis ( RA ) patients but returned to basal level in PBMCs from patients under anti - P01375 therapy . In - vitro treatment of PBMCs with TNFα upregulated ET system genes . CONCLUSION : These findings indicate that ET receptor antagonists , such as ___MASK56___ , might be useful in controlling RA . Moreover , it seems that ET mediation of arthritis is triggered by TNFα .",
"Synergism between bosutinib ( ___MASK40___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity . OBJECTIVE : O00300 ( O00300 ) is a soluble tumour necrosis factor - receptor - like molecule present in connective tissues , especially bone and vasculature . It is known to accumulate in the arterial wall in diabetes . As its synthesis in vascular cells is decreased by insulin , we wanted to elucidate the acute effects of insulin on plasma O00300 concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls . DESIGN : The study population consisted of ten type 2 diabetic , ten obese subjects , and ten lean subjects with no family history of diabetes . METHODS : All subjects underwent a 4 - h euglycemic - hyperinsulinemic clamp . Plasma O00300 , insulin , lactate , HbA1c , cholesterol , triglycerides , free fatty acids ( FFA ) , and glucose disposal rate were measured before and at the end of the clamp . RESULTS : Baseline O00300 concentrations did not differ significantly between groups . P01308 infusion decreased plasma O00300 concentrations in all groups ( P < 0 . 01 ) ; however , the fall in O00300 was 50 % less in obese and type 2 diabetic individuals ( P = 0 . 007 ) . Baseline O00300 correlated with fasting insulin , baseline lactate , and low density lipoprotein cholesterol in the diabetic group , and with baseline FFA in the lean group . The relative change of O00300 in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group . CONCLUSIONS : Acute hyperinsulinemia decreases plasma O00300 , but with diminished effect in individuals with type 2 diabetes and obesity . Increased levels of O00300 in arteries and plasma in diabetes together with the capability of plasma O00300 as a cardiovascular risk predictor may be related to the described effects of insulin .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK92___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"[ Genetic aspects of occupational chronic obstructive lung disease under exposure to various risk factors ] . The article deals with data on association of SNP rs1828591 of Q96QV1 gene with COLD development under exposure to dust and chemical factors . SNP rs1800470 of TGFbeta1 gene is associated with occupational COLD under exposure to dust and did not show connection with COLD under exposure to chemical aerosols . No association was seen between SNP rs4129267 of IL - 6R gene and SNP rs1051730 of P32297 gene with occupational COLD under exposure to the studied factors . SNP rs1828591 of Q96QV1 gene is associated with occupational COLD development under exposure to dust and chemical factors . Study of association of genotype and phenotypic features of COLD revealed the following trends : \" dust \" COLD patients with genotype AA SNP rs1800470 of TGFbeta1 gene show lower level of P02741 and P01375 , if compared with other genotypes .",
"DB00480 inhibits osteoclastogenesis , survival factors and bone - remodeling markers in multiple myeloma . Osteolytic bone disease in multiple myeloma ( MM ) is caused by enhanced osteoclast ( OCL ) activation and inhibition of osteoblast function . DB00480 and bortezomib have shown promising response rates in relapsed and newly diagnosed MM , and bortezomib has recently been reported to inhibit OCLs . We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib . Both drugs decreased alpha V beta 3 - integrin , tartrate - resistant acid phosphatase - positive cells and bone resorption on dentin disks . In addition , both agents decreased receptor activator of nuclear factor - kappaB ligand ( O14788 ) secretion of bone marrow stromal cells ( BMSCs ) derived from MM patients . We identified PU . 1 and pERK as major targets of lenalidomide , and nuclear factor of activated T cells of bortezomib , resulting in inhibition of osteoclastogenesis . Furthermore , downregulation of cathepsin K , essential for resorption of the bone collagen matrix , was observed . We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein - alpha , B - cell activating factor and a proliferation - inducing ligand . Importantly , in serum from MM patients treated with lenalidomide , the essential bone - remodeling factor O14788 , as well as the O14788 / O00300 ratio , were significantly reduced , whereas osteoprotegerin ( O00300 ) was increased . We conclude that both agents specifically target key factors in osteoclastogenesis , and could directly affect the MM - OCL - BMSCs activation loop in osteolytic bone disease .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK79___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"[ Expression of truncated fragment of human O00300 in CHO - P00374 - cells and its bioactivity characterization ] . AIM : To obtain high level expression of recombinant human truncated osteoprotegerin ( TOPG ) with higher bioactivity in CHO - P00374 (-) cells . METHODS : The recombinant vector pcDNA3 . 1 / P00374 - TOPG was constructed and transfected into CHO - P00374 (-) cells by the directions of LipofectAMINE 2000 for stable expression . The stable expression cell strains were screened by selective medium IMDM with 50 mL / L FCS , then serially passed in methotraxate ( MTX ) for gene amplification . The expression were analyzed by ELISA and RT - PCR . At last , the bioactivity analysis was performed in vitro . RESULTS : The expression level of recombinant truncated human O00300 was up to 6 mg / L x 72 h , and it had significant suppression effect on the formation of OLC ( P < 0 . 05 ) . CONCLUSION : Recombinant truncated human O00300 has high expression and bioactivity . The results make it possible for further studying and clinical implying of O00300 .",
"P01730 (+) regulatory T cells in autoimmunity and allergy . Regulatory T cells ( also referred to as suppressor T cells ) are important components of the homeostasis of the immune system , as impaired regulatory T cell activity can cause autoimmune diseases and atopy . It is now clear that the phrase ' regulatory T cells ' encompasses more than one cell type . For instance , P01730 (+) CD25 (+) regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo , but in several instances it has been shown that P01730 (+) CD25 (-) T cell populations also contain potent regulatory activity . Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor ( TNFR ) family members ( Q9Y5U5 and O14788 - R / Q9Y6Q6 ) in Treg biology , the improved understanding of the role of co - stimulatory molecules and cytokines P22301 and P60568 in the induction and function of Tregs , and the generation of CD25 (+) and CD25 (-) regulatory T cells in vivo through high - avidity T cell receptor interactions .",
"Signaling by proinflammatory cytokines : oligomerization of TRAF2 and Q9Y4K3 is sufficient for JNK and IKK activation and target gene induction via an amino - terminal effector domain . Interleukin - 1 ( IL - 1 ) and tumor necrosis factor ( P01375 ) stimulate transcription factors AP - 1 and NF - kappaB through activation of the Q96HU1 kinases JNK and p38 and the O15111 ( IKK ) , respectively . The P01375 and IL - 1 signals are transduced through TRAF2 and Q9Y4K3 , respectively . Overexpressed TRAF2 or Q9Y4K3 activate JNK , p38 , or IKK in the absence of extracellular stimulation . By replacing the carboxy - terminal TRAF domain of TRAF2 and Q9Y4K3 with repeats of the immunophilin P62942 , we demonstrate that their effector domains are composed of their amino - terminal Zn and RING fingers . Oligomerization of the TRAF2 effector domain results in specific binding to Q13233 , a protein kinase capable of JNK , p38 , and IKK activation , and induction of P01375 and IL - 1 responsive genes . P01375 also enhances the binding of native TRAF2 to Q13233 and stimulates the kinase activity of the latter . Thus , P01375 and IL - 1 signaling is based on oligomerization of TRAF2 and Q9Y4K3 leading to activation of effector kinases .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK88___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Immunohistochemical analysis of low - grade and high - grade prostate carcinoma : relative changes of parathyroid hormone - related protein and its parathyroid hormone 1 receptor , osteoprotegerin and receptor activator of nuclear factor - kB ligand . AIM : To investigate multiple bone cytokines produced by prostate carcinoma ( PCa ) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis . METHODS : A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution ( Fundación Jiménez Díaz ( Grupo Capio ) , Madrid , Spain ) between January 1991 and June 1998 were identified as low - grade ( < or = 4 ; n = 22 ) or high - grade ( > or = 7 , excluding 7 ( 3 + 4 ) cases ; n = 25 ) PCa according to Gleason grade . PCa specimens were immunostained for : parathyroid hormone ( PTH ) - related protein ( P12272 ) , the Q03431 , osteoprotegerin and receptor activator of nuclear factor - kappa B ligand ( O14788 ) , as well as Ki67 ( a proliferation marker ) and P28906 ( an angiogenesis marker ) . RESULTS : PCa samples showed an increased immunostaining for both osteoprotegerin and O14788 , associated with tumour grade and P12272 positivity , in the tumoral epithelium . Using a score value of 4 - corresponding to moderate staining - as cut - off , the best sensitivity value was for P12272 ( with C - terminal antiserum P13671 ; 100 % ) ; wheras the best specificity value was for O14788 ( 95 % ) . CONCLUSIONS : All the evaluated factors are overexpressed mainly in the high - grade tumours . Our findings indicate that , in most patients with PCa ( with Ki67 values between 1 % and 9 % ) , sequential determination of C - terminal P12272 and O14788 immunoreactivities is a useful approach to discriminate low - grade and high - grade tumours .",
"[ Production of cytokines by peripheral blood mononuclear cells -- correlation with clinicomorphological features in laryngeal carcinoma ] . INTRODUCTION : In studied analyzed role of the cytokines in pathology of neoplasms of various origin the importance of these proteins in regulation of immunocompetent cells function has been described . The aim of this study was to estimate of cho sen cytokines concentration produced by peripheral blood mononuclear cells and in whole blood in patients with laryngeal carcinoma and to analyze the connection of cytokines profile with clinicopathological features . MATERIALA AND METHODS : 55 patients with squamous cell carcinoma of the larynx treated at ENT Department Medical University of Lodz between 2003 - 2007 were analyzed . For estimation of cytokine secretion the cultures of isolated peripheral blood mononuclear cells ( T lymphocytes ) and the whole blood were established . Production of cytokines in supernatants was detected by Elisa . Connections with clinicomorphological features ( pT , pN , Anneroth , Batsakis i Lunas ' classification ) were analyzed . RESULTS : Authors reported statistical correlation between chosen cytokines concentration and clinicomorphological parameters : pT and P60568 , P05231 , P10145 , TNFalpha produced by isolated cells and P60568 , P05231 , TNFa and IFNgamma in whole blood , pN and P10145 , P22301 , IFNgamma ; P00519 score and P05231 , TNFalpha , IFNgamma produced by isolated cells and P60568 , P05231 , P22301 , TNFalpha , IFNgamma in whole blood . CONCLUSION : Our studied indicated the important influence of proinflammatory and regulatory cytokines produced by immunocompetent cells for course of neoplasm disease , aggressiveness and advance in laryngeal carcinoma .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"___MASK33___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK33___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"An in vitro osteoclast - forming assay to measure myeloma cell - derived osteoclast - activating factors . Much of the morbidity and mortality associated with the plasma cell ( PC ) malignancy , multiple myeloma ( MM ) , is owing to the severe osteolytic bone disease seen in patients with this disease . Although the molecular mechanisms responsible for osteolysis remain to be fully elucidated , it is clear from numerous studies that it is owing , in part , to an increase in osteoclastic bone resorption . Several known osteoclast ( OC ) - activating factors ( OAFs ) are produced by myeloma PCs ( MPCs ) , or by stromal cells in response to MPCs and include interleukin - 1beta ( IL - 1beta ) ; tumor necrosis factor - alpha ( P01375 ) ; P05231 ; parathyroid hormone - related protein ; macrophage inflammatory protein - 1alpha ; and , most recently , the P01375 - ligand family member receptor activator of nuclear factor - kappaB ligand ( O14788 ) . The identification and significance of any one of these myeloma - derived OAFs is dependent on robust and reliable assays that measure the de novo formation and activation of OCs . A number of in vitro assay systems have been described that examine the requirements for normal OC formation and are easily adaptable for examining which MM - derived Q86UD1 and to what extent it is responsible for the bone loss observed in individuals with myeloma . This chapter describes one such in vitro model system .",
"The alarmin P09429 acts in synergy with endogenous and exogenous danger signals to promote inflammation . The nuclear protein P09429 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release , yet its mode of action is still not well defined . Access to highly purified P09429 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to P09429 alone or after binding to cofactors . P09429 on its own could not induce detectable P05231 production . However , strong enhancing effects on induction of proinflammatory cytokine production occurred when the protein associated with each of the separate proinflammatory molecules , rhIL - 1beta , the O00206 ligand LPS , the Q9NR96 ligand CpG - ODN , or the Q15399 - O60603 ligand Pam3CSK4 . The bioactivities were recorded in cocultures with preformed P09429 complexes but not after sequential or simultaneous addition of P09429 and the individual ligands . Individual A - box and B - box domains of P09429 had the ability to bind LPS and enhance P05231 production . Heat denaturation of P09429 eliminated this enhancement . Cocultures with P09429 and other proinflammatory molecules such as P01375 , O14788 , or Q14116 did not induce enhancement . P09429 thus acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner .",
"Allogeneic activation is attenuated in a model of mouse lung perfused with magnesium - deficient blood . Hypomagnesemia , which is frequently observed in patients treated with calcineurin inhibitors to prevent rejection after allogeneic transplantation , has been associated with a faster rate of decline in allograft function . The effect of hypomagnesemia on lung allograft has not been reported yet . In our model of isolated mouse lung , we have evaluated the early effects of allogeneic lung perfusion with blood from magnesium ( Mg ) - deficient mice for 3 h on lung activation and remodelling , compared to isogeneic perfusion . Hypomagnesemia ( 0 . 21 +/- 0 . 07 mmol Mg ( 2 +)/ l ) was observed in blood from Mg - deficient mice , but no inflammatory pattern . The mRNA level of the intercellular adhesion molecule ( ICAM ) - 1 , but neither of the vascular cell adhesion molecule ( VCAM ) - 1 , nor of the cytokines tumor necrosis factor ( P01375 ) alpha and interleukin ( IL ) - 2 , was enhanced ( p < 0 . 05 ) . Although caspase - 3 mRNA was transiently enhanced , no apoptotic cells were evidenced in lung tissues even after 3 h . Using cDNA array , we found that the genes encoding O14788 , Q9Y6Q6 , P20333 , NFATX , IL - 1R2 , IL - 6R P40189 , O14543 , P09619 , Q9H3D4 , Q99062 , P09341 , P42830 , P78423 , P09603 , which are involved in inflammation and apoptosis regulation , were markedly up - regulated in allogeneic conditions . Our results support a limited allogeneic activation and an early stage of the inflammatory process in lung , at the time of inflammatory cell recruitment without lung tissue remodelling , as a result of hypomagnesemia . These findings suggest that cyclosporine - related hypomagnesemia , observed in most of the transplanted patients , does not constitute an additional risk for lung allograft outcome .",
"Inorganic lead enhances cytokine - induced elevation of matrix metalloproteinase P14780 expression in glial cells . Inorganic lead ( Pb ) is a ubiquitous environmental contaminant that produces a variety of deleterious effects in the central nervous system ( CNS ) . Matrix metalloproteinases ( MMPs ) , specifically P14780 , induced by inflammatory cytokines , are increasingly being implicated in CNS pathology . The present study demonstrates that low concentrations of either pro - inflammatory cytokines ( P01375 and IL - 1beta ) or Pb did not influence the P14780 expression in a glial cell line ( P13671 ) when added separately . However , combined administration of Pb and cytokines induced a marked synergized elevation of P14780 expression in spite of a reduction in the number of glial cells . These results demonstrate a possible new mechanism by which Pb may induce neuropathological processes .",
"___MASK6___ activates P46937 through nAChRs mediated signaling in esophageal squamous cell cancer ( ESCC ) . Cigarette smoking is an established risk factor for esophageal cancers . P46937 ( P46937 ) , the key transcription factor of the mammalian Hippo pathway , has been reported to be an oncogenic factor for many cancers . In this study , we find nicotine administration can induce nuclear translocation and activation of P46937 in ESCC . Consistently , we observed nuclear translocation and activation of P46937 by knockdown of P32297 , which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells . ___MASK6___ administration or P32297 depletion substantially increased proliferation and migration in esophageal cancer cells . Interestingly , we find that P46937 physically interacts with nAChRs , and nAChRs - signaling dissociates P46937 from its negative regulatory complex composed with α - catenin , β - catenin and 14 - 3 - 3 in the cytoplasm , leading to upregulation and nuclear translocation of P46937 . This process likely requires PKC activation , as PKC specific inhibitor Enzastaurin can block nicotine induced P46937 activation . In addition , we find nicotine signaling also inhibits the interaction of P46937 with Q9H3D4 , which contributes to the inhibitory effect of nicotine on apoptosis . Using immunohistochemistry analysis we observed upregulation of P46937 in a significant portion of esophageal cancer samples . Consistently , we have found a significant association between P46937 upregulation and cigarette smoking in the clinical esophageal cancer samples . Together , these findings suggest that the nicotine activated nAChRs signaling pathway which further activates P46937 plays an important role in the development of esophageal cancer , and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers .",
"Immunomodulatory drugs inhibit expression of cyclooxygenase - 2 from P01375 , IL - 1beta , and LPS - stimulated human PBMC in a partially P22301 - dependent manner . Immunomodulatory drugs ( IMiDs ) are potent inhibitors of P01375 and IL - 1beta and elevators of P22301 production in LPS - stimulated human PBMC . They are currently in clinical trials for various diseases , including multiple myeloma , myelodysplastic syndrome , and melanoma . In the present study , we have investigated the effects of thalidomide , DB00480 and CC - 4047 on the expression of P35354 by stimulated PBMC . Our results show that thalidomide and IMiDs inhibited the expression of P35354 but not the P23219 protein in LPS - P01375 and IL - 1beta stimulated PBMC and shortened the half - life of P35354 mRNA in a dose - dependent manner . They also inhibited the synthesis of prostaglandin E2 from LPS - stimulated PBMC . While anti - P01375 or IL - 1beta neutralizing antibodies had no effect on P35354 expression , anti - P22301 neutralizing antibody elevated the expression of P35354 mRNA , and protein from treated PBMC . These data suggest that the anti - inflammatory and anti - tumor effects of IMiDs may be due in part to elevation of P22301 production and its subsequent inhibition of P35354 expression .",
"___MASK6___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"Role of Q14116 in overt pain - like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain - like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl - p - benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose - dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid - induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ - induced writhes were diminished in P01579 (-/-) mice and by the treatment with ___MASK56___ ( mixed endothelin P25101 / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp - DAsp - Pro - DVal - DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N - cys - 2 , 6 dimethylpiperidinocarbonyl - l - methylleucyl - d - 1 - methoxycarboyl - d - norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ - induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain - like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK92___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK29___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand up - regulation via prostaglandin E2 synthesis . Previously , we discovered that periodontal ligament ( PDL ) cells not only support osteoclastogenesis through cell - to - cell contact , but also inhibit the formation of tartrate - resistant acid phosphatase - positive ( TRAP + ) multinucleated cells by a producing soluble factor ( s ) . Furthermore , PDL cells express both receptor activator of nuclear factor kappaB ligand ( O14788 ) and osteoprotegerin ( O00300 ) messenger RNA ( mRNA ) . Clinically , \" ankylosed teeth , \" which lack periodontal ligament , can not be moved with orthodontic tooth treatment . From this , we hypothesized that PDL cells under mechanical stress should play a pivotal role in osteoclast formation during orthodontic tooth movement . This study examined how mechanical stress affects the osteoclastogenesis - supporting activity of PDL cells . PDL cells were compressed continuously and then cocultured with peripheral blood mononuclear cells ( PBMCs ) for 4 weeks . PDL cells under mechanical stress up - regulated osteoclastogenesis from PBMCs . Furthermore , the expression of O14788 mRNA and protein in PDL cells increased with compressive force in parallel with the change in the number of osteoclasts . In addition , cyclo - oxygenase 2 ( P35354 ) mRNA expression was induced by compressive force , and indomethacin inhibited the O14788 up - regulation resulting from compressive force . PDL cells under compressive force exhibited significantly increased prostaglandin E2 ( DB00917 ) production in comparison with control PDL cells . Exogenous DB00917 treatment increased O14788 mRNA expression in PDL cells . Interestingly , O00300 expression remained constant throughout compressive force or DB00917 treatment . In conclusion , compressive force up - regulated O14788 expression in PDL cells . Furthermore , O14788 up - regulation in mechanically stressed PDL cells was dependent on DB00917 .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK29___ GITS , Diaprel MR ) . One daily dose of ___MASK29___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control ."
] |
[
"___MASK29___",
"___MASK33___",
"___MASK40___",
"___MASK44___",
"___MASK56___",
"___MASK6___",
"___MASK79___",
"___MASK88___",
"___MASK92___"
] |
___MASK92___
|
MH_train_370
|
interacts_with DB06626?
|
[
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .",
"Colocalization of the P15692 - R2 and the common P08700 / GM - P04141 receptor beta chain to lipid rafts leads to enhanced p38 activation . Previous studies suggested an important role for vascular endothelial growth factor ( P15692 ) and its receptors in postnatal haemopoiesis . However , it is unclear how P15692 receptor ( VEGFR ) signalling could interact with that issued from the activation of haematopoietic growth factor receptors . To elucidate this point we explored P15692 - R2 and granulocyte - macrophage colony - stimulating factor receptor ( GM - CSFR ) membrane localization and cell signalling in TF1 - P35968 cells ( TF1 leukaemic cells that overexpress P15692 - R2 / P35968 ) . Activation of either GM - CSFR or P15692 - R2 was shown to determine the migration of both receptor elements ( P15692 - R2 and the common beta - chain of the GM - CSFR ) to lipid rafts . The study of receptor phosphorylation showed that GM - P04141 induced the phosphorylation of its own receptor and the transphosphorylation of P15692 - R2 ; on the other hand , P15692 triggered the phosphorylation of its receptor and transphosphorylated the beta - chain of the GM - CSFR . Co - stimulation of TF1 - P35968 cells with both GM - P04141 and P15692 resulted in massive migration of both the common GM - CSFR beta - chain and P15692 - R2 to lipid rafts and sustained p38 mitogen - activated protein kinase activation . Disruption of lipid rafts inhibited the capacity of both GM - P04141 and P15692 to activate p38 . Experiments with specific p38 inhibitors showed that p38 activation was required to sustain the P15692 - and GM - P04141 - dependent proliferation of TF1 - P35968 and the survival of primary acute myeloid leukaemia blasts .",
"mTORC2 / rictor signaling disrupts dopamine - dependent behaviors via defects in striatal dopamine neurotransmission . Disrupted neuronal protein kinase B ( Akt ) signaling has been associated with dopamine ( DA ) - related neuropsychiatric disorders , including schizophrenia , a devastating mental illness . We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function . Akt is activated by phosphorylation of two key residues : Thr308 and Ser473 . Blunted Akt phosphorylation at Ser473 ( pAkt - 473 ) has been observed in lymphocytes and postmortem brains of schizophrenia patients , and psychosis - prone normal individuals . P42345 ( P42345 ) complex 2 ( mTORC2 ) is a multiprotein complex that is responsible for phosphorylation of Akt at Ser473 ( pAkt - 473 ) . We demonstrate that mice with disrupted mTORC2 signaling in brain exhibit altered striatal DA - dependent behaviors , such as increased basal locomotion , stereotypic counts , and exaggerated response to the psychomotor effects of amphetamine ( P49418 ) . Combining in vivo and ex vivo pharmacological , electrophysiological , and biochemical techniques , we demonstrate that the changes in striatal DA neurotransmission and associated behaviors are caused , at least in part , by elevated D2 DA receptor ( D2R ) expression and upregulated P27361 / 2 activation . DB00502 , a typical antipsychotic and D2R blocker , reduced P49418 hypersensitivity and elevated pERK1 / 2 to the levels of control animals . By viral gene delivery , we downregulated mTORC2 solely in the dorsal striatum of adult wild - type mice , demonstrating that striatal mTORC2 regulates P49418 - stimulated behaviors . Our findings implicate mTORC2 signaling as a novel pathway regulating striatal DA tone and D2R signaling .",
"The selective P17948 - 3 inhibitor axitinib ( AG - 013736 ) shows antitumor activity in human neuroblastoma xenografts . Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high - risk disease . Within the KidsCancerKinome project , we evaluated the new oral selective pan - VEGFR tyrosine kinase inhibitor axitinib ( AG - 013736 ) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR - N91 derived from a primary bone marrow metastasis . DB06626 reduced cell proliferation in a dose - dependent manner with IC ( 50 ) doses between 274 and > 10 , 000 nmol / l . Oral treatment with 30 mg / kg P55957 for 2 weeks in advanced tumors yielded significant tumor growth delay , with a median time to reach five times initial tumor volume of 11 . 4 days compared to controls ( p = 0 . 0006 ) and resulted in significant reduction in bioluminescence . Simultaneous inhibition of VEGFR downstream effector P42345 using rapamycin 20 mg / kg q2d × 5 did not statistically enhance tumor growth delay compared to single agent activities . DB06626 downregulated P35968 phosphorylation resulting in significantly decreased microvessel density ( P53602 ) and overall surface fraction of tumor vessels ( OSFV ) in all xenografts as measured by P28906 immunohistochemical staining ( mean P53602 ± SD and OSFV at 14 days 21 . 27 ± 10 . 03 in treated tumors vs . 48 . 79 ± 17 . 27 in controls and 0 . 56 % vs . 1 . 29 % ; p = 0 . 0006 , respectively ) . We further explored the effects of axitinib on circulating mature endothelial cells ( CECs ) and endothelial progenitor cells ( CEPs ) measured by flow cytometry . While only transient modification was observed for CECs , CEP counts were significantly reduced during and up to 14 days after end of treatment . DB06626 has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma .",
"P42345 pathway is involved in ADP - evoked astrocyte activation and DB00171 release in the spinal dorsal horn in a rat neuropathic pain model . BACKGROUND : DB00171 / ADP - evoked spinal astrocyte activation plays a vital role in the development of neuropathic pain . We aim to investigate the role of mammalian target of rapamycin ( P42345 ) pathway on the spinal astrocyte activation in the neuropathic pain development in rats . METHODS : Sprague Dawley ( SD ) rats were subjected to chronic constriction of the sciatic nerve ( CCI ) . DB00877 or ADP was intrathecally injected daily to explore their effects on spinal astrocyte activation and pain development . Expression of glial fibrillary acidic protein ( P14136 ) and P42345 in the spinal dorsal horn was assessed by immunohistochemistry . Von Frey hairs and Hargreaves paw withdrawal test were conducted to evaluate mechanical allodynia and thermal sensitivity , respectively . Firefly luciferase DB00171 assay was used to assess the change of DB00171 level in cerebrospinal fluid ( P04141 ) and medium of cultured astrocytes . RESULTS : P14136 expression was enhanced in the ipsilateral spinal dorsal horn from day 3 after surgery . P14136 and P42345 expression in the rat spinal dorsal horn on post - surgical day 14 was enhanced by daily intrathecal injection of ADP , which was inhibited by rapamycin . DB00877 decreased lower mechanical pain threshold and the thermal withdrawal latency . Intrathecal injection of ADP enhanced the DB00171 release , which was partially inhibited by rapamycin . Study of cultured astrocytes indicated that DB00171 could be released from astrocytes . CONCLUSION : Our data demonstrated that ADP enhanced neuropathic pain in CCI rats , which was inhibited by rapamycin . This study indicates that targeting P42345 pathway could serve as a novel therapeutic strategy in neuropathic pain management .",
"Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK52___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK77___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK77___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK77___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK77___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"DB06626 modulates hypoxia - induced blood - retina barrier permeability and expression of growth factors . This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor ( P15692 ) receptors 1 / 2 ( P17948 / 2 ) and platelet - derived growth factor ( PDGF ) receptor beta ( P09619 - β ) , hypoxia - induced increased tissue permeability , occludin , zonula occludens protein 1 ( ZO - 1 ) , P15692 , and PDGF expression of human retinal pigment epithelial ( Q96AT9 ) cells and human umbilical vein endothelial cells ( HUVECs ) . Primary human Q96AT9 cells and HUVECs were exposed to hypoxia and axitinib . Viability of cells , tissue permeability , and expression of occludin , ZO - 1 , P15692 , PDGF , P17948 / 2 and P09619 - β , and their mRNAs , were investigated by reverse transcription - polymerase chain reaction , enzyme - linked immunosorbent assay , western blotting , and immunohistochemistry . Treatment with axitinib reduced expression of P17948 / 2 and P09619 - β . Hypoxia decreased cell viability , occludin , and ZO - 1 expression and increased tissue permeability , expression , and secretion of P15692 and PDGF . DB06626 significantly reduced hypoxia - induced effects on HUVEC and Q96AT9 cells . Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema .",
"Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor - 2 enzymatic activity , autophosphorylation , and inhibition by axitinib . The catalytic domains of protein kinases are commonly treated as independent modular units with distinct biological functions . Here , the interactions between the catalytic and juxtamembrane domains of P35968 are studied . Highly purified preparations of the receptor tyrosine kinase P35968 catalytic domain without ( P35968 - CD ) and with ( P35968 - CD / JM ) the juxtamembrane ( JM ) domain were characterized by kinetic , biophysical , and structural methods . Although the catalytic parameters for both constructs were similar , the autophosphorylation rate of P35968 - CD / JM was substantially faster than P35968 - CD . The first event in the autophosphorylation reaction was phosphorylation of JM residue Y801 followed by phosphorylation of activation loop residues in the CD . The rates of activation loop autophosphorylation for the two constructs were determined to be similar . The autophosphorylation rate of Y801 was invariant on enzyme concentration , which is consistent with an intramolecular reaction . In addition , the first biochemical characterization of the advanced clinical compound axitinib is reported . DB06626 was found to have 40 - fold enhanced biochemical potency toward P35968 - CD / JM ( K ( i ) = 28 pM ) compared to P35968 - CD , which correlates better with cellular potency . Calorimetric studies , including a novel ITC compound displacement method , confirmed the potency and provided insight into the thermodynamic origin of the potency differences . A structural model for the P35968 - CD / JM is proposed based on the experimental findings reported here and on the JM position in c - Kit , P36888 , and P09603 / cFMS . The described studies identify potential functions of the P35968 JM domain with implications to both receptor biology and inhibitor design .",
"Ferulic acid is nephrodamaging while gallic acid is renal protective in long term treatment of chronic kidney disease . BACKGROUNDS & AIMS : The long term therapeutic effect of ferulic acid ( FA ) and gallic acid ( GA ) in treatment of chronic kidney disease ( CKD ) has been lacking . METHODS : Doxorubicin ( DR , DB00997 ) - induced CKD rat model was established for this study . RESULTS : DR significantly reduced levels of serum albumin , GOT , GPT , RBC , P01375 - α , and urinary creatinine and elevated serum cholesterol , TG , BUN , creatinine , uric acid , WBC , platelet count , and P05231 . In DRCKD rats , FA and GA significantly increased kidney weight and glomerular volume . FA reduced glomerular filtration rate but GA did not . FA enhanced more collagen deposition than GA in renal cortex and glomeruli . Both FA and GA showed crucial hyperlipidemic activity . The inhibitory effects of FA and GA on P08253 were very comparable . GA suppressed P08253 more effectively than FA in DRCKD rats . Both FA and GA induced SOD elevation and MDA elimination . In DRCKD rats , Western blot analysis indicated that FA further up - regulated P28906 , α - SMA , tissue pDGFR , p - P09619 , and TGF - β ; and down - regulated p - PI3K , and p - Akt . Since both DB00102 and TGF - β are considered to induce kidney prefibrosis stage , GA was proved to be more beneficial in this regard . CONCLUSIONS : GA tends to protect the CKD while FA is not recommended for the long term CKD therapy .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK41___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK29___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .",
"Comparison of the micro - and macro - vascular effects of glimepiride and gliclazide in metformin - treated patients with Type 2 diabetes : a double - blind , crossover study . AIMS : To compare the metabolic and vascular effects of two sulphonylureas ( SU ) , gliclazide ( specific for the pancreatic [ Q09428 ] receptor ) and glimepiride ( a nonspecific agent that also binds to vascular and cardiac [ SUR2 ] receptors ) , during chronic administration in metformin - treated patients with Type 2 diabetes ( T2DM ) . METHODS : A randomized , double - blind , crossover study of gliclazide 80 mg P55957 and glimepiride 2 mg OD , each for 4 weeks as add - on therapy to metformin , with a 4 - week washout period . Patients attended four study mornings after first dose and 4 weeks ' SU treatment for measurements of arterial distensibility ( Ax ) , pressor responsiveness to i . v . angiotensin II ( ANGII ) , and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) . RESULTS : Glycaemic responses were similar ( e . g . serum fructosamine was 315 vs 329 micro mol l - 1 after 4 weeks ) , and there was no change in augmentation index during treatment with either SU ( 9 . 1 vs 9 . 8 mmHg after 4 weeks [ 95 % confidence interval - 8 . 1 , 10 . 5 ] ) . Similarly , there were no differences between treatments in pressor responsiveness ( e . g . PD10 [ dose of agonist required to increase mean BP by 10 mmHg ] for ANGII was 1 . 37 vs 1 . 68 ng kg - 1 min - 1 [ - 4 . 3 , 6 . 9 ] ) or cutaneous microvascular vasodilator responses ( peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [ - 82 . 7 , 79 . 1 ] ) . CONCLUSIONS : There is no evidence that Q09428 - specific and nonspecific SUs have differential effects on arterial distensibility , endothelial function or vasodilator mechanisms in metformin - treated patients with T2DM .",
"DB11320 contributes to tissue remodeling via periostin expression . DB11320 is thought to have a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases . Recent studies revealed that periostin , a matricelluar protein , contributed to tissue remodeling ; however , a link between periostin and histamine remains unproven . We investigated whether periostin was involved in histamine - induced collagen production . Cultured dermal fibroblasts derived from wild - type ( WT ) or periostin knockout ( PN (-/-) ) mice were stimulated with histamine , and then collagen and periostin production was evaluated . DB11320 induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase , whereas no effect on collagen expression was observed in histamine - stimulated PN (-/-) fibroblasts . In WT fibroblasts , histamine directly induced periostin expression in a dose - dependent manner , and an H1 receptor antagonist blocked both periostin and collagen expression . DB11320 activated extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) through the H1 receptor . Q15063 induction was inhibited by either H1 antagonist or P27361 / 2 inhibitor treatment in vitro and was attenuated in P35367 (-/-) mice . Elevated expression of periostin was found in lesional skin from atopic dermatitis patients . These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor - mediated P27361 / 2 pathway ; furthermore , histamine may accelerate the chronicity of atopic dermatitis .",
"___MASK91___ block of cloned human T - type voltage - gated calcium channels . ___MASK91___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"___MASK16___ for joints and bones . ___MASK16___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK16___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK16___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK58___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK58___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Nardosinone protects H9c2 cardiac cells from angiotensin II - induced hypertrophy . Pathological cardiac hypertrophy induced by angiotensin II ( AngII ) can subsequently give rise to heart failure , a leading cause of mortality . Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis , a well - known traditional Chinese medicine . In order to investigate the effects of nardosinone on AngII - induced cardiac cell hypertrophy and the related mechanisms , the myoblast cell line H9c2 , derived from embryonic rat heart , was treated with nardosinone ( 25 , 50 , 100 , and 200 μmol / L ) or AngII ( 1 μmol / L ) . Then cell surface area and mRNA expression of classical markers of hypertrophy were detected . The related protein levels in PI3K / Akt / P42345 and MEK / P29323 signaling pathways were examined by Western blotting . It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII . The mRNA expression of P01160 , DB04899 and β - MHC was obviously elevated in AngII - treated H9c2 cells , which could be effectively blocked by nardosinone at the concentration of 100 μmol / L . Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K / Akt and MEK / P29323 signaling pathways . It was suggested that the inhibitory effect of nardosinone on Ang II - induced hypertrophy in H9c2 cells might be mediated by targeting PI3K / Akt and MEK / P29323 signaling pathways .",
"DB00877 inhibition of O75347 - induced lymphangiogenesis in P26678 is independent of mast cells . Elucidation of the events responsible for the interaction between lymphatic endothelial cells ( LECs ) and mast cells ( MCs ) may prove to be a valuable source for controlling lymphangiogenesis . In the present study , we compared immunohistochemical and RT - PCR findings of the popliteal lymph node ( P26678 ) and footpad skin in C57BL / 6J and WBB6F1 mice , the MC - deficient strain . The results indicated that MCs play certain role in complete Freund ' s adjuvant - induced intranodal lymphangiogenesis . P15692 , P35968 and P01375 - α were crucial factors in lymphangiogenesis both in the P26678 and skin . Moreover , the in vivo administration of the specific P42345 inhibitor , rapamycin inhibited lymphangiogenesis independent of MCs in P26678 rather than in the skin . Further study on anti - lymphangiogenic effect will contribute to our understanding of LEC and MC modulation in pathological lymphangiogenesis .",
"DB00762 synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo . AIMS : To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer . METHODS : Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer ( MIAPaCa - 2 , Capan - 1 ) cell lines exposed to SN - 38 , the active metabolite of irinotecan , axitinib , or their simultaneous combination for 72 hours . P27361 / 2 and Akt phosphorylation , the vascular endothelial growth factor ( P15692 ) , P15692 receptor - 2 , and thrombospondin - 1 ( P07996 - 1 ) concentration were measured by ELISAs . Q04656 and Q9UNQ0 gene expression was performed with real - time polymerase chain reaction and SN - 38 intracellular concentrations were measured by high - performance liquid chromatography . Capan - 1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination . RESULTS : A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib / SN - 38 combination on endothelial and cancer cells . P27361 / 2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines . DB06626 and SN - 38 combined treatment greatly inhibited the expression of the Q04656 and Q9UNQ0 genes in endothelial and cancer cells , increasing the SN - 38 intracellular concentration . Moreover , P07996 - 1 secretion was increased in cells treated with both drugs , whereas P35968 levels significantly decreased . In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization . CONCLUSIONS : In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells , suggesting a possible translation of this schedule into the clinics .",
"DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .",
"Effect of axitinib ( AG - 013736 ) on fatigue , thyroid - stimulating hormone , and biomarkers : a phase I study in Japanese patients . DB06626 is an oral , potent , and selective inhibitor of vascular endothelial growth factor receptor ( VEGFR ) 1 , 2 , and 3 . This phase I study evaluated the safety , pharmacokinetics , pharmacodynamics , antitumor activity , and recommended starting dose of axitinib in patients with advanced solid tumors . Twelve patients received single - dose axitinib 5 mg and were monitored for > or = 48 h . Continuous 5 mg twice - daily dosing was then initiated . One patient had dose - limiting toxicity ( grade 3 proteinuria and fatigue ) . Common treatment - related adverse events were anorexia , fatigue , and diarrhea . Grade 3 treatment - related adverse events were fatigue and hypertension . Maximum axitinib plasma concentration occurred 1 - 4 h after steady - state dosing . Eleven patients experienced thyroid - stimulating hormone elevation ; time - course change and fatigue onset appeared to be related in some patients . Significant correlation was observed between thyroid - stimulating hormone change and area under the plasma concentration - time curve ( AUC ; r = 0 . 80 , P = 0 . 005 ) . DB06626 decreased plasma soluble vascular endothelial growth factor receptor 2 ( s - P35968 ) , with significant correlation between change in s - P35968 and AUC ( r = - 0 . 92 , P < 0 . 0001 ) . Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib . Tumor size decreased in nine patients . The time - course of thyroid - stimulating hormone change appeared correlated with fatigue . There were significant correlations between thyroid - stimulating hormone or s - P35968 and axitinib exposure . DB06626 5 mg twice - daily is the recommended starting dose for Japanese patients . This trial is registered with ClinicalTrials . gov , identifier NCT00447005 .",
"P37231 and aging : one link through klotho ? P37231 , a transcription factor involved in adipogenesis , glucose homeostasis , bone turnover , and inflammation , has now been shown to increase klotho expression . Q9UEF7 is predominantly expressed by the kidney and functions at the tubule and in the circulation as an anti - aging factor and a hormone participating in mineral metabolism . The finding that klotho is upregulated by P37231 may prompt further exploration of the role and mechanism of action of P37231 in aging and bone diseases .",
"Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .",
"P49767 promotes survival of retinal vascular endothelial cells via vascular endothelial growth factor receptor - 2 . AIM : To determine vascular endothelial growth factor C ( P49767 ) expression in retinal endothelial cells , its antiapoptotic potential and its putative role in diabetic retinopathy . METHOD : Cultured retinal endothelial cells and pericytes were exposed to tumour necrosis factor ( P01375 ) alpha and P49767 expression determined by reverse transcriptase - polymerase chain reaction . Secreted P49767 protein levels in conditioned media from endothelial cells were examined by western blotting analysis . The ability of P49767 to prevent apoptosis induced by TNFalpha or hyperglycaemia in endothelial cells was assessed by flow cytometry . The expression of P49767 in diabetic retinopathy was studied by immunohistochemistry of retinal tissue . RESULT : P49767 was expressed by both vascular endothelial cells and pericytes . TNFalpha up regulated both P49767 and vascular endothelial growth factor receptor - 2 ( VEGFR ) - 2 expression in endothelial cells in a dose - dependent manner , but had no effect on P35916 . Flow cytometry results showed that P49767 prevented endothelial cell apoptosis induced by TNFalpha and hyperglycaemia and that the antiapoptotic effect was mainly via P35968 . In pericytes , the expression of P49767 mRNA remained stable on exogenous TNFalpha treatment . P49767 immunostaining was increased in retinal vessels in specimens with diabetes compared with retinal specimens from controls without diabetes . CONCLUSION : In retinal endothelial cells , TNFalpha stimulates the expression of P49767 , which in turn protects endothelial cells from apoptosis induced by TNFalpha or hyperglycaemia via P35968 and thus helps sustain retinal neovascularisation .",
"DB06626 for renal cell carcinoma . BACKGROUND : The approval of sunitinib , sorafenib and temsirolimus has dramatically altered the management of renal cell carcinoma ( RCC ) . DB00112 plus IFN may also be added to the therapeutic armamentarium . DB06626 ( AG - 013736 ) is an oral and selective tyrosine kinase inhibitor . OBJECTIVE : Data supporting the development of axitinib for RCC are reviewed . METHODS : Preclinical and clinical data available for axitinib for RCC are presented . RESULTS : DB06626 inhibits P17948 , P35968 and P35916 with picomolar potencies , and P16234 , P09619 and c - kit with nanomolar potencies . Phase II clinical trials of axitinib in pretreated RCC following sorafenib or cytokine treatment have demonstrated promising activity accompanied by a favorable toxicity profile . Further development of axitinib for RCC is warranted .",
"DB03843 - or adjuvant - induced peripheral inflammation increases neurokinin - 1 receptor gene expression in the mouse . Substance P ( SP ) has been widely studied as a mediator of nociception . The release of SP from primary afferent neurons is increased during nociception , and SP activates neurokinin - 1 ( NK - 1 ) receptors in the spinal cord and periphery . Nociception - evoked alterations in P25103 gene expression have been studied in rat models of persistent pain but have not been characterized in any murine models of peripheral inflammation . This study assessed behavioral responses and P25103 mRNA gene expression in mice receiving formalin or Freund ' s complete adjuvant ( O75347 ) as an inflammatory stimulus . Mechanical withdrawal thresholds were measured before injection of formalin or O75347 and hind paw licking / biting timed during the late - phase of the formalin response . Two and 24 hours after formalin or O75347 injection , mechanical withdrawal thresholds were measured and the mice euthanized . Solution hybridization - nuclease protection assays were used to quantify P25103 mRNA levels . Results demonstrated that inflamed hind paws were edematous , and the withdrawal thresholds of the inflamed hind paws were significantly lower after formalin or O75347 injection . Neurokinin - 1 receptor mRNA levels in the ipsilateral dorsal spinal cords of mice were higher at 24 h after formalin injection or 4 days after O75347 injection . These results confirm that mice are hyperalgesic at late time points after formalin or adjuvant injection when P25103 gene expression is elevated in the dorsal spinal cord . This supports the hypothesis that increased P25103 gene expression contributes to the development and maintenance of a hyperalgesic state .",
"Inhibition of platelet - derived growth factor receptor tyrosine kinase by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 ) is known to suppress platelet - derived growth factor ( PDGF ) - stimulated proliferation of rat cultured vascular smooth muscle cells . The present study examined whether P01160 inhibits the PDGF receptor ( P09619 ) tyrosine kinase activation , an initial event for PDGF cellular signaling . P01160 reduced the in vivo tyrosine phosphorylation of P09619 stimulated by PDGF in a dose - dependent manner . This effect was not due to the reduction in P09619 protein as detected by immunoblot analysis . 8 - Bromo - cyclic GMP , a membrane - permeable 3 ', 5 '- cyclic monophosphate ( cGMP ) derivative , mimicked the action of P01160 . HS - 142 - 1 , an antagonist for guanylate cyclase A ( P16066 ) and B , co - incubated with P01160 , restored the PDGF - induced P09619 autophosphorylation . The effect of P01160 was also observed in the presence of a protein tyrosine phosphatase inhibitor , sodium orthovanadate . To confirm that P01160 exerts its action by inhibiting protein tyrosine kinase ( PTK ) , an in vitro kinase assay was performed . Cyclic GMP inhibited PTK activity of P09619 partially purified by lectin affinity chromatography . In contrast , PTK activity in immobilized P09619 immunocomplexes was not inhibited by cGMP . However , exogenous cGMP dependent protein kinase ( PKG ) reduced the PTK activity in the presence of cGMP . These results demonstrate that P01160 suppresses P09619 PTK through P16066 probably by activating PKG . This may be an important mechanism by which P01160 exerts its anti - proliferative action antagonizing PDGF .",
"Q9UEF7 endows hepatoma cells with resistance to anoikis via P35968 / PAK1 activation in hepatocellular carcinoma . Q9UEF7 was originally characterized as an aging suppressor gene that predisposed Q9UEF7 - deficient mice to premature aging - like syndrome . Although Q9UEF7 was recently reported to exhibit tumor suppressive properties during various malignant transformations , the functional role and molecular mechanism of Q9UEF7 in hepatocarcinogenesis remains poorly understood . In our present study , immunohistochemical Q9UEF7 staining levels in a clinical follow - up of 52 hepatoma patients were significantly associated with liver cirrhosis , tumor multiplicity and venous invasion . The overall survival rate of hepatoma patients with high Q9UEF7 expression was significantly lower than those patients with low Q9UEF7 expression . Moreover , Q9UEF7 overexpression increased cellular migration , anchorage - independent growth , and anoikis resistance in hepatoma cells . Q9UEF7 overexpression elevated Q13153 ( PAK1 ) expression and shRNA - mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Q9UEF7 - overexpressed hepatoma cells . More importantly , the pivotal significance of upregulated P35968 protein levels mediated by Q9UEF7 expression was confirmed by P35968 inhibitor DB06626 and blocking antibody treatment in hepatoma cells . DB06626 treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Q9UEF7 - overexpressed hepatoma cells . Conversely , knockdown of Q9UEF7 reduced P35968 / PAK1 dependent anoikis resistance , which could be reversed by PAK1 T423E . These results revealed a novel oncogenic function of Q9UEF7 in promoting anoikis resistance via activating P35968 / PAK1 signaling , thus facilitating tumor migration and invasion during hepatoma progression , which could provide a putative molecular mechanism for tumor metastasis .",
"Src kinases mediate P35968 transactivation by the osteostatin domain of P12272 to modulate osteoblastic function . P12272 ( P12272 ) stimulates osteoblastic function through its N - and C - terminal domains . Since the osteogenic action of the latter domain appears to depend at least in part on its interaction with the vascular endothelial growth factor ( P15692 ) system , we aimed to explore the putative mechanism underlying this interaction in osteoblasts . Using native conditions for protein extraction and immunoblotting , we found that both P12272 ( 107 - 139 ) and the shorter P12272 ( 107 - 111 ) peptide ( known as osteostatin ) , at 100 nM , promoted the appearance of a P15692 receptor ( VEGFR ) 2 protein band of apparent Mr . wt . 230 kDa , which likely represents its activation by dimer formation , in mouse osteoblastic MC3T3 - E1 cells . Moreover , osteostatin ( 100 nM ) maximally increased P35968 phosphorylation at DB00135 - 1059 within 5 - 10 min in both MC3T3 - E1 and rat osteoblastic osteosarcoma UMR - 106 cells . This phosphorylation elicited by osteostatin appears to be P15692 - independent , but prevented by the P35968 activation inhibitor SU1498 and also by the Src kinase inhibitors SU6656 and P50391 . Furthermore , osteostatin induced phosphorylation of Src , extracellular signal - regulated kinase ( P29323 ) and Akt with a similar time course to that observed for P35968 activation in these osteoblastic cells . This osteostatin - dependent induction of P29323 and Akt activation was abrogated by SU6656 . Up - regulation of P15692 and osteoprotegerin gene expression as well as the pro - survival effect induced by osteostatin treatment were all prevented by both SU1498 and SU6656 in these osteoblastic cells . Collectively , these findings demonstrate that the osteostatin domain of C - terminal P12272 phosphorylates P35968 through Src activation , which represents a mechanism for modulating osteoblastic function .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"Key predictive factors of axitinib ( AG - 013736 ) - induced proteinuria and efficacy : a phase II study in Japanese patients with cytokine - refractory metastatic renal cell Carcinoma . BACKGROUND : DB06626 ( AG - 013736 ) is an oral , selective and potent inhibitor of vascular endothelial growth factor receptors ( VEGFR ) - 1 , 2 and 3 . This phase II study investigated axitinib efficacy , safety and biomarkers in Japanese patients with cytokine - refractory metastatic renal cell carcinoma ( mRCC ) . PATIENTS AND METHODS : In an open - label , multicentre study , 64 patients received an axitinib starting dose of 5mg twice daily . RESULTS : Objective response rate ( ORR ) was 50 . 0 % and median progression - free survival ( PFS ) was 11 . 0 months per independent review committee . Common treatment - related adverse events were hypertension ( 84 % ; 70 % grade ≥ 3 ) , hand - foot syndrome ( 75 % ; 22 % grade ≥ 3 ) and diarrhoea ( 64 % ; 5 % grade ≥ 3 ) . Eighteen patients ( 28 % ) developed proteinuria ≥ 2g / 24h and required dose reduction or treatment interruption / discontinuation . Proteinuria was a major cause for treatment discontinuation . Baseline urine protein levels were associated with development of proteinuria ≥ 2g / 24h ( hazard ratio [ HR ]= 5 . 457 , P = 0 . 0035 in patients with baseline proteinuria ≥ 1 + versus < 1 + ) . Baseline urine protein levels correlated more strongly with axitinib - related proteinuria than other baseline renal function test values or blood pressure . Patients with greater decreases in soluble P35968 concentrations had significantly higher ORR and longer PFS than those with smaller decreases ( ORR : 64 . 5 % versus 37 . 5 % , P = 0 . 045 ; median PFS : 12 . 9 months versus 9 . 2 months , HR = 0 . 42 , P = 0 . 01 ) . CONCLUSIONS : DB06626 showed significant antitumour activity and was well tolerated in Japanese mRCC patients . Baseline proteinuria and soluble P35968 levels may be key indicators of axitinib - induced proteinuria and efficacy , respectively .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK6___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Suppression of parathyroid hormone - related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues . The level of parathyroid hormone - related protein ( P12272 ) expressed in breast cancer tissue is closely related to the incidence of bone metastasis . We examined the P12272 mRNA expression in breast cancer tissues by coamplification polymerase chain reaction ( PCR ) in mole ratio to internal standard beta - actin mRNA . The P12272 expression was higher in premenopausal patients than in postmenopausal patients ( P < 0 . 05 ) . More pronounced difference by menopause found in estrogen receptor ( ER ) positive groups ( P < 0 . 001 ) indicated that the P12272 expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents . To clarify the changes of P12272 expression by endocrine therapy of breast cancer , we measured P12272 expression in the breast cancer tissue incubated for 24 h with 1 x 10 (- 8 ) M of estradiol ( E2 ) , 1 x 10 (- 6 ) M of tamoxifen ( TAM ) and 1 x 10 (- 5 ) M of medroxyprogesterone acetate ( ___MASK77___ ) . The P12272 expression was decreased significantly by ___MASK77___ ( P < 0 . 005 ) , while E2 and TAM did not change the P12272 expression . P06401 ( PgR ) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM . The results were well compatible with the better therapeutic effect of ___MASK77___ reported for the treatment of breast cancer with bone metastases . As a potential candidate for the receptor that mediates the suppressive effect of ___MASK77___ , androgen receptor ( AR ) is suggested most probable . Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen .",
"Q9UEF7 -- a common link in physiological and rheumatoid arthritis - related aging of human P01730 + lymphocytes . Human P01730 (+) T lymphocytes undergo aging - related changes leading to decreased immunity to infections and neoplasms , and to increased frequency of autoimmune diseases including rheumatoid arthritis ( RA ) . Certain changes , observed in the P01730 (+) cells of RA patients , resemble those observed during physiological aging , but occur at earlier age . Underlying cellular mechanism ( s ) of these similarities are so far largely unknown . Here we show that KLOTHO , a beta - glucuronidase gene whose activity changes are associated with aging phenotype , is down - regulated at the mRNA , protein , and enzymatic ( beta - glucuronidase ) activity levels both in the healthy elderly and especially in RA P01730 (+) lymphocytes . Although the exact role of Q9UEF7 activity for P01730 (+) cell function is unknown , we propose here that it might be involved in anti - inflammatory processes occurring in the young and healthy individuals , but reduced in both healthy elderly and RA patients . To support this hypothesis , we show here that the reduction of Q9UEF7 expression and activity in both elderly and patients ' lymphocytes occurs in concert with the down - regulation of T cell costimulatory molecule P10747 , the latter known to be dependent on increased levels of P01375 . Thus , a common mechanism of KLOTHO down - regulation , but executed at various times in life , may underlie both physiological and disease - related T cell aging . Q9UEF7 activity might become a target of anti - RA drug development as well as a tool to help increase the immune system efficiency in the elderly .",
"The combination of axitinib followed by paclitaxel / carboplatin yields extended survival in advanced P15056 wild - type melanoma : results of a clinical / correlative prospective phase II clinical trial . BACKGROUND : Simultaneous chemotherapy with vascular endothelial growth factor ( P15692 ) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma . We tested administration of the potent P15692 inhibitor axitinib followed by paclitaxel / carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity . METHODS : We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0 - 1 and normal organ function . DB06626 5 mg PO b . i . d . was taken on days 1 - 14 of each 21 - day treatment cycle , and carboplatin ( AUC = 5 ) with paclitaxel ( 175 mg m (- 2 ) ) was administered on day 1 starting with cycle 2 . 3 '- Deoxy - 3 '-( 18 ) F - fluorothymidine ( ( 18 ) F - P17948 ) - PET scans were performed in five patients to assess tumour proliferation on days 1 , 14 , 17 , and 20 of cycle 1 . Molecular profiling for P15056 was performed for all patients with cutaneous , acral , or mucosal melanoma . RESULTS : The treatment was well tolerated . The most common grade 3 AEs were hypertension , neutropenia , and anaemia . Grade 4 non - haematologic AEs were not observed . Four of five patients completing ( 18 ) F - P17948 - PET scans showed increases ( 23 - 92 % ) in SUV values during the axitinib holiday . Of 36 evaluable patients , there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors . Overall , 20 patients had SD and 8 had PD as the best response . The median PFS was 8 . 7 months and the median overall survival was 14 . 0 months . Five P15056 ( V600E / K ) patients had significantly worse PFS than patients without these mutations . CONCLUSIONS : DB06626 followed by carboplatin and paclitaxel was well tolerated and effective in P15056 wild - type metastatic melanoma . 3 '- Deoxy - 3 '-( 18 ) F - fluorothymidine - PET scans showed increased proliferation during axitinib withdrawal .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK52___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"P37231 ligands are potent inhibitors of angiogenesis in vitro and in vivo . P37231 ( PPARgamma ) is a nuclear receptor that functions as a transcription factor to mediate ligand - dependent transcriptional regulation . Activation of PPARgamma by the naturally occurring ligand , 15 - deoxy - Delta12 , 14 - prostaglandin J2 ( 15d - PGJ2 ) , or members of a new class of oral antidiabetic agents , e . g . BRL49653 and ciglitizone , has been linked to adipocyte differentiation , regulation of glucose homeostasis , inhibition of macrophage and monocyte activation , and inhibition of tumor cell proliferation . Here we report that human umbilical vein endothelial cells ( HUVEC ) express PPARgamma mRNA and protein . Activation of PPARgamma by the specific ligands 15d - PGJ2 , BRL49653 , or ciglitizone , dose dependently suppresses HUVEC differentiation into tube - like structures in three - dimensional collagen gels . In contrast , specific PPARalpha and - beta ligands do not affect tube formation although mRNA for these receptors are expressed in HUVEC . PPARgamma ligands also inhibit the proliferative response of HUVEC to exogenous growth factors . Treatment of HUVEC with 15d - PGJ2 also reduced mRNA levels of vascular endothelial cell growth factor receptors 1 ( Flt - 1 ) and 2 ( Flk / P35968 ) and urokinase plasminogen activator and increased plasminogen activator inhibitor - 1 ( P05121 ) mRNA . Finally , administration of 15d - PGJ2 inhibited vascular endothelial cell growth factor - induced angiogenesis in the rat cornea . These observations demonstrate that PPARgamma ligands are potent inhibitors of angiogenesis in vitro and in vivo , and suggest that PPARgamma may be an important molecular target for the development of small - molecule inhibitors of angiogenesis .",
"Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"O95760 augments DB05875 - induced P15692 secretion from human mast cells and is increased in psoriatic skin . The peptide DB05875 ( SP ) has been implicated in inflammatory conditions , such as psoriasis , where mast cells and P15692 are increased . A relationship between SP and P15692 has not been well studied , nor has any interaction with the proinflammatory cytokines , especially O95760 . Here we report that SP ( 0 . 1 - 10 microM ) induces gene expression and secretion of P15692 from human LAD2 mast cells and human umbilical core blood - derived cultured mast cells ( hCBMCs ) . This effect is significantly increased by coadministration of O95760 ( 5 - 100 ng / mL ) in both cell types . The effect of SP on P15692 release is inhibited by treatment with the P25103 antagonist 733 , 060 . SP rapidly increases cytosolic calcium , and so does O95760 to a smaller extent ; the addition of O95760 augments the calcium increase . SP - induced P15692 production involves calcium - dependent PKC isoforms , as well as the P29323 and JNK MAPKs . Gene expression of O95760 and histidine decarboxylase ( HDC ) , an indicator of mast cell presence / activation , is significantly increased in affected and unaffected ( at least 15 cm away from the lesion ) psoriatic skin , as compared with normal control skin . Immunohistochemistry indicates that O95760 is associated with endothelial cells in both the unaffected and affected sites , but is stronger and also associated with immune cells in the affected site . These results imply that functional interactions among SP , O95760 , and mast cells leading to P15692 release contribute to inflammatory conditions , such as the psoriasis , a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component .",
"Induction of cutaneous delayed - type hypersensitivity reactions in P15692 transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia . Vascular endothelial growth factor - A ( P15692 ) expression is up - regulated in several inflammatory diseases including psoriasis , delayed - type hypersensitivity ( DTH ) reactions , and rheumatoid arthritis . To directly characterize the biologic function of P15692 in inflammation , we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress P15692 specifically in the epidermis . P15692 transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month , whereas inflammation returned to baseline levels within 7 days in wild - type mice . Inflammatory lesions in P15692 transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia , impaired epidermal differentiation , and accumulation of dermal P01730 + T - lymphocytes and epidermal CD8 + lymphocytes . Surprisingly , P15692 also promoted lymphatic vessel proliferation and enlargement , which might contribute to the increased inflammatory response , as lymphatic vessel enlargement was also detected in human psoriatic skin lesions . Combined systemic treatment with blocking antibodies against P15692 receptor - 1 ( P17948 ) and P35968 potently inhibited inflammation and also decreased lymphatic vessel size . Together , these findings reveal a central role of P15692 in promoting lymphatic enlargement , vascular hyperpermeability , and leukocyte recruitment , thereby leading to persistent chronic inflammation . They also indicate that inhibition of P15692 bioactivity might be a new approach to anti - inflammatory therapy .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF - α / P15692 / Rho - GTPases : pivotal role of P35610 - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken - Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 and P08253 in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 and P08253 play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 ( DB00135 - 1175 ) , and expression of HIF - α . Rho - GTPases , which are regulated by P15692 play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up - regulated the expression of tumor suppressor RhoB . P35610 - 3 over - expression or P05231 treatment significantly induced HIF - 1α and P15692 expression ; however , BITC substantially suppressed P35610 - 3 as well as P35610 - 3 - induced HIF - 1α and P15692 expression . Finally , in vivo tumor growth and matrigel - plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 - 3 phosphorylation ( DB00135 - 705 ) , HIF - α , P35968 , P15692 , P08253 , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 - 3 - dependant pathway .",
"Investigation of immunomodulatory properties of human Wharton ' s Jelly - derived DB05914 after lentiviral transduction . Human Wharton ' s Jelly - derived Mesenchymal Stem Cells ( hWJ - MSCs ) are considered as an alternative for bone - marrow - derived MSCs . These cells have immunosuppressive properties . It was unclear whether the WJ - MSCs would sustain their immunomodulatory characteristics after lentiviral transduction or not . In this study , we evaluated immunomodulatory properties of WJ - MSCs after lentiviral transduction . HWJ - MSCs were transduced with lentiviral particles . Expression of transduced and un - transduced hWJ - MSCs surface molecules and secretion of P22301 , P14210 , P15692 and TGF - β was analyzed . Cell proliferation and frequency of P01730 (+) CD25 (+) CD127 ( low / neg ) Foxp3 (+) T regulatory cells was measured . There was no difference between the surface markers and secretion of P22301 , P14210 , P15692 and TGF - β in transduced and un - transduced hWJ - MSCs . Both cells inhibited the proliferation of PHA stimulated PBMCs , and improved the frequency of T regulatory cells . These findings suggest that lentiviral transduction does not alter the immunomodulatory function of hWJ - MSCs . However , lentiviral transduction may have a wide range of applications in gene therapy .",
"Treatment of hepatocellular carcinoma with adenoviral vector - mediated P49771 gene therapy . P36888 ligand ( P49771 ) plays an important role in development and activation of dendritic cells ( DCs ) and natural killer cells ( NK ) . It has been shown that administration of either tumor cells transfected in vitro with P49771 vectors or soluble P49771 fusion protein in a high dose can enhance host antitumor immunity in animal model systems . In this study , we developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse P49771 ( Ad - mFlt3L ) under control of cytomegalovirus promoter and investigated its biological efficacy in eliciting tumor - specific immune response against hepatocellular carcinoma in mouse hepatoma model . The constructed Ad - mFlt3L efficiently infected hepa 1 - 6 hepatoma cells both in vitro and in vivo , leading to a high production of mFlt3L proteins in association with accumulation of DCsNK cells and lymphocytes in local tumor tissues . Tumor cells infected with Ad - mFlt3L lost tumorigenicity and became more immunogenic in syngeniec animal models . Intratumoral injection of Ad - mFlt3L ( 10 ( 9 ) expression - forming unit ) x 3 significantly inhibited tumor growth with elicitation of long - lasting antitumor immunity , which is both preventive and curative . The tumor - specific immunity can be partially abrogated by depletion of either CD3 + P01730 + T cells or NK cells and can be also re - established in naïve animals by adoptive transfer of splenocytes from treated mice . The results suggest that adenovirus - mediated P49771 gene therapy may provide a useful strategy for treatment of cancers .",
"Mortality prediction using modern peptide biomarkers in hemodialysis patients -- a comparative analysis . BACKGROUND / AIMS : Determination of peptide biomarkers such as troponins , natriuretic peptides or the recently reported Q9GZV9 can be useful to identify hemodialysis patients with a high risk of mortality . However , it is desirable to focus on few robust parameters to warrant their routine application . METHODS : In a prospective cohort study with 239 prevalent hemodialysis patients we studied the prognostic significance of 10 simultaneously determined modern peptide biomarkers ( high sensitive troponin I and T , NT - pro - DB04899 , DB04899 , MR - pro - P01160 , MR - pro - P35318 , CT - pro - ET1 , copeptin , Q9GZV9 and a - Q9UEF7 ) and compared them with parameters traditionally associated with mortality ( PTH , Ca , Pi , albumin , CRP , cholesterol , AP ) . RESULTS : After a follow - up of 4 years , plasma concentration of troponins , natriuretic peptides , MR - pro - P35318 , Q9GZV9 as well as PTH , CRP , AP were significantly higher in deceased patients ( n = 95 ) . Hazard ratios from cox regression on a continuous scale ( doubling of plasma concentration ) or relative in tertiles were highest for high sensitive troponins , followed by natriuretic peptides and MR - pro - P35318 ( 1 . 6 - 2 . 0 and 2 . 3 - 5 . 5 , resp . ) . C - indices were also highest for troponins ( 0 . 708 - 0 . 746 ) , followed by natriuretic peptides ( 0 . 706 - 0 . 731 ) . Traditional parameters had low c - indices ( 0 . 598 - 0 . 655 ) . Stepwise cox regression revealed that among all parameters troponin I , NT - pro - DB04899 , PTH and CRP remained independent predictors of mortality and a composite score had the highest c - index ( 0 . 799 [ 0 . 740 - 0 . 849 ] ) . CONCLUSIONS : Among peptide biomarkers high sensitive troponins and to a lesser extent natriuretic peptides are strong predictors of mortality in asymptomatic hemodialysis patients , followed by markers of mineral - bone disease and inflammation .",
"Vascular endothelial growth factor receptors in osteoclast differentiation and function . Osteoclasts are derived from haematopoietic stem cell precursors of the monocyte / macrophage cell lineage , through interaction with factors that are believed to include P09603 and O14788 . P15692 is a proangiogenic cytokine that has been shown to promote osteoclast differentiation and survival . In this study , we assessed the role of P15692 and its receptors in osteoclastogenesis , in vitro , by culturing osteoclast precursors in the presence of P15692 , P15692 receptor - specific ligands , and blocking antibodies to P15692 receptors . Activation of P17948 in the presence of O14788 induces osteoclast differentiation . Stimulating the receptors individually induced increased resorption by osteoclasts compared to controls but not to the level observed when stimulating both receptors simultaneously . We have shown that P15692 induces osteoclast differentiation through its action on P17948 . The way in which P15692 mediates its effect on mature osteoclast activity , however , may be through its interaction with both receptor subtypes .",
"DB00877 generates anti - apoptotic human Th1 / Tc1 cells via autophagy for induction of xenogeneic GVHD . Murine T cells exposed to rapamycin maintain flexibility towards Th1 / Tc1 differentiation , thereby indicating that rapamycin promotion of regulatory T cells ( Tregs ) is conditional . The degree to which rapamycin might inhibit human Th1 / Tc1 differentiation has not been evaluated . In the presence of rapamycin , T cell costimulation and polarization with IL - 12 or IFN - α permitted human P01730 + and CD8 + T cell differentiation towards a Th1 / Tc1 phenotype ; activation of P42224 and Q14765 pathways essential for Th1 / Tc1 polarity was preserved during P42345 blockade but instead abrogated by P19957 kinase inhibition . Such rapamycin - resistant human Th1 / Tc1 cells : ( 1 ) were generated through autophagy ( increased LC3BII expression ; phenotype reversion by autophagy inhibition via 3 - MA or siRNA for Beclin1 ) ; ( 2 ) expressed anti - apoptotic bcl - 2 family members ( reduced Bax , Bak ; increased phospho - Bad ) ; ( 3 ) maintained mitochondrial membrane potentials ; and ( 4 ) displayed reduced apoptosis . In vivo , type I polarized and rapamycin - resistant human T cells caused increased xenogeneic graft - versus - host disease ( x - GVHD ) . Murine recipients of rapamycin - resistant human Th1 / Tc1 cells had : ( 1 ) persistent T cell engraftment ; ( 2 ) increased T cell cytokine and cytolytic effector function ; and ( 3 ) T cell infiltration of skin , gut , and liver . DB00877 therefore does not impair human T cell capacity for type I differentiation . Rather , rapamycin yields an anti - apoptotic Th1 / Tc1 effector phenotype by promoting autophagy .",
"The neutralizing function of the anti - HTLV - 1 antibody is essential in preventing in vivo transmission of HTLV - 1 to human T cells in NOD - SCID / γcnull ( Q13253 ) mice . BACKGROUND : Human T - cell leukemia virus type 1 ( HTLV - 1 ) causes both neoplastic and inflammatory diseases , including adult T - cell leukemia and HTLV - 1 - associated myelopathy / tropical spastic paraparesis ( HAM / P07996 ) . Because these life - threatening and disabling diseases are not yet curable , it is important to prevent new HTLV - 1 infections . FINDINGS : In this study , we have established a simple humanized mouse model of HTLV - 1 infection for evaluating prophylactic and therapeutic interventions . In this model , HTLV - 1 - negative normal human peripheral blood mononuclear cells ( PBMCs ) are transplanted directly into the spleens of severely immunodeficient NOD - SCID / γcnull ( Q13253 ) mice , together with mitomycin - treated HTLV - 1 - producing T cells . Using this model , we tested the efficacy of monoclonal antibodies ( mAbs ) specific to HTLV - 1 as well as human IgG isolated from HAM / P07996 patients ( HAM - IgG ) in preventing HTLV - 1 - infection . One hour before and 24 h after transplantation of the human cells , each antibody sample was inoculated intraperitoneally . On day 14 , human PBMCs isolated from the mouse spleens were tested for HTLV - 1 infection . Whereas fresh P01730 - positive and CD8 - positive T cells isolated from untreated mice or mice treated with isotype control mAb , HTLV - 1 non - neutralizing mAbs to envelope gp46 , gag p19 , and normal human IgG were all infected with HTLV - 1 ; the mice treated with either HTLV - 1 neutralizing anti - gp46 mAb or HAM - IgG did not become infected . CONCLUSIONS : Our data indicate that the neutralizing function of the antibody , but not the antigen specificity , is essential for preventing the in vivo transmission of HTLV - 1 . The present animal model will also be useful for the in vivo evaluation of the efficacy of candidate molecules to be used as prophylactic and therapeutic intervention against HTLV - 1 infection .",
"Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .",
"Prolonged high fat / alcohol exposure increases Q9HBA0 and its functional responses in pancreatic stellate cells . The present study investigated transient receptor potential vanilloid type 4 ( Q9HBA0 ) ion channels in pancreatic stellate cells ( PSCs ) isolated from rats with high - fat and alcohol diet ( HFA ) - induced chronic pancreatitis . Q9HBA0 is a calcium - permeable nonselective ion channel responsive to osmotic changes , alcohol metabolites arachidonic acid , anandamide , their derivatives , and injury - related lipid mediators . Male Lewis rats were fed HFA for 6 - 8 wk before isolation and primary culture of PSCs . Control PSCs were harvested from rats fed standard chow . Immunoreactivity for cytoskeletal protein activation product α - smooth muscle actin ( α - SMA ) and platelet - derived growth factor receptor - β subunit ( P09619 - β ) characterized the cells as PSCs . Q9HBA0 expression increased in PSCs of HFA - fed rats and control cultures after alcohol treatment ( 50 mM ) . Cell responses to activation of inducible Q9HBA0 were assessed with live cell calcium imaging . Threefold increased and sustained intracellular calcium mobilization responses occurred in 70 % of pancreatic stellate cells from HFA - fed rats in response to Q9HBA0 activators arachidonic acid , lipid second messenger , phorbol ester 4 α - phorbol 12 , 13 - didecanoate ( 4αPDD ) , and 50 % hypoosmotic media compared with relatively unresponsive PSCs from control rats . Activation responses were attenuated by nonselective TRPV channel blocker ruthenium red . P01375 - α ( P01375 - α , 1 ng / ml , 16 h ) increased responses to 4αPDD in control PSCs . These findings implicate Q9HBA0 - mediated calcium responses inducible after HFA exposure and inflammation in reactive responses of activated PSCs that impair pancreatic function , such as responsiveness to cytokines and the deposition of collagen fibrosis that precipitates ductal blockage and pain .",
"[ Bone metastasis in prostate cancer ] . Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients . In addition to established bone - targeted therapies , new drugs such as endothelin A receptor antagonists , MET and P35968 antagonists or radiopharmaceuticals are in the focus of development . The standard care in prostate cancer patients with bone metastases to prevent skeletal - related events ( SRE ) are bisphosphonates . ___MASK16___ , a human monoclonal antibody against O14788 , appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases - free survival . In contrast to zoledronic acid , denosumab clearance is not dependent on kidney function and can be administered subcutaneously . Similar rates of toxicity were observed for both substances ; however , long - term data for denosumab are limited .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Impact of KCNE subunits on P51787 ( Kv7 . 1 ) channel membrane surface targeting . The P51787 ( Kv7 . 1 ) channel plays an important role in cardiovascular physiology . Cardiomyocytes co - express P51787 with P15382 - 5 proteins . P51787 may co - associate with multiple KCNE regulatory subunits to generate different biophysically and pharmacologically distinct channels . Increasing evidence indicates that the location and targeting of channels are important determinants of their function . In this context , the presence of K (+) channels in sphingolipid - cholesterol - enriched membrane microdomains ( lipid rafts ) is under investigation . Lipid rafts are important for cardiovascular functioning . We aimed to determine whether KCNE subunits modify the localization and targeting of P51787 channels in lipid rafts microdomains . P29320 - 293 cells were transiently transfected with P51787 and P15382 - 5 , and their traffic and presence in lipid rafts were analyzed . Only P51787 and Q9Y6H6 , when expressed alone , co - localized in raft fractions . In addition , while Q9Y6J6 and Q9UJ90 notably stained the cell surface , P51787 and the rest of the KCNEs showed strong intracellular retention . P51787 targets multiple membrane surface microdomains upon association with KCNE peptides . Thus , while P51787 / P15382 and P51787 / Q9Y6J6 channels target lipid rafts , P51787 associated with Q9Y6H6 - 5 did not . Channel membrane dynamics , analyzed by fluorescence recovery after photobleaching ( P42345 ) experiments , further supported these results . In conclusion , the trafficking and targeting pattern of P51787 can be influenced by its association with KCNEs . Since P51787 is crucial for cardiovascular physiology , the temporal and spatial regulations that different KCNE subunits may confer to the channels could have a dramatic impact on membrane electrical activity and putative endocrine regulation .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK100___ ( ___MASK77___ ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , ___MASK77___ - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged ___MASK77___ therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of ___MASK77___ on IMPDH and the potential for pharmacodynamic monitoring of ___MASK77___ by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"Transduction of P28906 + cells with lentiviral vectors enables the production of large quantities of transgene - expressing immature and mature dendritic cells . BACKGROUND : Genetically engineered dendritic cells ( DC ) presenting specific antigens to T cells may be of great interest for immunotherapy . For this reason , the production of transgene - expressing DC derived from P28906 + cells transduced either shortly after ex vivo purification or during their differentiation into DC were evaluated . METHODS : P28906 + cells were transduced with lentivectors encoding for GFP before or after 21 days of culture with P36888 - ligand , thrombopoietin and stem cell factor and induction into DC with GM - P04141 + P05112 ( G4 ) or G4 + P01375 ( GT4 ) . GFP and DC - specific marker expression was assessed by flow cytometry , and allostimulatory capacity was evaluated on GFP + and GFP - sorted cells . RESULTS : Immature ( G4 - induced ) DC obtained from amplified P28906 + cells were transducible by lentiviral vectors while mature ( GT4 - induced ) DC were rather refractory . Moreover , since differentiated DC did not proliferate , large quantities of vectors were required to generate transgene - expressing cells with this protocol . In contrast , greater numbers of both immature and mature GFP - expressing DC were obtained with P28906 + cells exposed to lentivector shortly after purification . By the time of DC induction , GFP + cells had increased by approximately 170 - fold . After DC induction with G4 , 32 % of CD1a + , HLA - DR + , or P25942 + cells expressed GFP . CD1a + P12830 + GFP + Langerhans - like DC were also obtained . Incubation with P01375 induced mature Q01151 + GFP + DC that displayed a higher allostimulatory capacity than cells induced with G4 alone . CONCLUSION : The transduction of a small number of P28906 + cells with minimal doses of lentivector may allow for the production of a large number of DC expressing selected antigens useful for immunotherapy .",
"Dopamine modulating drugs influence striatal (+)-[ 11C ] DTBZ binding in rats : Q05940 binding is sensitive to changes in vesicular dopamine concentration . Binding of (+)-[ 11C ] DTBZ ( dihydrotetrabenazine ) to the striatal vesicular monoamine transporter ( Q05940 ) is widely considered to be a stable marker of dopamine neurone integrity . However , we now find that specific binding of a tracer dose of (+)-[ 11C ] DTBZ is modestly increased in rat striatum following dopamine depletion with alpha - methyl - p - tyrosine ( alpha - MPT , + 14 % ) or ___MASK6___ ( d - P49418 , 20 mg / kg , + 12 % ) and decreased following dopamine elevation with gamma - hydroxybutyrate ( DB01440 , - 16 % ) or levodopa ( - 20 % ) . We suggest that in vivo (+)-[ 11C ] DTBZ binding in imaging studies is subject to competition by vesicular dopamine and , in this respect , is not a \" stable \" dopamine biomarker as is generally assumed ."
] |
[
"___MASK100___",
"___MASK16___",
"___MASK29___",
"___MASK41___",
"___MASK52___",
"___MASK58___",
"___MASK6___",
"___MASK77___",
"___MASK91___"
] |
___MASK41___
|
MH_train_371
|
interacts_with DB01409?
|
[
"___MASK74___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .",
"Genetics and cardiovascular system : influence of human genetic variants on vascular function . Candidate gene association studies in cardiovascular diseases have provided evidence on the molecular basis of phenotypic differences between individuals . The comprehension of how inherited genetic variants are able to affect protein functions has increased the knowledge of how genes interact with environment in order to modulate a particular phenotype . Although it is known that the human genome contains more than 10 million SNPs , only a minor part of them are supposed to be functional . A causative SNP in a particular gene may confer a small to moderate effect in complex phenotypes , such as functions important to cardiovascular homeostasis . This paper is a selective review of the literature on the evidence for interactions between vascular function and naturally occurring genetic variants in endothelial nitric oxide synthase ( P29474 ) and beta - 2 adrenergic receptor ( P07550 ) , two genes among those influencing vascular phenotype and examples for which there is a strong evidence base . P29474 and P07550 will be characterized , as well as the mechanisms by which the enzyme and the receptor work to control vascular responses will be described . Understanding the molecular mechanisms underlying gene - mediated vascular function and their modification by genetic variants is expected to result in a better comprehension about individual ' s phenotypic differences .",
"Additive role of tiotropium in severe asthmatics and Arg16Gly in P07550 as a potential marker to predict response . BACKGROUND : Recent findings have raised new interests about the use of anticholinergics , especially tiotropium , for the treatment of asthma . This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics , and to identify factors capable of predicting the response to tiotropium , using a pharmacogenetic approach . METHODS : A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited . DB01409 18 microg was added once a day and lung functions were measured every 4 weeks . Responders were defined as those with an improvement of > or = 15 % ( or 200 ml ) in the forced expiratory volume in 1 s ( FEV1 ) that was maintained for at least 8 successive weeks . Eleven single nucleotide polymorphisms ( SNPs ) in P11229 - 3 ( coding muscarinic receptors one to three ) which were identified by re - sequencing , and Arg16Gly and Gln27Glu in P07550 ( coding beta ( 2 ) adrenoreceptor ) were scored in 80 of the 138 asthmatics . RESULTS : Forty - six of the 138 asthmatics ( 33 . 3 % ) responded to tiotropium treatment . Logistic regression analyses ( controlled for age , gender , and smoking status ) showed that Arg16Gly in P07550 [ P = 0 . 003 , OR ( 95 % CI ) = 0 . 21 ( 0 . 07 - 0 . 59 ) in a minor allele - dominant model ] was significantly associated with response to tiotropium . CONCLUSIONS : As many as 30 % of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium . The presence of Arg16Gly in P07550 may predict response to tiotropium .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK5___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Beta2 - adrenergic receptor signaling in P01730 + Foxp3 + regulatory T cells enhances their suppressive function in a PKA - dependent manner . Beta2 - adrenergic receptor ( P07550 ) signaling is known to impair Th1 - cell differentiation and function in a DB02527 - dependent way , leading to inhibition of cell proliferation and decreased production of P60568 and IFN - γ . P01730 (+) Foxp3 (+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self - tolerance . Nevertheless , very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function . Here we show that Foxp3 (+) Treg cells express functional P07550 . P07550 activation in Treg cells leads to increased intracellular DB02527 levels and to protein kinase A ( PKA ) - dependent CREB phosphorylation . We also found that signaling via P07550 enhances the in vitro suppressive activity of Treg cells . P07550 - mediated increase in Treg - cell suppressive function was associated with decreased P60568 mRNA levels in responder P01730 (+) T cells and improved Treg - cell - induced conversion of P01730 (+) Foxp3 (-) cells into Foxp3 (+) induced Treg cells . Moreover , P07550 signaling increased P16410 expression in Treg cells in a PKA - dependent way . Finally , we found that PKA inhibition totally prevented the P07550 - mediated increase in Treg - cell suppressive function . Our data suggest that sympathetic fibers are able to regulate Treg - cell suppressive activity in a positive manner through P07550 signaling .",
"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK51___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .",
"___MASK66___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK72___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK72___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK72___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK72___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK72___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"P10275 - mediated repression of novel target genes . BACKGROUND : The androgen receptor ( AR ) plays a pivotal role in prostate cancer ( PCa ) initiation and progression . To date , studies have focused disproportionately on androgen - stimulated genes such as prostate - specific antigen ( PSA ) , while repressed genes have gained little attention , even though they too may be involved in regulating cell growth , differentiation , and apoptosis . METHODS : ChIP Display was used to identify putative AR target genes in the ablation - resistant human PCa cell line , C4 - 2B . Quantitative real - time reverse transcription - PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone ( DB02901 ) timecourse and dose - response , as well as AR knock - down and bicalutamide - treatments . RESULTS : We report on three genes , Q5T5P2 , P11229 , and Q6UE05 , which were newly identified in a screen for AR - occupied regions in C4 - 2B PCa cells , and which were repressed by treatment with DB02901 . AR knock - down resulted in increased Q5T5P2 , P11229 , and Q6UE05 mRNA , indicating that , like PSA stimulation , AR represses these three genes even in the absence of added ligand . DB02901 decreased Q5T5P2 and P11229 pre - mRNA levels , suggesting AR - mediated transcriptional inhibition . Cycloheximide attenuated DB02901 - mediated repression of P11229 , suggesting the requirement of new protein synthesis . Furthermore , bicalutamide treatment did not mimic , but rather antagonized DB02901 - mediated Q5T5P2 repression . Unlike the handful of androgen - repressed genes studied thus far , AR occupancy at Q5T5P2 , P11229 , and Q6UE05 was mapped outside their respective 5 '- promoter regions . CONCLUSIONS : Many more genes likely share AR - mediated gene repression through distal regulatory elements . Further study of such targets and their transcriptional regulation may help explain the receptor ' s tumorigenicity in PCa .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK90___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"[ Relationship between genetic polymorphisms of β2 - adrenergic receptor gene and essential hypertension risk among the Han Chinese population : a Meta analysis ] . OBJECTIVE : To evaluate the relationship between A46G and C79G polymorphisms in the β2 - adrenergic receptor ( P07550 ) gene and the incidence of essential hypertension ( EH ) among the Han Chinese population . METHODS : We conducted a computer retrieval of PUBMED , EMBASE , CNKI , Wanfang and P01282 databases prior to May 2010 . Articles investigating the relationship of EH and P07550 gene polymorphism of Han group were found through literature search , including 15 articles on A46G and 10 articles on C79G . According to the including and excluding criteria , a Meta - analysis was conducted in EH and P07550 gene polymorphism of A46G and C79G . The association was examined by RevMan4 . 2 software through quantitative analysis . RESULTS : Eight articles on A46G polymorphism ( including 1078 EH cases and 788 control subjects ) and six articles on C79G polymorphism ( including 1367 EH cases and 1006 control subjects ) were included in the current study . Meta - analysis showed that there was a significant association between A46G polymorphism and EH : genotype GG / ( AA + AG ) ( fixed - effected model , OR = 1 . 35 , 95 % CI = 1 . 04 - 1 . 74 , P = 0 . 02 ) , genotype GG / AA ( fixed - effected model , OR = 1 . 41 , 95 % CI = 1 . 06 - 1 . 89 , P = 0 . 02 ) . No significant association was found between C79G polymorphism and EH of Han group in China : G / C allele comparison ( random - effected model , OR = 0 . 88 , 95 % CI = 0 . 55 - 1 . 39 , P = 0 . 57 ) . CONCLUSION : Significant association was found between A46G polymorphism of P07550 gene and EH , whereas no association could be found between C79G polymorphism and EH among Han Chinese population .",
"___MASK70___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK70___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK70___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK70___ inhibits activated T cells . We show that in vitro , ___MASK70___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK70___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK70___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK70___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK70___ to treat chronic inflammatory disease .",
"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .",
"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . DB00734 non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .",
"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK71___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .",
"Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK75___ , and 86 % ± 8 % in Q8NE62 - ___MASK75___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 ."
] |
[
"___MASK51___",
"___MASK5___",
"___MASK66___",
"___MASK70___",
"___MASK71___",
"___MASK72___",
"___MASK74___",
"___MASK75___",
"___MASK90___"
] |
___MASK51___
|
MH_train_372
|
interacts_with DB00796?
|
[
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK27___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK27___ peptide content within the pituitary , and plasma ___MASK27___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK27___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK27___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK27___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK45___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"DB00796 inhibits Toll - like receptor expression and activity both in vitro and in vivo . INTRODUCTION : Toll - like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis , atherosclerosis , and arthritis . O60603 and O00206 expression is upregulated in the inflammatory diseases . Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT ( 1 ) R . P30556 blocker ( ARB ) , widely used as an antihypertensive drug , has been reported to also have anti - inflammatory effects . Thus , we investigated whether an ARB exerts anti - inflammatory effects via inhibiting O60603 and O00206 expression . METHODS AND RESULTS : Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan . Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced O60603 and O00206 expression of both mRNA and protein levels ( P < 0 . 05 vs . control ) along with decrease in the activity of NF - kappaB and the expression of IL - 1beta , P05231 , P01375 , and P13500 . Furthermore , candesartan treated mice show decreased O60603 and O00206 expression compared to vehicle control mice . CONCLUSION : Pam3CSK4 and LPS induced O60603 and O00206 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo . Thus , we define a novel pathway by which candesartan could induce anti - inflammatory effects .",
"Unbalanced placental expression of imprinted genes in human intrauterine growth restriction . Imprinted genes control fetal and placental growth in mice and in rare human syndromes , but the role of these genes in sporadic intrauterine growth restriction ( IUGR ) is less well - studied . We measured the ratio of mRNA from a maternally expressed imprinted gene , Q53GA4 , to that from a paternally expressed imprinted gene , Q5EB52 , by Northern blotting in 38 IUGR - associated placentae and 75 non - IUGR placentae and found an increase in the Q53GA4 / Q5EB52 mRNA ratio in IUGR ( p = 0 . 0001 ) . Altered expression of Q53GA4 and Q5EB52 was not accompanied by changes in DNA methylation within their imprinting centers , and immunohistochemistry showed Q53GA4 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae . We next did a genome - wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under - perfusion compared to 15 non - IUGR placentae using Affymetrix U133A microarrays . In this series six imprinted genes were differentially expressed by Q9UNW9 with a Benjamini - Hochberg false discovery rate of 0 . 05 , with increased expression of Q53GA4 and decreased expression of Q5EB52 , Q9UI56 , P50440 , GNAS and Q9UM63 in IUGR placentae . At lower significance , we found P01344 mRNA decreased and P49918 mRNA increased in the IUGR cases . We confirmed the significant reduction in Q9UI56 non - translated RNA in IUGR placentae by Northern blotting . In addition to imprinted genes , the microarray data highlighted non - imprinted genes acting in endocrine signaling ( P41159 , P06850 , P15428 , P08476 ) , tissue growth ( IGF1 ) , immune modulation ( P14902 , PSG - family genes ) , oxidative metabolism ( P35754 ) , vascular function ( P30556 , P53805 ) and metabolite transport ( O00585 - family solute carriers ) as differentially expressed in IUGR vs . non - IUGR placentae .",
"[ ___MASK72___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK72___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .",
"Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK27___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .",
"Inhibitors of DB00171 - binding cassette transporters suppress interleukin - 12 p40 production and major histocompatibility complex II up - regulation in macrophages . DB00171 - binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and / or interferon ( IFN ) - gamma - induced interleukin ( IL ) - 12 p40 and tumor necrosis factor ( P01375 ) - alpha production , nitric oxide formation , as well as major histocompatibility complex II up - regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL - 12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4 , 4 '- diisothiocyanostilbene - 2 , 2 '- disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL - 12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2 , 2 '- iminodibenzoic acid failed to suppress the production of IL - 12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL - 12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL - 12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 / 44 mitogen - activated protein kinases or c - Jun kinase . ___MASK73___ also suppressed P01579 - induced up - regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and / or P01579 - induced macrophage activation .",
"Novel agents that potentially inhibit irinotecan - induced diarrhea . ___MASK11___ ( CPT - 11 , 7 - ethyl - 10 -[ 4 -( 1 - piperidino )- 1 - piperidino ] carbonyloxycamptothecin ) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting P11387 ( Topo I ) . However , severe and unpredictable dosing - limiting toxicities ( mainly myelosuppression and severe diarrhea ) hinder its clinical use . The latter consists of early and late - onset diarrhea , occurring within 24 hr or > or = 24 hr after CPT - 11 administration , respectively . This review highlights novel agents potentially inhibiting CPT - 11 - induced diarrhea , which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms . Early - onset diarrhea is observed immediately after CPT - 11 infusion and probably due to the inhibition of acetylcholinesterase activity , which can be eliminated by administration of atropine . Late - onset diarrhea appears to be associated with intestinal exposure to SN - 38 ( 7 - ethyl - 10 - hydroxycamptothecin ) , the major active metabolite of CPT - 11 , which may bind to Topo I and induce apoptosis of intestinal epithelia , leading to the disturbance in the absorptive and secretory functions of mucosa . CPT - 11 and SN - 38 may also stimulate the production of pro - inflammatory cytokines and prostaglandins ( PGs ) , thus inducing the secretion of Na (+) and Cl (-) . Early treatment of severe late - onset diarrhea with oral high - dose loperamide has decreased patient morbidity . Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models . These include intestinal alkalizing agents , oral antibiotics , enzyme inducers , P - glycoprotein ( PgP ) inhibitors , cyclooxygenase - 2 ( P35354 ) inhibitors , tumor necrosis factor - alpha ( P01375 ) inhibitors , or blockers of biliary excretion of SN - 38 . Further studies are needed to identify the molecular targets associated with CPT - 11 toxicity and safe and effective agents for alleviating CPT - 11 - induced diarrhea .",
"Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis . Chronic glomerulonephritis ( Q9P2M7 ) is one of the most severe kidney diseases . Genes of vascular reactivity are thought to play an important role in development and progression of Q9P2M7 . In this study , we analyzed association of genes of vascular homeostasis with hypertension and renal survival of Q9P2M7 patients . The study sample included 238 patients with Q9P2M7 and 304 healthy subjects of population control . Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction ( PCR ) , restriction fragment length polymorphism ( RFLP ) analysis and TaqMan assays . Association of the genotypes with renal survival was analyzed by the Kaplan - Meier estimator . Genotypes 311SC and 311SS of the Q15165 gene , (- 1166 ) AC and (- 1166 ) CC of the P30556 gene , (+ 46 ) AA of the P07550 gene , and 198KK and 198KN of the P05305 gene were associated with decreased rate of renal survival of the patients . Polymorphisms S311C Q15165 , (- 1166 ) A / C P30556 , (+ 46 ) G / A P07550 , and K198N P05305 were associated with the accelerated decline in kidney function in the Q9P2M7 patients .",
"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK8___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .",
"Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 - activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) - alpha up - regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down - regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 )- IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA ( 2 )- IIA and extracellular signal - regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 )- IIA was quantitatively measured by an enzyme - linked - immunosorbent - assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 - kinase ) inhibitor LY294002 and the cholesterol - depleting drug methyl - beta - cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 )- IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA ( 2 )- IIA through the Q9UNN8 - dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 - mediated expression of sPLA ( 2 )- IIA through the cleavage of P25116 . The Q9UNN8 - dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1 / 2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA ( 2 )- IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 - kinase dependent protective activity for thrombin such that its cleavage of the lipid - raft localized P25116 inhibits the P01375 - mediated expression of sPLA ( 2 )- IIA in HUVECs .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK11___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK11___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK11___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Regulation of P14061 and P18405 in lymphocytes . We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism ; however , only 17beta - HSD and 5alpha - reductase showed significant enzyme activity . We now investigate regulation of lymphocyte expression for genes encoding 17beta - HSD and 5alpha - reductase . Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin , PMA , ionomycin , various steroids , interleukin ( IL ) - 4 , and P05231 . Treatment with 10 or 50 microM forskolin resulted in a 20 - 60 % reduction of expression for P14061 ( encoding 17beta - HSD I ) in T and B lymphoid cell lines and peripheral blood mononuclear cells , although such a change was not observed in the expression of P18405 ( encoding 5alpha - reductase I ) . No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin . Incubation with 10 (- 9 ) to 10 (- 7 ) M androstenedione or estradiol increased expression of P14061 , while testosterone decreased the expression of this gene . P18405 expression was increased in the presence of 5alpha - ___MASK86___ although no consistent changes were observed when the cells were treated with testosterone . Other steroids , including dexamethasone , progesterone , and 6 - hydroxypregnanolone , produced no effects on expression of either P14061 or P18405 . Treatment with 0 . 1 - 10 ng / ml of P05112 or P05231 also did not effect significant changes in gene expression . These data implicate the involvement of the DB02527 - protein kinase signal transduction pathway in regulating lymphocyte expression of P14061 . Furthermore , it appears that lymphocyte P14061 and P18405 are regulated to some extent by specific steroids .",
"Cooperative regulation of extracellular signal - regulated kinase activation and cell shape change by filamin A and beta - arrestins . beta - Arrestins ( betaarr ) are multifunctional adaptor proteins that can act as scaffolds for G protein - coupled receptor activation of mitogen - activated protein kinases ( MAPK ) . Here , we identify the actin - binding and scaffolding protein filamin A ( P21333 ) as a betaarr - binding partner using Son of sevenless recruitment system screening , a classical yeast two - hybrid system , coimmunoprecipitation analyses , and direct binding in vitro . In P21333 , the betaarr - binding site involves tandem repeat 22 in the carboxyl terminus . betaarr binds P21333 through both its N - and C - terminal domains , indicating the presence of multiple binding sites . We demonstrate that betaarr and P21333 act cooperatively to activate the MAPK extracellular signal - regulated kinase ( P29323 ) downstream of activated muscarinic M1 ( M1MR ) and angiotensin II type 1a ( P30556 ) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr - P28482 complex formation by P21333 . In Hep2 cells , stimulation of M1MR or P30556 results in the colocalization of receptor , betaarr , P21333 , and active P29323 in membrane ruffles . Reduction of endogenous levels of betaarr or P21333 and a catalytically inactive dominant negative Q02750 , which prevents P29323 activation , inhibit membrane ruffle formation , indicating the functional requirement for betaarr , P21333 , and active P29323 in this process . Our results indicate that betaarr and P21333 cooperate to regulate P29323 activation and actin cytoskeleton reorganization .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK2___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Effect of polymorphisms on the pharmacokinetics , pharmacodynamics , and safety of risperidone in healthy volunteers . OBJECTIVE : To identify genetic markers capable of predicting the pharmacokinetics , pharmacodynamics , and adverse effects of risperidone . METHODS : Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone . ___MASK8___ and hydroxyrisperidone plasma levels were measured using high - performance liquid chromatography combined with tandem mass spectrometry . P01236 concentration was quantified by direct chemiluminescence . RESULTS : Poor P10635 metabolizers showed higher risperidone Cmax , area under the curve ( AUC ) , and t1 / 2 , as well as lower clearance . They also showed lower Cmax and AUC and higher t1 / 2 for hydroxyrisperidone . Furthermore , individuals with a mutant Q9BQB6 genotype had a lower risperidone AUC and t1 / 2 and higher clearance . The hydroxyrisperidone AUC was lower in individuals with the P21964 mutant genotype . ___MASK8___ increased prolactin levels ( iAUC and iCmax ) , which were higher in women than in men . The most frequent reactions were somnolence ( 47 . 1 % ) , headache ( 21 . 4 % ) , and dizziness ( 17 . 1 % ) . Women had neurological effects and headache more frequently than men . The incidence of headache was associated with polymorphisms in the P30556 and NAT2 ; neurological effects were associated with P33261 . CONCLUSIONS : Differences in the pharmacokinetics of risperidone are due to polymorphisms in P10635 , P21964 , and Q9BQB6 . Differences in adverse reactions can be explained by gender and polymorphisms in P33261 , P30556 , and NAT2 .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK64___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK72___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"[ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin - converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin - converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy - proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non - nephrotic proteinuria ( protein , 0 . 5 to 3 . 5 g / day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8 - week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0 . 05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type - IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type - IV collagen excretion was recognized in patients with chronic glomerulonephritis .",
"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .",
"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK8___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .",
"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity ."
] |
[
"___MASK11___",
"___MASK27___",
"___MASK2___",
"___MASK45___",
"___MASK64___",
"___MASK72___",
"___MASK73___",
"___MASK86___",
"___MASK8___"
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___MASK8___
|
MH_train_373
|
interacts_with DB00519?
|
[
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK48___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK8___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"Immunohistochemical studies of the epididymal duct in Egyptian water buffalo ( Bubalus bubalis ) . Using immunohistochemistry ( IHC ) , this study aimed to evaluate the regional distribution pattern of some biologically active proteins in the epididymis of Egyptian water buffalo and to determine the structural - functional relationships of the different epididymal structures . Wax - embedded sections from different regions of the epididymal duct from adult , clinically healthy , buffalo bulls were used . Primary antibodies against angiotensin converting enzyme ( P12821 ) , S - 100 , galactosyltransferase ( GalTase ) , alpha smooth muscle actin ( α - SMA ) , connexin 43 ( P17302 ) and vascular endothelial growth factor ( P15692 ) were used for immunohistochemical studies . The results showed that , in addition to the well - known principal and basal cells , the epididymal epithelium , similar to that of other species , possessed apical cells and intraepithelial leukocytes . IHC showed that , with the exception of P15692 which reacted negatively , all antibodies used displayed variable reactivity in the different epididymal structures . Apical cells expressed a strong reaction with P12821 along the entire length of the duct . The principal cells in the caput epididymis exhibited a distinct reactivity with S - 100 and GalTase . The peritubular muscular coat displayed a marked immunostaining for α - SMA and for P17302 . In conclusion these findings showed a regional - specific distribution pattern , distinct from that in bovine bulls . Some potential functional capacities , especially absorptive and secretory ones , are discussed in relation to the different epididymal regions .",
"Inhibition of matrix metalloproteinase - 9 activity by trandolapril after middle cerebral artery occlusion in rats . We investigated whether an angiotensin - converting enzyme ( P12821 ) inhibitor could inhibit matrix metalloproteinase ( MMP ) activities in cerebral infarct lesions after middle cerebral artery occlusion ( MCAO ) in rats . After placebo or trandolapril ( 5 mg / kg per day ) was administered orally for 7 days , we permanently occluded the right middle cerebral artery . P12821 activity in extracts from the infarct side of placebo - treated rats was significantly higher than that in extracts from the non - infarct side from 5 days after MCAO , though they did not differ at 1 day . P12821 activities in extracts from both hemispheric segments in the trandolapril - treated group were significantly decreased compared with those in the placebo - treated group before MCAO , and this significant reduction persisted even at 7 days after MCAO . In the placebo - treated group , P14780 and P08253 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO , respectively . DB00519 treatment significantly reduced P14780 and P08253 activities to 68 . 5 % and 53 . 2 % , respectively . Seven days after MCAO , the ratios of infarct areas to the hemispheric sectional areas in placebo - and trandolapril - treated rats were 55 . 4 +/- 2 . 1 % and 30 . 9 +/- 2 . 9 % , respectively , and this difference was significant . Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril - treated rats . Cumulative survival in trandolapril - treated rats was significantly increased compared with that in placebo - treated rats . Thus , the inhibition of P14780 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia .",
"Gene polymorphisms impact the risk of rejection with hemodynamic compromise : a multicenter study . BACKGROUND : Rejection with hemodynamic compromise ( P18577 ) is associated with high mortality in heart recipients . This study investigates the association between genetic polymorphisms and P18577 in pediatric heart recipients . METHODS : Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to P18577 by recipient race , age at transplantation , and genotype at 13 genetic polymorphisms ( P01375 - α A - 308G , P05231 G - 174C , P27352 - γ T + 874A , P22301 G - 1082A , C - 819T , and C - 592A ; FAS A - 670G , P48023 C - 843T , and P12821 I / D ; and P15692 A - 2578C , C - 1451T , C + 405G , and - 2549 I / D ) . RESULTS : P18577 occurred in 126 ( 23 . 7 % ) patients during the study period . Adjusting for age and race , P22301 G - 1082A , FAS A - 670G , and P12821 I / D genotypes were associated with P18577 . P22301 G - 1082A GG genotype was associated with decreased risk of P18577 with an adjusted hazard ratio ( HR ) of 0 . 49 ( 95 % confidence interval [ CI ] , 0 . 27 - 0 . 90 ; P = 0 . 020 ) . FAS A - 670G AA genotype was associated with increased risk of P18577 with an adjusted HR of 1 . 84 ( 95 % CI , 1 . 25 - 2 . 69 ; P = 0 . 002 ) . P12821 II genotype was associated with decreased risk of P18577 with an adjusted HR of 0 . 58 ( 95 % CI , 0 . 36 - 0 . 95 ; P = 0 . 031 ) . CONCLUSIONS : Recipients with a high anti - inflammatory and immune - regulatory genetic profile ( high interleukin - 10 ) were protected from P18577 . Conversely , recipients with a pro - apoptotic genetic profile ( high Fas ) or high angiotensin - 1 - converting enzyme producing genotype were at increased risk of P18577 . This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients .",
"M ( 3 ) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation , hyperresponsiveness and remodeling in mice . M ( 3 ) muscarinic receptors are localized on inflammatory cells , airway smooth muscle , and submucosal glands , known to mediate bronchoconstriction , mucus secretion , and airway remodeling . It is hypothesized bencycloquidium bromide ( BCQB ) , a novel M ( 3 ) receptor antagonist , might have potential effects on airway hyperresponsiveness , inflammation and airway remodeling in a murine model of asthma . Mice sensitized and challenged with ovalbumin developed airway inflammation . Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts , and cytokine levels . Lung tissues were evaluated for cell infiltration , mucus hypersecretion , airway remodeling , and the expression of inflammatory biomarkers . Airway hyperresponsiveness was monitored by direct airway resistance analysis . Inhalation administration of BCQB significantly not only reduced ovalbumin - induced airway hyperresponsiveness comparing to methacholine , and prevented the ovalbumin - induced increase in total cell counts and eosinophil counts . Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin - induced mRNA expression of eotaxin , P05113 , P05112 and P14780 , and increased mRNA expression of IFN - γ and P01033 in a dose - dependent manner . Substantial IFN - γ / P05112 ( Th1 / Th2 ) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment . In addition , histological studies showed that BCQB dramatically inhibited ovalbumin - induced lung tissue eosinophil infiltration , airway mucus production and collagen deposition in lung tissues . Results reported in current paper suggest that M ( 3 ) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation , hyperresponsiveness and remodeling .",
"___MASK8___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK8___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK54___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .",
"[ Adjustment effects of Herba epimedii , Fructus ligustrilucidi on NO / ET , Q9Y251 axis in asthmatic rats ] . OBJECTIVE : To study the neuro - endocrine adjustment effects of Herba Epimedii and Fructus Ligustrilucidi on the asthmatic rats . METHOD : Rat asthma model was duplicated by OVA ( ovalbumin ) through sensitizing and challenging . Fifty male rats were randomly divided into normal group , model group , adjustment group of Herba Epimedii and Fructus Ligustrilucidi , Peibenfang group and Asimei capsule group . Investigating levels of ET ( Endothelin ) , NO , P35228 ( inducible NOS ) , and P29474 ( constitutive NOS ) in blood serum and BALF ( bronchoalveolar lavage fluid ) , O00230 ( corticotrophin ) in serum , DB01285 ( adrenocorticotropin hormone ) in plasma , CHR ( corticotropin release hormone ) in hypothalamus , protein expression of GCR ( glucocorticoid receptor ) in lung tissue . RESULT : The adjustment of Herba Epimedii and Fructus Ligustrilucidi could inhibit ET and NO content in BALF ( all P < 0 . 05 ) , decrease the level of P35228 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , and increase the level of P29474 in serum and BALF ( P < 0 . 01 or P < 0 . 05 ) , raise the concentration of serum O00230 ( P < 0 . 01 ) , enhance the protein expression of GCR in lung tissue ( P < 0 . 05 ) . CONCLUSION : The preventive and therapeutic effect of Herba Epimedii and Fructus Ligustrilucidi on asthma relates to their adjustment effect on ET / NO and Q9Y251 axis .",
"Contribution of captopril thiol group to the prevention of spontaneous hypertension . We aimed to compare the effect of angiotensin converting enzyme ( P12821 ) inhibitors captopril ( containing thiol group ) and enalapril ( without thiol group ) on the development of spontaneous hypertension and to analyze mechanisms of their actions , particularly effects on oxidative stress and NO production . Six - week - old SHR were divided into three groups : control , group receiving captopril ( 50 mg / kg / day ) or enalapril ( 50 mg / kg / day ) for 6 weeks . At the end of experiment , systolic blood pressure ( SBP ) increased by 41 % in controls . Both captopril and enalapril prevented blood pressure increase , however , SBP in the captopril group ( 121 +/- 5 mmHg ) was significantly lower than that in the enalapril group ( 140 +/- 5 mmHg ) . Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group . ___MASK83___ and enalapril increased NO synthase activity in the heart and aorta to the similar level . Neither captopril nor enalapril was , however , able to increase the expression of P29474 . Both P12821 inhibitors increased the level of cGMP . However , cGMP level was significantly higher in the aorta of captopril group . We conclude that captopril , beside inhibition of P12821 , prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration .",
"Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis . DB00435 ( NO ) plays a central role in the pathogenesis of bacterial meningitis . However , the role of NO produced by endothelial NO synthase ( P29474 ) in meningitis is still unclear . We investigated the influence of P29474 depletion on the inflammatory host response , intracranial complications , and outcome in experimental pneumococcal meningitis . Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected P29474 - deficient mice than in infected wild type mice . This effect could be attributed to an increased expression of P16109 , macrophage inflammatory protein - 2 , keratinocyte - derived cytokine , and interleukin ( IL ) - 1beta in the brain of infected P29474 - deficient mice . However , no differences in the cerebral expression of intercellular adhesion molecule - 1 , tumor necrosis factor - alpha , and P05231 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice . In addition to enhanced leukocyte infiltration into the P04141 , meningitis - associated intracranial complications including blood - brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected P29474 - deficient mice . The aggravation of intracranial complications was paralleled by a worsening of the disease , as evidenced by a more pronounced hypothermia , an enhanced weight reduction , and an increased death rate . The current data indicate that P29474 deficiency is detrimental in bacterial meningitis . This effect seems to be related to an increased expression of ( certain ) cytokines / chemokines and adhesion molecules ; thus leading to increased meningeal inflammation and , subsequently , to aggravated intracranial complications .",
"Quality of life and the relevant factors in patients with chronic hepatitis B . BACKGROUND / AIMS : To assess HRQL in patients with chronic hepatitis B ( CHB ) and investigate the relevant factors . METHODOLOGY : A cross - sectional three - center study involving 407 inpatients with CHB was conducted . Subjects completed the epidemiological questionnaire and two validated questionnaires ( SF - 36 and QLICD - CH ) . Afterwards , the angiotensin - converting enzyme ( P12821 ) insertion / deletion ( I / D ) and dopamine receptor D4 ( P21917 ) gene polymorphisms were assessed in all patients . RESULTS : It was found that the scores of CHB patients in SF - 36 scale 8 domains were lower than those of the normal population ( all p < 0 . 001 ) . The anti - viral therapy could improve four - area - scores ( P20941 ( p = 0 . 004 ) , SOD ( p = 0 . 011 ) , SPD ( p = 0 . 032 ) , TOT ( p = 0 . 014 ) ) . Extraverted personality , social competence and ability to work were protective factors of HRQL , while severity of illness , better family economy and abnormal condition of liver function were risk factors . The scores in II genotype were higher than those in I / D + DD genotype of P12821 polymorphisms . The scores in short repeat sequences genotypes were higher than those in long repeat sequences genotype of P21917 polymorphisms . CONCLUSIONS : Patients with CHB had lower HRQL than normal population . Anti - viral treatments can improve their HRQL . Several health factors independently influence HRQL and P12821 and P21917 gene polymorphism is associated with HRQL of CHB patients .",
"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK83___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .",
"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .",
"DB04216 abrogates P05231 / P40763 signaling and inhibits glioblastoma cell line growth and migration . Evidence has suggested that P40763 functions as an oncogene in gliomagenesis . As a consequence , changes in the inflammatory microenvironment are thought to promote tumor development . Regardless of its origin , cancer - related inflammation has many tumor - promoting effects , such as the promotion of cell cycle progression , cell proliferation , cell migration and cell survival . Given that P05231 , a major cancer - related inflammatory cytokine , regulates P40763 activation and is upregulated in glioblastoma , we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by P05231 , and to determine the underlying mechanisms of action . In this study , we show that quercetin is a potent inhibitor of the P05231 - induced P40763 signaling pathway in T98G and U87 glioblastoma cells . Exposure to quercetin resulted in the reduction of P42704 , P23458 and P40763 activation by P05231 , as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by P05231 . Interestingly , quercetin also modulated the expression of two target genes regulated by P40763 , i . e . cyclin D1 and matrix metalloproteinase - 2 ( P08253 ) . Moreover , quercetin reduced the recruitment of P40763 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of P05231 . Overall , these results provide new insight into the role of quercetin as a blocker of the P40763 activation pathway stimulated by P05231 , with a potential role in the prevention and treatment of glioblastoma .",
"Strategy for a genetic assessment of antipsychotic and antidepressant - related proarrhythmia . Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic . In this field , accurate understanding of genetics , which per se is a non - controllable risk factor , may help clinicians to prevent life - threatening side effects . So far , a number of genes have been associated with arrhythmia : Q14524 , Q8IWT1 , CACNL1AC , Q12809 , P51787 , P15382 , Q01484 , Q5BKT4 , P63252 , Q9Y6J6 , Q92736 , Q9UK17 , Q9NZV8 , P12821 , O75052 , O14958 and Rad . These genes represent good candidates for the definition of a genetic pro - arrhythmic profile . A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed . Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics . A list of relevant rare mutations within the selected genes is presented , together with a complete list of Tag SNPs covering the whole genetic sequence . The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics . The selected variants , both mutations and polymorphisms , may help in defining a next - to - come genetic assessment to be performed before drug prescription in order to improve drug safety .",
"___MASK83___ attenuates matrix metalloproteinase - 2 and - 9 in monocrotaline - induced right ventricular hypertrophy in rats . Little is known about the influence of angiotensin converting enzyme ( P12821 ) inhibitors on matrix metalloproteinase ( MMP ) in right ventricular remodeling . We investigated the effect of captopril , an P12821 inhibitor , on P08253 and P14780 in monocrotaline - induced right ventricular hypertrophy . Six - week - old male Wistar rats were injected intraperitoneally with monocrotaline ( 60 mg / kg ) or saline . The rats were administrated captopril ( 30 mg / kg per day ) or a vehicle orally for 24 days from the day of monocrotaline injection . At day 25 , echocardiography was performed and hearts were excised . Expressions and activities of P08253 and P14780 were measured by Western blotting and by gelatin zymography , respectively . In monocrotaline - injected rats , right ventricular weight / tail length ratio increased significantly . Histological analysis revealed cardiomyocyte hypertrophy and fibrosis in right ventricular sections . Echocardiography showed right ventricular dysfunction compared with saline - injected rats . The right ventricular hypertrophy , fibrosis , and dysfunction were inhibited by captopril . However , captopril did not attenuate an increase in pulmonary artery pressure . P08253 and P14780 expressions and activities in right ventricles increased significantly in monocrotaline - injected rats and captopril inhibited them . These findings indicate that captopril attenuates the development of monocrotaline - induced right ventricular hypertrophy in association with inhibition of P08253 and P14780 in rats .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK56___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"P05231 in tear fluid after photorefractive keratectomy and its effects on keratocytes in culture . PURPOSE : To investigate the participation of interleukin - 6 ( P05231 ) after photorefractive keratectomy ( Q9H4B4 ) and its possible roles and sources in corneal wound healing . METHODS : P05231 , levels were measured in the tear fluids of patients before and after Q9H4B4 and in conditioned media of human corneal epithelial cells and keratocytes . Its effects on total collagen and collagen - type synthesis by keratocytes were studied with a 3H - proline incorporation assay and Northern blot analysis . Zymography was used to evaluate the metalloproteinase content in the conditioned medium of P05231 - stimulated keratocytes . RESULTS : P05231 is present in the tear fluid samples after photorefractive keratectomy , possibly synthesized by epithelial cells and keratocytes . CONCLUSIONS : P05231 stimulates collagen synthesis in general and collagen type I in particular . Furthermore , it reduces the production of P08253 , the latent form of the metalloproteinase , by cultured keratocytes . The results suggest that P05231 might be regarded as a mediator involved in corneal healing after excimer laser .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK75___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK75___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK75___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK75___ among adults with ADHD .",
"___MASK56___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .",
"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .",
"Q9Y251 regulates retention and proliferation of primitive Sca - 1 +/ c - Kit +/ Lin - cells via modulation of the bone marrow microenvironment . Q9Y251 is involved in tumor growth and metastasis . Because of its unique cleavage of heparan sulfate , which binds cytokines , chemokines and proteases , we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis . We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells in the bone marrow ( BM ) of mice overexpressing heparanase ( hpa - Tg ) . This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment , manifested in increased P48061 turnover . Furthermore , heparanase overexpression in mice was accompanied by reduced protease activity of P14780 , elastase , and cathepsin K , which regulate stem and progenitor cell mobilization . Moreover , increased retention of the progenitor cells also resulted from up - regulated levels of stem cell factor ( P21583 ) in the BM , in particular in the stem cell - rich endosteum and endothelial regions . Increased P21583 - induced adhesion of primitive Sca - 1 (+)/ c - Kit (+)/ Lin (-) cells to osteoblasts was also the result of elevation of the receptor c - Kit . Regulation of these phenomena is mediated by hyperphosphorylation of c - Myc in hematopoietic progenitors of hpa - Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro . Altogether , our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells .",
"Altered growth factor expression in the aging penis : the Brown - Norway rat model . The objective of the present study was to evaluate age - related changes in the protein and gene expression of modulators of erectile function ( nitric oxide [ NO ] and endothelin - 1 [ ET - 1 ] ) and growth factors such as transforming growth factor ( TGF - beta1 ) and vascular endothelial growth factor ( P15692 ) in the penile tissue of Brown - Norway ( BN ) rats . Young and old BN male rats were euthanized , and the penile tissue was processed for immunohistochemical and molecular analyses . Total RNA was extracted , and an Access reverse transcription - polymerase chain reaction ( RT - PCR ) system was used for messenger RNA ( mRNA ) expression analysis . Immunohistochemical studies showed a decreased expression of endothelial nitric oxide synthase ( P29474 ) protein and an increased staining for ET - 1 . Quantitative analysis of PCR products revealed decreased levels of P15692 mRNA expression in the old population of rats . The most significant decrease was detected between bands corresponding to splice forms 164 ( 21 % ) and 120 ( 18 % ) . The observed alterations in the gene expression of growth factors such as P15692 may contribute to the abnormal age - related morphological and physiological alterations in the erectile tissue .",
"DB00877 protects against myocardial ischemia - reperfusion injury through O60674 - P40763 signaling pathway . DB00877 ( Sirolimus ® ) is used to prevent rejection of transplanted organs and coronary restenosis . We reported that rapamycin induced cardioprotection against ischemia - reperfusion ( I / R ) injury through opening of mitochondrial K ( DB00171 ) channels . However , signaling mechanisms in rapamycin - induced cardioprotection are currently unknown . Considering that P40763 is protective in the heart , we investigated the potential role of this transcription factor in rapamycin - induced protection against ( I / R ) injury . Adult male ICR mice were treated with rapamycin ( 0 . 25mg / kg , i . p . ) or vehicle ( DB01093 ) with / without inhibitor of O60674 ( AG - 490 ) or P40763 ( stattic ) . One hour later , the hearts were subjected to I / R either in Langendorff mode or in situ ligation of left coronary artery . Additionally , primary murine cardiomyocytes were subjected to simulated ischemia - reoxygenation ( SI / RO ) injury in vitro . For in situ targeted knockdown of P40763 , lentiviral vector containing short hairpin RNA was injected into the left ventricle 3 weeks prior to initiating I / R injury . Infarct size , cardiac function , and cardiomyocyte necrosis and apoptosis were assessed . DB00877 reduced infarct size , improved cardiac function following I / R , and limited cardiomyocyte necrosis as well as apoptosis following SI / RO which were blocked by AG - 490 and stattic . In situ knock - down of P40763 attenuated rapamycin - induced protection against I / R injury . DB00877 triggered unique cardioprotective signaling including phosphorylation of P29323 , P40763 , P29474 and glycogen synthase kinase - 3ß in concert with increased prosurvival Bcl - 2 to Bax ratio . Our data suggest that O60674 - P40763 signaling plays an essential role in rapamycin - induced cardioprotection . We propose that rapamycin is a novel and clinically relevant pharmacological strategy to target P40763 activation for treatment of myocardial infarction .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK27___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"___MASK37___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK37___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK37___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK37___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"P00797 status does not predict the anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans . DB00519 Multicenter Study Group . The angiotensin - converting enzyme ( P12821 ) inhibitor trandolapril , a non - sulfhydryl prodrug which is hydrolysed into trandolaprilat , was studied in 322 hypertensives of African - American descent using a double - blind , randomised , placebo - controlled , parallel study design . Following 6 weeks of double - blind treatment with placebo or 0 . 25 to 16 mg / day trandolapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre - treatment plasma renin activity , and trandolaprilat concentration was performed . Two mg was the lowest effective trandolapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma trandolaprilat concentration . Pre - treatment plasma renin activity was not a reliable indicator of anti - hypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin - angiotensin - aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti - hypertensive response to angiotensin - converting enzyme inhibition in African - Americans .",
"An P12821 inhibitor reduces Th2 cytokines and TGF - beta1 and TGF - beta2 isoforms in murine lupus nephritis . BACKGROUND : P12821 ( P12821 ) inhibitors , such as captopril , are used to control hypertension . In patients and animals with primary nephropathies , these agents improve renal function more than that would be expected from their control of hypertension . Here , we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism ( s ) by which this agent exerts its renoprotective effects . METHODS : Lupus - prone , NZB / NZW F1 and MRL - lpr / lpr , mice were treated with captopril or with a control antihypertensive agent , verapamil . Mice were monitored for nephritis , and their sera and tissues analyzed for cytokine and transforming growth factor - beta ( TGF - beta ) expression . RESULTS : ___MASK83___ treatment delayed the onset of proteinuria when administered to prenephritic mice , whereas verapamil did not . ___MASK83___ treatment also retarded disease progression when given to lupus mice that had early disease , and even reversed severe proteinuria in at least some older animals with advanced disease . It reduced chronic renal lesions , but had no effect on autoantibody production . The improvement in renal disease correlated with reduced TGF - beta expression , particularly of the TGF - beta1 and TGF - beta2 isoforms , in the kidneys . Interestingly , in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines , interleukin ( IL ) - 4 and P22301 , suggesting a possible role of the immune system in captopril - mediated disease modulation . CONCLUSION : Since type 2 cytokines are known to promote lupus glomerulosclerosis , decreased P05112 and P22301 production in captopril - treated mice may be related to this agent ' s renoprotective effects . We argue here that P12821 inhibitors not only act as selective TGF - beta inhibitors , but also as selective immunomodulators , to improve lupus nephritis .",
"Des - γ - carboxy prothrombin ( P12821 ) as a potential autologous growth factor for the development of hepatocellular carcinoma . Des - γ - carboxy prothrombin ( P12821 ) is a prothrombin precursor produced in hepatocellular carcinoma ( HCC ) . Because of deficiency of vitamin K or γ - glutamyl carboxylase in HCC cells , the 10 glutamic acid ( DB00142 ) residues in prothrombin precursor did not completely carboxylate to γ - carboxylated glutamic acid ( Gla ) residues , leaving some DB00142 residues remained in N - terminal domain . These prothrombin precursors with DB00142 residues are called DCPs . P12821 displays insufficient coagulation activity . Since Liebman reported an elevated plasma P12821 in patients with HCC , P12821 has been used in the diagnosis of HCC . Recently , its biological malignant potential has been specified to describe P12821 as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells . P12821 was found to stimulate HCC growth through activation of the P12821 - DB00134 - P23458 - P40763 signaling pathway . P12821 might increase HCC invasion and metastasis through activation of matrix metalloproteinase ( MMPs ) and the P27361 / 2 MAPK signaling pathway . P12821 has also been found to play a crucial role in the formation of angiogenesis . P12821 could increase the angiogenic factors released from HCC and vascular endothelial cells . These effects of P12821 in angiogenesis might be related to activation of the P12821 - P35968 - P98160 - γ - MAPK signaling pathway . In this article , we summarized recent studies on P12821 in biological roles related to cancer progression and angiogenesis in HCC .",
"Acute erythropoietin cardioprotection is mediated by endothelial response . Increasing evidence indicates that high levels of serum erythropoietin ( Epo ) can lessen ischemia - reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect . To clarify the mechanisms underlying this cardioprotection , we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells ( ΔEpoR ) . Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase ( P29474 ) activity in vitro and in vivo , and enhanced nitric oxide ( NO ) production that was determined directly by real - time measurements of gaseous NO release . Epo stimulated phosphoinositide 3 - kinase ( PI3K ) / protein kinase B ( AKT ) and mitogen - activated protein kinase kinase ( MEK ) / extracellular signal regulated kinase ( P29323 ) signaling pathways , and inhibition of PI3K , but not MEK activity , blocked Epo - induced NO production . To verify the potential of this Epo effect in cardioprotection in vivo , ΔEpoR - mice with Epo response in heart restricted to endothelium were treated with Epo . These mice exhibited a similar increase in P29474 phosphorylation in coronary artery endothelium as that found in wild type ( WT ) mice . In addition , in both WT - and ΔEpoR - mice , exogenous Epo treatment prior to myocardial ischemia provided comparable protection . These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect . The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection .",
"Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice . BACKGROUND : Asthma is associated with airway hyperresponsiveness and enhanced T - cell number / activity on one hand and increased levels of exhaled nitric oxide ( NO ) with expression of inducible NO synthase ( P35228 ) on the other hand . These findings are in paradox , as NO also relaxes airway smooth muscle and has immunosuppressive properties . The exact role of the endothelial NOS ( P29474 ) isoform in asthma is still unknown . We hypothezised that a delicate regulation in the production of NO and its bioactive forms by P29474 might be the key to the pathogenesis of asthma . METHODS : The contribution of P29474 on the development of asthmatic features was examined . We used transgenic mice that overexpress P29474 and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin . RESULTS : P29474 overexpression resulted in both increased P29474 activity and NO production in the lungs . Isolated thoracic lymph nodes cells from P29474 overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines P01579 , P05113 and P22301 . No difference in serum IgE levels could be found . Further , there was a 50 % reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals . Finally , airway hyperresponsiveness to methacholine was abolished in P29474 overexpressing mice . CONCLUSION : These findings demonstrate that P29474 overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma . We suggest that a delicate balance in the production of bioactive forms of NO derived from P29474 might be essential in the pathophysiology of asthma .",
"Increased serum levels of neutrophil gelatinase - associated lipocalin in patients with essential thrombocythemia and polycythemia vera . Neutrophil gelatinaase - associated lipocalin ( P80188 ) is a glycoprotein bound with matrix metalloproteinase - 9 ( P14780 ) in human neutrophils , and elevated tissue P80188 expression has been documented in different infectious and inflammatory conditions . Recent evidence suggests that P80188 expression is induced in many types of human cancer . Moreover , P80188 is required for P11274 - P00519 - induced tumorigenesis . The aim of the present study was to measure serum levels of P80188 in patients with essential thrombocythemia ( ET ) and polycythemia vera ( PV ) . We also evaluated P80188 levels in patients with ET and PV with and without thrombotic events , to explore a possible correlation of P80188 with platelet and leukocyte activation , and in patients with sepsis . Serum P80188 levels in the study population were significantly higher than in healthy adults and in subjects with sepsis . A correlation between P80188 and the number of white cells and neutrophils was found in patients with PV and ET . P80188 serum levels were not different depending on the presence or not of the O60674 mutation , and a mutant allele dosage effect was not observed for P80188 levels . Patients with PV and ET with thrombosis did not have significantly higher levels of P80188 . We were unable to demonstrate a significant association between serum P80188 levels and CD11b or CD62 expression . In conclusion , our study reports evidence demonstrating that increased levels of P80188 appear to be a characteristic of patients with PV and ET .",
"Polymorphisms in the angiotensin - converting enzyme gene are associated with unipolar depression , P12821 activity and hypercortisolism . P12821 ( P12821 ) is assumed to influence the activity of the hypothalamic - pituitary - adrenocortical ( Q9Y251 ) system , which shows hyperactivity in the majority of patients with major depression . The P12821 gene , known to be associated with cardiovascular disorders , which in turn are accompanied with an increased susceptibility for depression , is therefore a promising candidate gene for affective disorders . We investigated the genetic association between 35 single - nucleotide polymorphisms ( SNPs ) and an insertion / deletion ( I / D ) - polymorphism in the P12821 gene and the susceptibility for unipolar major depression together with the genetic association with P12821 serum activity and functional parameters of the Q9Y251 system . Two independent case / control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated . A case / control sample was screened to detect genetic associations with unipolar major depression . In addition , a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression . In the screening sample , two SNPs within the P12821 gene were significantly associated with unipolar major depression . The association with unipolar major depression of one SNP ( rs4291 ) located in the promoter region of the P12821 gene was confirmed in our replication sample . The T - allele of this SNP was associated with depression and depressed T - allele carriers showed higher P12821 serum activity and Q9Y251 - axis hyperactivity . Variants of the P12821 gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression . We could show that SNP rs4291 influences P12821 activity and Q9Y251 - axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK43___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Endothelial dysfunction in congestive heart failure : P12821 inhibition vs . angiotensin II antagonism . BACKGROUND : Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure ( CHF ) . The present study systematically investigated the effect of angiotensin II ( AT ( 1 ) ) - receptor blockade on vascular superoxide ( O ( 2 )(-) ) production and endothelial dysfunction . METHODS AND RESULTS : Vasodilator responses and O ( 2 )(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham - operated animals ( Sham ) . Rats were either treated with placebo ( P ) , with the AT ( 1 )- receptor antagonist Irbesartan ( 50 mg kg (- 1 ) day (- 1 ) ) or with the P12821 inhibitor DB00519 ( 0 . 3 mg kg (- 1 ) day (- 1 ) ) . In CHF - P , endothelium - dependent , acetylcholine - induced relaxation was significantly attenuated compared with Sham - P . Chronic treatment with DB00519 or Irbesartan significantly improved endothelium - dependent relaxation . Aortic O ( 2 )(-) formation was markedly increased in CHF , and was not significantly affected by DB00519 treatment , while it was reduced by Irbesartan . P29474 expression was reduced in CHF and normalised by both treatments . CONCLUSION : Endothelial vasomotor function in CHF rats was normalised by long - term treatment with an P12821 inhibitor or an AT ( 1 )- antagonist . Reduced aortic P29474 expression was normalised by both treatments , whereas aortic superoxide formation was only reduced by the AT ( 1 )- antagonist Irbesartan .",
"Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy . A number of candidate genes for lithium prophylactic efficacy have been proposed , some of them being also associated with a predisposition to bipolar illness . The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder , in relation to the putative role of these genes in the pathogenesis of this disorder . Some association with lithium prophylactic efficacy was found for the polymorphisms of P31645 , P21728 , P21964 , P23560 and P06241 genes , but not for 5HT2A , 5HT2C , P14416 , P35462 , P21917 , GSK - 3 , Q16620 , Q13224 and P14780 . Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed .",
"Synthetic triterpenoids , CDDO - Imidazolide and CDDO - Ethyl amide , induce chondrogenesis . Novel methods for inducing chondrogenesis are critical for cartilage tissue engineering and regeneration . Here we show that the synthetic oleanane triterpenoids , CDDO - Imidazolide ( CDDO - Im ) and CDDO - Ethyl amide ( CDDO - EA ) , at concentrations as low as 200 nM , induce chondrogenesis in organ cultures of newborn mouse calvaria . The cartilage phenotype was measured histologically with metachromatic toluidine blue staining for proteoglycans and by immunohistochemical staining for type II collagen . Furthermore , real - time polymerase chain reaction ( PCR ) analysis using mRNA from calvaria after 7 - day treatment with CDDO - Im and CDDO - EA showed up - regulation of the chondrocyte markers P48436 and type II collagen ( alpha1 ) . In addition , TGF - β ; BMPs 2 and 4 ; Smads 3 , 4 , 6 , and 7 ; and TIMPs - 1 and - 2 were increased . In contrast , P14780 was strongly down - regulated . Treatment of human bone marrow - derived DB05914 with CDDO - Im and CDDO - EA ( 100 nM ) induced expression of P48436 , collagen IIα1 , and aggrecan , as well as P12643 and phospho - Q99717 , confirming that the above triterpenoids induce chondrogenic differentiation . This is the first report of the use of these drugs for induction of chondrogenesis .",
"Transient estrogen exposure from birth affects uterine expression of developmental markers in neonatal gilts with lasting consequences in pregnant adults . Disruption of estrogen - sensitive , estrogen receptor ( ER ) - dependent events during porcine uterine development between birth ( postnatal day = P01160 0 ) and P01160 14 affects patterns of uterine morphoregulatory gene expression in the neonate with lasting consequences for reproductive success . Uterine capacity for conceptus support is reduced in pregnant adult gilts exposed to estradiol valerate ( EV ) for 14 days from birth . Objectives here were to determine effects of EV exposure from birth through P01160 13 on neonatal uterine and adult endometrial markers of growth , patterning , and remodeling . Targets included the relaxin receptor ( Q9HBX9 ) , estrogen receptor - alpha ( P03372 ) and vascular endothelial growth factor ( P15692 ) , morphoregulatory markers P31260 and O00755 , and the matrix metalloproteinases ( MMP ) 2 and P14780 . Gilts were treated daily with EV ( 50 microg / kg body weight per day , i . m . ) or corn oil vehicle from birth through P01160 13 . Uteri were obtained from neonates on P01160 14 and from adults on pregnancy day 12 ( PxD 12 ) . In neonates , EV exposure from birth increased uterine Q9HBX9 gene expression , and both P03372 and P15692 proteins . At PxD 12 , endometrial Q9HBX9 mRNA remained elevated , while P03372 protein was reduced . Early EV treatment decreased neonatal uterine O00755 , but increased P31260 expression . O00755 expression was reduced in EV - treated adults . Transient EV exposure increased P14780 transcripts at P01160 14 , whereas both latent and active P14780 activity was increased due to early EV treatment in adults on PxD 12 . Results support the hypothesis that transient , estrogen - induced disruption of porcine uterine development from birth alters early programming events that lead to functional consequences in the adult ."
] |
[
"___MASK27___",
"___MASK37___",
"___MASK43___",
"___MASK48___",
"___MASK54___",
"___MASK56___",
"___MASK75___",
"___MASK83___",
"___MASK8___"
] |
___MASK75___
|
MH_train_374
|
interacts_with DB00862?
|
[
"Murine lupus susceptibility locus Sle1a controls regulatory T cell number and function through multiple mechanisms . The Sle1 locus is a key determinant of lupus susceptibility in the NZM2410 mouse model . Within Sle1 , we have previously shown that Sle1a expression enhances activation levels and effector functions of P01730 (+) T cells and reduces the size of the P01730 (+) CD25 (+) Foxp3 (+) regulatory T cell subset , leading to the production of autoreactive T cells that provide help to chromatin - specific B cells . In this study , we show that Sle1a P01730 (+) T cells express high levels of Q9Y6W8 , which is consistent with their increased ability to help autoreactive B cells . Furthermore , Sle1a P01730 (+) CD25 (+) T cells express low levels of Foxp3 . Mixed bone marrow chimeras demonstrated that these phenotypes require Sle1a to be expressed in the affected P01730 (+) T cells . Expression of other markers generally associated with regulatory T cells ( Tregs ) was similar regardless of Sle1a expression in Foxp3 (+) cells . This result , along with in vitro and in vivo suppression studies , suggests that Sle1a controls the number of Tregs rather than their function on a per cell basis . Both in vitro and in vivo suppression assays also showed that Sle1a expression induced effector T cells to be resistant to Treg suppression , as well as dendritic cells to overproduce P05231 , which inhibits Treg suppression . Overall , these results show that Sle1a controls both Treg number and function by multiple mechanisms , directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells .",
"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .",
"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .",
"High biochemical selectivity of tadalafil , sildenafil and vardenafil for human phosphodiesterase 5A1 ( O76074 ) over PDE11A4 suggests the absence of PDE11A4 cross - reaction in patients . The physiological role of phosphodiesterase ( PDE ) 11 is unknown and its biochemical characteristics are poorly understood . We have expressed human DB00117 - tagged PDE11A4 and purified the enzyme to apparent homogeneity . PDE11A4 displays K ( m ) values of 0 . 97 microM for cGMP and 2 . 4 microM for DB02527 , and maximal velocities were 4 - to 10 - fold higher for DB02527 than for cGMP . Given the homology between PDE11 and O76074 , we have compared the biochemical potencies of tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , vardenafil ( DB00862 , Bayer - GSK ) , and sildenafil ( Viagra , Pfizer Inc . ) for PDE11A4 and PDE5A1 . PDE5A1 / PDE11A4 selectivities are 40 - , 9300 - , and 1000 - fold for tadalafil , vardenafil , and sildenafil , respectively . This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients .",
"Hu23F2G , an antibody recognizing the leukocyte CD11 / P05107 integrin , reduces injury in a rabbit model of transient focal cerebral ischemia . Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion . Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell ' s intercellular adhesion molecule ( P05362 ) through the leukocyte integrin , CD11 / P05107 . We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11 / P05107 integrin in a rabbit model of transient focal ischemia . Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral , anterior cerebral , and internal carotid arteries using aneurysm clips for 2 h , followed by 6 h of reperfusion . Treatment with a maximally saturating dose ( 4 mg / kg ) of a humanized CD11 / P05107 monoclonal antibody ( Hu23F2G , Q9Y6W8 Corp . , Bothell , WA ) ( n = 8 ) or placebo ( n = 7 ) was administered 20 min after occlusion and given as a single intravenous bolus . Hemispheric ischemic neuronal damage ( IND ) as seen on hematoxylin - and eosin - stained sections was significantly reduced in Hu23F2G - treated animals by 57 % ( Hu23F2G : 15 +/- 6 . 9 % ; placebo : 35 +/- 5 % ; mean +/- SEM , P < 0 . 05 , t - test ) . Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains . Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration . ( No . of neutrophils / IND area : Hu23F2G 36 . 1 +/- 36 . 7 cm - 2 , placebo 460 . 6 +/- 101 . 8 cm - 2 , P = 0 . 001 . ) Antagonism of neutrophil migration at the level of the CD11 / P05107 integrin reduces ischemic injury in experimental stroke .",
"B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK39___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"[ ___MASK8___ sodium ( Photofrin - II ) ] . ___MASK8___ sodium ( ___MASK8___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK8___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"___MASK13___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .",
"Radiolabeled ligand binding to the catalytic or allosteric sites of O76074 and PDE11 . Cyclic nucleotide phosphodiesterases ( PDEs ) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes . Phosphodiesterase - 5 ( O76074 ) , which is highly specific for guanosine 3 '- 5 '- cyclic - monophosphate ( cGMP ) at both its catalytic site and its allosteric sites , has generated particular interest because it is potently and specifically inhibited by three drugs : sildenafil ( Viagra , Pfizer ) , tadalafil ( DB00820 , Lilly - Q9Y6W8 ) , and vardenafil ( DB00862 , Bayer GSK ) . Previously , we have used [( 3 ) H ] cGMP to directly study the interaction of cGMP with the allosteric sites of O76074 , but because cGMP binds with relatively low affinity to the catalytic site , it has been difficult to devise a binding assay for this particular binding reaction . This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme . We now use a similar approach to study the characteristics of high - affinity [( 3 ) H ] inhibitor binding to the O76074 catalytic domain . For these studies , we have prepared [( 3 ) H ] sildenafil and [( 3 ) H ] tadalafil , two structurally different competitive inhibitors of O76074 . The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of O76074 . We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on O76074 . These techniques have also been successfully applied to the study of binding of radiolabeled O76074 inhibitors to PDE11 , suggesting that these methods are applicable to the study of other PDEs , and perhaps other enzyme families .",
"___MASK31___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK31___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"A novel anti - human O75144 monoclonal antibody that enhances IgG production of B cells . O75144 , a newly identified member of the P33681 superfamily , plays a major role in immune responses . In this study , a functional anti - human O75144 monoclonal antibody ( MAb ) 3B3 was obtained and characterized by means of flow cytometry , Western blot , and competition assay . This MAb could specifically recognize a distinct epitope of the O75144 molecule . As a functional antibody , MAb 3B3 could inhibit the proliferation of T lymphocytes stimulated by O75144 - L929 transfectants . Furthermore , it could enhance IgG production of PWM - driven B cells . The results indicate that the Q9Y6W8 - O75144 signal is critically involved in specific humoral immunity .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK75___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK80___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"P04035 inhibitors deplete circulating classical and non - classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 , CD16 , CD49d , CD64 , P33681 and CD195 ) . RESULTS : There were fewer circulating classical ( p = 0 . 0001 ) and non - classical ( p = 0 . 0013 ) monocytes in patients treated with a statin . CD64 expression was down - regulated ( p = 0 . 011 and p = 0 . 049 ) whereas CD49d expression was up - regulated ( p = 0 . 004 and p = 0 . 022 ) on classical and non - classical monocytes in this group . Patients receiving ___MASK39___ had fewer circulating classical monocytes ( p = 0 . 001 ) compared to patients administered DB00175 . Patients receiving DB00175 had fewer circulating non - classical monocytes ( p = 0 . 029 ) compared to patients administered ___MASK39___ . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .",
"P01730 + CD25 + regulatory T cells inhibit the maturation but not the initiation of an autoantibody response . To investigate the mechanism by which T regulatory ( Treg ) cells may control the early onset of autoimmunity , we have used an adoptive transfer model to track Treg , Th , and anti - chromatin B cell interactions in vivo . We show that anti - chromatin B cells secrete Abs by day 8 in vivo upon provision of undeviated , Th1 - or Th2 - type P01730 + T cell help , but this secretion is blocked by the coinjection of P01730 + CD25 + Treg cells . Although Treg cells do not interfere with the initial follicular entry or activation of Th or B cells at day 3 , Q9Y6W8 levels on Th cells are decreased . Furthermore , Treg cells must be administered during the initial phases of the Ab response to exert full suppression of autoantibody production . These studies indicate that CD25 + Treg cells act to inhibit the maturation , rather than the initiation , of autoantibody responses .",
"___MASK58___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Q9Y6W8 costimulation requires P60568 and can be prevented by P16410 engagement . We investigated the relationship between Q9Y6W8 , P10747 , P16410 , and P60568 to gain a better understanding of this family of costimulatory receptors in the immune response . Using magnetic beads coated with anti - CD3 and varying amounts of anti - Q9Y6W8 and anti - P16410 Abs , we show that P16410 ligation blocks Q9Y6W8 costimulation . In addition to inhibiting cellular proliferation , P16410 engagement prevented Q9Y6W8 - costimulated T cells from producing P05112 , P22301 , and P35225 . Both an indirect and direct mechanism of P16410 ' s actions were examined . First , P16410 engagement on resting cells was found to indirectly block Q9Y6W8 costimulation by interferring with the signals needed to induce Q9Y6W8 cell surface expression . Second , on preactivated cells that had high levels of Q9Y6W8 expression , P16410 ligation blocked the Q9Y6W8 - mediated induction of P05112 , P22301 , and P35225 , suggesting an interference with downstream signaling pathways . The addition of P60568 not only overcame both mechanisms , but also greatly augmented the level of cellular activation suggesting synergy between Q9Y6W8 and P60568 signaling . This cooperation between Q9Y6W8 and P60568 signaling was explored further by showing that the minimum level of P60568 produced by Q9Y6W8 costimulation was required for T cell proliferation . Finally , exogenous P60568 was required for sustained growth of Q9Y6W8 - costimulated T cells . These results indicate that stringent control of Q9Y6W8 costimulation is maintained initially by P16410 engagement and later by a requirement for exogenous P60568 .",
"Identification of Mycobacterium tuberculosis - specific Th1 , Th17 and Th22 cells using the expression of P29965 in tuberculous pleurisy . Important advances have been made in the immunodiagnosis of tuberculosis ( TB ) based on the detection of Mycobacterium tuberculosis ( MTB ) - specific T cells . However , the sensitivity and specificity of the immunological approach are relatively low because there are no specific markers for antigen - specific Th cells , and some of the Th cells that do not produce cytokines can be overlooked using this approach . In this study , we found that MTB - specific peptides of ESAT - 6 / P27918 - 10 can stimulate the expression of P29965 specifically in P01730 (+) T cells but not other cells from pleural fluid cells ( PFCs ) in patients with tuberculous pleurisy ( P20226 ) . P01730 (+) P29965 (+) but not P01730 (+) P29965 (-) T cells express IFN - γ , P60568 , P01375 - α , Q16552 or Q9GZX6 after stimulation with MTB - specific peptides . In addition , P01730 (+) P29965 (+) T cells were found to be mostly polyfunctional T cells that simultaneously produce IFN - γ , P60568 and P01375 - α and display an effector or effector memory phenotype ( CD45RA (-) CD45RO (+) P32248 (-) CD62L (-) Q9Y6W8 (-) ) . To determine the specificity of P01730 (+) P29965 (+) T cells , we incubated PFCs with ESTA - 6 / P27918 - 10 peptides and sorted live P01730 (+) P29965 (+) and P01730 (+) P29965 (-) T cells by flow cytometry . We further demonstrated that sorted P01730 (+) P29965 (+) , but not P01730 (+) P29965 (-) fractions , principally produced IFN - γ , P60568 , P01375 - α , Q16552 and Q9GZX6 following restimulation with ESTA - 6 / P27918 - 10 peptides . Taken together , our data indicate that the expression of P29965 on MTB - specific P01730 (+) T cells could be a good marker for the evaluation and isolation of MTB - specific Th cells and might also be useful in the diagnosis of TB .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"___MASK60___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK60___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Emerging oral drugs for erectile dysfunction . Erectile dysfunction ( ED ) is a common medical condition that affects the sexual life of millions of men worldwide . Many drugs are now available for the treatment of ED , with oral pharmacotherapy representing the first - line option for most patients . DB00203 citrate , an inhibitor of the enzyme phosphodiesterase type 5 ( O76074 ) , is the most widely prescribed oral agent and has a very satisfactory efficacy - safety profile in all patient categories . DB00820 ( DB00820 ; Eli Lilly & Co . , Q9Y6W8 ) and vardenafil ( DB00862 ; Bayer Pharmaceuticals , GlaxoSmithKline ) are new O76074 inhibitors that have recently been approved worldwide . Both have been associated with significant positive efficacy - safety profiles . DB00714 sublingual is a dopamine D1 and D2 receptor agonist , which has been approved for marketing in Europe . It is best selected for treating patients with mild - to - moderate ED , but it is seldom used in clinical practice due to its limited efficacy and side effects , particularly nausea . Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy . The efficacy of second - line treatment is high , but the attrition rate remains significant . For the purpose of this review , clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy , including O76074 inhibitors and sublingual apomorphine .",
"P06850 and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons . The stress - related neuropeptide DB05394 ( CRF ) and the serotonin system are both critically involved in the pathophysiology of mental disorders , including anxiety and depression . To understand the potential link between them , we investigated the impact of CRF on 5 - HT functions in pyramidal neurons of the prefrontal cortex ( P27918 ) , a brain region that is crucial for the control of emotion and cognition . One prominent function of serotonin in P27918 is to regulate GABAergic inhibitory transmission , as indicated by a 5 - HT - induced large , desensitizing ( approximately 4 min ) enhancement of the amplitude and frequency of spontaneous IPSCs ( sIPSCs ) . In P27918 slices exposed to CRF treatment , the regulation of sIPSCs by 5 - HT was significantly prolonged ( 8 - 10 min ) , and this effect of CRF was blocked by treatment with the competitive CRF receptor antagonist alpha - helical CRF9 - 41 and with the P34998 - specific antagonist astressin . Inhibiting phospholipase C or protein kinase C ( PKC ) abolished the prolongation by CRF of the effects of 5 - HT on sIPSCs . In P27918 slices prepared from animals previously exposed to acute stress ( forced swim or elevated platform ) , the regulation of sIPSCs by 5 - HT was significantly prolonged , mimicking the effect of CRF treatment . The stress - induced prolongation of the effects of 5 - HT on sIPSCs was diminished by alpha - helical CRF9 - 41 treatment , mimicked by direct activation of PKC , and reversed by short - term treatment with drugs that have anxiolytic efficacy . These results show that in response to stressful stimuli , CRF alters the serotonergic regulation of GABA transmission through a mechanism that is dependent on PKC . The interaction between CRF and 5 - HT may play an important role in psychiatric disorders , in which both are highly implicated .",
"Characterization of intratumoral follicular helper T cells in follicular lymphoma : role in the survival of malignant B cells . Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma ( FL ) has a key role in both lymphomagenesis and patient outcome . Malignant FL B cells are found admixed to specific stromal and immune cell subsets , in particular P01730 ( pos ) T cells displaying phenotypic features of follicular helper T cells ( T ( FH ) ) . The goal of our study was to functionally characterize intratumoral P01730 ( pos ) T cells . We showed that P32302 ( hi ) Q9Y6W8 ( hi ) P01730 ( pos ) T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features : ( i ) CD25 ( pos ) follicular regulatory T cells ( T ( FR ) ) , and ( ii ) CD25 ( neg ) T ( FH ) displaying a FL - B cell supportive activity without regulatory functions . Furthermore , despite their strong similarities with tonsil - derived T ( FH ) , purified FL - derived T ( FH ) displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis , in particular P01375 , P01374 , P05112 or P29965 . Interestingly , we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab - induced apoptosis . Altogether , our study demonstrates that tumor - infiltrating P01730 ( pos ) T cells are more heterogeneous than previously presumed , and underlines for the first time the crucial role of T ( FH ) in the complex set of cellular interactions within FL microenvironment ."
] |
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___MASK75___
|
MH_train_375
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interacts_with DB08870?
|
[
"DB00099 - induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy : safety , feasibility and evidence for an efficient in vivo purging . Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia ( CML ) . Further , the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation ( P09683 ) reduces the number of therapeutic options in a number of patients . To assess the possibility of stem cell mobilization ( DB00919 ) during imatinib therapy we performed granulocyte colony - stimulating factor ( filgrastim )- induced DB00919 and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients . Aphaeresis was successful in 13 patients ( 72 % ) ( > or = 2 . 0 x 10 ( 6 ) P28906 + cells / kg body weight ) and five ( 28 % ) harvests could be obtained , which were negative for P11274 / P00519 mRNA as assessed by nested - reverse transcription polymerase chain reaction ( RT - PCR ) . All harvests , except one , were negative after first round RT - PCR , implicating a low level of CML cell contamination . There was no significant change in peripheral P11274 / P00519 transcript load after DB00919 as assessed by quantitative real - time RT - PCR . Fifteen patients remained stable in complete cytogenetic remission ( CCR ) during a median observation period of 9 . 3 months . One patient achieved a molecular remission shortly after DB00919 . Another patient who exhibited rising P11274 / P00519 mRNA levels before DB00919 achieved CCR after autologous P09683 with the generated harvest . One patient with a Philadelphia chromosome - negative , P11274 / P00519 - positive CML showed a cytogenetic relapse 6 months after DB00919 . We conclude that filgrastim - induced P28906 + cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients . Additionally , we found evidence that this procedure could generate stem cell harvests that exhibit non - detectable levels of P11274 / P00519 mRNA .",
"Comparison of variations detection between whole - genome amplification methods used in single - cell resequencing . BACKGROUND : Single - cell resequencing ( SCRS ) provides many biomedical advances in variations detection at the single - cell level , but it currently relies on whole genome amplification ( WGA ) . Three methods are commonly used for WGA : multiple displacement amplification ( MDA ) , degenerate - oligonucleotide - primed PCR ( DOP - PCR ) and multiple annealing and looping - based amplification cycles ( MALBAC ) . However , a comprehensive comparison of variations detection performance between these WGA methods has not yet been performed . RESULTS : We systematically compared the advantages and disadvantages of different WGA methods , focusing particularly on variations detection . Low - coverage whole - genome sequencing revealed that DOP - PCR had the highest duplication ratio , but an even read distribution and the best reproducibility and accuracy for detection of copy - number variations ( CNVs ) . However , MDA had significantly higher genome recovery sensitivity ( ~ 84 % ) than DOP - PCR ( ~ 6 % ) and MALBAC ( ~ 52 % ) at high sequencing depth . MALBAC and MDA had comparable single - nucleotide variations detection efficiency , false - positive ratio , and allele drop - out ratio . We further demonstrated that SCRS data amplified by either MDA or MALBAC from a gastric cancer cell line could accurately detect gastric cancer CNVs with comparable sensitivity and specificity , including amplifications of 12p11 . 22 ( P01116 ) and 9p24 . 1 ( O60674 , Q9NZQ7 , and Q9BQ51 ) . CONCLUSIONS : Our findings provide a comprehensive comparison of variations detection performance using SCRS amplified by different WGA methods . It will guide researchers to determine which WGA method is best suited to individual experimental needs at single - cell level .",
"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK27___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"JunB induced by constitutive P28908 - extracellular signal - regulated kinase 1 / 2 mitogen - activated protein kinase signaling activates the P28908 promoter in anaplastic large cell lymphoma and reed - sternberg cells of Hodgkin lymphoma . High expression of P28908 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . Possible interactions of P28908 and JunB were examined in this study . We found that the P28908 promoter in tumor cells of both nucleophosmin ( P06748 ) - anaplastic lymphoma kinase ( Q9UM73 ) - positive and P06748 - Q9UM73 - negative ALCL and HL is regulated by a constitutively active P28908 - extracellular signal - regulated kinase ( P29323 ) 1 / 2 mitogen - activated protein kinase ( MAPK ) . Phosphorylation of P27361 / 2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL . P28908 - P27361 / 2 MAPK signals induce JunB expression , which maintains high activity of the P28908 promoter . JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL . These results show a common mechanism of P28908 overexpression in ALCL and HL , although the outcome of P28908 signaling differs between P06748 - Q9UM73 - positive ALCL and P06748 - Q9UM73 - negative ALCL , cutaneous ALCL , and HL as we recently reported .",
"Microtubule - depolymerizing agents used in antibody - drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody - drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target - specificity and high therapeutic activity in patients with cancer . DB08870 represents a first - in - class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor - resident DCs to the tumor - draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen - specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin - based therapies , such as brentuximab vedotin , with immune - based therapies .",
"DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti - P28908 antibody - drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high - risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high - dose chemotherapy with autologous stem - cell support . There has been no standard therapy for relapsed / refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .",
"Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha - mediated ceramide de novo synthesis in colon cancer cells . PURPOSE : Cannabinoids have been recently proposed as a new family of potential antitumor agents . The present study was undertaken to investigate the expression of the two cannabinoid receptors , P21554 and CB2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation . EXPERIMENTAL DESIGN : Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD - 1 and HT29 colon cancer cell lines . The effects of the P21554 agonist arachinodyl - 2 '- chloroethylamide and the CB2 agonist N - cyclopentyl - 7 - methyl - 1 -( 2 - morpholin - 4 - ylethyl )- 1 , 8 - naphthyridin - 4 ( 1H )- on - 3 - carboxamide ( CB13 ) on tumor cell apoptosis and ceramide and tumor necrosis factor ( P01375 ) - alpha production were evaluated . The knockdown of P01375 mRNA was obtained with the use of selective small interfering RNA . RESULTS : We show that the P21554 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor . The activation of the P21554 and , more efficiently , of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD - 1 and HT29 cells . Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis . The CB2 agonist CB13 also reduced the growth of DLD - 1 cells in a mouse model of colon cancer . The knockdown of P01375 mRNA abrogated the ceramide increase and , therefore , the apoptotic effect induced by cannabinoid receptor activation . CONCLUSIONS : The present study shows that either P21554 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells . Our data unveiled , for the first time , that P01375 acts as a link between cannabinoid receptor activation and ceramide production .",
"Subclones with the t ( 9 ; 22 )/ P11274 - P00519 rearrangement occur in AML and seem to cooperate with distinct genetic alterations . In AML , cooperation of mutations suppressing differentiation ( ' class - II - mutations ' ) with ' class - I - mutations ' increasing cell proliferation is frequent . In rare cases of myeloid malignancies , the P11274 - P00519 fusion was reported to cooperate as class - I - mutation with class - II - mutations , but most cases had to be classified as blast phase of chronic myeloid leukaemia ( CML ) . We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions : 1 : 220 patients with inv ( 16 )/ Q13951 - P35749 ( 0 · 5 % ) , 2 : 272 AML cases with t ( 8 ; 21 )/ Q01196 - Q06455 ( 0 · 7 % ) , 1 : 1029 P06748 - mutated AML ( 0 · 1 % ) , and one patient with s - AML following P43034 with a 5q - deletion . Four patients had m - P11274 ( e1a2 ) P11274 - P00519 transcripts ; one case only had an M - P11274 ( b3a2 ) breakpoint . These cases allow some interesting conclusions : The P11274 - P00519 rearrangement apparently can cooperate with the P06748 mutation similar to other class - I - mutations . The identification of Philadelphia positive subclones in < 1 % of patients with Q03701 - leukaemias fits well with previous observations that most Q03701 - AML are accompanied by activating mutations in genes enhancing proliferation . Since we observed the occurrence of the Philadelphia positive subclones at diagnosis , at relapse , or throughout the disease , the time point of the emergence of Philadelphia subclones seems variable in AML . Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact .",
"P04141 - 1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow - derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS - induced P01375 and P05231 secretion in human monocyte - derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 / IFN - inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up - regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK30___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"DB08870 : its role in the treatment of anaplastic large cell and Hodgkin ' s lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin ' s lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody - drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre - existing frontline chemotherapies and as a stand - alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1 - 2 adverse reactions such as neutropenia and there have been reports of grade 3 - 4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects .",
"[ Melanoma : from molecular studies to the treatment breakthrough ] . Melanoma holds a leading position in the mortality from skin tumors . Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients . Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and , consequently , to the development of novel targeted drugs . More than a half of melanomas contain amine acid substitutions in serine - threonine kinase P15056 . Clinical trials involving specific P15056 inhibitors -- vemurafenib and dabrafenib -- demonstrated high efficacy of these agents towards P15056 - mutated melanoma . MEK inhibitors may show activity against both P15056 -- and P01111 - driven tumors . Mucosal and acral melanomas frequently contain mutation in P10721 receptor and can be successfully treated by imatinib . There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules P16410 , P18621 and Q9NZQ7 . In some instances these drugs allow to obtain exceptionally prolonged responses . Whole genome sequencing led to the identification of new melanoma genes , e . g . Q12879 , Q9Y4A5 , Q70Z35 , P63000 , P49842 , O00743 , etc . Molecular testing , especially P15056 mutation analysis , has become a mandatory part of melanoma diagnosis . Nevertheless , despite the revolution in melanoma treatment , the prevention of excessive ultraviolet exposure , cancer awareness and early diagnosis remain the main tools for the management of this disease .",
"[ Establishment of hematological malignancy model in ex vivo cell culture ] . The aim of this study was to develop an ex vivo cell culture system for establishing the hematological malignancy model . Mouse bone marrow cells were transfected with GFP - expressed retroviral vectors encoding various leukemia / lymphoma - associated fusion proteins ( P41212 - P09619 , Rabaptin5 - P09619 , p210BCR - P00519 , Q01196 - Q06455 , P06748 - Q9UM73 ) . After transfection , the cells were cultured in IMDM containing 10 % FCS without growth factors , or with one of the following growth factor combinations : ( 1 ) murine c - kit ligand ( KL ) plus human flt3 ligand ( FL ) ; ( 2 ) P08700 , thrombopoietin , DB00099 , and hyper - P05231 ( 3 / T / G / Q9NP08 ) ; ( 3 ) KL / FL plus 3 / T / G / Q9NP08 . The flow cytometry was used to detect the ability of combinations of growth factors to complement the oncogene fusion protein to support self - renewal of the transfected cells . The results showed that the transfected cells could be amplified sustainably in the logarithmic growth way . The indicated combination of P21583 ( KL ) with flt - 3 ligand ( FL ) supported the self - renewal of the marrow cells transfected with vectors encoding P41212 - P09619 , Rabaptin5 - P09619 , Q01196 - Q06455 and P06748 - Q9UM73 , in addition to KL / FL , the self - renewal of Q92817 P11274 - P00519 transfected - marrow cells also required P08700 . The morphology of cells emerged from culture can be the predictor of the corresponding oncogene - associated malignancy . It is concluded that this study establishes a culture system ex vivo which provides a generalized method for studying hematological malignancies , and may facilitate the screening for therapeutic agents .",
"Sulphomucin colonic type intestinal metaplasia and carcinoma in the stomach . A histochemical study of 115 cases obtained by biopsy . One hundred fifteen gastroscopic biopsy specimens ( 54 cases of carcinoma and 61 of gastritis ) were used in this histochemical study . Intestinal metaplasia ( IM ) was classified into small intestinal type ( ST ) and colonic type ( CT ) . The former may be a reactive change only . The incidence of sulphomucin colonic type ( P09683 ) metaplasia was higher in gastric carcinomas than in benign lesions ( P less than 0 . 01 ) , and a relation between P09683 metaplasia and cancer was demonstrated by both histologic and histochemical procedures . This suggests that P09683 IM is correlated with certain precancerous lesions . There was no significant difference in the incidence of O - acetyl sialomucin colonic type ( O75051 ) metaplasia between benign and malignant diseases . Further study is needed to determine why slightly more than half of the P09683 IM was accompanied by O75051 IM .",
"Growth of Enterococcus mundtii O95980 in medium filtrate and purification of bacteriocin O95980 by cation - exchange chromatography . Bacteriocin O95980 ( bacST15 ) , produced by Enterococcus mundtii O95980 , inhibited the growth of a variety of bacteria , including exopolysaccharide ( EPS ) - producing strains isolated from biofilms in stainless steel pipes . Maximal production of bacST15 ( 51200 AU / ml ) was recorded after 20 h of growth in P59665 broth ( Biolab ) , which was maintained throughout fermentation . Only 12800 AU / ml bacST15 has been recorded in P59665 filtrate with components smaller than 8000 Da , suggesting that nutrients larger than 8000 Da are required for optimal bacST15 production . Cation - exchange chromatography yielded an active peptide , which is 3944 . 00 Da , according to electron - spray mass spectrometry and tricin - SDS PAGE . BacST15 is smaller than the 4287 Da reported for bacteriocins ATO6 and KS produced by E . mundtii . The iso - electric point of bacST15 is between 7 and 9 , and similar to that reported for pediocin P18621 .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK66___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"___MASK36___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Synovium infiltrating T cells induce excessive synovial cell function through P10747 / P33681 pathway in patients with rheumatoid arthritis . OBJECTIVE : To clarify involvement of synovial T cells in the development of synovial inflammation in patients with rheumatoid arthritis ( RA ) , we analyzed cellular interactions between synovial cells and infiltrating T cells via P10747 / P33681 - 1 and P33681 - 2 . METHODS : Synovial cells and infiltrating T cells were recovered separately from RA synovial tissues . Expression of P10747 , P33681 - 1 , and P33681 - 2 of synovial cells was analyzed by immunohistochemical staining and immunofluorescence analysis . Interleukin 1beta ( IL - 1beta ) , P05231 , and matrix metalloprotease 3 ( P08254 ) secreted by synovial cells in the presence of infiltrating T cells were measured by ELISA . Nuclear transcription factor P10747 responsive complex was detected by a gel shift assay . RESULTS : Both P10747 + T cells and P33681 - 1 / P33681 - 2 + cells were found accumulating in the mononuclear cell infiltrate of RA synovial tissues and P33681 - 1 / P33681 - 2 + cells were mainly LeuM3 + synovial cells . P10747 responsive complex was detected in nuclear extracts of freshly isolated lymphocytes from RA synovial tissues , but not those from osteoarthritis synovial tissues or normal peripheral blood , suggesting in vivo activation of T cells by the P10747 / P33681 - 1 / P33681 - 2 interactions . The irradiated autologous synovium infiltrating T cells notably enhanced IL - 1beta , P05231 , and P08254 production by the synovial cells . The enhancement of proinflammatory cytokine and P08254 production by the synovial cells co - cultured with the T cells was abolished by the addition of P16410 - Ig , anti - P33681 - 1 , and anti - P33681 - 2 monoclonal antibodies . CONCLUSION : These results suggest that cellular interactions between synovium infiltrating T lymphocytes and synovial cells via P33681 / P10747 pathways are intimately associated with development and exacerbation of inflammation in RA synovial cells .",
"Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .",
"Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity . Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti - cancer , anti - diabetic , anti - atherosclerotic , anti - bacterial , and anti - inflammatory activities . However , the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet . In this study , we aimed to evaluate the anti - inflammatory mechanism of scutellarein ( P09683 ) , a flavonoid isolated from Erigeron breviscapus , Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil . For this purpose , a nitric oxide ( NO ) assay , polymerase chain reaction ( PCR ) , nuclear fractionation , immunoblot analysis , a kinase assay , and an overexpression strategy were employed . Scutellarein significantly inhibited NO production in a dose - dependent manner and reduced the mRNA expression levels of inducible NO synthase ( P35228 ) and tumor necrosis factor ( P01375 ) - α in lipopolysaccharide ( LPS ) - activated RAW264 . 7 cells . In addition , P09683 also dampened nuclear factor ( NF ) - κB - driven expression of a luciferase reporter gene upon transfection of a TIR - domain - containing adapter - inducing interferon - β ( Q8IUC6 ) construct into Human embryonic kidney 293 ( P29320 293 ) cells ; similarly , NF - κ B nuclear translocation was inhibited by P09683 . Moreover , the phosphorylation levels of various upstream signaling enzymes involved in NF - κB activation were decreased by P09683 treatment in LPS - treated RAW264 . 7 cells . Finally , P09683 strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src . Therefore , our data suggest that P09683 can block the inflammatory response by directly inhibiting Src kinase activity linked to NF - κB activation .",
"Design and application of a novel PNA probe for the detection at single cell level of JAK2V617F mutation in Myeloproliferative Neoplasms . BACKGROUND : Mutation ( s ) of the O60674 gene ( V617F ) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms ( Q9BQR3 ) patients and its detection is now a cornerstone in the diagnostic algorithm . METHODS : We developed a novel assay based on peptide nucleic acid ( PNA ) technology coupled to immuno - fluorescence microscopy ( PNA - Q5TCZ1 ) for the specific detection at a single cell level of O60674 - mutation thus improving both the diagnostic resolution and the study of clonal prevalence . RESULTS : Using this assay we found a percentage of mutated P28906 + cells ranging from 40 % to 100 % in Polycythemia Vera patients , from 15 % to 80 % in Essential Thrombocythemia and from 25 % to 100 % in Primary Myelofibrosis . This method allows to distinguish , with a high degree of specificity , at single cell level , between P28906 + progenitor stem cells harbouring the mutated or the wild type form of O60674 in P06748 patients . CONCLUSIONS : This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK62___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK62___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK86___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .",
"Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non - transplanted cohort . Metachromatic leukodystrophy ( O15121 ) is a rare inborn error of metabolism leading to severe neurological symptoms and early death . Hematopoietic P09683 ( HSCT ) is considered a treatment option , but results are inconsistent and comparison with natural history is practically missing . We compare a girl with juvenile O15121 10 years after allogeneic HSCT not only with her untreated sister , but also with a large cohort of untreated patients . The girl received HSCT at the age of 5 years when first motor signs appeared . Over 10 years she was stable with respect to her clinical course and gained cognitive abilities . Magnetic resonance imaging ( Q9BWK5 ) showed clear regression of white matter changes and magnetic resonance spectroscopy ( P59665 ) demonstrated a reversal of the initial choline increase and N - acetyl - aspartate ( NAA ) decrease . Only axonal demyelinating neuropathy showed some progression . Her gross motor function and Q9BWK5 - scores were clearly better compared with her sister and the cohort of untreated patients . Difference to her sister became apparent only 4 years after HSCT . We conclude that HSCT , early in the course of disease , can lead to stabilization of juvenile O15121 with a course clearly different from the natural history . HSCT may prevent disease progression , if performed sufficient time before loss of walking , which typically initiates rapid deterioration .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK55___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"Serum macrophage migration inhibitory factor ( MIF ) levels after allogeneic hematopoietic stem cell transplantation . P14174 ( MIF ) may play an important role in the pathogenesis of acute graft - versus - host disease ( aGVHD ) after allogeneic hematopoietic stem cell transplantation ( allo - HSCT ) , as MIF plays an important role to regulate the production of tumor necrosis factor - alpha ( P01375 ) , one of the inflammatory cytokines which induces and exacerbates aGVHD . We examined the association between serum MIF levels and aGVHD vs . chronic GVHD ( cGVHD ) in allo - P09683 patients in this study . We found a significant increase in the peak serum MIF ( 14 . 46 ng +/- 1 . 47 ng / ml ) at onset in patients that developed aGVHD ( n = 23 , P = 0 . 009 ) . We also found that mean serum MIF levels in patients who developed extensive type cGVHD within 6 months ( 12 . 58 +/- 2 . 18 ng / ml , n = 13 ) were significantly higher than MIF levels before allo - HSCT ( 7 . 86 +/- 1 . 17 ng / ml , n = 19 , P = 0 . 04 ) . Therefore , we speculated that serum MIF levels increase during the active phase of both aGVHD and cGVHD .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and / or refractory Hodgkin ' s lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR - HL ) have poor outcomes . DB08870 ( BV ) , an antibody - drug conjugate comprising an anti - P28908 antibody conjugated to the potent anti - microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo - P09683 ) in patients with RR - HL treated by BV in a named patient program in two French institutions . Twenty - four adult patients with histologically proven P28908 (+) RR - HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45 . 8 % ) , while five patients were in partial response ( 20 . 8 % ) , with an overall response rate of 66 . 6 % . Eight patients failed to respond to BV ( 33 . 3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto - P09683 ) , three patients received a tandem auto - P09683 / allo - P09683 , nine patients received allo - P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment - related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow - up of 20 months ( range 10 . 5 - 43 . 2 ) , none of them relapsed or died . BV followed by allo - P09683 represents an effective salvage regimen in patients with RR - HL .",
"Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via P40763 - dependent induction of P14902 . Hepatic stellate cells ( HSCs ) are critical for hepatic wound repair and tissue remodeling . They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver . The functional relationship between HSCs and the professional migratory APCs in the liver , that is , dendritic cells ( DCs ) , has not been evaluated . In this article , we report that murine liver DCs colocalize with HSCs in vivo under normal , steady - state conditions , and cluster with HSCs in vitro . In vitro , HSCs secrete high levels of DC chemoattractants , such as MΙP - 1α and P13500 , as well as cytokines that modulate DC activation , including P01375 - α , P05231 , and IL - 1β . Culture of HSCs with conventional liver myeloid ( m ) DCs resulted in increased P05231 and P22301 secretion compared with that of either cell population alone . Coculture also resulted in enhanced expression of costimulatory ( P33681 , P42081 ) and coinhibitory ( Q9NZQ7 ) molecules on mDCs . P19526 - induced mDC maturation required cell - cell contact and could be blocked , in part , by neutralizing MΙP - 1α or P13500 . P19526 - induced mDC maturation was dependent on activation of P40763 in mDCs and , in part , on P19526 - secreted P05231 . Despite upregulation of costimulatory molecules , mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation , which was independent of Q9NZQ7 , but dependent upon P19526 - induced P40763 activation and subsequent upregulation of P14902 . In conclusion , by promoting P14902 expression , HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity .",
"Functional validation of the anaplastic lymphoma kinase signature identifies P17676 and Q16548 as critical target genes . Anaplastic large cell lymphomas ( ALCLs ) represent a subset of lymphomas in which the anaplastic lymphoma kinase ( Q9UM73 ) gene is frequently fused to the nucleophosmin ( P06748 ) gene . We previously demonstrated that the constitutive phosphorylation of Q9UM73 chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that Q9UM73 activity is strictly required for the survival of Q9UM73 - positive ALCL cells . To elucidate the signaling pathways required for Q9UM73 - mediated transformation and tumor maintenance , we analyzed the transcriptomes of multiple Q9UM73 - positive ALCL cell lines , abrogating their Q9UM73 - mediated signaling by inducible Q9UM73 RNA interference ( RNAi ) or with potent and cell - permeable Q9UM73 inhibitors . Transcripts derived from the gene expression profiling ( GEP ) analysis uncovered a reproducible signature , which included a novel group of Q9UM73 - regulated genes . Functional RNAi screening on a set of these Q9UM73 transcriptional targets revealed that the transcription factor C / EBPbeta and the antiapoptotic protein Q16548 are absolutely necessary to induce cell transformation and / or to sustain the growth and survival of Q9UM73 - positive ALCL cells . Thus , we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions .",
"Advances in immunotherapy of chronic myeloid leukemia CML . Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene P11274 - P00519 . However , these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation . Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations . Compelling evidence indicates that more modern , antigen - specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective . Amongst these , particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia - associated antigens , since this approach allows to circumvent HLA - restriction of the leukemia - associated T cell epitopes that have been eventually identified . Combining these strategies with monoclonal antibodies , such as anti - P16410 or anti - P18621 , may help to obtain even stronger immune responses and better clinical results . This narrative review addresses this topic by focusing in particular on the cell - based immunotherapeutic strategies for CML and on the issue of the leukemia - associated antigens to be selected for targeting .",
"Particle size of latex beads dictates IL - 1β production mechanism . Macrophages ( Mϕ ) are well documented to produce IL - 1β through various signaling pathways in response to small particles such as silica , asbestos and urea crystals , in the presence of lipopolysaccharide ( LPS ) . However , it has not been clear to what extent particle size affects the response . To investigate this point , we stimulated bone marrow - derived macrophages ( BMDM ) with size - defined latex beads ( LxB ) . Although both nano - sized ( 20 nm ) and micro - sized ( 1 , 000 nm ) LxB induced IL - 1β production , only the nano - sized particles formed large intracellular vacuoles . In contrast , 100 nm LxB did not induce either of the responses . The same cellular responses were also observed in primary microglia cells . Although K (+) efflux and Q96P20 activation in BMDM were crucial in response to both 20 and 1 , 000 nm LxB , only IL - 1β production by 20 nm LxB was sensitive to cathepsin B and Q99572 , a receptor for DB00171 . The response by 1 , 000 nm LxB relied on a robust production of reactive oxygen species ( ROS ) , since IL - 1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium ( DPI ) and DB06151 ( Q9C000 ) . In contrast , IL - 1β production by 20 nm LxB was augmented by Q9C000 and in BMDM deficient in thioredoxin - binding protein - 2 ( P20226 - 2 ) , a negative regulator of the ROS scavenger thioredoxin . These results suggest that the cells responded differently in their secretion of IL - 1β depending on particle size , and that there is a range within which neither pathway works .",
"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .",
"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK55___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .",
"Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high - fat diet induced obese mice . Calorie restriction is the most effective way of expanding life - span and decreasing morbidity . It improves insulin sensitivity and delays the age - related loss of dopamine receptor D ( 2 ) ( P14416 ) expression in the brain . Conversely , high - fat feeding is associated with obesity , insulin resistance and a reduced number of P14416 binding sites . We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate P14416 transmission . The food intake of wild - type C57Bl6 male mice was restricted to 60 % of ad lib . intake while they were treated with the P14416 antagonist haloperidol or vehicle using s . c . implanted pellets . Mice with ad lib . access to food receiving vehicle treatment served as controls . All mice received high - fat food throughout the experiment . After 10 weeks , an i . p . glucose tolerance test was performed and , after 12 weeks , a hyperinsulinaemic euglycaemic clamp . Hypothalamic P14416 binding was also determined after 12 weeks of treatment . Calorie - restricted ( CR ) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib . ( AL ) fed vehicle mice . CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice . ___MASK73___ completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice . The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic P14416 binding . In conclusion , blocking P14416 curtails the metabolic effects of calorie restriction . Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction , restricting access to high - fat food does not increase ( hypothalamic ) P14416 binding capacity , which argues against this inference .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Effects of C - phycocyanin and Spirulina on salicylate - induced tinnitus , expression of DB01221 receptor and inflammatory genes . Effects of C - phycocyanin ( C - PC ) , the active component of Spirulina platensis water extract on the expressions of N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , tumor necrosis factor - α ( P01375 - α ) , interleukin - 1β ( IL - 1β ) , and cyclooxygenase type 2 ( P35354 ) genes in the cochlea and inferior colliculus ( IC ) of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate . The results showed that 4 - day salicylate treatment ( unlike 4 - day saline treatment ) caused a significant increase in Q13224 , P01375 - α , and IL - 1β mRNAs expression in the cochlea and IC . On the other hand , dietary supplementation with C - PC or Spirulina platensis water extract significantly reduced the salicylate - induced tinnitus and down - regulated the mRNAs expression of Q13224 , P01375 - α , IL - 1β mRNAs , and P35354 genes in the cochlea and IC of mice . The changes of protein expression levels were generally correlated with those of mRNAs expression levels in the IC for above genes .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .",
"Altered expression of P11021 , P11142 and Q99497 in spinocerebellar ataxia type 17 identified by 2 - dimensional fluorescence difference in gel electrophoresis . BACKGROUND : Expansion of the CAG repeat of the TATA - box binding protein ( P20226 ) gene has been identified as the causative mutations in spinocerebellar ataxia 17 ( SCA17 ) . P20226 is ubiquitously expressed in both central nervous system and peripheral tissues . The underlying molecular changes of SCA17 are rarely explored . METHODS : To study the molecular mechanisms underlying SCA17 , we generated stably induced isogenic 293 cells expressing normal P20226 - Q ( 36 ) and expanded P20226 - Q ( 61 ) and analyzed the expressed proteins using two - dimensional difference in gel electrophoresis ( 2D - DIGE ) , followed by mass spectrometry and immunoblotting . RESULTS : Upon induction with doxycycline , the expanded P20226 - Q ( 61 ) formed aggregates with significant increase in the cell population at subG1 phase and cleaved caspase - 3 . Proteomics study identified a total of 16 proteins with expression changes greater than 1 . 5 fold . Among the 16 proteins , Q99497 , O76003 , P09651 , Q14691 , P06733 , P61978 and P06748 are increased , and P05154 , P11021 , P18206 , Q92945 , P11142 , P31943 , Q16891 , P55072 and P14866 are decreased in cells expressing P20226 - Q ( 61 ) compared with those expressing P20226 - Q ( 36 ) . The altered expression of P11021 , P11142 and Q99497 were further validated by 2D and Western immunoblot analyses . CONCLUSIONS : The results illustrate the utility of proteomics to identify alterations of proteins which underlie pathogenesis of SCA17 , and may serve as potential therapeutic targets .",
"Mammalian Q99572 receptor pharmacology : comparison of recombinant mouse , rat and human Q99572 receptors . BACKGROUND AND PURPOSE : Acute activation of Q99572 receptors rapidly opens a non - selective cation channel . Sustained Q99572 receptor activation leads to the formation of cytolytic pores , mediated by downstream recruitment of hemichannels to the cell surface . Species - and single - nucleotide polymorphism - mediated differences in Q99572 receptor activation have been reported that complicate understanding of the physiological role of Q99572 receptors . Studies were conducted to determine pharmacological differences between human , rat and mouse Q99572 receptors . EXPERIMENTAL APPROACH : Receptor - mediated changes in calcium influx and Yo - Pro uptake were compared between recombinant mouse , rat and human Q99572 receptors . For mouse Q99572 receptors , wild - type ( BALB / c ) and a reported loss of function ( C57BL / 6 ) Q99572 receptor were also compared . KEY RESULTS : BzATP [ 2 , 3 - O -( 4 - benzoylbenzoyl )- DB00171 ] was more potent than DB00171 in stimulating calcium influx and Yo - Pro uptake at rat , human , BALB / c and C57BL / 6 mouse Q99572 receptors . Two selective Q99572 receptor antagonists , A - 740003 and A - 438079 , potently blocked Q99572 receptor activation across mammalian species . Several reported P51575 receptor antagonists [ e . g . P59665 2159 ( 4 - [ ( 4 - formyl - 5 - hydroxy - 6 - methyl - 3 - [ ( phosphonooxy ) methyl } - 2 - pyridinyl ) azo ] - benzoic acid ) , PPNDS and NF279 ] blocked Q99572 receptors . NF279 fully blocked human Q99572 receptors , but only partially blocked BALB / c Q99572 receptors and was inactive at C57BL / 6 Q99572 receptors . CONCLUSIONS AND IMPLICATIONS : These data provide new insights into Q99572 receptor antagonist pharmacology across mammalian species . Q99572 receptor pharmacology in a widely used knockout background mouse strain ( C57BL / 6 ) was similar to wild - type mouse Q99572 receptors . Several structurally novel , selective and competitive Q99572 receptor antagonists show less species differences compared with earlier non - selective antagonists .",
"Intracellular capture of P33681 in antigen - presenting cells reduces costimulatory activity . P16410 gene constructs were designed to express P16410 exclusively in the endoplasmic reticulum ( ER ) . Four different P16410 gene constructs were transfected into P29320 293 ( human embryonic kidney ) and A20 ( Balb / c mouse B lymphoma ) cells . All constructs contained an ER retention signal and coded for P16410 expression in the ER . One of the constructs , which contained the membrane part of P16410 , coded for an expression both on the cell surface and in the ER . Three of the expressed P16410 types ( including the ER - membrane - expressed form ) caused a reduced surface expression of P33681 in the A20 cells . Only constructs which allow dimerization of P16410 showed this effect . It is assumed that intracellular P16410 bound P33681 and inhibited therefore the transport of P33681 to the surface . The binding obviously caused also an enhanced degradation of the complexes because both proteins showed a low concentration in the transfected cell lines . P16410 - transfected and P33681 - reduced A20 cells showed a diminished costimulating activity upon T cells . This was demonstrated by a reduced proliferation of T cells from ovalbumin - immunized Balb / c mice , incubated with ovalbumin peptide - primed P16410 - transfected A20 cells .",
"Microenvironment of the murine mammary carcinoma 4T1 : endogenous P01579 affects tumor phenotype , growth , and metastasis . P01579 has a profound influence on growth and metastasis of solid tumors . This is true for the murine mammary carcinoma 4T1 which grows faster and metastasizes much more readily when transplanted into the mammary fatpads of P01579 (-/-) mice . We were interested in determining which infiltrating hematopoietic cells produce P01579 within the 4T1 tumor microenvironment . 4T1 tumors were infiltrated with progressively increasing numbers of F4 / 80 (+)/ CD11c (+) myeloid cells , many of which were also Gr - 1 (+) , and Gr - 1 (+)/ CD11b (+) granulocytes . Only small numbers of P01730 T cells , CD8 T cells , NK cells , and gammadelta T cells , the most likely P01579 - producing cells , were seen at any time point . Sensitive intracellular cytokine staining and flow cytometry revealed no tumor - infiltrating hematopoietic cells with detectable levels of intracellular P01579 , although P01579 mRNA transcripts were detected in tumor tissue . However , a progressive increase in the expression of three P01579 - inducible surface membrane proteins ( Q9NZQ7 , I - A ( d ) , and P05362 ) on growing 4T1 tumor cells indicated the presence of biologically active P01579 in the tumor microenvironment . Moreover , 4T1 tumor cells from in vitro culture expressed these surface molecules 48 h after intratumoral injection into mature tumors . These data suggest that very low amounts of endogenous P01579 elaborated by infiltrating hematopoietic cells within the microenvironment of a solid tumor can achieve biologically active concentrations and affect tumor phenotype , growth , and metastasis .",
"[ Cutaneous non - tuberculous mycobacterial infection following cord blood stem cell transplantation ] . We describe a 4 - year - old - girl with familial hemophagocytic lymphohistiocytosis ( FHL ) who developed disseminated cutaneous nontuberculous mycobacterial ( Q9P121 ) infection after unrelated cord blood stem cell transplantation ( uCBSCT ) . After transplantation , the patient developed steroid - refractory acute graft - versus - host disease , and was given methylprednisolone , cyclosporin and mycophenolate mofetil . Six months after uCBSCT , cutaneous lesions that looked like insect bites appeared and spread widely over the thighs . Q9P121 infection was diagnosed by skin biopsy although no organism could be identified . DB01017 ( MINO ) and sulfamethoxazole / trimethoprim ( ST ) were administered . However , the cutaneous disease followed a course of remissions and exacerbations . One month after the skin biopsy , mycobacterium chelonae was detected by bacteriological culture of abscess drainage . Ten months after uCBSCT , the cutaneous lesions quickly progressed and the inguinal lymph nodes became enlarged and painful . Then the antibiotics were switched from MINO and ST to amikacin and clarithromycin ( P62158 ) based on the results of mycobacterial susceptibility test . The cutaneous lesions gradually improved after continuous administration of P62158 . Cutaneous Q9P121 infection is rare , but it may occur in immunocompromised patients after P09683 .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK49___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK49___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Proteomic , cellular , and network analyses reveal new P51452 interactions with nucleolar proteins in HeLa cells . P51452 ( or Vaccinia virus phosphatase P28562 - related ; P51452 ) is a small dual - specificity phosphatase known to dephosphorylate c - Jun N - terminal kinases and extracellular signal - regulated kinases . In human cervical cancer cells , P51452 is overexpressed , localizes preferentially to the nucleus , and plays a key role in cellular proliferation and senescence triggering . Other P51452 functions are still unknown , as illustrated by recent and unpublished results from our group showing that this enzyme mediates DNA damage response or repair processes . In this study , we sought to identify new interactions between P51452 and proteins directly or indirectly involved in or correlated with its biological roles in HeLa cells exposed to gamma or UV radiation . By using Q86UG4 - DUSP as bait , we pulled down interacting proteins and identified them by LC - MS / MS . Of the 46 proteins obtained , six hits were extensively validated by immune techniques ; the proteins P06748 , HnRNP C1 / P06681 , and P19338 were the most promising targets found to directly interact with P51452 . We then analyzed the P51452 interactomes using physical protein - protein interaction networks using our hits as the seed list . The validated hits as well as unvalidated hits fluctuated on the P51452 interactomes of HeLa cells , independent of the time post radiation , which confirmed our proteomic and experimental data and clearly showed the proximity of P51452 to proteins involved in processes intimately related to DNA repair and senescence , such as P12956 and Tert , via interactions with nucleolar proteins , which were identified in this study , that regulate DNA / RNA structure and functions .",
"Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs : behavioural and biochemical evidence . Clinical evidence suggests that stimulation of the D ( 1 ) rather than P14416 is related to the development of dyskinesias in Parkinson ' s disease ( PD ) . We evaluated , in the 6 - hydroxydopamine rat model of PD , sensitization of contralateral turning ( P09683 ) behaviour and abnormal involuntary movements ( AIMs ) as behavioural parameters of dyskinetic response , and changes in zif - 268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D ( 2 )/ D ( 3 ) agonist ropinirole , defined as a mild dyskinetic drug in the clinic . Results were compared with previous findings on repeated L - dopa treatment . Ropinirole displayed a mild dyskinetic response characterized by P09683 only , which contrasted with the presence of P09683 in association with AIMs elicited by repeated L - dopa . Zif - 268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole , in contrast to hyper - expression of zif - 268 mRNA selectively induced by L - dopa in striatonigral neurons . Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats ; in contrast , a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole .",
"Kinetics of Th1 / Th2 cytokines and lymphocyte subsets to predict chronic GVHD after allo - P09683 : results of a prospective study . The role of different cytokines and cells of immune system in the pathogenesis of chronic GVHD ( cGVHD ) is still controversial . Earlier studies , which were either retrospective or analysed one or a few factors , did not show unequivocal results . We prospectively evaluated cytokine levels and lymphocyte subsets in 30 patients who underwent Allo - P09683 to investigate their possible correlation with cGVHD . Levels of P05112 , P05231 , P22301 , P01579 , tumour necrosis factor - alpha ( P01375 ) and its soluble receptors were assessed by ELISA in 30 patients at different times after P09683 . Lymphocyte subsets were evaluated by flow cytometry in peripheral blood at the same times as cytokines . A multivariate analysis was performed using principal component analysis and multi - factor Q9UNW9 ( analysis of variance ) . Eighteen patients developed cGVHD at a median time of 6 months ( range , 5 - 9 ) after P09683 . In multivariate analysis , we observed a correlation between cGVHD and clusters of cytokines and lymphocyte subsets from the third to the sixth month after P09683 . These clusters changed their composition over time , but they constantly included natural killer ( NK ) and P16410 + T cells as negative predictors of cGVHD . P01375 prevailed among other cytokines before the onset of cGVHD . This prevalence could be related partly to the defect of immunoregulatory cells .",
"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . ___MASK73___ was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .",
"___MASK73___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK73___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin ' s lymphoma . PURPOSE : DB08870 is an antibody - drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 - expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 - positive lymphomas . PATIENTS AND METHODS : In this multinational , open - label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin ' s lymphoma ( HL ) after autologous stem - cell transplantation ( auto - P09683 ) . Patients had histologically documented P28908 - positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1 . 8 mg / kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression - free survival time for all patients was 5 . 6 months , and the median duration of response for those in CR was 20 . 5 months . After a median observation time of more than 1 . 5 years , 31 patients were alive and free of documented progressive disease . The most common treatment - related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto - P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy .",
"3 , 4 - Dimethoxyphenyl bis - benzimidazole derivative , mitigates radiation - induced DNA damage . Radiation - induced DNA damage initiates a series of overlapping responses that include DNA damage recognition and repair , induction of cell cycle checkpoints , senescence and / or apoptosis . This study assessed the DNA damage response and whole genome expression profile in two mammalian cell lines ( P29320 and U87 ) in response to ( 5 -{ 4 - methylpiperazin - 1 - yl }- 2 -[ 2 '-( 3 , 4 - dimethoxyphenyl )- 5 '- benzimidazolyl ] benzimidazole ) P28067 and ionizing radiation . P28067 has been shown to act as a potent radiation protector , yielding significant levels of protection , i . e . , 20 . 9 % in P29320 cells and 21 . 2 % in U87 cells . Our findings revealed treatment with P28067 significantly reduced γ - P16104 , Q12888 and Rad51 foci formation after irradiation . Q96HU1 kinase , WNT signaling and p53 pathways were found to be activated in P28067 - treated cells . In addition , the DNA damage response genes , HSP70 , P10809 , Q06830 , Q9BXM0 , P27797 , P06748 , P0CG48 , and Q01105 showed differential regulation in P28067 , P28067 + radiation and radiation - treated cells . The data suggest that P28067 - influenced repertoire of repair proteins , which are an indispensable part of the cell , interplay with each other to reduce DNA damage and maintain the genomic integrity of the cell .",
"Induction of oral tolerance to oxidized low - density lipoprotein ameliorates atherosclerosis . BACKGROUND : Oxidation of low - density lipoprotein ( LDL ) and the subsequent processing of oxidized LDL ( oxLDL ) by macrophages results in activation of specific T cells , which contributes to the development of atherosclerosis . Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis . METHODS AND RESULTS : Tolerance to oxLDL and malondialdehyde - treated LDL ( MDA - LDL ) was induced in P01130 -/- mice fed a Western - type diet by oral administration of oxLDL or MDA - LDL before the induction of atherogenesis . Oral tolerance to oxLDL resulted in a significant attenuation of the initiation ( 30 % to 71 % ; P < 0 . 05 ) and progression ( 45 % ; P < 0 . 05 ) of atherogenesis . Tolerance to oxLDL induced a significant increase in P01730 + CD25 + Foxp3 + cells in spleen and mesenteric lymph nodes , and these cells specifically responded to oxLDL with increased transforming growth factor - beta production . Tolerance to oxLDL also increased the mRNA expression of Foxp3 , P16410 , and CD25 in the plaque . In contrast , tolerance to MDA - LDL did not affect atherogenesis . CONCLUSIONS : OxLDL - specific T cells , present in P01130 -/- mice and important contributors in the immune response leading to atherosclerotic plaque , can be counteracted by oxLDL - specific P01730 + CD25 + Foxp3 + regulatory T cells activated via oral tolerance induction to oxLDL . We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis .",
"Q9UM73 as a novel lymphoma - associated tumor antigen : identification of 2 HLA - A2 . 1 - restricted CD8 + T - cell epitopes . Oncogenic anaplastic lymphoma kinase ( Q9UM73 ) fusion proteins ( P06748 / Q9UM73 and associated variants ) are expressed in about 60 % of anaplastic large cell lymphomas ( ALCLs ) but are absent in normal tissues . In this study , we investigated whether Q9UM73 , which is expressed at high levels in lymphoma cells , could be a target for antigen - specific cell - mediated immunotherapy . A panel of Q9UM73 - derived peptides was tested for their binding affinity to HLA - A * 0201 molecules . Binding peptides were assessed for their capacity to elicit a specific immune response mediated by cytotoxic T lymphocytes ( CTLs ) both in vivo , in HLA - A * 0201 transgenic mice , and in vitro in the peripheral blood lymphocytes ( PBLs ) from healthy donors . Two HLA - A * 0201 - restricted CTL epitopes , p280 - 89 ( SLAMLDLLHV ) and p375 - 86 ( GVLLWEIFSL ) , both located in the Q9UM73 kinase domain were identified . The p280 - 89 - and p375 - 86 - induced peptide - specific CTL lines were able to specifically release interferon - gamma ( P01579 ) on stimulation with Q9UM73 peptide - pulsed autologous Epstein - Barr virus - transformed B cells ( LCLs ) or P24752 cells . Anti - Q9UM73 CTLs lysed HLA - matched ALCL and neuroblastoma cell lines endogenously expressing Q9UM73 proteins . CTL activity was inhibited by anti - HLA - A2 monoclonal antibody CR11 . 351 , consistent with a class I - restricted mechanism of cytotoxicity . These results show the existence of functional anti - Q9UM73 CTL precursors within the peripheral T - cell repertoire of healthy donors , clearly indicating Q9UM73 as a tumor antigen and Q9UM73 - derived peptides , p280 - 89 and p375 - 86 , as suitable epitopes for the development of vaccination strategies .",
"Association between high interleukin - 6 levels and adverse outcome after autologous haemopoietic stem cell transplantation . We studied interleukin - 6 ( P05231 ) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation ( P09683 ) ( either peripheral blood stem cell transplantation ( PBSCT ) or bone marrow transplantation ( BMT ) ) for neoplastic diseases to determine if there was a relationship between P05231 level and rate of haemopoietic recovery , length of stay in hospital , and survival . There was no apparent delay in post - transplant recovery associated with elevated P05231 levels . However , increased values of P05231 tended to be associated with an increased length of stay in hospital ( P = 0 . 083 ) . There was a highly significant adverse association between higher P05231 levels and survival following transplantation ( P = 0 . 0001 ) . This association remained significant ( P = 0 . 013 ) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT ( that is , excluding patients who had undergone PBSCT ) ( n = 13 ) . Knowledge of P05231 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic P09683 .",
"Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 ."
] |
[
"___MASK27___",
"___MASK30___",
"___MASK36___",
"___MASK49___",
"___MASK55___",
"___MASK62___",
"___MASK66___",
"___MASK73___",
"___MASK86___"
] |
___MASK49___
|
MH_train_376
|
interacts_with DB01233?
|
[
"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .",
"The relationship between gastric motility and nausea : gastric prokinetic agents as treatments . Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying . The mechanisms and treatments are unclear ( anti - emetic drugs are not fully effective against nausea ) . Can nausea be relieved by stimulating gastric emptying ? Physostigmine ( together with atropine ) has been shown experimentally to stimulate gastric motility , relieve nausea and restore normal gastric motility . Is this mimicked by gastric prokinetic drugs ? The answer is complicated by mixed pharmacology . DB01233 increases gastric motility by activating myenteric Q13639 receptors but also directly inhibits vomiting via D2 and 5 - Q9H205 receptor antagonism ; relationships between increased gastric motility and relief from nausea are therefore unclear . Similarly , the D2 receptor antagonist domperidone has direct anti - emetic activity . Nevertheless , more selective Q13639 and motilin receptor agonists ( erythromycin , directly stimulating gastric motility ) inhibit vomiting in animals ; low doses of erythromycin can also relieve symptoms in patients with gastroparesis . Ghrelin stimulates gastric motility and appetite mostly via vagus - dependent pathways , and inhibits vomiting in animals . To date , ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis . We conclude that nausea can be relieved by gastric prokinetic drugs , but more clinical studies are needed using drugs with selective activity . Other mechanisms ( e . g . ghrelin , vagal and central pathways , influencing a mechanistic continuum between appetite and nausea ) also require exploration . These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology , which focusses on mechanisms of nausea and vomiting .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Comparison of three GPCR structural templates for modeling of the Q9H244 nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP - activated G protein - coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 ( P61073 ) . By criteria of sequence analysis ( 25 . 6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly - binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N - terminus , the P61073 - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R - CXC agree with previously published site - directed mutagenesis studies of Arg256 and Lys280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174 ( EL2 ) side chain . The docking poses of the irreversibly - binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist ___MASK57___ were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4 . 7 Å ) to the sulfur atom of a disulfide bridge involving Cys175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly - binding small molecules , consistent with observed pharmacology and mutagenesis studies .",
"17 DB00783 overcomes a P55008 block induced by P04035 inhibitors and fosters cell cycle progression without inducing P27361 and - 2 Q96HU1 kinases activation . P04035 inhibitors , such as ___MASK6___ and Simvastatin , cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media . Cells are induced to pause in P55008 and can readily resume growth upon removal of the enzymatic block . DB00286 , acting via their nuclear receptor , are mitogens for different normal and transformed cell types , where they foster cell cycle progression and cell division . In estrogen - responsive MCF - 7 human breast cancer cells , but not in non responsive cells , 17 beta - estradiol ( E2 ) induces cells arrested with ___MASK6___ or Simvastatin to proliferate in the presence of inhibitor , without restoring P04035 activity or affecting the protein prenylation pattern . Mitogenic stimulation of P55008 - arrested MCF - 7 cells with E2 includes primary transcriptional activation of c - fos , accompanied by transient binding in vivo of the estrogen receptor and / or other factors to the ERE and the estrogen - responsive DNA region of this proto - oncogene , as detected by dimethylsulphate genomic footprinting analysis . Mitogenic stimulation of growth - arrested MCF - 7 cells by E2 occurs , under these conditions , without evident activation of P27361 and - 2 kinases , and thus independently from the mitogen - responsive signal transduction pathways that converge on these enzymes .",
"Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP - PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .",
"Single - walled carbon nanotubes ( SWCNTs ) enhance DB00761 - , acetylcholine - , and serotonin - induced contractions and evoke oxidative stress on rabbit ileum . We examined the effects of intravenous administration of purified arc - discharge single - walled carbon nanotubes ( SWCNTs ) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases . The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals . SWCNTs increased the contractile responses induced by DB00761 , acetylcholine ( ACh ) , and serotonin ( 5 - HT ) in rabbit ileum . Verapamil , apamin , glibenclamide , quinine and charybdotoxin reduced the contractile responses induced by ACh and 5 - HT in ileum from rabbits treated with SWCNTs , indicating that voltage - dependent Ca2 + channels and small , intermediate , and large - conductance Ca ( 2 +)- activated , DB00171 - sensitive , and voltage - dependent K + channels are involved in these effects . Atropine and hexamethonium reduced the ACh response , indicating that muscarinic and nicotinic receptors are involved in this effect . DB00904 and GR 113808 reduced the 5 - HT response , indicating that serotonin 5 - Q9H205 and Q13639 receptors are involved in this effect . SWCNTs increased the malondialdehyde plus 4 - hydroxyalkenals and carbonyl levels in rabbit plasma and ileum , indicating that SWCNTs produce oxidative stress . SWCNTs did not produce relevant histological changes or modify the levels of the inflammatory mediators P35228 and P35354 in the ileum . In conclusion , this study demonstrates that the intravenous administration of SWCNTs can evoke oxidative stress and affect contractility in rabbit ileum . These effects could reduce the possibility of using the arc - discharge SWCNTs as cell markers or drug carriers to treat intestinal diseases .",
"DB01233 stimulates catecholamine - and granin - derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 ( Q13639 ) receptors . The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas . The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 ( 5 - HT ( 4 ) ) receptors in pheochromocytoma tissues . Tissue explants , obtained from 18 pheochromocytomas including the tumor removed from a 46 - year - old female patient who experienced life - threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas ( 9 benign and 8 malignant ) were studied . Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5 - HT ( 4 ) receptor ligands . In addition , total mRNAs were extracted from all the 18 tumors . Catecholamine - and granin - derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays . In addition , expression of 5 - HT ( 4 ) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase - PCR . RESULTS : DB01233 and the 5 - HT ( 4 ) receptor agonist cisapride were found to activate catecholamine - and granin - derived peptide secretions by cultured tumor cells . DB01233 - and cisapride - evoked catecholamine - and granin - derived peptide productions were inhibited by the 5 - HT ( 4 ) receptor antagonist GR 113808 . 5 - HT ( 4 ) receptor mRNAs were detected in the patient ' s tumor and the series of 17 additional pheochromocytomas . This study shows that pheochromocytomas express functional 5 - HT ( 4 ) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine - and granin - derived peptide secretion . All 5 - HT ( 4 ) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma .",
"Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK3___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK43___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .",
"Effects of cholinoceptor and 5 - hydroxytryptamine3 receptor antagonism on erythromycin - induced canine intestinal motility disruption and emesis . 1 . Erythromycin administration is associated with gastrointestinal problems , disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin ( 7 mg kg - 1 ) increased contractions of the proximal small intestine , and caused emesis in all fasted dogs and in 5 dogs after food . Atropine ( 50 mg kg - 1 min - 1 ) and hexamethonium ( 10 mg kg - 1 h - 1 ) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . DB01233 at a high dose ( 2 mg kg - 1 h - 1 ) reduced the incidence of emesis in the presence of increased intestinal motility , but a low dose ( 150 micrograms kg - 1 h - 1 ) was ineffective . 5 . A 5 - hydroxytryptamine3 ( 5 - Q9H205 ) receptor antagonist , MDL 72222 ( 1 mg kg - 1 ) , reduced emesis when given alone and combined with metoclopramide ( low dose ) . The Q13639 receptor agonist BRL24924 ( DB04917 , 1 mg kg - 1 ) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion , erythromycin - induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated , emesis occurs at least in part via a 5 - hydroxytryptaminergic mechanism , but does not involve the dopamine system .",
"Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization - activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f - channel isoforms expressed in the human atrium ( O60741 , 2 and 4 ) , Q9Y3Q4 mRNA levels measured by RT - PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 ) ; concurrently , miR - 1 expression was significantly reduced . In patch - clamped atrial myocytes , current - specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0 . 01 ) . β - Adrenergic and Q13639 receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 - mediated effect was significantly reduced ( P < 0 . 02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain - of - function of If , which may contribute to enhanced atrial ectopy .",
"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK99___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK84___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Analysis of neurogenic contractions induced by ML - 1035 and other benzamides in the guinea - pig non - stimulated isolated ileum . 4 - Amino - 5 - chloro - substituted benzamides have been shown to increase gastric motility in - vivo and enhance field - stimulated and peristaltic contractions in - vitro . The present experiments examined the contractile response to a series of benzamides in the guinea - pig non - stimulated ileum . Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine ( % acetylcholine response = 12 +/- 2 , 19 +/- 3 , 26 +/- 2 , 51 +/- 3 , n = 13 , 8 , 17 , and 21 , with EC50 values of 0 . 85 , 1 . 8 , 5 . 7 , and 14 . 2 microM for cisapride , zacopride , metoclopramide , and ML - 1035 ( 4 - amino - 5 - chloro - 2 -(( 2 - methylsulphinyl )- ethoxy )- N - ( 2 -( diethylamino )- ethyl ) - benzamide hydrochloride ) , respectively ) . ML - 1035 contractions were completely blocked by atropine and tetrodotoxin , while ganglionic blockade with hexamethonium was ineffective . DB01233 has been reported to sensitize postjunctional muscarinic receptors , however , ML - 1035 did not enhance acetylcholine - induced contractions . Tropisetron ( ICS 205 - 930 , 1 microM ) , caused a parallel rightward shift in the concentration - response curve for both ML - 1035 and zacopride ( EC50 = 14 . 2 +/- 1 . 3 and 1 . 8 +/- 0 . 8 microM in the absence , and 26 +/- 2 . 7 and 6 . 9 +/- 2 . 3 microM in the presence of tropisetron for ML - 1035 and zacopride , respectively ) with apparent pKB values of 5 . 9 and 6 . 0 for the respective compounds . 5 - Hydroxytryptaminergic receptor desensitization by 2 - methyl - 5 - hydroxytryptamine ( 5 - Q9H205 ) and 5 - methoxytryptamine ( Q13639 ) , attenuated the response to ML - 1035 . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK91___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .",
"5 - hydroxytryptamine and its receptors in systemic vascular walls . 5 - hydroxytryptamine ( 5 - HT ) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system . 5 - HT released from activated platelets dramatically changes the function of vascular smooth muscle cells ( VSMCs ) and endothelial cells ( ECs ) . In VSMCs , 5 - HT induces proliferation and migration via 5 - Q13049 receptors . These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II . 5 - Q13049 receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase - 2 and reduction of nitric oxide ( NO ) by suppressing inducible NO synthase . Evidence showing that 5 - HT in ECs plays a principal role in angiogenesis now exists . Stimulation of 5 - HT1 and / or 5 - HT2 receptors has been implicated in the angiogenic effect of 5 - HT . The extracellular signal - regulated kinase and endothelial NO synthase ( P29474 ) activation - dependent pathways are involved in the mechanisms . Moreover , Q13639 receptors in ECs have been shown to also regulate angiogenesis . Recent reports show sarpogrelate , a selective antagonist of the 5 - Q13049 receptor , indirectly enhances the function of P28222 receptors in ECs via inhibition of 5 - Q13049 receptors in VSMCs or platelets . This indirect action of P28222 receptors in ECs may increase NO production derived from P29474 and a vasodilator response . Furthermore , sarpogrelate and other 5 - Q13049 receptor antagonists have been shown to reduce the constitutive activity of 5 - Q13049 receptors . It is believed that increasing evidence on the role of 5 - HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate , and to the development of new 5 - HT receptor - related drugs for treating cardiovascular diseases .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"The additive effect of neurotransmitter genes in pathological gambling . As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling , known as pathological gambling . Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role . Polymorphisms at 31 different genes involved in dopamine , serotonin , norepinephrine , GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age , race , and sex - matched controls . Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable , and the 31 coded genes as the independent variables . Fifteen genes were included in the regression equation . The most significant were the P14416 , P21917 , Q01959 , P17752 , P18825 , NMDA1 , and P49768 genes . The r ( 2 ) or fraction of the variance was less than 0 . 02 for most genes . Dopamine , serotonin , and norepinephrine genes contributed approximately equally to the risk for pathological gambling . These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling . Multi - gene profiles in specific individuals may be of assistance in choosing the appropriate treatment .",
"A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36 , 320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 , P61073 , P80370 , P48380 , Q9H3S1 , Q8IUC6 and P19474 ) , nervous system ( Q96NK8 , O95897 , MAGI1 , Q9H3S1 and Q13639 ) and skin and hair properties ( P24530 , TRSP1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK2___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"___MASK6___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Pharmacogenomics of antiplatelet drugs . ___MASK57___ , a platelet Q9H244 inhibitor , is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications . It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system , especially the P33261 enzyme . Candidate gene studies and genome - wide association studies have identified loss - of - function P33261 variants to be associated with a diminished pharmacologic response . Specifically , compared with noncarriers , carriers of at least one copy of a loss - of - function P33261 allele have ∼ 30 % lower levels of active clopidogrel metabolite and ∼ 25 % relatively less platelet inhibition with clopidogrel . Moreover , in patients treated with clopidogrel predominantly for percutaneous coronary intervention , carriers of 1 or 2 P33261 loss - of - function alleles are at increased risk for major adverse cardiovascular outcomes , with an ∼ 1 . 5 - fold increase in the risk of cardiovascular death , myocardial infarction , or stroke as well as an ∼ 3 - fold increase in risk for stent thrombosis . Tripling the dose of clopidogrel in carriers of a P33261 loss - of - function allele can achieve on - treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild - type individuals , but the impact on clinical outcomes remains unknown . Alternatively , 2 third - generation Q9H244 inhibitors are available : prasugrel and ticagrelor . These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by P33261 loss - of - function alleles .",
"p - Chloroamphetamine , a serotonin - releasing drug , elicited in rats a hyperglycemia mediated by the P08908 and P41595 / 2C receptors . The effects of a serotonin ( 5 - HT ) releasing drug , p - chloroamphetamine , on plasma glucose levels were investigated in rats . p - Chloroamphetamine elicited a significant hyperglycemia . The hyperglycemic effects of p - chloroamphetamine were completely prevented by the 5 - HT synthesis inhibitor , p - chlorophenylalanine . Prior adrenodemedullation abolished the hyperglycemia elicited by p - chloroamphetamine . p - Chloroamphetamine - induced hyperglycemia was prevented by methysergide , which blocks the 5 - HT1 and 5 - HT2 receptor , the P08908 / 1B / 2C receptor antagonist , (-)- propranolol , the selective P08908 receptor antagonist , 4 - ( 2 '- methoxyphenyl - 1 - [ 2 '- n - 2 \" pyridinyl ) - p - iodobenzamido ] - ethyl - pi perazine ( p - MPPI ) , the 5 - Q13049 / 2B / 2C receptor antagonists , ritanserin and 4 - isopropyl - 7 - methyl - 9 -( 2 - hydroxy - 1 - methyl - propoxycarbonyl )- 4 , 6A , 7 , 8 , 9 , 10 , 10A - octahydro - indolo [ 4 , 3 - FG ] quinolone maleate ( LY 53857 ) . However , the 5 - Q9H205 and Q13639 receptor antagonist , tropisetron , the Q13639 receptor antagonist , 2 - methoxy - 4 - amino - 5 - chloro - benzoic acid 2 -( diethylamino ) ethyl ester ( SDZ 205 - 557 ) , and the 5 - Q13049 receptor antagonist , ketanserin , did not affect the p - chloroamphetamine - induced hyperglycemia . These results suggest that p - chloroamphetamine - induced hyperglycemia is elicited by an enhanced 5 - HT release and facilitated adrenaline release . Moreover , our results indicate that p - chloroamphetamine - induced hyperglycemia is mediated by P08908 and P41595 / 2C receptors .",
"Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , ___MASK2___ , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .",
"Chronic Q13639 receptor activation decreases Aβ production and deposition in hAPP / P49768 mice . Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer ' s disease ( AD ) , because Aβ is postulated to play an important role in the pathogenesis of AD . Q13639 receptors are an interesting drug target in this regard , as their activation might stimulate α - secretase processing , which increases sAPPα and reduces Aβ , at least according to the central dogma in P05067 processing . Here we describe a novel high - affinity Q13639 receptor agonist SSP - 002392 that , in cultured human neuroblastoma cells , potently increases the levels of DB02527 and sAPPα at 100 - fold lower concentrations than the effective concentrations of prucalopride , a known selective Q13639 receptor agonist . Chronic administration of this compound in a hAPP / P49768 mouse model of Alzheimer ' s disease decreased soluble and insoluble Aβ in hippocampus , but the potential mechanisms underlying these observations seem to be complex . We found no evidence for direct α - secretase stimulation in the brain in vivo , but observed decreased P05067 and P56817 - 1 expression and elevated astroglia and microglia responses . Taken together these results provide support for a potential disease - modifying aspect when stimulating central Q13639 receptors ; however , the complexity of the phenomena warrants further research .",
"Fatal rhabdomyolysis in a patient with liver cirrhosis after switching from simvastatin to fluvastatin . P04035 inhibitors ( statins ) are widely used to treat hypercholesterolemia . Among the adverse effects associated with these drugs are statin - associated myopathies , ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis . ___MASK91___ - induced fatal rhabdomyolysis has not been previously reported . We describe here a patient with liver cirrhosis who experienced fluvastatin - induced fatal rhabdomyolysis . This patient had been treated with simvastatin ( 20 mg / day ) for coronary artery disease and was switched to fluvastatin ( 20 mg / day ) 10 days before admission . He was also taking aspirin , betaxolol , candesartan , lactulose , and entecavir . Rhabdomyolysis was complicated and continued to progress . He was treated with massive hydration , urine alkalization , intravenous furosemide , and continuous renal replacement therapy for acute renal failure , but eventually died due to rhabdomyolysis complicated by hepatic failure . In conclusion , fluvastatin should be used with caution in patients with liver cirrhosis , especially with other medications metabolized with P11712 .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Effect of metoclopramide , ondansetron and granisetron on aldosterone secretion in man . The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 ( 5 - Q9H205 & 4 ) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i . v . in a randomised , cross - over sequence : ondansetron 8 mg , granisetron 3 mg , metoclopramide 20 mg , and saline 20 ml . DB01233 significantly increased the mean plasma aldosterone level to 196 % of basal level at 5 min . It rose to 234 % at 15 min and remained at more than 185 % of basal level for the duration of the experiment . The response to ondansetron and granisetron did not differ significantly from placebo . If dopamine antagonism is discounted , the results suggest that metoclopramide - induced aldosterone secretion results from its agonist activity at Q13639 receptors , although slow neuronal depolarization via an unidentified receptor remains a possibility . Antagonism at the 5 - Q9H205 receptor plays no role , as the selective antagonist , granisetron , did not elicit a significant response . It seems unlikely that the Q13639 receptor is the second , low affinity binding site of ondansetron , unless it had no agonist activity at this receptor .",
"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .",
"DB01233 does not increase gastric muscle contractility in newborn rats . Feeding intolerance resulting from delayed gastric emptying is common in premature neonates . DB01233 ( MCP ) , the most frequently used prokinetic drug in neonates , enhances gastric muscle contractility through inhibition of dopamine receptors . Although its therapeutic benefit is established in adults , limited data are available to support its clinical use in infants . Hypothesizing that developmentally dependent differences are present , we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn , juvenile , and adult rats . The muscle strips were either contracted with electrical field stimulation ( O43281 ) to induce cholinergic nerve - mediated acetylcholine release or carbachol , a cholinergic agonist acting directly on the muscarinic receptor . Although in adult rats MCP increased O43281 - induced contraction by 294 ± 122 % of control ( P < 0 . 01 ) , no significant effect was observed in newborn fundic muscle . MCP had no effect on the magnitude of the carbachol - induced and / or bethanechol - induced gastric muscle contraction at any age . In response to dopamine , an 80 . 7 ± 5 . 3 % relaxation of adult fundic muscle was observed , compared with only a 8 . 4 ± 8 . 7 % response in newborn tissue ( P < 0 . 01 ) . P14416 expression was scant in neonates and significantly increased in adult gastric tissue ( P < 0 . 01 ) . In conclusion , the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression . To the extent that these novel data can be extrapolated to neonates , the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation .",
"Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the Q13639 receptor . OBJECTIVE : Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at Q13639 receptors . The 5 - Q9H205 antagonist tropisetron is thought to act as an antagonist at Q13639 receptors . In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the Q13639 receptor in aldosterone secretion . METHODS : Following a single - blind , random design , ten normal male volunteers received one of the following regimens on three occasions , with at least 2 - week intervals : metoclopramide 10 mg i . v . ; tropisetron 5 mg by slow i . v . i . , or ; tropisetron by slow i . v . i . , followed by 10 mg metoclopramide i . v . RESULTS : In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149 % of basal level and remained significantly elevated for the next 20 min . With tropisetron alone , there was a significant 37 . 8 % drop at 60 min and the aldosterone levels remained low for the duration of the experiment . DB01233 reversed the decline mediated by tropisetron significantly at 30 and 90 min . DB04630 levels after the latter regimen also did not differ significantly from baseline at any time period . CONCLUSION : These results would suggest the existence of a tonic stimulatory influence of 5 - HT via Q13639 receptors on aldosterone secretion , which could be augmented by metoclopramide and blocked by tropisetron . However , the effect of tropisetron per se should be interpreted with caution given the lack of a saline group .",
"Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK89___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK89___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK89___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Effects of enhancement and antagonism of 5 - hydroxytryptamine activity on the influence of metoclopramide on gastric emptying . This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying . Six subjects received the following pretreatments before metoclopramide and paracetamol : fluoxetine ( 5 - HT uptake inhibitor ) ; meterogoline ( 5 - HT1 antagonist ) ; pizotifen ( 5 - HT2 antagonist ) or methysergide ( 5 - HT1 and 5 - HT2 antagonist ) . One regimen consisted of metoclopramide ( 5 - Q9H205 antagonist and Q13639 agonist ) alone . Gastric emptying was measured by the mean cumulative fraction absorbed - time profiles of paracetamol . Methysergide / metoclopramide significantly delayed gastric emptying from 30 min onwards . DB01233 with either metergoline or pizotifen did not retard gastric emptying to the same extent , suggesting a greater influence with simultaneous 5 - HT1 and 5HT2 blockade . DB01233 / fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen . It was assumed that the influence of metoclopramide was not optimal at this stage , therefore possibly indicating domination of 5 - Q9H205 over Q13639 effects , resulting in gastric delay . It therefore seems as if all the 5 - HT receptors present in the gut have a role to play in the control of gastric emptying .",
"Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK99___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines ."
] |
[
"___MASK2___",
"___MASK3___",
"___MASK43___",
"___MASK57___",
"___MASK6___",
"___MASK84___",
"___MASK89___",
"___MASK91___",
"___MASK99___"
] |
___MASK99___
|
MH_train_377
|
interacts_with DB00005?
|
[
"Effects of DB00005 and DB01017 in a rat model of spinal cord injury . Loss of function is usually considered the major consequence of spinal cord injury ( SCI ) . However , pain severely compromises the quality of life in nearly 70 % of SCI patients . The principal aim of this study was to assess the contribution of P01375 alpha ( P01375 ) to SCI pain . P01375 blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain , especially following SCI . Following T13 spinal cord hemisection , we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept , a fusion protein blocker of P01375 . Immediate treatment ( starting at the time of injury ) with etanercept resulted in markedly reduced mechanical allodynia 1 , 2 , 3 and 4 weeks after SCI . Delayed treatment had no effect . Immediate etanercept treatment also reduced spinal microglial activation assessed by OX - 42 immunostaining , a putative marker of activated microglia . To assess whether the effects of etanercept were mediated via decreased microglial activation , we examined the effects of the microglial inhibitor , minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment . DB01017 also significantly reduced microglial OX - 42 expression . Furthermore , minocycline decreased the expression of noxious - stimulation - induced c - Fos , suggesting an effect on evoked neuronal activity . This study demonstrates that P01375 plays an important role in the establishment of neuropathic pain following SCI , seemingly dependent on microglial activation . Pharmacological targeting of P01375 may offer therapeutic opportunities for treating SCI pain .",
"Potential role of pharmacogenetics in anti - P01375 treatment of rheumatoid arthritis and Crohn ' s disease . DB00005 , infliximab and adalimumab have shown clinical benefit in immune - mediated inflammatory diseases ; however , the outcome of treatment with these tumour - necrosis factor inhibitors remains insufficient in approximately 40 - 60 % and approximately 25 - 40 % of individuals with rheumatoid arthritis and Crohn ' s disease , respectively . Moreover , their use is accompanied by adverse events and unintentional immune suppression . Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression , and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn ' s disease . Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome . As we discuss here , replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice .",
"The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis . OBJECTIVE : The frequency of osteoclast precursors ( OCPF ) and the presence of bone marrow oedema ( BMO ) are potential response biomarkers in psoriatic arthritis ( PsA ) . Previous studies suggest a central role for tumour necrosis factor ( P01375 ) in the formation of osteoclast precursors . To better understand this association , the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis . METHODS : A total of 20 PsA patients with active erosive PsA were enrolled . DB00005 was administered twice weekly for 24 weeks . OCPF was measured and clinical assessments were performed at baseline , 2 , 12 and 24 weeks . Gadolinium enhanced MR images were obtained at baseline and 24 weeks . RESULTS : Significant improvements in joint score ( p < 0 . 001 ) , HAQ scores ( p < 0 . 001 ) and SF - 36 parameters were observed after 6 months of therapy with etanercept compared to baseline . The median OCPF decreased from 24 . 5 to 9 ( p = 0 . 04 ) and to 7 ( p = 0 . 006 ) after 3 months and 6 months of treatment , respectively . MR images were available for 13 patients . The BMO volume decreased in 47 and increased in 31 sites at 6 months . No correlation was noted between OCPF , BMO and clinical parameters . CONCLUSION : The rapid decline in OCPF and overall improvement in BMO after anti - TNFalpha therapy provides one mechanism to explain the anti - erosive effects of P01375 blockade in PsA . Persistence of BMO after etanercept treatment , despite a marked clinical response , was unexpected , and suggests ongoing subchondral inflammation or altered remodelling in PsA bone .",
"DB00065 but not etanercept induces apoptosis in lamina propria T - lymphocytes from patients with Crohn ' s disease . BACKGROUND & AIMS : Steroid - refractory Crohn ' s disease responds to therapy with the chimeric anti - tumor necrosis factor ( P01375 ) - alpha antibody infliximab . DB00005 , a recombinant P01375 receptor / immunoglobulin G fusion protein , is highly effective in rheumatoid arthritis but not in Crohn ' s disease . Because both infliximab and etanercept are P01375 - neutralizing drugs , we investigated the differences in P01375 - neutralizing capacity and human lymphocyte binding and apoptosis - inducing capacity of both molecules . METHODS : We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study P01375 neutralization by infliximab and etanercept . Lymphocyte binding and apoptosis - inducing capacity was investigated using fluorescence - activated cell sorter analysis , annexin V staining , and cleaved caspase - 3 immunoblotting using mixed lymphocyte reaction - stimulated peripheral blood lymphocytes ( PBL ) from healthy volunteers and lamina propria T cells from patients with Crohn ' s disease . RESULTS : Both infliximab and etanercept neutralized P01375 effectively . DB00065 bound to activated PBL and lamina propria T cells , whereas binding of etanercept was equal to a nonspecific control antibody . DB00065 but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody . DB00065 activated caspase 3 in a time - dependent manner , whereas etanercept did not . CONCLUSIONS : Although both infliximab and etanercept showed powerful P01375 neutralization , only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes . These data may provide a biological basis for the difference in efficacy of the 2 P01375 - neutralizing drugs .",
"P01375 - α blocker therapy and solid malignancy risk in ANCA - associated vasculitis . ANCA - associated vasculitides ( AAV ) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality . This group includes granulomatosis with polyangiitis ( Wegener ´ s , P02724 ) , microscopic polyangiitis ( DB00603 ) , and eosinophilic granulomatosis with polyangiitis ( Churg - Strauss , EGPA ) . The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs . These have broad mechanisms of action as well as important adverse effects . Efforts have been made to investigate novel agents with better - defined and narrower mechanisms of action , such as biologics , including P01375 - α blockers . DB00005 , a well - known P01375 - α blocker evaluated for P02724 in the Wegener ' s Granulomatosis DB00005 Trial ( WGET ) , was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period . A 5 - year follow - up after the WGET trial showed a sustained increase in incidence of solid malignancies , but this could no longer be solely attributed to etanercept exposure . These studies raised concerns about the use of the family of P01375 - α blockers in AAV . Here , we review the evidence about the association between therapeutic inhibition of tumor necrosis factor ( P01375 - α ) by etanercept and other P01375 - α blockers with the development of solid malignancies in P02724 and other AAV .",
"The attenuation of experimental lung metastasis by a bile acid acylated - heparin derivative . The inhibitory efficacies of new bile acid acylated - heparin derivative ( heparin - DOCA ) were evaluated on experimental lung metastasis . We evaluated the effect of heparin - DOCA on intercellular interactions including those between B16F10 and thrombin - activated platelets and P01375 - activated HUVECs , and between B16F10 and immobilized mouse P16109 . In addition , the inhibitory effects of heparin - DOCA on adhesion and invasion of B16F10 to Matrigel were studied . In an animal mouse study , the blood clot formation and the retention of red fluorescence protein ( RFP ) - B16F10 in lungs were assessed after heparin - DOCA and RFP - B16F10 intravenous administration . Furthermore , we investigated the anti - metastatic effect of heparin - DOCA against lung metastasis induced by B16F10 and SCC7 . ___MASK8___ - DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P - and P16581 - mediated interactions . Moreover , it reduced adhesion and invasion of B16F10 to Q13201 , thereby affecting the reduction of early retention of B16F10 in the lung . ___MASK8___ - DOCA attenuated lung colony formation on the surfaces and in interior of the lung , and attenuated metastasis by B16F10 and SCC7 . These results suggest that heparin - DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK78___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Changes of urinary bladder contractility in high - fat diet - fed mice : the role of tumor necrosis factor - α . OBJECTIVES : To study the role of tumor necrosis factor - α in bladder dysfunction associated with obesity . METHODS : Male 8 - week - old C57BL / 6J mice were divided into three groups : ( i ) control mice ; ( ii ) vehicle - treated high - fat diet - fed mice ; and ( iii ) etanercept - treated high - fat diet - fed mice . High - fat diet feeding lasted for 12 weeks , vehicle or etanercept ( 0 . 8 mg / kg / day , a tumor necrosis factor - α antagonist ) treatment was given during the last 4 weeks . At the end of the treatment period , serum tumor necrosis factor - α , total cholesterol , triglyceride and blood glucose were measured . Bladder strip contractile responses to 1 μmol / L acetylcholine or 50 mmol / L DB00761 were studied in an organ bath . Bladder protein kinase Cζ , nuclear factor - κB and intercellular adhesion molecule - 1 expressions were analyzed using western blots . RESULTS : Serum levels of tumor necrosis factor - α total cholesterol , triglyceride and glucose were significantly elevated in high - fat diet - fed mice ; and the levels were not ameliorated by etanercept treatment . High - fat diet - fed mouse bladder showed reduced contractile responses to acetylcholine and DB00761 stimulation accompanied by high expression levels of phospho - protein kinase Cζ , nuclear nuclear factor - κB and intercellular adhesion molecule - 1 . DB00005 restored normal bladder contractile responses , as well as protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 expressions . CONCLUSIONS : A high - fat diet induces bodyweight gain , hyperlipidemia and hyperglycemia in mice . Elevated serum tumor necrosis factor - α level associated with increased protein kinase Cζ phosphorylation , nuclear factor - κB nuclear migration , intercellular adhesion molecule - 1 expression and impaired muscle contractility are shown in the high - fat diet - fed mouse bladder . P01375 - α antagonist treatment restores normal bladder contractility , and protein kinase Cζ nuclear factor - κB and intercellular adhesion molecule - 1 levels .",
"___MASK47___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK47___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK47___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .",
"DB00005 maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects . OBJECTIVE : To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab , but presented side effects . METHODS : Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects . Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped . Disease Activity Score computed on 44 joints ( DAS - 44 ) , erythrocyte sedimentation rate ( P03372 ) 1st hour , Visual Analogue Scale ( VAS ) of pain , Health Assessment Questionnaire ( HAQ ) , and C reactive protein ( CRP ) were assessed every 8 weeks . RESULTS : 37 patients were analysed . Adverse events to infliximab were mostly infusion reactions . No statistically significant difference between infliximab , before withdrawal , and etanercept , after 24 weeks , was detected in terms of DAS - 44 ( 2 . 7 and 1 . 9 , respectively ) , HAQ ( 0 . 75 and 0 . 75 , respectively ) , P03372 ( 21 and 14 , respectively ) and CRP ( 0 . 5 and 0 . 3 , respectively ) . VAS pain decreased significantly after switching to etanercept treatment ( 40 and 24 , respectively ; p < 0 . 05 ) . CONCLUSIONS : Our study shows that etanercept maintains the clinical benefit achieved by infliximab , and suggests that a second tumour necrosis factor ( P01375 ) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events .",
"A non - innovator version of etanercept for treatment of arthritis . DB00005 is a soluble tumor necrosis factor ( P01375 ) receptor originally approved for treatment of moderate - to - severe rheumatoid arthritis , juvenile rheumatoid arthritis , and psoriatic arthritis . We have developed a non - innovator version of the recombinant protein etanercept , with the investigational name AVG01 ( trade name AVENT ™ ) , using a novel expression vector - based technology . Here we show , by extensive analytical characterization , that AVG01 is highly similar to the reference product Enbrel ® and demonstrates similar efficacy in pre - clinical studies .",
"P01375 blockade aggravates experimental chronic Chagas disease cardiomyopathy . Chronic Chagas disease cardiomyopathy ( CCC ) , caused by Trypanosoma cruzi , is an inflammatory dilated cardiomyopathy associated with increased circulating levels of P01375 . We investigate whether P01375 blockade with DB00005 during the chronic phase of T . cruzi infection could attenuate experimental CCC development . The effect of DB00005 was evaluated after 11 months of T . cruzi infection on survival , parasitism , left ventricular function , intensity of myocarditis , fibrosis , and left ventricular mRNA expression of cytokines and P01375 - induced genes . Left ventricular function was significantly reduced in treated animals as compared to infected untreated animals . Blood and cardiac parasitism as well as survival rate were not altered with DB00005 treatment . Inflammatory infiltrates were located predominantly in the subendocardic region in treated animals , whereas in untreated animals inflammation was scattered throughout the myocardium . Left ventricular mRNA P22301 expression was significantly higher , and P35228 , significantly lower in treated than in untreated animals . mRNA expression of P01375 , P01579 , TGF - beta , A20 and P01160 was similar in both groups . Our results suggest that P01375 / P01374 blockade with DB00005 enhances left ventricular dysfunction in T . cruzi - induced chronic cardiomyopathy and the absence of P01375 signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK10___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK10___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK10___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK10___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK10___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK10___ increased the protein expression of hepatic P05181 and ___MASK10___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK10___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK10___ and RFP - induced hepatotoxicity .",
"Newly available treatments for psoriatic arthritis and their impact on skin psoriasis . Far from being a \" benign \" arthropathy , as it was initially characterized , psoriatic arthritis ( PsA ) affects approximately 0 . 2 % of the US population and can be associated with considerable joint damage , symptomatology , and quality of life impairment . PsA shares many characteristics with rheumatoid arthritis ( RA ) , and new , rationally designed drugs that are effective in RA also are proving active in PsA . Two such drugs , etanercept and infliximab , target tumor necrosis factor ( P01375 ) , a key component of the inflammatory response . This review discusses the rationale for and experience with the use of these agents in PsA . DB00005 is a dimeric fusion protein that binds specifically to P01375 , blocking its interaction with cell surface P01375 receptors . DB00065 is a chimeric ( murine / human ) monoclonal antibody that binds to P01375 and inhibits its binding to its receptor . A randomized placebo - controlled trial of etanercept in PsA found statistically significant benefits for this agent in measures of arthritic activity and psoriatic severity . There have been anecdotal reports of the efficacy of infliximab in PsA , but results from controlled clinical trials of this agent in PsA have not been reported . P01375 inhibitors represent new therapeutic options for patients with PsA . The potential advantages of treatment with etanercept and infliximab early in the disease course are discussed .",
"Characterization of the pattern of the nongenomic signaling pathway through which TCDD - induces early inflammatory responses in U937 human macrophages . 2 , 3 , 7 , 8 - Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up - regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up - regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 +) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct \" nongenomic \" pathway which , is clearly discernable from the classical , \" genomic \" action pathway of the P35869 by not requiring the participation of P27540 .",
"Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under DB00005 Therapy . The use of tumor necrosis factor - α ( P01375 - α ) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics . Squamous cell carcinoma is the second most common cancer of the skin , usually affecting sun - exposed areas of the body . We present here the case of a 75 - year - old woman with rheumatoid arthritis , who developed an intertoe squamous cell carcinoma ( SCC ) of the right foot . According to her history , she received etanercept and methotrexate for 5 years for rheumatoid arthritis . The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti - P01375 - α treatment . This is the first reported case of an interdigital SCC developed under the use of an anti - P01375 - α agent .",
"[ DB00005 and infections ] . The biological treatments for psoriasis , mainly the tumor necrosis factor - alpha inhibitors ( P01375 ) , have demonstrated their efficacy and safety beginning with the clinical trials up to their subsequent marketing . However , pharmacovigilance studies have detected a mild increase in infections . For the management of infectious risk in patients with psoriasis being treated with etanercept or other anti - P01375 medications , an evaluation should be made of the adequacy of its use in patients infected by HCV , HBV , HIV , with localized or generalized infections , with risk of sepsis ( carriers of intravenous catheter and indwelling urinary catheter ) or with underlying disorders that could predispose them to infections ( diabetes , hemodialysis ) . If a patient under treatment with etanercept presents an infection , if the infection is serious , treatment should be discontinued and if it is mild , the patient should be closely monitored and treatment interrupted if decided based on the evolution . Long experience on the use of etanercept in different diseases has made it possible to state that it has a good safety profile in regards to infections , if precautions are taken in regards to tuberculosis and the concomitance of other active infections during the treatment .",
"Does route of administration affect the outcome of P01375 antagonist therapy ? The tumor necrosis factor ( P01375 ) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis . Although infliximab , etanercept , and adalimumab are all members of this class , they differ in route of administration and dosing regimen . In the USA and in Europe , infliximab , in combination with oral methotrexate , is administered intravenously , initially at a dose of 3 mg / kg at weeks 0 , 2 , and 6 , then every 8 weeks thereafter . The US Food and Drug Administration ( FDA ) has further approved that the dosage can be increased to 10 mg / kg and the doses can be given as often as every 4 weeks to optimize patient outcome ( information based on the US package insert dated June 2002 ) . DB00005 and adalimumab are given subcutaneously and can be self - injected . The FDA - approved dose of etanercept is 25 mg twice weekly , and of adalimumab is 40 mg every 2 weeks with methotrexate , or 40 mg alone . Medication adherence , possibly the most important factor in maintaining the benefits of anti - P01375 therapy , is influenced by the interaction between the patient and his or her healthcare team , the patient ' s attitude toward the disease and medication regimen , and the choice of therapy .",
"Pilot study of etanercept in patients with relapsed cutaneous T - cell lymphomas . BACKGROUND : P01375 ( P01375 ) - alpha has been implicated in the pathogenesis of cutaneous T - cell lymphoma ( CTCL ) . OBJECTIVE : To assess the toxicity , safety , and efficacy of etanercept ( soluble P01375 receptor ) in patients with relapsed CTCL . METHODS : DB00005 was administered twice weekly at a dose of 25 mg subcutaneously . Patients with improvement after two months could be continued on treatment . RESULTS : Twelve out of the 13 patients enrolled on study were evaluable ( Stage I - IIA , 3 patients ; Stage IIB - IV disease , 9 patients ) . The median number of previous therapies was 7 ( range , 3 - 12 ) . DB00005 induced partial remission in one patient ( 8 % ) and minor response in one patient ( 8 % ) , both of whom had Stage IB disease . Most patients experienced no side effects . CONCLUSION : This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL . The effect of etanercept in a larger cohort of patients with early disease merits investigation .",
"Inhibitors of P78536 and P29466 as anti - inflammatory drugs . P01375 neutralising agents such as DB00065 ( Remicade ) , DB00005 ( Enbrel ) and the IL - 1 receptor antagonist DB00026 ( Kineret ) , are currently used clinically for the treatment of many inflammatory diseases such as Crohn ' s disease , rheumatoid arthritis , ankylosing spondylitis , juvenile rheumatoid arthritis , psoriatic arthritis and psoriasis . These protein preparations are expensive to manufacture and administer , need to be injected and can cause allergic reactions . An alternative approach to lowering the levels of P01375 and IL - 1beta in inflammatory disease , is to inhibit the enzymes that generate these cytokines using cheaper small molecules . This paper is a broad overview of the progress that has been achieved so far , with respect to small molecule inhibitor design and pharmacological studies ( in animals and humans ) , for the metalloprotease Tumour Necrosis Factor - alpha Converting Enzyme ( P78536 ) and the cysteine protease P29466 ( Interleukin - 1beta Converting Enzyme , ICE ) . Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti - inflammatory agents in the future .",
"Sulindac metabolism and synergy with tumor necrosis factor - alpha in a drug - inflammation interaction model of idiosyncratic liver injury . Sulindac ( SLD ) is a nonsteroidal anti - inflammatory drug ( NSAID ) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs . In previous studies , cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide ( LPS ) led to liver injury , whereas neither SLD nor LPS alone caused liver damage . In studies presented here , further investigation of this animal model revealed that the concentration of tumor necrosis factor - alpha ( P01375 ) in plasma was significantly increased by LPS at 1 h , and SLD enhanced this response . DB00005 , a soluble P01375 receptor , reduced SLD / LPS - induced liver injury , suggesting a role for P01375 . SLD metabolites in plasma and liver were determined by LC / MS / MS . Cotreatment with LPS did not increase the concentrations of SLD or its metabolites , excluding the possibility that LPS contributed to liver injury through enhanced exposure to SLD or its metabolites . The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells ; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone . P01375 augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells . These results suggest that P01375 can enhance SLD sulfide - induced hepatotoxicity , thereby contributing to liver injury in SLD / LPS - cotreated rats .",
"DB00005 - induced anti - Jo - 1 - antibody - positive polymyositis in a patient with rheumatoid arthritis : a case report and review of the literature . Antitumor necrosis factor ( P01375 ) therapy has been associated with adverse immunologic events including systemic lupus erythematosus . However , the development of polymyositis ( PM ) / dermatomyositis ( DM ) associated with anti - P01375 therapy is extremely rare . We experienced a case of a 48 - year - old female with rheumatoid arthritis ( RA ) who had anti - Jo - 1 antibodies and interstitial lung disease but no previous history of PM / DM and who developed PM soon after the initiation of etanercept ( DB01613 ) therapy for RA . The patient recovered upon withdrawal from DB01613 and corticosteroid ( CS ) therapies . Only four reports of PM / DM associated with anti - P01375 therapy for RA could be found in the literature . The patients described in three of the four reports were positive for anti - Jo - 1 antibodies before the initiation of anti - P01375 therapy , and in all the cases , recovery occurred after the cessation of anti - P01375 - agent administration and CS therapy . These results suggest a relationship between the onset of PM / DM with anti - Jo - 1 antibody and anti - P01375 therapy for RA .",
"[ Juvenile psoriatic arthritis ] . A case of juvenile psoriatic arthritis in a 12 year - old boy was reported . The patient had a history of one and half a year of bilateral heel pain , followed by pain in the right knee and ankle and right hip joint . He developed psoriatic lesions affecting his nails and skin . He had increased erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) contents . Human leukocyte antigen ( HLA ) Q8TCY5 was detected but serum rheumatoid factor was not in the patient . A skin biopsy revealed psoriasis and ultrasonography demonstrated synovitis in right knee and ankle . Juvenile psoriatic arthritis was diagnosed based on his physical , laboratory and skin biopsy findings . A treatment with nonsteroidal anti - inflammatory drugs and sulfasalazine produced no effect . Leflunomide in conjunction with anti - P01375 biologic agents ( DB00005 ) was administered , followed by symptomatic improvement 2 weeks later .",
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"[ Anti - P01375 treatment and spondyloarthropathies ] . Spondyloarthropathies are characterized by both axial and peripheral joint involvement , by the association with \" other diseases \" mainly Psoriasis , Crohn ' s and Anterior Uveitis and by the high prevalence of HLA B - 27 . While disease modifying drugs , such as DB00563 or Sulfasalazine , are only partially effective in controlling peripheral arthritis , the treatment of the axial part remained only symptomatic . The recently introduced anti - P01375 drugs DB00065 ( Remicade ) and DB00005 ( Enbrel ) for the treatment of Crohn ' s disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with highly promising results . The rationale and the early beneficial results of this new approach in spondyloarthropathies are reviewed .",
"DB00005 in psoriatic arthritis . Psoriatic arthritis ( PsA ) , an inflammatory arthritis associated with psoriasis , can lead to disability from progressive joint destruction and bony fusion . To date , conventional disease modifying antirheumatic drugs ( DMARDS ) have not convincingly lessened joint pain and inflammation in PsA and there is very little data on the limitation of radiographic progression with these agents . The biological agent etanercept ( Enbrel , Amgen , Inc , Thousand Oaks , California , USA ) is a soluble P01375 receptor fusion protein with proven efficacy in the treatment of rheumatoid arthritis ( RA ) . In a Phase II and Phase III trial , conducted in moderate - to - severe PsA , etanercept significantly reduced joint pain and swelling and lowered the erythrocyte sedimentation rate ( P03372 ) and P02741 ( CRP ) level . A significant decline in structural damage was observed as early as 6 months after starting the drug . DB00005 also improved quality of life measures ( Health Assesment Questionnaire [ HAQ ] and global assessment scores ) . Up to a third of patients experienced transient injection - site reactions . Rare cases of opportunistic infection , demyelinating disorders and aplastic anaemia have been reported , but a causal link has not been established . In summary , etanercept is a safe and effective agent for the treatment of PsA and represents a major advance in the therapy of this potentially crippling disease .",
"P01375 antagonist therapy and lymphoma development : twenty - six cases reported to the Food and Drug Administration . OBJECTIVE : DB00005 and infliximab are tumor necrosis factor ( P01375 ) antagonists that have been recently approved for the treatment of rheumatoid arthritis ( RA ) and Crohn ' s disease ( CD ) . This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents . METHODS : Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed . RESULTS : We identified 26 cases of lymphoproliferative disorders following treatment with etanercept ( 18 cases ) or infliximab ( 8 cases ) . The majority of cases ( 81 % ) were non - Hodgkin ' s lymphomas . The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short ( median 8 weeks ) . In 2 instances ( 1 infliximab , 1 etanercept ) , lymphoma regression was observed following discontinuation of anti - P01375 treatment , in the absence of specific cytotoxic therapy directed toward the lymphoma . CONCLUSION : Although data from a case series such as this can not establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease , the known predisposition of patients with RA and CD to lymphoma , the known excess of lymphoma in other immunosuppressed populations , and the known immunosuppressive effects of the anti - P01375 drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association .",
"Adverse reactions during biological drug therapy in psoriasis : clinical series and a review of the literature . AIM : Psoriasis is a chronic , inflammatory skin disorder , histologically characterized by epidermal hyperplasia , anomalous keratinocyte differentiation , angiogenesis , and by inflammatory cell infiltrate . Psoriasis has a significant impact on quality of life and is often associated with serious psychological effects . The use of biological agents is expanding worldwide as alternative treatment for chronic inflammatory diseases including psoriasis . The European Medicines Agency ( EMEA ) approved the use of DB00095 , DB00005 , DB00065 and DB00051 in the treatment of psoriasis on the basis of the positive findings obtained from well - designed clinical trials . The ongoing monitoring of tolerability and possible side - effects of these drugs has , however , recently lead to the EMEA suspending DB00095 on the grounds that the possible risks of its use outweighed the benefits . METHODS : Fifty - four patients treated with the two classes of biological drug ( DB00095 and anti - P01375 - α ) were studied . The choice of biological drug therapy was conditioned by the extent and seriousness of the disease and by the presence of concomitant pathologies . RESULTS : Nineteen patients presented adverse reactions , of which 9 necessitated interruption in treatment ( 6 DB00095 and 3 anti - P01375 - α ) . CONCLUSION : This work reports the adverse reactions to these biological therapies found in our patients along with a review of the literature concerning adverse reactions in psoriasis treatment . From our experience and basing ourselves on the literature reporting studies conducted in large centres , we feel that it is indispensable to continue monitoring any reactions during biological drug treatment . In this way , there is more likelihood of preventing , where possible , or better managing any reactions linked to the use of these drugs .",
"Rheumatoid arthritis in pregnancy : successful outcome with anti - P01375 agent ( DB00005 ) .",
"Use of etanercept in human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) patients . BACKGROUND : DB00005 ( Enbrel , Amgen , Thousand Oaks , CA ) , a soluble p75 tumor necrosis factor receptor : FC ( TNFR : FC ) fusion protein for plasma cytokines , specifically tumor necrosis factor - alpha ( P01375 ) , is used in the treatment of immune - mediated rheumatic diseases . To our knowledge , the use of etanercept in patients with human immunodeficiency virus ( HIV ) and acquired immunodeficiency syndrome ( AIDS ) is relatively uncommon . OBJECTIVE : The main purpose of this short review is to examine the safety of etanercept in patients with HIV / AIDS . METHODS : A Medline search was conducted using the keywords etanercept and HIV and / or AIDS for any published articles between 1966 to the present ( September 2004 ) . RESULTS : A case report , one case series , and one clinical trial pertained to the use of etanercept in HIV patients . No reports were found on the use of etanercept in AIDS . In addition , two case reports were found documenting the use of infliximab in HIV patients . DISCUSSION : Preliminary reports indicate that the administration of etanercept does not appear to increase the morbidity or mortality rates in HIV . The inhibition of P01375 may actually improve the symptoms of HIV / AIDS - associated aphthous ulcers , cachexia , dementia , fatigue , and fever , as well as help manage concomitant rheumatic diseases and psoriasis . CONCLUSION : The use of etanercept shows promise for applications in disease management in patients with HIV / AIDS . Continued research efforts are necessary to establish the long - term safety and efficacy of etanercept and other biologic agents in this patient population .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK42___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"P62158 interacts with angiotensin - converting enzyme - 2 ( Q9BYF1 ) and inhibits shedding of its ectodomain . P12821 - 2 ( Q9BYF1 ) is a regulatory protein of the renin - angiotensin system ( DB01367 ) and a receptor for the causative agent of severe - acute respiratory syndrome ( P49591 ) , the P49591 - coronavirus . We have previously shown that Q9BYF1 can be shed from the cell surface in response to phorbol esters by a process involving P01375 converting enzyme ( P78536 ; P78536 ) . In this study , we demonstrate that inhibitors of calmodulin also stimulate shedding of the Q9BYF1 ectodomain , a process at least partially mediated by a metalloproteinase . We also show that calmodulin associates with Q9BYF1 and that this interaction is decreased by calmodulin inhibitors .",
"The silent progression of metastatic malignancy during the treatment with soluble tumor necrosis factor receptor . DB00005 is singular among anti - tumor necrosis factor alpha ( P01375 ) agents , for being a soluble antibody to both P01375 and lymphtoxin - alpha . The long - term neutralization of two cachexins by etanercept would theoretically compromise early detection of malignancy . This case reports a patient who was treated by etanercept for 21 months due to ankylosing spondylitis . Metastatic malignancy of unknown origin developed , and silently led the patient to lethal hepatic rupture . With an example of a malignancy masking effect of soluble P01375 receptor , this article questions a need for vigilant attention to de novo carcinoma during the therapy , and calls for refined strategies in modulating autoimmune diseases .",
"Effects of etanercept , a tumour necrosis factor - alpha antagonist , in an experimental model of periodontitis in rats . BACKGROUND AND PURPOSE : DB00005 is a tumour necrosis factor antagonist with anti - inflammatory effects . The aim of our study was to evaluate , for the first time , the therapeutic efficacy of in vivo inhibition of P01375 in an experimental model of periodontitis . EXPERIMENTAL APPROACH : Periodontitis was induced in adult male Sprague - Dawley rats by placing a nylon thread ligature around the lower 1st molars . DB00005 was administered at a dose of 5 mg kg - 1 , s . c . , after placement of the ligature . KEY RESULTS : Periodontitis in rats resulted in an inflammatory process characterized by oedema , neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells , production of a range of inflammatory mediators , tissue damage , apoptosis and disease . Treatment of the rats with etanercept ( 5 mg kg - 1 , s . c . , after placement of the ligature ) significantly reduced the degree of ( 1 ) periodontitis inflammation and tissue injury ( histological score ) , ( 2 ) infiltration of neutrophils ( P05164 evaluation ) , ( 3 ) P35228 ( the expression of nitrotyrosine and cytokines ( eg P01375 ) ) and ( 4 ) apoptosis ( Bax and Bcl - 2 expression ) . CONCLUSIONS AND IMPLICATIONS : Taken together , our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury , events associated with periodontitis .",
"A case of tuberculous arthritis following the use of etanercept . DB00005 is a tumor necrosis factor ( P01375 ) inhibitor that has been used for the treatment of chronic inflammatory diseases including rheumatoid arthritis , ankylosing spondylitis and psoriatic arthritis . Because of its immunosuppressive activity , opportunistic infections have been noted in treated patients , most notably caused by Mycobacterium tuberculosis . Tuberculosis may present in an extrapulmonary or disseminated form . Since P01375 inhibitors have been used in Korea , a few cases of P01375 inhibitor associated tuberculosis have been described . However , tuberculous arthritis has not been previously reported . We describe a case of tuberculous arthritis in a 57 - year - old woman with rheumatoid arthritis who was treated with etanercept .",
"Clock gene modulation by P01375 depends on calcium and p38 Q96HU1 kinase signaling . A 24 - h treatment with the cytokine tumor necrosis factor - alpha ( P01375 ) suppresses transcription of E - box - driven clock genes ( D - site albumin promoter binding protein , Dbp ; Tyrotroph embryonic factor , Tef ; Q16534 , Hlf ; Period homolog to Drosophila 1 / 2 / 3 , Per1 , Per2 , and Per3 ) by yet unknown molecular mechanisms . The attenuation of clock genes has been suggested as a putative cause for the development of sickness behavior syndrome in infectious and autoimmune diseases . Here , the authors studied the effect of P01375 at early time points ( < 3 h ) on intracellular signaling events and clock gene expression in fibroblasts . Interaction of P01375 with P19438 ( Tnfrsf1a , CD120a , p55 ) , but not P20333 ( Tnfrsf1b , DB00005 , p75 ) , leads to fast downregulation of gene expression of Dbp and upregulation of negative regulators of the molecular clock , Per1 and Per2 , Q16526 ( Cry1 ) , and Differentiated embryo chondrocytes - 1 ( Dec1 ) . Since the decrease of Dbp is also observed in cells deficient for Per1 / Per2 , Cry1 / Cry2 , or Dec1 , these genes are unlikely to be responsible for inhibition of Dbp . The early effect of P01375 on the clock gene Per1 is dependent on p38 , mitogen - activated protein kinase ( MAPK ) , and / or calcium signaling , whereas the effect on Dbp is independent of p38 MAPK , but also involves calcium signaling . Both genes remain unaffected by the NF - kappaB and AP - 1 pathway . Taken collectively these data show p38 MAPK - and calcium - dependent P19438 - mediated transient increase of the negative regulator Per1 and an independent decrease of Dbp .",
"Central P01375 inhibition results in attenuated neurohumoral excitation in heart failure : a role for superoxide and nitric oxide . This study examined the effect of central tumor necrosis factor - alpha ( P01375 ) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus ( PVN ) and ventrolateral medulla ( VLM ) , key autonomic regulators , and their contribution to enhanced sympathetic drive in mice with congestive heart failure ( CHF ) . We also used a P01375 gene knockout ( KO ) mouse model to study the involvement of P01375 in body fluid homeostasis and sympathoexcitation in CHF . After implantation of intracerebroventricular ( ICV ) cannulae , myocardial infarction ( MI ) was induced in wild - type ( WT ) and KO mice by coronary artery ligation . Osmotic mini - pumps were implanted into one set of WT + MI / Sham mice for continuous ICV infusion of DB00005 ( DB01613 ) , a P01375 receptor fusion protein , or vehicle ( VEH ) . Gene expressions of neuronal nitric oxide synthase ( NOS ) and angiotensin receptor - type 2 were reduced , while those of inducible NOS , Nox2 homologs , superoxide , peroxynitrite and angiotensin receptor - type 1 were elevated in the brainstem and hypothalamus of MI + VEH . Plasma norepinephrine levels and the number of Fos - positive neurons were also increased in the PVN and VLM in MI + VEH . MI + DB01613 and KO + MI mice exhibited reduced oxidative stress , reduced sympathoexcitation and an improved cardiac function . These changes in WT + MI were associated with increased sodium and fluid retention . These results indicate that elevated P01375 in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide , contributing to fluid imbalance and sympathoexcitation in CHF .",
"[ Cytokines -- causes , players or bystanders in heart failure ] . BACKGROUND : Cytokines are important mediators of the immune system and are of pathophysiological relevance for different cardiac diseases . Currently , 18 cytokines carrying the name interleukin ( IL ) are known ; they can be subdivided into pro - and anti - inflammatory interleukins . CARDIAC CYTOKINES : They partly act in a negative inotropic manner and cause destruction of cardiomyocytes resulting in myocardial fibrosis . The proinflammatory cytokine tumor necrosis factor ( P01375 -) alpha induces cardiodepressive effects and causes apoptosis . P01375 , P05231 , soluble P01375 - receptor - 1 and - 2 are independent predictors of increased mortality of patients with heart failure . Experimental and clinical evidence has shown that plasma and tissue levels of P01375 were elevated to such extent as to explain at least some of the symptoms of heart failure due to the actions of this cytokine . CLINICAL TRIALS : Two multicenter studies ( RENAISSANCE , RECOVER ) , based on promising pilot studies , have disclosed no effect for the P01375 antagonists ( DB00005 ) on mortality and morbidity . It is not possible , however , to draw the conclusion from the data of these studies that P01375 plays no significant pathophysiological role in the etiology and progression of heart failure .",
"Inguinal Herniation of the Urinary Bladder Presenting as Recurrent Urinary Retention . Herniation of the urinary bladder into the inguinal canal is an uncommon finding , observed in 0 . 5 - 4 % of inguinal hernias ( Curry ( 2000 ) ) . It is usually associated with other conditions that increase intra - abdominal pressure such as bladder neck obstruction due to prostatic hypertrophy . Consequently , in men , it is usually associated with some degree of urinary retention . We present a 42 - year - old man in whom herniation of the urinary bladder was the cause of urinary retention , and not vice versa . The patient was on tumor necrosis factor alpha antagonist ( P01375 ) ( DB00005 ) for severe Ankylosing spondylitis . Initially , the urinary retention was thought to be a side effect of the medication , but after the drug was discontinued , urinary retention persisted . CT and Q9BWK5 demonstrated huge herniation of the urinary bladder into the inguinal canal . Immediately after the hernia was repaired , bladder function was restored . P01375 treatment was restarted , and no further urinary symptoms were observed in the next two years of follow - up . In this case , the primary illness and its treatment were distracting barriers to early diagnosis and treatment . In younger patients with a large hernia who develop unexpected urinary retention , herniation of the urinary bladder should be highly considered in the differential diagnosis .",
"Prospective open - label trial of etanercept as adjunctive therapy for kawasaki disease . OBJECTIVE : To determine the safety and pharmacokinetics of etanercept ( Amgen , Thousand Oaks , California ) a tumor necrosis factor - α receptor blocker , in children with acute Kawasaki disease ( KD ) . Standard therapy of acute KD includes intravenous immunoglobulin ( IVIG ) and high - dose aspirin , but a substantial number of patients are refractory and require additional treatment . P01375 - α levels are elevated in children with KD , suggesting a role for etanercept in treatment . STUDY DESIGN : We performed a prospective open - label trial of etanercept in patients with KD ( age range , 6 months - 5 years ; n = 17 ) meeting clinical criteria and with fever ≤ 10 days . All received IVIG and high - dose aspirin . They received etanercept immediately after IVIG infusion and then weekly two times . For the initial safety evaluation , the first 5 patients received 0 . 4 mg / kg / dose . Subsequent subjects received 0 . 8 mg / kg / dose . RESULTS : Fifteen patients completed the study . The pharmacokinetics were similar to that in older children in published series . No serious adverse events related to etanercept occurred . No patient demonstrated prolonged or recrudescent fever requiring re - treatment with IVIG . No patient showed an increase in coronary artery diameter or new coronary artery dilation / cardiac dysfunction . CONCLUSION : DB00005 appears to be safe and well tolerated in children with KD . The data support performance of a placebo - controlled trial .",
"DB00005 in psoriatic arthritis . In this update on etanercept ( DB01613 ) in psoriatic arthritis ( PsA ) we analyze this drug ' s mechanism of action , clinical efficacy / effectiveness , optimal dosage , disease - modifying antirheumatic drugs ( DMARD ) association , radiological progression , safety , switching aspects , and pharmacoeconomy . The efficacy / effectiveness of DB01613 in PsA has been demonstrated in randomized placebo - controlled trials as well as in observational studies representing routine clinical practice . At 1 and 2 years , DB01613 inhibited radiographic disease progression , assessed by the modified total Sharp score . DB01613 ( generally at a dosage of 50 mg / weekly ) can be used either in monotherapy or in combination with DMARD such as methotrexate . A systematic search of randomized , placebo - controlled trials of DB01613 to treat adults with plaque psoriasis or PsA suggests that the short - term risk / benefit ratio is favorable . Longterm studies , such as observational studies , confirmed this safety profile of DB01613 . A variable percentage of patients withdrew anti - tumor necrosis factor - α ( P01375 - α ) inhibitor treatment owing to inefficacy or poor tolerability . Observational studies showed that in the case of treatment failure with 1 agent , switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available P01375 - α blockers . The clinical effect of DB01613 is associated with favorable pharmacoeconomic considerations .",
"DB00005 : long - term clinical experience in rheumatoid arthritis and other arthritis . DB00005 is a dimeric fusion protein based on the p75 P01375 receptor . It binds to P01375 and blocks its biologic activity . In randomized , double - blind , placebo - controlled trials , etanercept has therapeutic activity in rheumatoid arthritis , psoriatic arthritis , polyarticular - course juvenile idiopathic arthritis and ankylosing spondylitis . DB00005 improves joint inflammation , physical function and slows / halts structural damage , especially when combined with methotrexate . A sustained response is observed in a substantial percentage of patients . Although some safety issues should be considered before starting etanercept treatment , in general terms , etanercept is a well tolerated drug with an acceptable safety profile . The use of any P01375 antagonist must be in agreement with the National Recommendations for Biologic Therapy , and in difficult clinical situations , a balance between risk / benefit needs to be obtained .",
"Clastogenic plasma factors in psoriasis -- comparison of phototherapy and anti - P01375 - α treatments . As previously described , Psoralen plus UVA ( PUVA ) therapy induces chromosome damage in psoriatic patients . This study evaluates whether these effects are transitory or persistent . In addition , we studied these effects after narrowband UVB ( nUVB ) and anti - tumor necrosis factor ( P01375 ) - α treatments . Among 40 responder patients , 10 received PUVA , 10 nUVB , 10 DB00065 and 10 DB00005 . Disease activity was determined with Psoriasis Area and Severity Index . Chromosomal breakage was evaluated by the clastogenic factor ( CF ) test . Potential clastogenic agents , malondialdehyde ( MDA ) and P01375 - α were measured . Before treatment , the plasma - adjusted clastogenic scores ( ACS ) of patients were increased . During treatment , a further increase in ACS was observed in both phototherapy groups . Chromosome damage persisted for PUVA patients at week 32 , while it diminished after nUVB to ACS values lower than before treatment . MDA and P01375 - α values were also increased at baseline . MDA decreased during treatment in all groups , but without reaching normal levels . Plasma P01375 - α remained unchanged in PUVA and nUVB but decreased in both anti - P01375 - α treatment groups . Psoriasis is accompanied by CF - induced chromosomal breakage that increases during PUVA and nUVB treatments . Plasma clastogenic activity persisted in the follow - up after PUVA , while after nUVB ACS returned to values even lower than baseline . Clastogenic activity during the induction phase with anti - P01375 - α remained unchanged .",
"___MASK80___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"Tumor - infiltrating macrophages induce apoptosis in activated CD8 (+) T cells by a mechanism requiring cell contact and mediated by both the cell - associated form of P01375 and nitric oxide . We have investigated the ability of different cells present in murine tumors to induce apoptosis of activated CD8 (+) T cells in vitro . Tumor cells do not induce apoptosis of T cells ; however , macrophages that infiltrate tumors are potent inducers of apoptosis . Tumor macrophages express cell surface - associated P01375 , P01375 type I ( CD120a ) and II ( DB00005 ) receptors , and , upon contact with T cells which induces release of P01579 from T cells , secrete nitric oxide . Killing of T cells in vitro is blocked by Abs to P01579 , P01375 , CD120a , or DB00005 , or N - methyl - L - arginine . In concert with that finding , tumor macrophages isolated from either P01375 type I or type II receptor -/- mice are not proapoptotic and do not produce nitric oxide upon contact with activated T cells . Control macrophages do not express P01375 receptors or release nitric oxide . Tumor cells or tumor - derived macrophages do not express P48023 , and blocking Abs to either Fas or P48023 have no effect on macrophage - mediated T cell killing . These results demonstrate that macrophages which infiltrate tumors are highly proapoptotic and may be responsible for elimination of activated antitumor T cells within the tumor bed .",
"Managing moderate - to - severe psoriasis in the elderly . Managing psoriasis in the elderly can be difficult for physicians , who must consider comorbidities , the resulting polypharmacy , and progressive functional impairment of several organs . Indeed , topical agents are the first - line treatment for limited disease . Phototherapy is recommended if topical drugs are not sufficient and the patient has multiple comorbidities and risk factors that make them a poor candidate for an oral or injectable systemic agent . The most important pharmacokinetic alteration in the elderly population is the decreased excretory capacity of the kidney ; thus , cyclosporine should be considered a last resort treatment , and the administered dose of methotrexate should be lowered according to the reduction in estimated creatinine clearance . Acitretin can be used in the absence of severe renal insufficiency , paying attention to lipid profile , treating eventual hyperlipidemia , and closely monitoring liver enzymes . Available data on biological drugs in the elderly are limited . Biologics are associated with a small but significant overall risk of infections . However , there is no convincing evidence that the relative risk of infection with anti - tumor necrosis factor ( P01375 ) - α therapy increases with age . Nevertheless , the package inserts for biologics recommend caution when administering these medications to the geriatric population , due to the high baseline risk of infection in such patients . DB00005 seems to be well tolerated , possibly because of its lower immunosuppressive characteristics compared with other biologics . However , studies with larger sample sizes are needed to confirm its safety .",
"DB00005 ( Enbrel ) : update on therapeutic use . Tumour necrosis factor ( P01375 ) is an important inflammatory disease mediator in a wide spectrum of articular diseases , including adult and juvenile rheumatoid arthritis ( RA , JRA ) . DB00005 ( Enbrel ) , approved in the United States and in Europe for use in patients with RA and JRA , is an effective inhibitor of P01375 that has been shown to provide rapid and sustained improvement in both of these diseases . Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time . To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate , and to examine the effect of etanercept on radiographic progression , a double blind , placebo controlled study was recently conducted , comparing etanercept with methotrexate ( median dose 20 mg per week ) . Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA , and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions . In patients with severe psoriatic arthritis ( PsA ) , a double blind , placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA . DB00005 has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases .",
"DB00005 in the treatment of active refractory Crohn ' s disease : a single - center pilot trial . OBJECTIVES : DB00005 , an injectable tumor necrosis factor ( P01375 ) receptor fusion protein , binds and inactivates human P01375 and is used in active rheumatoid arthritis . Blocking P01375 with monoclonal antibodies has also been beneficial in Crohn ' s disease . We attempted to determine the efficacy and safety of etanercept for induction of clinical , endoscopic , and histological improvement in patients with moderate to severe Crohn ' s disease despite standard treatment . METHODS : Ten patients with active Crohn ' s disease were treated with etanercept ( 25 mg s . c . ) twice per week for 12 wk . Background therapy was kept stable during the trial . Crohn ' s disease activity index ( CDAI ) , Inflammatory Bowel Disease Questionnaire , and P02741 levels were measured at weeks 0 , 2 , 4 , 8 , and 12 . Colonoscopies were performed before and after therapy in responders ; endoscopic biopsies were scored for inflammation . RESULTS : At week 2 after the start , a clinical response ( deltaCDAI > or = 70 ) was observed in 6 / 10 patients ( median = 305 [ 294 - 418 ] to 166 [ 107 - 392 ] ) , with reduction in serum P02741 levels ( median = 17 . 2 [ 6 . 8 - 67 . 2 ] to 9 . 1 [ 0 . 9 - 17 . 2 ] mg / dl ) . Colonoscopies showed a reduction in inflammatory lesions in the four patients who attained remission ( CDAI < 150 ) , whereas the inflammatory score of the biopsies did not decrease significantly . No moderate or severe adverse events were observed . CONCLUSIONS : DB00005 may be effective in Crohn ' s disease refractory to standard therapy .",
"DB00005 - induced Henoch - Schönlein purpura in a patient with ankylosing spondylitis . Ankylosing spondylitis ( AS ) is a chronic inflammatory disease that primarily affects the axial skeleton . Extra - articular manifestations are less common relative to other rheumatic diseases , and vasculitic complications typically involve the ascending aorta and aortic valve . The use of tumor necrosis factor inhibitors is efficacious in the treatment of patients with AS . Since their routine use , however , tumor necrosis factor inhibitors have been associated with the development of drug - induced complications including the induction of lupus and both cutaneous and systemic vasculitis . In this report , we describe a patient with severe longstanding AS , who developed Henoch - Schönlein purpura after commencing therapy with etanercept . P01375 inhibitor - induced Henoch - Schönlein purpura has been very rarely reported and has been mostly recognized in patients with rheumatoid arthritis .",
"Leukopenia and thrombocytopenia induced by etanercept : two case reports and literature review . P01375 - alpha ( P01375 ) is a proinflammatory cytokine , and its excess can lead to severe consequences . Those effects are known to be antagonized by P01375 inhibitors . DB00005 is a fusion protein that inhibits P01375 action . As P01375 regulation is related to cellular differentiation of various cellular types involved in immune response through expression of several other cytokines , it is possible that the use of its inhibitors may cause cytopenia . We report two cases of bicytopenia induced by etanercept . Both cases recovered after drug withdrawal . We discuss the need of introduction of routine laboratorial tests in patients using anti - P01375 therapy , in order to identify possible hematological changes .",
"P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .",
"Human tumor necrosis factor receptor p75 / 80 ( DB00005 ) gene structure and promoter characterization . P01375 receptor p75 ( P01375 - R p75 ) is a 75 - kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage . P01375 - R p75 belongs to the P01375 receptor superfamily characterized by cysteine - rich extracellular regions composed of three to six disulfide - linked domains . In the present report we have characterized , for the first time , the complete gene structure for human P01375 - R p75 , which spans approximately 43 kbp . The gene consists of 10 exons ( ranging from 34 base pairs to 2 . 5 kilobase pairs ) and nine introns ( 343 base pairs to 19 kilobase pairs ) . Consensus elements for transcription factors involved in T cell development and activation were noted in the 5 '- flanking region including T cell factor - 1 , Ikaros , AP - 1 , CK - 2 , interleukin - 6 receptor E ( IL - 6RE ) , ISRE , GAS , NF - kappaB , and Sp1 . The unusual ( GATA ) n and ( P10253 ) ( GGA ) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus . Characterization of the human P01375 - R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function , autoimmune disease , and nonrandom translocations in hematopoietic malignancies .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK90___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"Thalidomide suppresses Up - regulation of human immunodeficiency virus coreceptors P61073 and P51681 on P01730 + T cells in humans . Concurrent infection in patients with human immunodeficiency virus ( HIV ) infection increases the expression of HIV coreceptors P61073 and P51681 . Thalidomide has beneficial effects in a number of HIV - associated diseases . The effect of thalidomide on P61073 and P51681 expression on P01730 + T cells was determined . Thalidomide produced a dose - dependent inhibition of lipopolysaccharide ( LPS ) - induced up - regulation of P61073 and P51681 in vitro . Antibody to tumor necrosis factor - alpha ( P01375 ) also attenuated the LPS - induced HIV coreceptor up - regulation , which was not further reduced by thalidomide . Thalidomide ( 400 mg ) was orally administered to 6 men , and their blood was stimulated ex vivo with LPS , staphylococcal or mycobacterial antigens , or antibody to CD3 or P10747 cells . All stimuli induced up - regulation of HIV coreceptors , which was reduced after ingestion of thalidomide . Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up - regulation of P61073 and P51681 expression on P01730 + T cells induced by bacterial and mycobacterial antigens , by a mechanism that involves inhibition of P01375 .",
"Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .",
"[ Anti - P01375 - α in the treatment of uveitis in the Besançon Hospital ] . BACKGROUND : Noninfectious chronic uveitis is a difficult - to - treat situation in which corticosteroids , immunosuppressive agents , and more recently , anti - tumor necrosis factor ( P01375 ) - α are used to prevent and / or reverse severe visual impairment . This single - center retrospective study was designed to assess the use ( indications , efficacy , and side effects ) of anti - P01375 - α agents in noninfectious uveitis . PATIENTS AND METHODS : Eight patients were analyzed : three children ( age , 7 - 15 years ) and five adults ( age , 27 - 44 years ) . Anti - P01375 - α agents were etanercept ( three patients ) , adalimumab ( four patients ) , and infliximab ( four patients ) . Diagnoses were Behçet ' s diseases ( n = 3 ) , sarcoidosis ( n = 1 ) , juvenile chronic arthritis ( n = 2 ) , spondyloarthropathy ( n = 2 ) , one of the latter two combined with Crohn disease . In all cases , anti - P01375 - α therapies were prescribed because uveitis and / or associated disease were not under control . RESULTS : DB00051 and infliximab were effective for all patients . One patient with infliximab needed to add corticosteroids and immunosuppressive agents because of relapse . DB00005 was stopped in all cases due to a lack of effectiveness or a change in indication . In all patients , anti - P01375 - α agents improved uveitis and the underlying systemic disease . In children , their use improved quality of life by corticosteroid weaning . Prescriptions did not comply with regulations for three children , because of age limits ( etanercept , one ; adalimumab , two ) . No adverse event was recorded . CONCLUSION : In this short case series , anti - P01375 - α agents were effective both on uveitis and the underlying systemic disease and were well tolerated in patients with noninfectious chronic uveitis .",
"DB00005 , a P01375 - α inhibitor , does not impede fracture healing .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK95___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK2___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK2___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions ."
] |
[
"___MASK10___",
"___MASK2___",
"___MASK42___",
"___MASK47___",
"___MASK78___",
"___MASK80___",
"___MASK8___",
"___MASK90___",
"___MASK95___"
] |
___MASK47___
|
MH_train_378
|
interacts_with DB06441?
|
[
"P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .",
"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .",
"Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor : a direct , parenteral Q9H244 receptor antagonist . The purpose of this study is to evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers . Twenty - two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens : a 15 - microg / kg bolus followed by a 2 - microg / kg / min infusion or a 30 - microg / kg bolus followed by a 4 - microg / kg / min infusion . The infusion is continued for 60 minutes , and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters . Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes . Moreover , extensive platelet inhibition is maintained throughout the infusion period with near - full recovery of platelet function within 60 to 90 minutes of terminating the infusion . The effect of high - dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate - induced P16109 expression ; how ever , no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function . DB06441 administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function .",
"Clinical overview of promising nonthienopyridine antiplatelet agents . Three novel nonthienopyridine antiplatelet agents -- cangrelor , ticagrelor ( AZD6140 ) , and P35240 530348 -- are in advanced clinical testing in patients with coronary artery disease . DB06441 and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5 '- diphosphate Q9H244 receptor , whereas P35240 530348 is a thrombin receptor antagonist . Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention . We review the clinical features of these new platelet inhibition therapies .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK97___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"DB06441 for treatment of arterial thrombosis . INTRODUCTION : Percutaneous coronary intervention ( P05154 ) is a highly effective treatment for obstructive coronary artery disease . Oral platelet Q9H244 receptor antagonists reduce ischemic events in patients treated with P05154 . However , there are several limitations to their use , including variable pharmacodynamics , a slow onset and offset , and in those patients who are pretreated but subsequently require cardiac surgery , increased bleeding . DB06441 is an intravenous agent that provides rapid and intensive inhibition of the Q9H244 receptor that quickly dissipates after discontinuation . A recent , Phase III randomized clinical trial of P05154 patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding . AREAS COVERED : This review outlines the pharmacodynamics , pharmacokinetics , and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned P05154 . EXPERT OPINION : DB06441 is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients , without increasing major bleeding or the need for transfusion . DB06441 will have particular benefit in clopidogrel - naïve patients with high anatomical complexity and / or increased clinical risk ( where the absolute risk for thrombotic and ischemic complications of P05154 is greatest ) .",
"Echicetin coated polystyrene beads : a novel tool to investigate GPIb - specific platelet activation and aggregation . P04275 / ristocetin ( P04275 / R ) induces GPIb - dependent platelet agglutination and activation of αIIbβ3 integrin , which also binds P04275 . These conditions make it difficult to investigate GPIb - specific signaling pathways in washed platelets . Here , we investigated the specific mechanisms of GPIb signaling using echicetin - coated polystyrene beads , which specifically activate GPIb . We compared platelet activation induced by echicetin beads to P04275 / R . Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling . Echicetin beads induced αIIbβ3 - dependent aggregation of washed platelets , while under the same conditions P04275 / R treatment led only to αIIbβ3 - independent platelet agglutination . The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation , while the total amount of echicetin used for activation is not critical . Echicetin beads induced strong phosphorylation of several proteins including p38 , P29323 and P31749 . Synergistic signaling via Q9H244 and thromboxane receptor through secreted ADP and TxA2 , respectively , were important for echicetin bead triggered platelet activation . Activation of PKG by the NO / sGC / cGMP pathway inhibited echicetin bead - induced platelet aggregation . Echicetin - coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb - triggered pathways .",
"Knockdown of receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) affects EMT - associated gene expression in human hepatoma cells . BACKGROUND : Receptor - interacting serine / threonine protein kinase - 2 ( O43353 ) has been reported to be an important regulator of tumor proliferation , differentiation and wound repair . We investigated the effects of O43353 knockdown in human hepatoma cells on epithelial - to - mesenchymal transition ( EMT ) - associated gene expression . MATERIALS AND METHODS : HepG2 cells stably expressing O43353 - shRNA ( HepG2 - shRIPK2 ) were generated after puromycin selection . Total RNAs from HepG2 - shRIPK2 and from HepG2 - shcontrol cells were isolated and PCR - based arrays were performed to compare the 84 EMT - associated gene expressions . RESULTS : We observed that knockdown of O43353 down - regulated mRNA expression of jagged 1 ( P78504 ) ; plasminogen activator inhibitor - 1 ( P05121 ) ; regulator of G - protein signalling 2 , 24 kDa ( P41220 ) ; P12830 ( CDH1 ) ; fibroblast growth factor binding protein 1 ( Q14512 ) ; snail homolog 2 ( O43623 ) ; protein tyrosine phosphatase type IVA , member 1 ( Q93096 ) ; keratin 19 ( P08727 ) ; vimentin ( P08670 ) ; and survival of motor neuron protein - interacting protein 1 ( SIP1 ) . CONCLUSION : We found that knockdown of O43353 down - regulated nuclear factor kappa B ( NF - κB ) - dependent P05121 and P08670 gene expressions . O43353 might play an important role in hepatic cell migration . These findings could shed new light on carcinogenesis and on liver regeneration .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK65___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro - drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter - individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non - CABG - related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . ___MASK2___ is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non - CABG - related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor - treated patients compared to clopiodgrel - treated patients to limit the severity of post - surgical bleeding .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK2___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"DB06441 : review of the drug and the CHAMPION programme ( including PHOENIX ) . Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions ( P05154 ) . Thienopyridines and ticagrelor are oral drugs developed for this purpose . DB06441 is an intravenous , non - thienopyridine antagonist of the Q9H244 receptor with a rapid , potent , predictable , and quickly reversible effect . DB06441 has been studied in a broad population intended to receive P05154 in the CHAMPION program , where it was compared with different clopidogrel regimens . The first two trials , CHAMPION P05154 and PLATFORM , failed their primary objective , likely for challenges in the adjudication of P05154 - related myocardial infarction . In a third trial that implemented the universal definition of MI , CHAMPION PHOENIX , a reduction of thrombotic events , including stent thrombosis , was observed . In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery . DB06441 appears a promising agent in patients who require P05154 or when a rapid reversal is needed .",
"___MASK42___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK42___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK42___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .",
"Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation . Angiogenic cytokines have been shown to influence vessel injury , and platelets represent a disposable circulating pool of angiogenic molecules . In the present study , objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation . We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg / day . We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor ( P15692 ) - A and its soluble receptor forms P17948 and P35968 , placenta growth factor , and stromal cell - derived factor - 1 . We also quantified soluble P16581 and P04275 to evaluate endothelial activation . Blood samples were drawn just before the first clopidogrel intake on day 1 , and after the last dosing ( day 7 ) . As expected , we observed a decrease in platelet reactivity in response to clopidogrel , confirmed by vasodilator - stimulated phosphoprotein phosphorylation assay . However , the 7 - day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation . These results show that circulating angiogenic factor level in healthy subjects is not driven by Q9H244 platelet receptor - induced activation and clopidogrel does not modify in a significant way the endothelial activation level .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Emerging antithrombotic drugs for acute coronary syndrome . INTRODUCTION : Acute coronary syndrome ( ACS ) encompasses acute myocardial infarction ( MI ) and unstable angina . Activation of platelets and coagulation cascade plays a central role in the development of ACS . Over the past decade , there have been substantial improvements in the strategies for secondary prevention of ACS , including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor . However , therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable . AREAS COVERED : This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents ; cangrelor ( an intravenous Q9H244 receptor antagonist ) , vorapaxar ( protease - activated receptor - 1 inhibitor ) and rivaroxaban ( an oral factor Xa inhibitor ) . EXPERT OPINION : DB06441 appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed . DB09030 in addition to standard oral antiplatelet therapy was effective in patients with prior MI , but was not safe in patients with a prior stroke . Low dose rivaroxaban decreased cardiovascular events and mortality in patients post - ACS compared to placebo , although bleeding was increased .",
"Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .",
"New Q9H244 blockers . A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome ( ACS ) . This article reviews the pharmacology and clinical development of three of these agents : prasugrel , cangrelor , and ticagrelor . Prasugrel , a third - generation , oral thienopyridine , has been shown to be superior to clopidogrel , the current gold standard , in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention ( P05154 ) , although the bleeding rate was higher . DB06441 , a chemical analog of adenosine triphosphate , is a potent direct platelet Q9H244 antagonist . In development as an intravenous agent , cangrelor is currently being evaluated in two phase III studies in patients requiring P05154 . ___MASK2___ is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by Q9H244 ; it is currently being studied in a phase III trial in patients with ACS .",
"Variation in glucose homeostasis traits associated with Q99572 polymorphisms in mice and humans . CONTEXT : Extracellular nucleotide receptors are expressed in pancreatic B - cells . Purinergic signaling via these receptors may regulate pancreatic B - cell function . OBJECTIVE : We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction . DESIGN : In humans , we mined genome - wide meta - analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes . We performed additional testing in two genomic regions ( Q99571 / Q99572 and P47900 ) in a cohort from the Prevalence , Prediction , and Prevention of Diabetes in Botnia ( n = 3504 ) , which includes more refined measures of glucose homeostasis . In mice , we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background . RESULTS : Variants in five genes were associated with glycemic traits and in three genes with diabetes risk . In the Prevalence , Prediction , and Prevention of Diabetes in Botnia study , the minor allele in the missense functional variant rs1718119 ( A348T ) in Q99572 was associated with increased insulin sensitivity and secretion , consistent with its known effect on increased pore function . Both male and female P2x7 - C57 mice demonstrated impaired glucose tolerance compared with matched P2x7 - 129 mice . P01308 tolerance testing showed that P2x7 - C57 mice were also less responsive to insulin than P2x7 - 129 mice . CONCLUSIONS : We show association of the purinergic signaling pathway in general and hypofunctioning Q99572 variants in particular with impaired glucose homeostasis in both mice and humans .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK36___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Chk2 - dependent phosphorylation of P18887 in the DNA damage response promotes base excision repair . The DNA damage response ( DDR ) has an essential function in maintaining genomic stability . Ataxia telangiectasia - mutated ( Q13315 ) - checkpoint kinase 2 ( Chk2 ) and Q13315 - and Rad3 - related ( ATR ) - Chk1 , triggered , respectively , by DNA double - strand breaks and blocked replication forks , are two major DDRs processing structurally complicated DNA damage . In contrast , damage repaired by base excision repair ( BER ) is structurally simple , but whether , and how , the DDR is involved in repairing this damage is unclear . Here , we demonstrated that Q13315 - Chk2 was activated in the early response to oxidative and alkylation damage , known to be repaired by BER . Furthermore , Chk2 formed a complex with P18887 , the BER scaffold protein , and phosphorylated P18887 in vivo and in vitro at DB00156 ( 284 ) . A mutated P18887 lacking DB00156 ( 284 ) phosphorylation was linked to increased accumulation of unrepaired BER intermediate , reduced DNA repair capacity , and higher sensitivity to alkylation damage . In addition , a phosphorylation - mimic form of P18887 showed increased interaction with glycosylases , but not other BER proteins . Our results are consistent with the phosphorylation of P18887 by Q13315 - Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition / excision step to promote BER .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK53___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK53___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .",
"Purinergic receptors involved in the immunomodulatory effects of DB00171 in human blood . We recently showed that the physiological compound DB00171 simultaneously inhibited P01375 and stimulated P22301 release in LPS - PHA stimulated blood . The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of DB00171 on P01375 and P22301 . Incubation of blood with DB00171 in the presence of selective P2 receptor antagonists showed that the stimulatory effect of DB00171 on P22301 release was completely annihilated by both 2 - MeSAMP ( a Q9H244 / 13 receptor antagonist ) and PSB - 0413 ( a Q9H244 receptor antagonist ) . On the other hand , the inhibitory effect of DB00171 on P01375 release was completely reversed by 5 '- P30566 ( a Q96G91 receptor antagonist ) as well as by H - 89 , an inhibitor of DB02527 - activated PKA . The concerted inhibition by DB00171 of P01375 release via Q96G91 activation and stimulation of P22301 release via Q9H244 activation implicates a novel approach towards immunomodulation by altering the balance among pro - and anti - inflammatory cytokines .",
"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK2___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK2___ is in clinical development as an orally active agent .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK78___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Contribution of the Q9H244 receptor - mediated pathway to platelet hyperreactivity in hypercholesterolemia . BACKGROUND : In hypercholesterolemia , platelets demonstrate increased reactivity and promote the development of cardiovascular disease . OBJECTIVE : This study was carried out to investigate the contribution of the ADP receptor Q9H244 - mediated pathway to platelet hyperreactivity due to hypercholesterolemia . METHODS : P01130 - deficient mice and C57Bl / 6 wild - type mice were fed on normal chow and high - fat ( Western or Paigen ) diets for 8 weeks to generate differently elevated cholesterol levels . Q9H244 receptor - induced functional responses via G ( i ) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin . Platelet aggregation and secretion , α ( IIb ) β ( 3 ) receptor activation and the phosphorylation of extracellular signal - regulated protein kinase ( P29323 ) and Akt were analyzed . RESULTS : Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL (- 1 ) depending on diet in mice with different genotypes . Agonist - dependent aggregation , dense and α - granule secretion and JON / A binding were gradually and significantly ( P < 0 . 05 ) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels , even if elevated thromboxane generation was blocked . These functional responses were induced via increased levels of G ( i ) - mediated P29323 and Akt phosphorylation in hypercholesterolemic mice vs . normocholesterolemic animals . In addition , blocking of the Q9H244 receptor by AR - C69931MX ( DB06441 ) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls . CONCLUSIONS : These data revealed that the Q9H244 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK28___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"The influence of variation in the Q9H244 receptor gene on in vitro platelet inhibition with the direct Q9H244 antagonist cangrelor . Novel Q9H244 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used Q9H244 inhibitor clopidogrel . DB06441 is an intravenously administered Q9H244 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action , and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel . It was the objective of this study to determine the contribution of variation in the Q9H244 receptor gene to platelet aggregation after in vitro partial Q9H244 receptor blockade with the direct antagonist cangrelor . Optical aggregometry was performed at baseline and after in vitro addition of 0 . 05 and 0 . 25 microM cangrelor to the platelet - rich plasma of 254 healthy subjects . Five haplotype - tagging ( ht )- SNPs covering the entire Q9H244 receptor gene were genotyped ( rs6798347C > t , rs6787801T > c , rs9859552C > a , rs6801273A > g and rs2046934T > c [ T744C ] ) and haplotypes were inferred . The minor c allele of SNP rs6787801 was associated with a 5 % lower 20 microM ADP - induced peak platelet aggregation ( 0 . 05 microM cangrelor , p < 0 . 05 ) . Aa homozygotes for SNP rs9859552 showed 20 % and 17 % less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes ( 0 . 05 and 0 . 25 microM cangrelor respectively ; p < 0 . 05 ) . Results of the haplotype analyses were consistent with those of the single SNPs . Polymorphisms of the Q9H244 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the Q9H244 antagonist cangrelor .",
"Clinical effects and outcomes with new Q9H244 inhibitors in ACS . Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses . Newly developed Q9H244 inhibitors are more potent , more predictable , and have a faster onset of action than clopidogrel , characteristics that make them particularly attractive for high - risk percutaneous coronary intervention ( P05154 ) . Four new Q9H244 inhibitors have been tested each of them having particular individual properties . Prasugrel is an oral pro - drug leading to irreversible blockade of the Q9H244 receptor and is approved worldwide for ACS P05154 . ___MASK2___ is a direct - acting and reversible inhibitor of the Q9H244 receptor with potentially more pleiotropic effects . DB06441 is an intravenous direct and reversible inhibitor of the Q9H244 receptor providing the highest level of inhibition , and elinogrel is an intravenous and oral Q9H244 antagonist with a direct and reversible action . Both prasugrel and ticagrelor , opposed to clopidogrel , have shown that stronger Q9H244 inhibition led respectively to significant 19 and 16 % relative risk reduction of a similar primary end point combining cardiovascular death , non - fatal myocardial infarction , or non - fatal stroke . Both drugs showed a significant 0 . 6 % absolute excess of TIMI major bleeding not related to CABG surgery . Because in clinical trials , patients perceived to be at higher risk of bleeding usually are excluded , the risk of major and even fatal bleeding might even be higher in a ' real - world ' setting , i . e . in the elderly patient with comorbidities . On the other hand , these newly developed Q9H244 inhibitors decrease mortality after P05154 compared with clopidogrel . The risk / benefit ratio is particularly favorable in P05154 for patients with STEMI .",
"DB06441 : a novel Q9H244 receptor antagonist . Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions . Current antiplatelet agents ( aspirin , clopidogrel and glycoprotein IIb / IIIa antagonists ) have demonstrated the capacity to reduce major adverse cardiac events . However , these agents have limitations that compromise their clinical utility . The platelet Q9H244 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies . DB06441 is a potent , competitive inhibitor of the Q9H244 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP - induced platelet aggregation . This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis .",
"DB06441 for treatment during percutaneous coronary intervention . Dual antiplatelet therapy consisting of aspirin and a Q9H244 - receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention ( P05154 ) . The current Q9H244 - receptor antagonists are only available for oral administration and exhibit a delayed onset of action . Furthermore , several days are required for platelet function to return to normal following cessation of therapy . DB06441 is an intravenous DB00171 analog that directly , selectively and reversibly inhibits Q9H244 receptors on platelets . A 30 - μg / kg bolus dose followed by a 4 - μg / kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration . DB06441 also demonstrates a fast offset as normal platelet function is restored 1 - 2 h after cessation of the infusion . Three large , double - blind , randomized trials - CHAMPION PLATFORM , CHAMPION P05154 and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel ( during or immediately after P05154 ) or placebo in the setting of P05154 . In the most recent CHAMPION PHOENIX trial , cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding . Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset , cangrelor may provide benefit in certain patients undergoing P05154 .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK19___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Autocrine regulation of γ - irradiation - induced DNA damage response via extracellular nucleotides - mediated activation of Q15077 and Q9H244 receptors . A key component of the response to DNA damage caused by ionizing radiation is DNA repair . Release of extracellular nucleotides , such as DB00171 , from cells plays a role in signaling via P2 receptors . We show here that release of DB00171 , followed by activation of P2Y receptors , is involved in the response to γ - irradiation - induced DNA damage . Formation of phosphorylated histone variant P16104 ( γ P16104 ) foci , which are induced in nuclei by DNA damage and contribute to accumulation of DNA - repair factors , was increased at 1 - 3h after γ - ray irradiation ( 2 . 0Gy ) of human lung cancer A549 cells . Focus formation was suppressed by pre - treatment with the ecto - nucleotidase apyrase . Pre - treatment with ecto - nucleotidase inhibitor ARL67156 or post - treatment with DB00171 or UTP facilitated induction of γ P16104 , indicating that extracellular nucleotides play a role in induction of γ P16104 foci . Next , we examined the effect of P2 receptor inhibitors on activation of ataxia telangiectasia mutated ( Q13315 ; a protein kinase ) and accumulation of Q12888 ( a DNA repair factor ) , both of which are important for DNA repair , at DNA damage sites . Q15077 receptor antagonist MRS2578 , Q9H244 receptor antagonist clopidogrel , and Q99572 receptor antagonists A438079 and oxATP significantly inhibited these processes . Release of DB00171 was detected within 2 . 5min after irradiation , but was blocked by A438079 . Activation of Q13315 and accumulation of Q12888 were decreased in Q15077 or Q9H244 receptor - knockdown cells . We conclude that autocrine / paracrine signaling through Q99572 - dependent DB00171 release and activation of Q15077 and Q9H244 receptors serves to amplify the cellular response to DNA damage caused by γ - irradiation ."
] |
[
"___MASK19___",
"___MASK28___",
"___MASK2___",
"___MASK36___",
"___MASK42___",
"___MASK53___",
"___MASK65___",
"___MASK78___",
"___MASK97___"
] |
___MASK42___
|
MH_train_379
|
interacts_with DB00277?
|
[
"Histone deacetylase - 2 and airway disease . The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones , whereas histone deacetylase - 2 ( Q92769 ) suppresses inflammatory gene expression . Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting Q92769 to the nuclear factor - kappaB - activated inflammatory gene complex . This involves deacetylation of the acetylated glucocorticoid receptor . In P48444 , severe asthma and asthmatics who smoke , Q92769 is reduced , thus preventing corticosteroids from suppressing inflammation . The reduction in Q92769 appears to be secondary to increased oxidative and nitrative stress in the lungs . Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in P48444 , but this can also be achieved by low concentrations of theophylline and curcumin , which act as HDAC activators . DB00277 is a direct inhibitor of oxidant - activated phosphoinositide - 3 - kinase - delta , which is involved in inactivation of Q92769 . In the future selective O00329 inhibitors and more direct activators of Q92769 may be used to treat corticosteroid - resistant inflammatory diseases of the lung , including P48444 , severe asthma and asthma in smokers .",
"___MASK27___ binding to human and rat dopamine and 5 - HT receptors . ___MASK27___ ( ___MASK27___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK27___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK27___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK27___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Targeting the phosphatidylinositol 3 - kinase pathway in airway smooth muscle : rationale and promise . The phosphatidylinositol 3 - kinase ( PI3K ) signaling pathway plays a critical role in regulating cell growth , proliferation , survival , and motility . Structural alterations , e . g . airway remodeling , in asthma and chronic obstructive pulmonary disease ( P48444 ) are associated with increased airway smooth muscle ( P17405 ) cell growth and proliferation due to the frequent stimulation of P17405 by inflammatory mediators , contractile agonists , and growth factors . The critical role of the PI3K signaling pathway in regulating P17405 cell growth and proliferation is well established . However , recent discovery of the tumor suppressor proteins tuberous sclerosis complex 1 ( Q92574 ) and P49815 , also known as hamartin and tuberin , as downstream effectors of PI3K and upstream regulators of the mammalian target of rapamycin ( P42345 ) and S6 kinase 1 ( P23443 ) shed a new light on the PI3K signaling cascade in regulating cell growth and proliferation . The activity of Q92574 / P49815 is regulated by growth factors , nutrients , and energy ; thus , Q92574 / P49815 serves as a signaling module for protein translational regulation , cell cycle progression , and cell size , which are key events controlling cell growth and proliferation . This article highlights the potential contribution of the PI3K - Q92574 / P49815 - P42345 / P23443 pathway in smooth muscle remodeling . Pharmacologic manipulation of this signaling pathway could have a major impact on treatment of asthma and P48444 .",
"Decreased exercise - induced expression of nuclear factor - κB - regulated genes in muscle of patients with P48444 . BACKGROUND : Nuclear factor ( NF ) - κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with P48444 . Therefore , we investigated NF - κB activity and expression of NF - κB - regulated genes in muscle of patients with P48444 and control subjects before and after exercise . METHODS : Quadriceps specimens were obtained before , immediately after , and 2 h after a submaximal cycle ergometry test from seven patients with P48444 ( 50 . 6 ± 5 . 7 SEM Q99581 ( 1 ) of patients with P48444 ) and seven age - matched control subjects . NF - κB DNA - binding activity in muscle and peripheral blood mononuclear cells ( PBMCs ) was determined using electrophoretic mobility shift assay and enzyme - linked immunosorbent assay , respectively . mRNA expression and protein carbonylation were measured by real - time polymerase chain reaction and Western blot , respectively . RESULTS : In control subjects , P05231 , IκBα , tumor necrosis factor - α , IL - 1β , superoxide dismutase , thioredoxin , heme oxygenase 1 , and heat shock protein - 70 were upregulated in muscle after exercise , whereas in patients with P48444 only P05231 mRNA was increased . Exercise - induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with P48444 compared with control subjects . Basal muscle protein oxidation was higher in patients with P48444 than in control subjects , but attenuated in response to exercise . No exercise - induced changes in NF - κB DNA - binding activity in muscle and PBMCs of either group were detected . CONCLUSIONS : Skeletal muscle of patients with P48444 is characterized by an impaired response to exercise of NF - κB - regulated genes encoding inflammatory cytokines , antioxidants , stress proteins , and survival factors .",
"How corticosteroids control inflammation : Quintiles Prize Lecture 2005 . Corticosteroids are the most effective anti - inflammatory therapy for many chronic inflammatory diseases , such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease ( P48444 ) . Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors , such as nuclear factor - kappaB and activator protein - 1 , that bind to and activate coactivator molecules , which then acetylate core histones to switch on gene transcription . Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases , such as asthma , mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors ( GR ) to coactivators and recruitment of histone deacetylase - 2 ( Q92769 ) to the activated transcription complex . At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti - inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects . In patients with P48444 and severe asthma and in asthmatic patients who smoke Q92769 is markedly reduced in activity and expression as a result of oxidative / nitrative stress so that inflammation becomes resistant to the anti - inflammatory actions of corticosteroids . DB00277 , by activating HDAC , may reverse this corticosteroid resistance . This research may lead to the development of novel anti - inflammatory approaches to manage severe inflammatory diseases .",
"Phosphatidylinositol - 3 - OH kinase and nutrient - sensing P42345 pathways control T lymphocyte trafficking . Phosphatidylinositol - 3 - OH kinase ( PI ( 3 ) K ) and the nutrient sensor P42345 are evolutionarily conserved regulators of cell metabolism . Here we show that PI ( 3 ) K and P42345 determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes . The key lymph node - homing receptors CD62L ( P14151 ) and P32248 were highly expressed on naive T lymphocytes but were downregulated after immune activation . CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription . The O00329 subunit of PI ( 3 ) K controlled CD62L proteolysis through mitogen - activated protein kinases , whereas control of CD62L transcription by O00329 was mediated by P42345 through regulation of the transcription factor Q9Y5W3 . PI ( 3 ) K - P42345 nutrient - sensing pathways also determined expression of the chemokine receptor P32248 and regulated lymphocyte trafficking in vivo . Hence , lymphocytes use PI ( 3 ) K and P42345 to match metabolism and trafficking .",
"Critique on application of diaphragmatic time - tension index to spontaneously breathing humans . Bellemare and Grassino ( J . Appl . Physiol . 53 : 1196 - 1206 , 1982 ) have reported that the diphragmatic time - tension index ( TTdi ) ( i . e . , the product of mean transdiaphragmatic pressure / maximum transdiaphragmatic pressure and the inspiratory duty cycle ) can be used as a predictor of diaphragmatic fatigue in humans . However , the publications of these authors do not directly address the question of whether inspiratory flow or transdiaphragmatic pressure should be used to calculate the inspiratory duty cycle . To gather data on this point , we computed TTdi by both methods in spontaneously breathing normal adult males ( Q9BXJ7 ) and age - matched males with chronic obstructive pulmonary disease ( P48444 ) at rest and during treadmill exercise . During rest and exercise in both Q9BXJ7 and P48444 , the fraction of the breathing cycle over which diaphragmatic tension was maintained ( Tdi / TT ) exceeded the fraction of the breathing cycle over which inspiratory airflow was maintained ( TI / TT ) . Therefore , TTdi calculations using Tdi / TT were greater ( P less than 0 . 05 ) than TTdi computations using TI / TT . However , this difference in TTdi values was relatively small ( approximately 15 % ) .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK38___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"___MASK72___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK72___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK72___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK72___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Genome - wide association study identifies five loci associated with lung function . Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease ( P48444 ) . We tested genome - wide association with forced expiratory volume in 1 s ( Q99581 ( 1 ) ) and the ratio of Q99581 ( 1 ) to forced vital capacity ( FVC ) in the SpiroMeta consortium ( n = 20 , 288 individuals of European ancestry ) . We conducted a meta - analysis of top signals with data from direct genotyping ( n < or = 32 , 184 additional individuals ) and in silico summary association data from the CHARGE Consortium ( n = 21 , 209 ) and the Health 2000 survey ( n < or = 883 ) . We confirmed the reported locus at 4q31 and identified associations with Q99581 ( 1 ) or Q99581 ( 1 )/ FVC and common variants at five additional loci : 2q35 in Q9HBL0 ( P = 1 . 11 x 10 (- 12 ) ) , 4q24 in Q8NEC7 ( 2 . 18 x 10 (- 23 ) ) , 5q33 in Q13639 ( P = 4 . 29 x 10 (- 9 ) ) , 6p21 in Q15109 ( P = 3 . 07 x 10 (- 15 ) ) and 15q23 in Q6ZMP0 ( P = 7 . 24 x 10 (- 15 ) ) . mRNA analyses showed expression of Q9HBL0 , Q8NEC7 , Q15109 , Q13639 and Q6ZMP0 in human lung tissue . These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK87___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK87___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK87___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK87___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK87___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK87___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK87___ .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Epigenetic modification of gene expression by methylation of DNA and various post - translational modifications of histones may affect the expression of multiple inflammatory genes . Acetylation of histones by histone acetyltransferases activates inflammatory genes , whereas histone deacetylation results in inflammatory gene repression . Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes , but mainly by recruiting histone deacetylase - 2 ( Q92769 ) to activated inflammatory genes . Q92769 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma . In chronic obstructive pulmonary disease ( P48444 ) , there is resistance to the antiinflammatory actions of corticosteroids , which is explained by reduced activity and expression of Q92769 . This can be reversed by a plasmid vector , which restores Q92769 levels , but may also be achieved by low concentrations of theophylline . Oxidative stress causes corticosteroid resistance by reducing Q92769 activity and expression by activation of phosphoinositide - 3 - kinase - delta , resulting in Q92769 phosphorylation via a cascade of kinases . DB00277 reverses corticosteroid resistance by directly inhibiting oxidant - activated O00329 and is mimicked by O00329 knockout or by selective inhibitors . Other treatments may also interact in this pathway , making it possible to reverse corticosteroid resistance in patients with P48444 , as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate . Other histone modifications , including methylation , tyrosine nitration , and ubiquitination may also affect histone function and inflammatory gene expression , and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies , particularly in corticosteroid - resistant inflammation .",
"P00747 activator inhibitor - 1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells . P00747 activator inhibitor - 1 ( P05121 ) plays a role in regulating levels of some cytokines and cell migration in addition to its classic role in inhibiting fibrinolysis . P05121 levels in induced - sputum of chronic obstructive pulmonary disease ( P48444 ) patients were elevated significantly and correlated negatively with pulmonary function . To study the role of P05121 in inflammatory process in P48444 , the authors transfected alveolar epithelial cells ( AECs ) with siRNA - targeted P05121 and stimulated the cells by cigarette smoke extraction ( CSE ) or lipopolysaccharides ( LPS ) . The expression of inflammatory factors , interleukin - 8 ( P10145 ) and leukotriene B4 ( LTB4 ) , and the monocyte migration were detected . The exposure to CSE or LPS induced the expression of P05121 , P10145 , and LTB4 in AECs and monocyte migration to AECs . However , they were attenuated after transfection with siRNA - targeted P05121 . In conclusion , P05121 stimulates inflammation induced by CSE or LPS in AECs through up - regulation of inflammatory factors and promoting inflammatory cell migration . P05121 may play a proinflammatory role in the pathogenesis of P48444 .",
"Molecular and behavioral effects mediated by Gs - coupled adenosine A2a , but not serotonin 5 - Ht4 or 5 - Ht6 receptors following antipsychotic administration . Typical antipsychotic agents are potent antagonists of Gi - coupled dopamine D2 receptors , but their mechanisms of action following this initial blockade remain poorly understood . We hypothesized that in striatal neurons , interruption of this inhibitory dopamine D2 input would unmask endogenous striatal Gs - coupled receptors . An increase in DB02527 levels generated by these unopposed receptors would then lead to the well - described behavioral and molecular effects of antipsychotic administration such as catalepsy and striatal c - fos and neurotensin gene transcription . We examined three striatal Gs - coupled receptor systems ( serotonin Q13639 , serotonin P50406 and adenosine A2a ) to assess their potential involvement in the mechanism of action of the typical antipsychotic haloperidol . Antagonists of each of these three receptor systems together with a 1 mg / kg dose of haloperidol were co - administered to Sprague - Dawley rats , and both the degree of catalepsy produced in the animals and the induction of striatal c - fos and neurotensin messenger RNAs were measured . Both the specific adenosine A2a antagonist 8 -( 3 - chlorostyryl )- caffeine and the general adenosine antagonist theophylline reduced haloperidol - dependent induction of striatal neurotensin and c - fos messenger RNA . Administration of these agents also greatly reduced the degree of catalepsy induced by haloperidol . Antagonists of the P50406 receptor failed to block the induction of striatal messenger RNAs , but the P50406 antagonist clozapine ( an important atypical antipsychotic agent in its own right ) was a potent inhibitor of catalepsy . Q13639 agents were unable to alter haloperidol ' s effects on striatal messenger RNA levels or catalepsy . We conclude that the striatal Gs - coupled adenosine A2a receptor is an important mediator of the molecular and behavioral sequelae following haloperidol administration .",
"Flavone as P09874 inhibitor : its effect on lipopolysaccharide induced gene - expression . The nuclear enzyme poly ( ADP - ribose ) polymerase - 1 ( P09874 ) which was initially known for its role in the repair of oxidative stress - induced DNA damage , has also been reported to play a mediating role in the inflammatory response . Studies with P09874 knockout models have shown that P09874 is a co - activator of Nuclear Factor - kappa B ( NF - kappaB ) , although this appears not to require its enzyme activity . In addition , drug - induced inhibition of the enzyme activity of P09874 was observed to reduce the production of pro - inflammatory mediators . In this study , the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of P09874 . Further evaluation of flavone in N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) - treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD (+) levels , as well as the formation of PAR - polymers was dose - dependently attenuated by flavone . In addition , flavone was found to reduce the lipopolysaccharide ( LPS ) - induced interleukin ( IL ) - 8 production in pulmonary epithelial cells , which was confirmed by transcription analysis . Furthermore , the transcription Inhibitor kappa B alpha ( of P25963 ) was significantly increased by flavone . The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases . P09874 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease ( P48444 ) and diabetes , by preservation of cellular NAD (+) levels and attenuating inflammatory conditions .",
"[ Moclobemide ( ___MASK82___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK21___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines . Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer , the molecular mechanisms accounting for this are still unclear . Selective estrogen receptor modulators ( SERMs ) mimic estrogen action in certain tissues while opposing it in others . The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear . Here , we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha ( ERalpha ) . 17beta - Estradiol ( E2 ) induced the gene expression of c - Myc and DB01277 and increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 . ERalpha silencing abolished the E2 - stimulated c - Myc expression . E2 induced the recruitment of co - activators such as Q15788 , Q9Y6Q9 and CBP to the promoters of c - Myc and DB01277 , and Q15788 silencing abolished both the E2 - stimulated c - Myc expression and cell - cycle progression . In contrast , although raloxifene increased the binding of ERalpha to the P05412 site of the promoters of c - Myc and DB01277 , raloxifene had no effect on the gene expression of c - Myc or DB01277 . Raloxifene induced the recruitment of co - repressors such as Q92769 , O75376 and Q9Y618 to the promoter of DB01277 . Thus , the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ERalpha appear to be dependent on the recruitment of co - regulators .",
"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK95___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK95___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .",
"Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease . Products of the prostaglandin H synthase ( PGHS ) metabolic pathway are thought to play a role in the pathogenesis of asthma . We determined the level of expression of the constitutive ( P23219 ) and inducible ( P35354 ) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma , patients with chronic obstructive pulmonary disease ( P48444 ) , and unaffected control subjects by immunocyto - and immunohistochemistry . Immunoreactivity for P35354 was significantly greater in the induced sputum of patients with asthma and patients with P48444 compared with unaffected control subjects . The level of P35354 was greater in asthma than in P48444 . Immunoreactivity for P23219 increased in cells in the induced sputum of patients with asthma and patients with P48444 compared with that of unaffected control subjects . Immunostained cells included macrophages , eosinophils , and neutrophils . Greater P35354 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects . In summary , we demonstrate an induction of P35354 in asthma , suggesting increased formation of prostanoids , which may contribute to the inflammatory process .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK35___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK35___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK35___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK73___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared ."
] |
[
"___MASK21___",
"___MASK27___",
"___MASK35___",
"___MASK38___",
"___MASK72___",
"___MASK73___",
"___MASK82___",
"___MASK87___",
"___MASK95___"
] |
___MASK95___
|
MH_train_380
|
interacts_with DB00714?
|
[
"Pharmacological Q9BWK5 mapping of age - associated changes in basal ganglia circuitry of awake rhesus monkeys . While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson ' s disease ( PD ) are well studied , little is known about functional changes in the neural circuitry of this area during normal aging . Here we report the first survey of age - associated changes in the basal ganglia of behaviorally characterized , awake rhesus monkeys , using pharmacological Q9BWK5 to map responses to dopaminergic stimulation . DB00714 , a mixed D ( 1 )/ P14416 agonist , evoked little change in the substantia nigra ( SN ) of aged animals while significantly reducing activation in young adult monkeys . Compared to young animals , both apomorphine and DB01576 ( which increases synaptic dopamine levels ) significantly increased activation of the aged rhesus globus pallidus externa ( GPe ) . In addition , the aged animals showed decreased activity in the putamen in response to DB01576 administration . Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD , the apomorphine - evoked activation of their GPe corresponded with apomorphine - induced increases in neuronal activity seen in Parkinson ' s patients and animal models . Given the major role of the GPe in regulating motor behavior , the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age .",
"___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"Intermediate phenotype analysis of patients , unaffected siblings , and healthy controls identifies Q05940 as a candidate gene for psychotic disorder and neurocognition . Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members , suggesting that genetic vulnerability to psychotic disorder impacts neurocognition . The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms ( SNPs ) are associated with ( 1 ) neurocognitive functioning across populations at different genetic risk for psychosis ( 2 ) and psychotic disorder . The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder . Follow - up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects . In the patients , 13 associations between SNPs and cognitive functioning were significant at P < . 05 , situated in P21728 , P35462 , Q01959 , P23560 , P09038 , Q05940 , Q13451 , and Q9UBC3 . Follow - up of these SNPs revealed a significant and directionally similar association for Q05940 ( alternatively Q05940 ) rs363227 in siblings ( B = - 0 . 13 , P = . 04 ) and a trend association in control subjects ( B = - 0 . 10 , P = . 12 ) . This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele ( linear OR = 1 . 51 , 95 % CI 1 . 10 - 2 . 07 , P = . 01 ) , which was reduced when covarying for cognitive performance ( OR = 1 . 29 , 95 % CI 0 . 92 - 1 . 81 , P = . 14 ) , suggesting mediation . Genetic variation in Q05940 may be linked to alterations in cognitive functioning underlying psychotic disorder , possibly through altered transport of monoamines into synaptic vesicles .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK47___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Influence of P14416 and Q8NFD2 genotypes on apomorphine - induced growth hormone ( GH ) response in alcohol - dependent patients . BACKGROUND : D ( 2 ) receptor function can be assessed by growth hormone ( GH ) response to apomorphine . Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol - dependent subjects yielded inconsistent results . In this pilot study , we tested polymorphisms from the P14416 region for GH response to apomorphine challenge in more detail . METHODS : DB00714 challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence ; patients were genotyped for 11 polymorphisms including P14416 , Q8NFD2 , P13591 and Q9H892 . RESULTS : Associations ( p < 0 . 05 ) were found for Q8NFD2 ( rs11604671 , rs1800497 ) and P14416 ( rs6276 , rs1076560 ) , which are located on adjacent chromosomal positions . Consistent with PET studies suggesting a reduced D ( 2 ) receptor availability in patients carrying the Q8NFD2 rs1800497 T polymorphism ( formerly known as P14416 TaqI A1 ) we found a reduced GH response to apomorphine in those subjects . CONCLUSION : This has been the first study showing significant associations between apomorphine - induced GH response and SNPs in P14416 and Q8NFD2 in alcohol - dependent patients . In this respect , our preliminary results are in line with other reports which suggested that P14416 and Q8NFD2 polymorphisms influence D ( 2 ) receptor availability and signal transduction in the dopaminergic pathways . Small sample size in our study limits the generalizability of our results .",
"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .",
"___MASK20___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK20___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK20___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK20___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK20___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .",
"Regulation of the natural killer cell response to interferon - alpha by biogenic amines . Monocytes , recovered from human peripheral blood by counter - current centrifugal elutriation ( CCE ) , suppressed baseline natural killer ( NK ) cell cytotoxicity ( NKCC ) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon - alpha ( IFN - alpha ) by a cell contact - dependent mechanism . Monocyte - induced suppression of resting and IFN - activated NK cells was abrogated by the biogenic amines histamine [ via H2 - type receptors ( P25021 ) ] and serotonin [ via P08908 - type receptors ( 5 - HT1AR ) ] . Our data are suggestive of a monocyte / NK cell interaction that is subject to regulation by biogenic amines .",
"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .",
"D2 - dopamine receptor and alpha2 - adrenoreceptor - mediated analgesic response of quercetin . DB04216 , a bioflavonoid ( 100 - 300 mg / kg ) produced dose dependent increase in tail - flick latency , the analgesic effect being sensitive to reversal by naloxone ( 1 mg / kg ) . Prior treatment with haloperidol ( 1 mg / kg ) , D1 / D2 receptor antagonist haloperidol , sulpiride ( 50 mg / kg ) , a selective D2 receptor antagonist , yohimbine ( 5 mg / kg ) , a alpha2 - adrenoreceptor antagonist but not by P35240 23390 a , selective D1 receptor antagonist blocked this response . DB00714 ( 1 mg / kg ) a mixed D1 / D2 dopamine receptor agonist , and quinpirole ( 0 . 5 mg / kg ) , a selective D2 receptor agonist also produced antinociception , that was reversed by haloperidol ( 1 mg / kg ) , sulpiride ( 50 mg / kg ) , but not by yohimbine ( 5 mg / kg ) . The antinociceptive action of quercetin ( 200 mg / kg ) was potentiated by D2 agonist quinpirole ( 0 . 2 mg / kg ) . P21728 agonist SKF38393 ( 10 and 15 mg / kg ) failed to alter the antinociceptive effect of quercetin ( 200 mg / kg ) . DB04216 ( 200 mg / kg ) reversed reserpine ( 2 mg / kg - 4 hr ) induced hyperalgesia , which was reversed by sulpiride but not by yohimbine . Thus , a role of dopamine D2 and alpha2 - adrenoreceptors is postulated in the antinociceptive action of quercetin .",
"Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) - mediated osteoclast differentiation from monocyte / macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate - resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264 . 7 cells suppressed O14788 - induced osteoclastogenesis by inhibiting the expression of c - Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia - associated transcription factor ( O75030 ) independent of sumoylation . Down - regulation of Q9Y6X2 markedly enhances O14788 - mediated osteoclastogenesis in RAW264 . 7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down - regulates O14788 expression induced by interleukin - 6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down - regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL - 6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 - mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts .",
"Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder . In utero exposure of rodents to valproic acid ( DB00313 ) , a histone deacetylase ( HDAC ) inhibitor , has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder ( P51689 ) . We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of P51689 . We employed the social approach avoidance paradigm as a measure of social reciprocity , detection of biological motion that is crucial to social interactions , and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to DB00313 . We found no significant change in the expression of neural cell adhesion molecule polysialylation state ( P13591 PSA ) , a measure of construct validity , but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning . Finally , in all cases , we found chronic HDAC inhibition , with either pan - specific or Q13547 - 3 isoform - specific inhibitors , to significantly ameliorate deficits in both social cognition and its associated neuroplastic response . We conclude that in utero exposure to DB00313 provides a robust animal model for the social cognitive deficits of P51689 and a potential screen for the development of novel therapeutics for this condition .",
"Enhancement and inhibition of apomorphine - induced sensitization in rats exposed to immobilization stress : relationship with adaptation to stress . Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre - dispose to depression . Pre - clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress . The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine - induced sensitization . DB00714 was injected either before exposure or after the termination of immobilization , daily for 5 days , to monitor drug - induced behavioral sensitization and tolerance in immobilization stress - induced anorexia . We find that apomorphine - induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode . Conversely , apomorphine - induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode . It shows that apomorphine , if experienced during stress , produces greater sensitization and impairs stress tolerance . Conversely , sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode . It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and P08908 influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress . The results may help develop potential pharmacotherapies when substance abuse / dependence disorder and depression occur together .",
"DB00714 - induced aggressiveness and [ 3H ] citalopram binding after antidepressant treatment in rats . The effects of acute and repeated administration of antidepressive drugs on apomorphine - induced aggressive behavior and [ 3H ] citalopram binding were studied . In acute behavioral experiments with apomorphine pretreated ( 1 . 0 mg / kg , once daily ) animals , desipramine ( 10 mg / kg ) and clomipramine ( 10 mg / kg ) enhanced , buspirone ( 2 . 5 and 5 . 0 mg / kg ) completely blocked , but fluoxetine , amitriptyline , imipramine ( 10 mg / kg ) , and citalopram ( 10 and 20 mg / kg ) had no effect on the intensity of aggressive behavior . Repeated concomitant apomorphine ( 1 . 0 mg / kg ) and citalopram ( 10 mg / kg ) administration reduced the affinity ( Kd ) of the 5 - HT transporter binding sites in three brain regions . This finding was confirmed by an additional experiment as the effect of citalopram treatment . Repeated apomorphine ( 1 . 0 mg / kg ) or apomorphine ( 1 . 0 mg / kg ) plus desipramine ( 10 mg / kg ) treatment had no unidirectional effect on Kd , the maximal number of apparent binding sties ( Bmax ) was unchanged in all experiments . Our study indicates that the 5 - HT reuptake blockade has no major influence on the apomorphine - induced aggressive behavior , but the P08908 receptor subtype may be involved in the mediation of the aggressive behavior in this paradigm .",
"___MASK58___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK58___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .",
"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .",
"Novel cinnamyl hydroxyamides and 2 - aminoanilides as histone deacetylase inhibitors : apoptotic induction and cytodifferentiation activity . Four novel series of cinnamyl - containing histone deacetylase ( HDAC ) inhibitors 1 - 4 are described , containing hydroxamate ( 1 and 3 ) or 2 - aminoanilide ( 2 and 4 ) derivatives . When screened against class I ( maize HD1 - B and human Q13547 ) and class II ( maize HD1 - A and human P56524 ) HDACs , most hydroxamates and 2 - aminoanilides displayed potent and selective inhibition toward class I enzymes . Immunoblotting analyses performed in U937 leukemia cells generally revealed high acetyl - H3 and low acetyl - α - tubulin levels . Exceptions are compounds 3 f - i , 3 m - o , and 4 k , which showed higher tubulin acetylation than ___MASK16___ . In U937 cells , cell - cycle blockade in either the G₂ / M or G₁ / S phase was observed with 1 - 4 . Five hydroxamates ( compounds 1 h - l ) effected a two - to greater than threefold greater percent apoptosis than ___MASK16___ , and in the CD11c cytodifferentiation test some 2 - aminoanilides belonging to both series 2 and 4 were more active than MS - 275 . The highest - scoring derivatives in terms of apoptosis ( 1 k , 1 l ) or cytodifferentiation ( 2 c , 4 n ) also showed antiproliferative activity in U937 cells , thus representing valuable tools for study in other cancer contexts .",
"Stimulatory effects of 5HT1A receptor agonists on luteinizing hormone - releasing hormone release from cultured fetal rat hypothalamic cells : interactions with progesterone . Previous works have suggested an interactive stimulatory effect of progesterone ( P ) and serotonin ( 5 - HT ) on luteinizing hormone release . The purpose of the present study was to determine whether 5 - HT via P08908 receptors interacts with P in the process of luteinizing hormone - releasing hormone ( P01148 ) release . Using fetal hypothalamic neurons in primary cell cultures the first goal of this study was to determine the effects of P08908 receptor agonists on P01148 secretion . 8 - Hydroxy - 2 ( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) or ipsapirone ( 10 (- 5 ) M ) significantly stimulated P01148 release . Pharmacological studies have allowed to rule out the possible involvement of alpha 2 - or beta - adrenoreceptors , or 5 - HT uptake sites , in the stimulatory effect of 8 - OH - DPAT on P01148 release , thus demonstrating the specific involvement of P08908 receptors in the stimulation of P01148 release . The second goal was to test the ability of P to stimulate P01148 release from fetal hypothalamic neurons . P ( 10 (- 6 ) M ) applied for 30 or 120 min significantly stimulated P01148 secretion . The maintenance of the stimulation of P01148 release by P after a cycloheximide treatment or by an impermeable analog of P , P - 3 - BSA , has suggested a nongenomic effect of P on P01148 release . The effects of a pretreatment of cells by P on 8 - OH - DPAT - induced P01148 release were tested . While 10 (- 7 ) M P alone did not stimulate P01148 release , this concentration of steroid potentiated the P01148 response to 10 (- 5 ) M 8 - OH - DPAT . These findings led to the conclusion that P acting at the level of the plasma membrane potentiates the stimulatory effect of P08908 receptor agonists on P01148 release .",
"P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .",
"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK68___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"Neural cell adhesion molecule ( P13591 ) promotes the differentiation of hippocampal precursor cells to a neuronal lineage , especially to a glutamatergic neural cell type . Rat hippocampal precursor cells isolated from hippocampi of embryonic day 16 . 5 ( E16 . 5 ) rat embryos were found to proliferate in the presence of basic fibroblast growth factor . Addition of soluble neural cell adhesion molecule ( P13591 ) to these precursor cells reduced cell proliferation in a dose dependent manner and enhanced the induction of precursor cells ' differentiation to the neuronal lineage . Given these findings that P13591 induces the differentiation of hippocampal precursor cells , we investigated possible effects of P13591 on the expression of basic helix - loop - helix ( bHLH ) transcription factors during the differentiation . Soluble P13591 upregulated the transcription of bHLH transcription factors , neurogenin1 and Q13562 , but decreased Q5TA89 . Western blot analysis showed that P13591 increased the expression levels of CaMKII , p - MAPK , GluR1 and Q9UHB4 but decreased p - P40763 . These results support a role for P13591 in the inhibition of proliferation and the induction of neural differentiation of hippocampal neural precursor cells , and act as developmental regulators of the bHLH families , ultimately leading to the generation of glutamatergic neural cell types in the differentiation of hippocampal precursor cells .",
"Development of peptidomimetic ligands of Pro - DB00149 - DB00145 - NH ( 2 ) as allosteric modulators of the dopamine D ( 2 ) receptor . A variety of stable , small - molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro - DB00149 - DB00145 - NH ( 2 ) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro - bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β - turn . In addition , studies with peptidomimetics designed to mimic either a type VI β - turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH ( 2 ) pharmacophore in the same topological space as that seen in the type II β - turn . Extensive studies with the spiro - bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro - bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics .",
"___MASK92___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK92___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK92___ is a promising pharmacological tool in the treatment of renal edema .",
"Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .",
"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .",
"P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .",
"___MASK70___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK70___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .",
"Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Post - synaptic P08908 receptor involvement in yawning and penile erections induced by apomorphine , physostigmine and mCPP in rats . DB00714 and mCPP induced yawning associated with penile erections in rats , whereas physostigmine induced only yawns . DB00714 - induced yawning and penile erections were antagonized by low doses of raclopride , whereas physostigmine - induced yawning and mCPP - induced effects were only partly inhibited at high doses of raclopride . DB00747 as well as clozapine antagonized yawning and penile erections induced by apomorphine , mCPP and physostigmine . Similarly , the P08908 agonists 8 - OH - DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine , mCPP and physostigmine , and at similar doses induced lower lip retraction and hyperreactivity to handling . The beta / P08908 antagonist tertatolol reversed the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections and increased apomorphine - and physostigmine - induced yawn frequency but not penile erection frequency . Like tertatolol , propranolol increased apomorphine - and physostigmine - induced yawn frequency , whereas ICI 118551 increased only physostigmine - induced yawning . 8 - OH - DPAT - and S 14506 - induced lower lip retraction and hyperreactivity to handling were also significantly antagonized by tertatolol . Finally , p - chlorophenylalanine pretreatment produced about 95 % depletion in 5 - HT in hypothalamus , hippocampus , striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8 - OH - DPAT and S 14506 on drug - induced yawning and penile erections . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .",
"___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK16___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .",
"Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .",
"Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells . Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment . We report that mesoderm commitment from human embryonic stem cells ( hESCs ) is initiated by epithelial - to - mesenchymal transition ( EMT ) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins , EpCAM / CD326 and P13591 / CD56 . Molecular and functional assays reveal that the earliest CD326 - CD56 + cells , generated from hESCs in the presence of activin A , P12644 , P15692 , and P09038 , represent a multipotent mesoderm - committed progenitor population . CD326 - CD56 + progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic , endothelial , mesenchymal ( bone , cartilage , fat , fibroblast ) , smooth muscle , and cardiomyocytes , while lacking the pluripotency of hESCs . CD326 - CD56 + cells are the precursors of previously reported , more lineage - restricted mesodermal progenitors . These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK58___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .",
"Switching brain serotonin with oxytocin . Serotonin ( 5 - HT ) and oxytocin ( P01178 ) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism . We asked whether these chemical messengers interact in the regulation of emotion - based behavior by administering P01178 or placebo to 24 healthy subjects and mapping cerebral 5 - HT system by using 2 '- methoxyphenyl -( N - 2 '- pyridinyl )- p -[( 18 ) F ] fluoro - benzamidoethylpiperazine ( [( 18 ) F ] MPPF ) , an antagonist of P08908 receptors . P01178 increased [( 18 ) F ] MPPF nondisplaceable binding potential ( BPND ) in the dorsal raphe nucleus ( DRN ) , the core area of 5 - HT synthesis , and in the amygdala / hippocampal complex , insula , and orbitofrontal cortex . Importantly , the amygdala appears central in the regulation of 5 - HT by P01178 : [( 18 ) F ] MPPF BPND changes in the DRN correlated with changes in right amygdala , which were in turn correlated with changes in hippocampus , insula , subgenual , and orbitofrontal cortex , a circuit implicated in the control of stress , mood , and social behaviors . P01178 administration is known to inhibit amygdala activity and results in a decrease of anxiety , whereas high amygdala activity and 5 - HT dysregulation have been associated with increased anxiety . The present study reveals a previously unidentified form of interaction between these two systems in the human brain , i . e . , the role of P01178 in the inhibitory regulation of 5 - HT signaling , which could lead to novel therapeutic strategies for mental disorders .",
"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"The human interleukin 18 gene Q14116 maps to 11q22 . 2 - q22 . 3 , closely linked to the P14416 gene locus and distinct from mapped IDDM loci .",
"Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high P23759 levels that sustain migration and invasiveness . Rhabdomyosarcoma is a muscle - derived malignant tumor mainly affecting children . The most frequent variant , embryonal rhabdomyosarcoma ( ERMS ) is characterized by overexpression of the transcription factor , P23759 which prevents ERMS cells from exiting the cell cycle and terminally differentiating . However , a role for P23759 in the invasive properties of ERMS cells has not been investigated in detail thus far . Here we show that ectopic expression of receptor for advanced glycation end - products ( RAGE ) in human ERMS cells results in the activation of a RAGE / myogenin axis which downregulates P23759 by transcriptional and post - translational mechanisms , as in normal myoblasts , and reduces metastasis formation . High P23759 sustains migration and invasiveness in ERMS cells by upregulating P29320 and P20827 and downregulating P13591 thus decreasing the neural cell adhesion molecule ( P13591 ) / polysialylated - P13591 ratio . Microarray gene expression analysis shows that compared with the RAGE (- ve ) TE671 / WT cells and similarly to primary human myoblasts , TE671 / RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion , and downregulation of cell migration related and major histocompatibility complex class I genes . Our data reveal a link between P23759 and metastasis occurrence in ERMSs , and support a role for the RAGE / myogenin axis in metastasis suppression . Thus , low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior .",
"[ Breast carcinoma with predominant neuroendocrine differentiation ] . Neuroendocrine differentiation can be identified in a subset of human breast carcinomas , either as scattered cells or as a predominant neuroendocrine component . We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells . Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma , a 67 - years - old woman presented with a metastastic neuroendocrine sternal mass . To establish a relationship between mammary carcinoma and bone metastasis , histological slides of both the breast tumor and axillary lymph nodes were reviewed , and an immunohistochemical study was performed . They showed that : a ) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin + , P13591 + , chromogranin - ( 80 % ) , associated with 2 other differentiated non endocrine components , one of metaplastic squamous carcinoma ( 10 % ) and the other of ductal carcinoma ( 10 % ) ; b ) 4 axillary lymph nodes were involved by the ductal component which contained few P13591 + but synaptophysin - cells ; c ) Estrogen and progesterone receptors and P04626 were negative in the breast tumor and the metastatic nodes . We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation , the outcome of each component and the prognostic relevance of such a diagnosis .",
"Design , synthesis and biological evaluation of pazopanib derivatives as antitumor agents . A novel series of pazopanib derivatives were designed , synthesized , and evaluated for their inhibitory activity against a series of kinases including P35968 , P00533 , P31749 , P37023 , and P00519 . The anti - angiogenic activities ex vivo of some compounds were also investigated . Compounds P2d and P2e demonstrated outstanding inhibitory activity against P35968 and P00519 and higher anti - angiogenic activity compared with ___MASK58___ , the reference standard . These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK56___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"In vitro analysis of the centripetal migration mechanisms of developing P01148 neurons . This study was designed to gain insight into the underlying mechanisms of the centripetal migration of developing P01148 neurons . The medial wall of the nasal pit ( Q8WYA6 ) of 12 . 5 - day - old rat embryos ( Q96BH3 . 5 ) was cultured singly or together with the Q96BH3 . 5 medial - basal wall of the forebrain vesicles ( mFV ) or with the Q14207 . 5 median eminence - arcuate complex ( ME - Arc ) . Further , the Q8WYA6 was cultured with the mFV and ME - Arc or with the mFV and nasal mesenchyme ( NM ) , which lay between the mFV and the Q8WYA6 , of Q96BH3 . 5 embryos ( triple culture ) . The Q8WYA6 gave rise first to fibers labeled with anti - neural cell adhesion molecules ( P13591 ) and then to P01148 neurons . In co - cultures , Q8WYA6 - and brain - derived P13591 fibers connected the Q8WYA6 and brain cultures , and frequently linked with each other to form knots at the periphery . P01148 neurons migrating along the Q8WYA6 - derived fibers directly or indirectly entered brain cultures . In the latter case , the cells strayed along the way from the Q8WYA6 - derived fibers to the brain - derived fibers at the knots and migrated retrogradely along the latter fibers to enter into the brain tissues ; this occurred most frequently into the Q14207 . 5 ME - Arc . In triple cultures , abundant P13591 fibers emerging from the Q8WYA6 were only found when the NM lay between the Q8WYA6 and mFV ; the fibers converged further to the mFV . These findings help elucidate the mechanisms underlying the centripetal P01148 cell migration from the Q8WYA6 to the hypothalamus .",
"Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population - based twin studies demonstrate that approximately 40 - 50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 , Q01959 3 ' VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38 . 51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five - Factor Inventory , Spielberger ' s State - Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9 / 9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO - FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .",
"Penile erection and yawning induced by P28335 receptor agonists in male rats : relationship with dopaminergic and oxytocinergic transmission . 1 -( 3 - Chlorophenyl ) piperazine ( m - CPP ) ( 0 . 1 - 4 mg / kg s . c . ) and N -( 3 - trifluoromethylphenyl )- piperazine ( TFMPP ) ( 0 . 5 - 4 mg / kg s . c . ) , P28335 receptor agonists , but not 8 - hydroxy - dipropylamino - tetralin ( 8 - OH - DPAT ) ( 0 . 1 and 0 . 2 mg / kg s . c . ) , a P08908 receptor agonist , induced penile erection and yawning with a U - inverted dose - response curve in male rats . The maximal effect was found with 0 . 5 mg / kg s . c . of m - CPP and with 1 mg / kg s . c . of TFMPP . The m - CPP ( 0 . 5 mg / kg s . c . ) and TFMPP ( 1 mg / kg s . c . ) responses were prevented by mianserin ( 0 . 2 mg / kg s . c . ) and by ritanserin ( 1 mg / kg s . c . ) given 15 min before m - CPP and TFMPP . In contrast , m - CPP - or TFMPP - induced penile erection and yawning were not antagonized by haloperidol ( 0 . 1 mg / kg s . c . ) or by [ d ( CH2 ) 5Tyr ( Me ) 2 , Orn8 ] vasotocin ( 5 micrograms i . c . v . ) . DB00714 - and oxytocin - induced penile erection , but not yawning , was also antagonized by mianserin and less effectively by ritanserin . The results suggest that P28335 receptor agonist - induced penile erection and yawning are not mediated by increased dopaminergic and / or oxytocinergic transmission , and raise the possibility that a neuronal dopamine - oxytocin - 5 - HT link is involved in the control of penile erection and not necessarily of yawning in male rats .",
"Redistribution of membrane glycoproteins in platelets activated under flow conditions . A reduction in the ability of GPIb to bind specific MoAbs or ligands ( P04275 ) has been reported in platelets exposed to thrombin in suspension . We have analyzed modifications in the presence of glycoproteins ( GPs ) on platelets activated under flow conditions in a system which allows limited thrombin and fibrin generation . Normal blood anticoagulated with low molecular weight heparin ( LMWH , ___MASK70___ 20 IU / ml ) was recirculated for up to 10 min at 800 s - 1 through annular chambers containing denuded arterial segments . Aliquots of blood were removed from the reservoir at 0 , 1 , 5 and 10 min and immediately mixed with paraformaldehyde . Membrane glycoproteins : GPIb ( CD42b ) , P08514 - IIIa ( CD41a ) , P16671 ( P16671 ) ; and activation dependent antigens : P16109 ( CD62P ) and lysosomal glycoprortein ( P08962 ) , were detected in whole blood by dual color flow cytometry . Circulation of through the perfusion system resulted in platelet activated as demonstrated by the increased percentage of platelets positive for antigens CD62P and P08962 . A gradual increase in the binding of MoAbs directed against GPIb , P08514 - IIIa , and P16671 epitopes was noted during the entire perfusion period . Observed differences in mean fluorescence intensities at all the observation times were statistically significant ( P < 0 . 001 ) . Our results obtained on platelets in an experimental thrombosis system indicate that GPIb , P08514 - IIIa and P16671 remain on the surface of activated platelets and actually increase their expression . Alterations detected at the level of GPIb in platelets activated by thrombin in suspension may not take place under in vivo situations .",
"Clinical trials in thrombolytic therapy , Part 2 : The open - artery hypothesis and RAPID - 1 and RAPID - 2 . The open - artery hypothesis as supported by thrombolytic study results is discussed . The open - artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct - related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct - related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO - 1 ) trial suggested that early and complete patency is essential for short - term survival after AMI . Subsequent observations indicated that an open infarct - related artery at the time of hospital discharge is associated with improved long - term survival . In the ___MASK47___ Angiographic Phase II International Dose - Finding ( RAPID - 1 ) trial , complete patency was more frequent in patients who received a double - bolus regimen of reteplase than in patients who received standard - dose alteplase . Similar results were obtained in the ___MASK47___ versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID - 2 ) trial , which compared the same double - bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . ___MASK47___ seems more likely to produce normal blood flow soon after AMI than either standard - dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open - artery hypothesis .",
"Proteolysis of highly polysialylated P13591 by the tissue plasminogen activator - plasmin system in rats . P00750 ( tPA ) , a serine protease which converts the zymogen plasminogen to the active protease plasmin , is believed to regulate neurite extension and neural cell migration by modulating extracellular metabolism . The highly polysialylated form of the neural cell adhesion molecule ( P13591 - H ) is strongly expressed in the developing brain and is believed to play a role in organizing the neural network . In this report , we incubated neonatal rat brain homogenates with human tPA and rat plasminogen in order to determine whether P13591 - H would be degraded . P13591 - H was degraded by plasmin which was formed from rat plasminogen by human tPA . The degradation was inhibited by the addition of plasminogen activator inhibitor type 1 ( P05121 ) or aprotinin . These results suggest a possible contribution of the tPA - plasmin system to P13591 - H turnover in the developing brain .",
"Lack of allelic association of dopamine D1 and D2 ( TaqIA ) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism . Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA - polymorphisms of the dopamine D1 and D2 receptor ( P21728 , P14416 ) genes and is associated with poor treatment outcome . Therefore , 97 alcohol - dependent patients were assessed according to their sensitivity of central dopamine receptors ( apomorphine - induced secretion of growth hormone ) , clinical outcome during a 6 - month observation period , and genotypic constitution of the TaqIA restriction fragment length polymorphism ( RFLP ) at the P14416 locus and of the Bsp1286I RFLP at the P21728 locus . On the 1st day of detoxification , dopamine receptor hyposensitivity was found in treatment nonresponders , but not in responders . DB00714 - induced growth hormone release did not differ significantly in alcoholics with different genotypes of the P21728 and P14416 RFLPs . Neither did we find a significant allelic association with treatment response . Thus , we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome ."
] |
[
"___MASK16___",
"___MASK20___",
"___MASK3___",
"___MASK47___",
"___MASK56___",
"___MASK58___",
"___MASK68___",
"___MASK70___",
"___MASK92___"
] |
___MASK56___
|
MH_train_381
|
interacts_with DB09079?
|
[
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK21___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK21___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK50___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK50___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK6___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma ___MASK43___ , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"___MASK91___ response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . ___MASK91___ is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post - stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress - coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro - hypertrophic nuclear factor of activated T - cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild - type European brown trout , Salmo trutta . A positive correlation between post - stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post - stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well - known from mammalian cardiology .",
"___MASK91___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK91___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti - tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( ___MASK11___ , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI - 571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) .",
"Skeletal receptors for steroid - family regulating glycoprotein hormones : A multilevel , integrated physiological control system . Pituitary glycoprotein hormone receptors , including Q01718 , P16473 , and P23945 , occur in bone . Their skeletal expression reflects that central endocrine control is evolutionarily recent . ___MASK43___ receptors , in osteoblasts or the adrenal cortex , drive P15692 synthesis . P15692 is essential to maintain vasculature . In bone , ___MASK43___ suppression by glucocorticoids can cause osteonecrosis . DB00024 receptors occur on osteoblasts and osteoclasts , in both cases reducing activity . Thus , DB00024 directly reduces skeletal turnover , consistent with evolutionary adaptation to stress . DB00094 receptors accelerate bone resorption , whereas estrogen promotes bone formation , the forces usually balancing . With ovarian failure , low estrogen with high DB00094 causes rapid bone loss . The skeletal DB00094 effect in the menopause seems paradoxical , but it is a logical adaptation in lactation , where prolonged DB00094 elevation also occurs . In addition to receptors , there is some synthesis of pituitary glycoproteins at distributed sites ; this is not well studied , but it may further modify the paradigm of central endocrine regulation .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK14___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"___MASK97___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case - control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 , P14780 and 10 , P05121 , P15692 , P03950 , Q16790 and P02649 ) was assessed by enzyme - linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0 . 88 ( 95 % CI 0 . 84 - 0 . 93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK71___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK71___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Regulatory roles of sex hormones in cutaneous biology and immunology . Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin . Pregnancy , menstruation and the menopause modulate the natural course of psoriasis , indicating a female hormone - induced regulation of skin inflammation . Estrogen in vitro down - regulates the production of the neutrophil , type 1 T cell and macrophage - attracting chemokines , P10145 , P02778 , P13501 , by keratinocytes , and suppresses IL - 12 production and antigen - presenting capacity while enhancing anti - inflammatory P22301 production by dendritic cells . These data indicate that estrogen may attenuate inflammation in psoriatic lesions . Estrogen , alone or together with progesterone , prevents or reverses skin atrophy , dryness and wrinkles associated with chronological or photo - aging . Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy . Estrogen also enhances collagen synthesis , and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts , thereby maintaining skin thickness . Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis . Progesterone increases sebum secretion . Estrogen accelerates cutaneous wound healing stimulating P01138 production in macrophages , GM - P04141 production in keratinocytes and P09038 and TGF - beta1 production in fibroblasts , leading to the enhancement of wound re - innervation , re - epithelialization and granulation tissue formation . In contrast , androgens prolong inflammation , reduce deposition of extracellular matrix in wounds , and reduce the rate of wound healing . Estrogen enhances P15692 production in macrophages , an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy . These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis , aging , chronic wounds or granuloma pyogenicum .",
"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 ."
] |
[
"___MASK11___",
"___MASK14___",
"___MASK21___",
"___MASK43___",
"___MASK50___",
"___MASK6___",
"___MASK71___",
"___MASK91___",
"___MASK97___"
] |
___MASK21___
|
MH_train_382
|
interacts_with DB01277?
|
[
"P01308 - like growth factor - 1 activation of extracellular signal - related kinase - 1 and - 2 in growth hormone - secreting cells . Intracellular pathways mediating feedback regulation by insulin - like growth factor - 1 ( DB01277 ) of pituitary GH gene expression remain incompletely understood . Extracellular signal - related kinases ( ERKs ) , a family of serine / threonine kinases , are activated by tyrosine kinase - associated growth factor receptors . To further define the DB01277 postreceptor events occurring in GH - secreting cells , we investigated the activity of ERKs in response to DB01277 in GC cells following stable transfection with either wild type human DB01277 receptor cDNA ( WT cells ) or a mutant cDNA encoding a truncated , kinase - defective DB01277 receptor with a dominant negative effect on endogenous receptor function ( 952STOP cells ) . Zymography of immunoprecipitated ERKs in myelin basic protein ( MBP ) - containing polyacrylamide gels demonstrated dose - dependent induction of P27361 and - 2 activity by DB01277 in GC cells with maximal activity occurring at 6 min . DB01277 - induced P29323 activity in WT - transfected cells was up to 80 - fold basal and 4 - fold that observed in GC cells . 952STOP cells expressing the tyrosine kinase - deficient receptor were refractory to DB01277 action , demonstrating minimal P29323 induction . In contrast , 12 - O - tetradecanoylphorbol 13 - acetate stimulated P29323 activity to the same degree in all three cell types regardless of their P08069 status . DB02587 ( 50 microM ) , isobutylmethylxanthine ( 0 . 5 mM ) , and forskolin / isobutylmethylxanthine in combination attenuated DB01277 - induced P29323 activity in WT cells by 54 , 55 , and 75 % respectively . The rapid , dose - dependent , and DB01277 receptor - dependent activation of ERKs and the attenuation of this effect by DB02527 suggest an interrelated role for both molecules in DB01277 signal transduction in GH - secreting cells .",
"Hypermethylation of P30279 May Reflect a Smoking - Induced Precancerous Change in the Lung . It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event , specific to overt cancer tissue . Using MethyLight assays , we analyzed 316 lung tissue samples from 151 cancer - free subjects ( 121 ever - smokers and 30 never - smokers ) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers . Only P25054 ( 39 % ) , P30279 ( 21 % ) , CDH1 ( 7 % ) , and P10826 ( 4 % ) were hypermethylated in > 2 % of these cancer - free subjects . P30279 was hypermethylated more frequently in ever - smokers ( 26 % ) than in never - smokers ( 3 % ) . P30279 hypermethylation was also associated with increased age and upper lobe sample location . P25054 was frequently hypermethylated in both ever - smokers ( 41 % ) and never - smokers ( 30 % ) . Q8NE79 , P55290 , CDKN2A ( p16 ) , P42772 , P53355 , P17936 , Q9BY67 , Q8NCM2 , Q96L42 , P16455 , Q14982 , P29122 , Q9NS23 , RUNX , and Q9ULZ3 were rarely hypermethylated ( < 2 % ) in all subjects . Hypermethylation of P30279 may reflect a smoking - induced precancerous change in the lung .",
"Growth factors and glucose homeostasis in diabetic rats : effects of exercise training . To investigate the alterations of glucose homeostasis and variables of the insulin - like growth factor - 1 ( DB01277 ) growth system in sedentary and trained diabetic ( TD ) rats , Wistar rats were divided into sedentary control ( SC ) , trained control ( TC ) , sedentary diabetic ( SD ) , and TD groups . Diabetes was induced by Alloxan ( 35 mg kg (- 1 ) b . w . ) . Training program consisted of swimming 5 days week (- 1 ) , 1 h day (- 1 ) , during 8 weeks . Rats were sacrificed and blood was collected for determinations of serum glucose , insulin , growth hormone ( GH ) , DB01277 , and IGF binding protein - 3 ( P17936 ) . Muscle and liver were removed to evaluate glycogen content . Cerebellum was extracted to determinate DB01277 content . Diabetes decreased serum GH , DB01277 , P17936 , liver glycogen , and cerebellum DB01277 peptide content in baseline condition . Physical training recovered liver glycogen and increased serum and cerebellum DB01277 peptide in diabetic rats . Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum DB01277 concentrations .",
"Serum measurements of testosterone , insulin - like growth factor 1 , and insulin - like growth factor binding protein - 3 in the diagnosis of prostate cancer among Korean men . AIM : To investigate the relationships of serum testosterone , insulin - like growth factor ( IGF ) - 1 and IGF - binding protein ( IGFBP ) - 3 levels with prostate cancer risk and also with known prognostic parameters of prostate cancer in Korean men who received radical retropubic prostatectomy ( O75783 ) for clinically - localized prostate cancer . METHODS : Serum levels of total testosterone , free testosterone , DB01277 and P17936 were determined in 592 patients who subsequently received prostate biopsy . Results were compared between patients who eventually received O75783 for prostate cancer ( n = 159 ) and those who were not diagnosed with prostate cancer from biopsy ( control group , n = 433 ) . Among the prostate cancer only patients , serum hormonal levels obtained were analyzed in relation to serum prostate specific antigen ( PSA ) , pathological T stage and pathological Gleason score . RESULTS : Prostate cancer patients and the control group demonstrated no significant differences regarding serum levels of total testosterone , free testosterone , DB01277 and P17936 across the different age groups . Among the cancer only patients , no significant associations were observed for serum levels of total testosterone , free testosterone , DB01277 and P17936 levels with pathological T stage , pathological Gleason score and preoperative PSA . CONCLUSION : Our data indicate that simple quantifications of serum testosterone and DB01277 along with P17936 levels might not provide useful clinical information in the diagnosis of clinically localized prostate cancer in Korean men . Also , our results suggest that serum levels of testosterone , DB01277 and P17936 might not be significantly associated with known prognostic factors of clinically localized prostate cancer in Korean men .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK59___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"P17936 is a poor parameter for assessment of clinical activity in acromegaly . OBJECTIVE : Elevated serum P05019 and IGF binding protein - 3 ( P17936 ) levels have been found in patients with active acromegaly . We have studied the relative diagnostic merits of measurements of P17936 compared with P05019 as a parameter of disease activity in these patients . DESIGN / PATIENTS : Thirty untreated patients with acromegaly were compared with 30 healthy adults . MEASUREMENTS : Twenty - four - hour sampling for serum GH in patients with acromegaly , serum P05019 and P17936 . RESULTS : Mean P05019 levels were 22 . 0 nmol / l ( range 6 . 5 - 38 . 4 ) in the healthy adults and 118 . 7 nmol / l ( range 67 . 7 - 206 . 0 ) in patients with acromegaly . Mean P17936 levels were 3 . 5 mg / l ( range 2 . 1 - 4 . 8 ) in controls and 5 . 4 mg / l ( range 4 . 2 - 6 . 6 ) in patients with acromegaly . Mean P05019 / P17936 ratios were 6 . 5 nmol / mg ( range 1 . 9 - 14 . 5 ) in the healthy adults and 22 . 0 nmol / mg ( range 14 . 3 - 32 . 7 ) in patients with acromegaly . There was a considerable overlap for P17936 levels but not for P05019 levels , between normals and acromegalics . The P05019 / P17936 ratio also showed overlap between normals and acromegalics . There was a significant correlation between the mean 24 - hour GH and P17936 levels ( P = 0 . 036 ) and between the P05019 and P17936 levels ( P < 0 . 002 ) in acromegaly . In patients with acromegaly , the P17936 levels showed a decrement , but the P05019 / P17936 ratio did not change significantly with age . CONCLUSIONS : P18065 has no additional discriminatory value over DB01277 measurements for the assessment of clinical activity in acromegaly . In acromegaly , P17936 decreases with increasing age . In acromegaly , P17936 levels significantly correlate with mean 24 - hour GH levels and P05019 levels .",
"Analysis of mRNA transcripts for insulin - like growth factor receptors and binding proteins in bovine embryos derived from somatic cell nuclear transfer . The low efficiency of animal production using somatic cell nuclear transfer procedures is considered to be the result of an incomplete reprogramming of donor cell nucleus , which leads to abnormal expression of developmentally important genes . The objective of this study was to determine the abundance of gene transcripts of insulin - like growth factor ( IGF ) - related genes in cloned bovine embryos reconstructed with somatic cells . Single embryos derived from nuclear transfer reconstructed with somatic cells ( NT - SC ) or embryo blastomeres ( NTEM ) , in vitro fertilization ( IVF ) , in vivo production ( Vivo ) , and parthenogenetic treatment ( PA ) were analyzed . The relative abundance of mRNA was examined by real - time PCR . Transcripts of the DB01277 receptor ( r ) and IGF binding protein ( BP ) - 2 were detected in all embryos , regardless of origin . IGF - IIr and P17936 transcripts signals in NT - SC embryos were detected with significantly lower frequencies of 25 and 50 % , respectively . Although IGF - Ir and IGFIIr transcript levels were not significantly different in NT - SC , NT - EM , IVF , Vivo , and PA embryos , the relative abundance in individual embryos indicated large variation in NT - SC . P18065 and P17936 levels were high in the Vivo embryos compared with NT - SC , NT - EM , IVF , or PA embryos . These results suggest differences in levels of transcripts of IGF - related genes in the bovine embryos produced by NT compared with IVF , Vivo , and PA .",
"Diagnostic utility of serum GH , DB01277 and P17936 in patients of acromegaly with uncontrolled diabetes : a pilot study . PURPOSE : Diagnosis of acromegaly in presence of uncontrolled diabetes mellitus is not well validated . METHOD : The study included 10 patients of active acromegaly with uncontrolled blood glucose , 10 patients of type 2 diabetes mellitus with poor glycemic control and 10 healthy subjects . The growth hormone level following oral glucose tolerance test and insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor - binding protein - 3 ( P17936 ) were done at baseline in all the 3 groups and it was repeated after short term glycemic control in type 2 diabetics and acromegalics with diabetics RESULTS : In the acromegalic group the basal GH value was very high ( 36 . 5 + 1 . 6 ) ng / ml and it was non - suppressible ( 32 . 5 + 1 . 43 ) ng / ml after OGTT . The mean DB01277 and P17936 values were also high at baseline ( 208 . 38 + 38 . 51 ) ng / ml , and 7322 + 370 ng / ml respectively . In the non - acromegalic diabetic patients , the basal growth hormone value was marginally elevated ( 2 . 3 + 0 . 02 ) ng / ml . However , it was suppressible to 0 . 2 + 0 . 04 ng / ml after oral glucose load . In them the DB01277 and P17936 values were not elevated and comparable to that of healthy controls . CONCLUSIONS : Basal serum GH and P17936 levels are not influenced by degree of glycemic control however serum DB01277 levels should be interpreted with caution in patients of acromegaly with diabetes . Oral glucose load test has discriminating ability to diagnose acromegaly even with poorly controlled diabetes .",
"[ Chronic renal failure and growth hormone : effects on GH - IGF axis and leptin ] . AIM : To analyze the changes in DB01277 , P17936 , leptin and insulin after replacement doses of recombinant human growth hormone ( rhGH ) in short prepubertal children with chronic renal failure ( CRF ) . PATIENTS AND METHODS : Eleven children ( 3F : 8M ) , with mean age of 9 . 6 years , were treated with rhGH ( 0 . 23 mg / Kg weekly for 12 months ) . Serum leptin , insulin , glucose , DB01277 and P17936 were measured before , 6 and 12 months after beginning rhGH treatment . RESULTS : The serum levels of leptin , insulin and glucose did not vary during the treatment ; normal leptin and glucose levels and high insulin were observed . There was a significant increment of DB01277 and P17936 during the use of rhGH . CONCLUSIONS : The replacement doses of rhGH during 12 months in a selected group of CRF children determined an increment in DB01277 and P17936 , associated to normal serum leptin and insulin resistance .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK82___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"P05019 enhances cortisol secretion from guinea - pig adrenal gland : in vivo and in vitro study . P01308 - like growth factor ( IGF ) - I is a ubiquitously synthesized peptide that , along with P01344 , acts via the IGF - R type I receptor . P05019 and its receptor are expressed in the adrenal gland of humans and bovines , the secretion of which they seem to stimulate . As in humans and cows , the main glucocorticoid hormone secreted by guinea - pig adrenals is cortisol , and hence we have studied the adrenocortical effects of P05019 in this species . In vivo experiments showed that prolonged P05019 administration raised the plasma concentration of cortisol in both normal and dexamethasone / captopril - treated guinea pigs , thereby ruling out the possibility that P05019 may act by activating the hypothalamic - pituitary - adrenal axis and the renin - angiotensin system . In vitro experiments demonstrated that P05019 enhanced basal , but not maximally agonist [ DB01285 and angiotensin - II ( Ang - II ) ] - stimulated , cortisol secretion from freshly dispersed guinea - pig inner adrenocortical cells . The P05019 immuno - neutralization suppressed the P05019 secretagogue effect , without altering the cortisol response to both DB01285 and Ang - II . P05019 raised cyclic - AMP and inositol triphosphate release from dispersed guinea - pig cells , and the effect was reversed by the adenylate cyclase inhibitor SQ - 22536 and the phospholipase - C ( P98160 ) inhibitor U - 73122 . SQ - 22536 , U - 73122 , the protein kinase ( PK ) A inhibitor H - 89 and the PKC inhibitor calphostin - C decreased by approximately 50 % the cortisol response of dispersed cells to P05019 , and the combined exposure to SQ - 22536 and U - 73122 abolished it . We conclude that P05019 stimulates glucocorticoid secretion from guinea - pig adrenocortical cells , acting via selective receptors coupled to both the adenylate cyclase / PKA - and P98160 / PKC - dependent signaling cascades .",
"Short - term isotretinoin treatment decreases insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 levels : does isotretinoin affect growth hormone physiology ? BACKGROUND : DB00982 is an effective treatment for acne vulgaris . However , it has numerous side - effects . It was previously reported that serum growth hormone ( GH ) levels decreased with isotretinoin treatment . OBJECTIVES : To analyse whether isotretinoin has any effects on insulin - like growth factor - 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and GH levels . METHODS : Forty - seven patients aged 21 . 5 +/- 5 . 1 years ( mean +/- SD ) with acne vulgaris were included in this study . DB00982 therapy was initiated at a dose of 0 . 5 - 0 . 75 mg kg (- 1 ) daily and then adjusted to 0 . 88 mg kg (- 1 ) daily as maintenance dosage after 1 month . Screening for biochemical and hormonal parameters was performed just before initiation and after 3 months of isotretinoin treatment . RESULTS : DB01277 and P17936 levels decreased significantly after treatment ( P < 0 . 01 ) , while GH levels did not change . Post - treatment , significant increases were seen in aspartate aminotransferase , total cholesterol , low - density lipoprotein cholesterol , triglycerides and low - density lipoprotein cholesterol / high - density lipoprotein cholesterol ratio ( P < 0 . 0001 ) while high - density lipoprotein cholesterol levels were significantly decreased ( P < 0 . 0001 ) . CONCLUSIONS : DB00982 therapy may have an effect on GH physiology , and further studies are needed to understand this association .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK32___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK32___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK32___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK32___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Phase 2 trial of cixutumumab in children , adolescents , and young adults with refractory solid tumors : a report from the Children ' s Oncology Group . PURPOSE : This phase 2 study was designed to assess the efficacy of single agent cixutumumab ( DB05759 ) and gain further information about associated toxicities and pharmacodynamics in children , adolescents , and young adults with recurrent or refractory solid tumors . PATIENTS AND METHODS : Patients with relapsed or refractory solid tumors were treated with 9 mg / kg of cixutumumab as a 1 - hour IV infusion once weekly . Strata included : osteosarcoma , Ewing sarcoma , rhabdomyosarcoma , neuroblastoma ( evaluable disease ) , neuroblastoma ( measurable disease ) , Wilms tumor , adrenocortical carcinoma , synovial sarcoma , hepatoblastoma , and retinoblastoma . Correlative studies in consenting patients included an assessment of c - peptide , P17936 , DB01277 , IGF - 2 , hGH , and insulin in consenting patients . RESULTS : One hundred sixteen patients with 114 eligible having a median age of 12 years ( range , 2 - 30 ) were enrolled . Five patients achieved a partial response : 4 / 20 with neuroblastoma ( evaluable only ) and 1 / 20 with rhabdomyosarcoma . Fourteen patients had stable disease for a median of 10 cycles . Hematologic and non - hematologic toxicities were generally mild and infrequent . Serum DB01277 and P17936 increased in response to therapy with cixutumumab . CONCLUSION : Cixutumumab is well tolerated in children with refractory solid tumors . Limited objective single - agent activity of cixutumumab was observed ; however , prolonged stable disease was observed in 15 % of patients . Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway .",
"Association of IGF1 and P17936 polymorphisms with colorectal polyps and colorectal cancer risk . PURPOSE : DB01277 ( IGF1 ) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis . The bioavailability of IGF1 is regulated by the insulin - like growth factor binding protein 3 ( P17936 ) . The purpose of this study was to examine the association of genetic variants in IGF1 ( rs6214 , rs6220 , and rs35767 ) and P17936 ( rs2854744 and rs2854746 ) with risk of colorectal polyps and colorectal cancer . METHODS : In this ongoing colorectal cancer study of Austria ( CORSA ) , a total of 3 , 360 Caucasian participants , consisting of 178 colorectal cancer patients , 328 patients with high risk polyps , 1 , 059 patients with low risk colorectal polyps , and 1 , 795 colonoscopy - negative controls , were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna . Multiple logistic regression was applied to compare individuals of the control group against three different risk groups , namely , colorectal cancer group , high risk polyp group , and low risk polyp group . RESULTS : Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk ( OR = 1 . 79 , 95 % CI 1 . 04 - 1 . 90 ) compared to the colonoscopy - negative controls ; this was also found when combining colorectal cancer cases and high risk polyp group ( OR = 1 . 39 , 95 % CI 1 . 01 - 1 . 90 ) . CONCLUSION : Our results suggest that the SNP rs6214 of IGF1 could have an impact on developing colorectal cancer and colorectal polyps with villous elements .",
"Efficacy of ganitumab ( Q99217 479 ) , alone and in combination with rapamycin , in Ewing ' s and osteogenic sarcoma models . Ewing ' s and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents . Recent data suggest that sarcomas may depend on the insulin - like growth factor type 1 ( DB01277 ) receptor ( P08069 ) and / or the insulin receptor ( P06213 ) to drive tumor growth , survival , and resistance to mammalian target of rapamycin complex 1 ( mTORC1 ) inhibitors . We evaluated the therapeutic value of ganitumab ( Q99217 479 ; C ( 6472 ) H ( 10028 ) N ( 1728 ) O ( 2020 ) S ( 42 ) ) , an anti - P08069 , fully human monoclonal antibody , alone and in combination with rapamycin ( mTORC1 inhibitor ) in Ewing ' s ( SK - ES - 1 and A673 ) and osteogenic ( SJSA - 1 ) sarcoma models . P08069 was activated by DB01277 but not by insulin in each sarcoma model . P06213 was also activated by DB01277 in the SJSA - 1 and SK - ES - 1 models , but not in the A673 model where insulin was the preferred P06213 ligand . Ganitumab significantly inhibited the growth of SJSA - 1 and SK - ES - 1 xenografts ; inhibition was associated with decreased P08069 and Akt phosphorylation , reduced total P08069 and bromodeoxyuridine detection , and increased caspase - 3 expression . Ganitumab inhibited rapamycin - induced P08069 , Akt , and glycogen synthase kinase - 3β hyperphosphorylation in each sarcoma model . However , ganitumab in combination with rapamycin also resulted in a marked increase in P06213 expression and activity in the SJSA - 1 and A673 models . The in vivo efficacy of ganitumab in the two ganitumab - sensitive models ( SJSA - 1 and SK - ES - 1 ) was significantly enhanced in combination with rapamycin . Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that P06213 signaling is an important mechanism of resistance to P08069 blockade .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK68___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Inflammatory responses of the substantia nigra after acute hypoxia in neonatal rats . The neocortex and the striatum are the brain regions most known to be particularly vulnerable to acute insults like hypoxia or ischemia . In this work , we assess the possibility of cellular damage to the substantia nigra ( SN ) after hypoxia - reoxygenation in the new born rat . The aim of the present paper was to evaluate the expression of growth factor P05019 , and growth factor binding proteins P17936 and P24593 genes and induction of NOS family members ( P29475 , P29474 and P35228 ) and P01375 genes together with glia activation , in the SN at 5 and 48 h after severe hypoxia in the 7 day - old rat , a model for the term human fetus . At early time , while IGFs remain unchanged , we found a transient increase in P29474 and P29475 . Two days after the injury , P29475 expression remained high , P35228 and P01375 increased and also P14136 protein expression was observed together with a profusion of reactive astrocytes distributed throughout the SN . This study on the acute effects of hypoxia on the developing brain provides additional insights into the vulnerability of the SN , a brain region involved in neurodegenerative pathologies .",
"P42345 complex 2 in adipose tissue negatively controls whole - body growth . P42345 ( P42345 ) , a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors , is found in 2 structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . mTORC2 , which consists of rictor , Q9BPZ7 , Q9BVC4 , and P42345 , is activated by insulin / IGF1 and phosphorylates DB00133 - 473 in the hydrophobic motif of Akt / P31749 . Though the role of P42345 in single cells is relatively well characterized , the role of P42345 signaling in specific tissues and how this may contribute to overall body growth is poorly understood . To examine the role of mTORC2 in an individual tissue , we generated adipose - specific rictor knockout mice ( rictor ( ad -/-) ) . Rictor ( ad -/-) mice are increased in body size due to an increase in size of nonadipose organs , including heart , kidney , spleen , and bone . Furthermore , rictor ( ad -/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic , but glucose tolerant , and display elevated levels of insulin - like growth factor 1 ( IGF1 ) and IGF1 binding protein 3 ( P17936 ) . These effects are observed in mice on either a high - fat or a normal diet , but are generally more pronounced in mice on a high - fat diet . Our findings suggest that adipose tissue , in particular mTORC2 in adipose tissue , plays an unexpectedly central role in controlling whole - body growth .",
"Ramadan fasting and the GH / DB01277 axis of trained men during submaximal exercise . AIMS : The aim of this study was to explore possible changes in body composition , blood glucose regulation , plasma growth hormone ( GH ) , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) , and insulin concentrations of trained athletes in response to the intermittent fasting and dehydration of Ramadan observance . METHODS : Nine trained male rugby players ( age 19 +/- 2 years , height 1 . 78 +/- 0 . 74 m ) were tested 3 times : before Ramadan ( C ) , at the end of the first week ( Q96GN5 ) , and during the fourth week ( R2 ) . They performed a progressive cycle ergometer test at each visit . The work rate was increased in 6 - min stages corresponding to 20 , 30 , 40 , 50 and 60 % of W max . Substrate oxidation was evaluated by indirect calorimetry . On each occasion , substrate and plasma hormone concentrations were measured at rest and at the end of the exercise . RESULTS : Ramadan fasting induced a significant decrease in body mass and body fat ( R2 vs . C , p < 0 . 001 ) . Plasma concentrations of glucose , insulin , GH , DB01277 and P17936 did not change significantly between C and R2 , either at rest or following exercise . CONCLUSION : Ramadan fasting induces positive changes in body composition without disturbing glucose regulation or activity of the GH / DB01277 system .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK85___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK85___ .",
"Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV - 1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin - positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 - related Drosophila models has further strengthened the hypothesis that both Q13148 \" loss - of - function \" and \" gain - of - function \" mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies .",
"Effect of individualized exercise training combined with diet restriction on inflammatory markers and DB01277 / P17936 in obese children . AIMS : The present study was designed to examine the possible changes in body composition , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor - binding protein - 3 ( P17936 ) and inflammatory markers of obese children in response to a 2 - month program of exercise training combined with dietary restriction . METHODS : Twenty - eight obese children ( age 13 . 2 +/- 0 . 7 years , body mass index 30 . 9 +/- 1 . 3 ) were randomly assigned to a diet / training group or a control group and were tested two times : once before and once at the end of the experimental period . They performed a progressive cycle ergometer test at each visit . Substrate oxidation was evaluated by indirect calorimetry . Training was individualized at the point when fat oxidation was maximal ( Lipox ( max ) ) . RESULTS : Diet / training induced a significant decrease in body weight and body fat ( after vs . before , p < 0 . 01 ) . Plasma concentrations of DB01277 , P17936 and inflammatory markers were significantly decreased after the completion of the program . The diet / training program resulted in an increase in VO ( 2max ) ACSM ( 24 . 6 +/- 2 . 5 to 33 . 1 +/- 3 . 1 ml / min / kg , p < 0 . 001 ) at the end of the intervention period . CONCLUSION : These data suggest that in the presence of weight loss , exercise training improves inflammatory markers and DB01277 and P17936 levels in obese children .",
"Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .",
"Tyrosine phosphorylation of insulin receptor substrate - 1 ( P35568 ) by oxidant stress in cerebellar granule neurons : modulation by N - methyl - D - aspartate through calcineurin activity . P06213 - substrate - 1 ( P35568 ) is a docking protein for several tyrosine kinase receptors . Upon tyrosine phosphorylation , P35568 binds to signaling molecules that express Src homology 2 ( SH - 2 ) binding domains , including phosphatidylinositol 3 - kinase ( PI 3 - kinase ) , phosphotyrosine phosphatase Q06124 ( Syp ) , Nck , Crk and Grb - 2 . Hydrogen peroxide ( H ( 2 ) O ( 2 ) ) induces tyrosine phosphorylation of key signaling mediators presumably by inhibition of tyrosine phosphatases . In many cell types , the activation of extracellular signal - related kinases ( e . g . MAPK ) and other protein kinases by H ( 2 ) O ( 2 ) leads to transcriptional activation . In the current study , we examined the effect of H ( 2 ) O ( 2 ) on P35568 tyrosine phosphorylation in primary cultured rat cerebellar granule neurons . H ( 2 ) O ( 2 ) stimulated the rapid tyrosine phosphorylation of P35568 and Q8NFH3 / Q8TCB0 Q96HU1 kinase , and induced its association with PI 3 - kinase . H ( 2 ) O ( 2 )- induced P35568 phosphorylation was rapidly reversible ( 5 min ) whereas MAPK phosphorylation persisted for up to 1 h . DB01221 reversed H ( 2 ) O ( 2 )- mediated tyrosine phosphorylation of P35568 and its association with PI 3 - kinase . The dephosphorylation of P35568 by DB01221 was calcium - dependent and was inhibited by the calcineurin inhibitor cyclosporine . P62158 - dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine - phosphorylated P35568 as substrates . These data highlight the role of multiple phosphatases in the regulation of P35568 tyrosine phosphorylation and identify a novel functional property of calcineurin .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK45___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Matrix metalloproteinase 19 regulates insulin - like growth factor - mediated proliferation , migration , and adhesion in human keratinocytes through proteolysis of insulin - like growth factor binding protein - 3 . Unlike most other matrix metalloproteinases ( MMPs ) Q99542 is expressed in undifferentiated basal keratinocytes of healthy human skin . The human keratinocyte cell line HaCaT , which like basal keratinocytes constitutively expresses Q99542 , down - regulated the expression of Q99542 at high calcium concentrations . DB01373 - regulation occurred through P12830 mediated cell - cell contacts because neutralizing anti - P12830 antibodies restored Q99542 expression in high calcium . Overexpression of Q99542 in HaCaT cells ( HaCaT - WT ) increased cellular proliferation , as well as migration and adhesion on type I collagen . This was due to proteolysis of the insulin - like growth factor ( IGF ) binding protein - 3 by Q99542 , which augmented signaling through the P08069 , as evidenced by its increased autophosphorylation . Conversely , these effects were not observed in cells transfected with P08253 or a catalytically inactive Q99542 mutant . As further proof that increased IGF - signaling promoted adhesion and migration in HaCaT - WT cells , we reproduced these effects by treating parental HaCaT with P05019 . We observed dephosphorylation of the focal adhesion kinase in HaCaT - WT as well as P05019 - treated HaCaT cells , suggesting that inactivating focal adhesion kinase is a mechanism by which P05019 enhances adhesion . Furthermore , P05019 - triggered motility on type I collagen was mediated by MMP activity , which , however , was distinct from Q99542 . Considering the coexpression of P17936 and Q99542 in the skin , we conclude that Q99542 is a likely candidate to be the major P17936 degrading MMP in the quiescent epidermis . This activity might have widespread consequences for the behavior of epidermal keratinocytes .",
"Growth hormone reserve in adult beta thalassemia patients . Reduced serum insulin - like growth factor - 1 ( DB01277 ) and hypogonadotrophic hypogonadism are common features of adult beta - thalassemia , and warrant evaluation of the growth hormone ( GH ) - DB01277 axis . The aim of this study was to determine GH reserve in beta - thalassemia patients ( 9 females , 7 males , 15 major , 1 intermedia ) , age 29 . 3 +/- 6 . 9 years , BMI 21 . 3 +/- 1 . 9 kg / m2 , and in 20 age , sex and BMI - matched healthy controls , using the GH - releasing hormone ( P01286 ) - arginine test . The associations between peak GH response and hormonal and biochemical indices were evaluated . Using BMI - related cut - off limits for peak GH response in the P01286 - arginine test , 4 / 16 beta - thalassemia patients had peak GH lower than 11 . 5 microg / l , the cut - off limit suggested for lean subjects , and were diagnosed as GH deficient ( GHD ) . Using 9 microg / l as the cut - off limit 2 / 16 patients were GHD . Reduced serum DB01277 and P17936 were present in 69 % and 19 % of the patients , respectively . Peak GH did not correlate with serum DB01277 , DB00024 , and fT4 levels or gonadal status . Neither peak GH nor DB01277 correlated with serum ferritin . Our findings suggest that GHD is present in up to a quarter of adult beta - thalassemia patients . The clinical benefits of GH therapy need to be determined . GHD alone does not account for the high prevalence of reduced DB01277 in adult beta - thalassemia .",
"Effects of alternate - day or daily prednisone treatment on GH and cortisol levels in growth - retarded children after renal transplantation . Growth retardation after renal transplantation ( RTx ) is generally attributed to prednisone ( PDN ) administration , although the exact mechanism is poorly understood . In a group of 19 growth - retarded patients after RTx , we studied the effect of alternate - day ( group AD , n = 12 ) and daily ( group D , n = 7 ) PDN treatment on the spontaneous plasma growth hormone ( GH ) and cortisol profiles , for 48 h in group AD and for 24 h in group D . The maximal plasma GH response to arginine provocation ( ATT ) and plasma levels of insulin - like growth factor - 1 ( DB01277 ) , IGF - 2 and serum IGF - binding proteins ( IGFBP ) were also determined . For both groups the PDN doses were recalculated as daily doses for comparison . The median PDN dose in both groups was similar , 0 . 15 mg / kg / day , with a range of 0 . 10 - 0 . 25 mg / kg / day . Glomerular filtration rate ( Q92565 ) was above 20 ml / min / 1 . 73 m2 in all patients . We hypothesized that alternate - day PDN therapy and even more so daily PDN therapy would have a deleterious effect on GH and cortisol secretion and would result in lower GH - dependent growth factors as compared to control data of healthy children . Our findings revealed that growth - retarded renal allograft patients , receiving either alternate - day or daily PDN therapy , have significantly lower mean plasma GH levels than controls , but normal diurnal rhythm of GH and cortisol secretion as well as normal immunoreactive DB01277 and - 2 levels . Mean serum P08833 levels were normal , but mean serum P17936 levels were significantly increased , while a significant negative correlation was found between the Q92565 and serum P17936 levels . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Evaluation of the synergistic effect of insulin resistance and insulin - like growth factors on the risk of breast carcinoma . BACKGROUND : The purpose of the current study was to investigate the association between insulin resistance ( which was measured using fasting blood C - peptide ) and its joint association with insulin - like growth factors ( DB01277 , IGF - 2 , and IGF binding protein - 3 [ P17936 ] ) on the risk of breast carcinoma . METHODS : Included in the current study were 400 case - control pairs from the Shanghai Breast Cancer Study . Pretreatment biospecimens and interview data were collected from all breast carcinoma cases and their individually matched controls . RESULTS : Breast carcinoma risk was found to be statistically significantly increased when higher blood levels of C - peptide and IGFs were noted in a dose - response manner . There was a statistically significant twofold to threefold increased risk of breast carcinoma for women in the highest quartile of C - peptide , DB01277 , or P17936 compared with women in the lowest quartiles . Women with high levels of both C - peptide and DB01277 or P17936 also were found to have a substantially higher risk of breast carcinoma than those women with a high level of only one of these molecules . The adjusted odds ratios ( ORs ) were 3 . 79 ( 95 % confidence interval [ 95 % CI ] , 2 . 03 - 7 . 08 ) for those with a higher level of both C - peptide and DB01277 and 4 . 03 ( 95 % CI , 2 . 06 - 7 . 86 ) for those with a higher level of both C - peptide and P17936 . CONCLUSIONS : The results of the current study suggest that insulin resistance and IGFs may synergistically increase the risk of breast carcinoma .",
"Syngeneic living - donor liver transplantation for hemangioendothelioma : a clinical model for studying liver regeneration . A 22 - year - old Caucasian patient underwent living - donor liver transplantation ( LDLT ) for hepatic hemangioendothelioma in a healthy liver . The organ donor was his monozygotic twin brother . Surgery was uneventful in both donor and recipient , who received the same postoperative treatment ( i . e . no immunosuppression for the recipient ) . Although both donor and recipient achieved a full liver function recovery , the volume of the recipient ' s graft increased much more than the donor ' s residual liver in the first postoperative month ( 1 . 6 - fold vs . 1 . 2 - fold ) . This different growth rate correlated with growth hormone ( GH ) / insulin growth factor ( IGF ) axis dynamics : the donor had significantly lower insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor 2 ( IGF - 2 ) and insulin - like growth factor binding protein 3 ( P17936 ) values than the recipient on postoperative days ( POD ) 3 - 30 , although they had similar GH values . Other potential regenerative factors , e . g . tumor necrosis alpha , interleukin 6 ( P05231 ) , insulin and C peptide did not correlate with liver regeneration rate . The particular endocrine picture of the graft may be explained by a modified GH - hepatocyte interaction due to cold ischemia during preservation resulting in a higher IGF production . Whether this is a potential molecular tool by means of which transplanted partial livers promote their regeneration remains to be seen in a larger number of patients .",
"Q12778 content is reduced in cystic fibrosis and increases with P05019 treatment . Cystic fibrosis - related diabetes is to date the most frequent complication in cystic fibrosis ( CF ) . The mechanisms underlying this condition are not well understood , and a possible role of insulin resistance is debated . We investigated insulin signal transduction in CF . Total insulin receptor , P35568 , p85 PI3K , and AKT contents were substantially normal in CF cells ( CFBE41o - ) , whereas winged helix forkhead ( FOX ) O1 contents were reduced both in baseline conditions and after insulin stimulation . In addition , CF cells showed increased P27361 / 2 , and reduced β2 arrestin contents . No significant change in O14508 was observed . By using a P13569 inhibitor and siRNA , changes in Q12778 were related to P13569 loss of function . In a CF - affected mouse model , Q12778 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild - type . DB01277 ( P05019 ) increased Q12778 content in vitro and in vivo in muscle and adipose tissue . In conclusion ; we present the first description of reduced Q12778 content in CF , which is compatible with reduced gluconeogenesis and increased adipogenesis , both features of insulin insensitivity . P05019 treatment was effective in increasing Q12778 , thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis - related diabetes .",
"Phase II open label , multi - center clinical trial of modulation of intermediate endpoint biomarkers by 1α - hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin . BACKGROUND : Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention . Major risk factors for this disease have been associated with low serum levels of vitamin D . Here , we evaluate the biologic activity of a less calcemic vitamin D analog 1α - hydroxyvitamin D2 [ 1α - OH - D2 ] ( Bone Care International , Inc . ) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia ( HG P63167 ) . METHODS : Patients with clinically organ - confined prostate cancer and HG P63167 were randomized to 1α - OH - D2 versus placebo for 28 days prior to radical prostatectomy . Intermediate endpoint biomarkers included serum vitamin D metabolites , TGFß 1 / 2 , free / total PSA , DB01277 , P17936 , P09038 , and P15692 . Tissue endpoints included histology , MIB - 1 and TUNEL staining , microvessel density and factor VIII staining , androgen receptor and PSA , vitamin D receptor expression and nuclear morphometry . RESULTS : The 1α - OH - D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days . While serum vitamin D metabolite levels only slightly increased , evidence of biologic activity was observed with significant reductions in serum PTH levels . TGF - ß2 was the only biomarker significantly altered by vitamin D supplementation . Whether reduced TGF - ß2 levels in our study is an early indicator of response to vitamin D remains unclear . CONCLUSIONS : While further investigation of vitamin D may be warranted based on preclinical studies , results of the present trial do not appear to justify evaluation of 1α - OH - D2 in larger clinical prostate cancer prevention studies .",
"Effects of insulin - like growth factor ( IGF ) binding protein - 3 ( P17936 ) on endometrial cancer ( HHUA ) cell apoptosis and P01133 stimulated cell proliferation in vitro . OBJECTIVE : P17936 has been demonstrated to stimulate or inhibit cell proliferation independently of its ability to bind IGF and a specific P17936 receptor has been proposed . P01133 has been implicated in the cancer development and carcinogenesis . Only limited data are available on the crosstalk between P17936 signaling and P01133 induced cell survival and signal transduction . The current studies were undertaken to characterize P17936 binding to endometrial cancer cells ( HHUA ) and determine its biological effects , as well as whether P17936 exposure alters the cell proliferation stimulated by P01133 . METHODS : Cell proliferation and apoptosis were analyzed by ELISA using specific antibodies . The interaction between HHUA cell and P17936 was analyzed using a biosensor . The phosphorylation abundance of specific proteins and their phosphorylation in response to P01133 and P17936 was analyzed by immunoprecipitation followed by immunoblotting . RESULTS : Biosensor analysis showed that P17936 could bind to HHUA cell surface . P17936 inhibited BrdU uptake , potentiated ssDNA production and induced p53 in HHUA cells . Although P01133 stimulated HHUA cell proliferation and Akt phosphorylation , P17936 inhibited cell proliferation and Akt phosphorylation that had been stimulated by P01133 . However , P01133 receptor phosphorylation and expression were not reduced by P17936 . Since HHUA cells lack IGF receptors and do not show biological response to IGF these results suggest that P17936 can bind to HHUA cells , inhibit cell proliferation and induce apoptosis independently of its ability to bind to IGFs possibly by binding to an P17936 receptor . CONCLUSIONS : Taken together these findings demonstrate that P17936 binds to HHUA cell surface , and inhibits cell division induced by P01133 , possibly by modulating the P01133 - mediated signal transduction system .",
"Effects of the route of oestrogen administration on DB01277 and P17936 in healthy postmenopausal women : results from a randomized placebo - controlled study . OBJECTIVE : Oestrogens can modulate the action or secretion of GH . Previous studies in postmenopausal women have shown a differential effect between transdermal 17beta - oestradiol and oral ethynyl - oestradiol on GH and DB01277 concentrations . This secondary analysis , based on a large randomized trial , aimed to estimate the effect of the route of administration of 17beta - oestradiol in combined hormone replacement therapy with progesterone on DB01277 and P17936 levels . DESIGN : DB01277 and P17936 were evaluated in a randomized study of 196 healthy postmenopausal women who were randomly allocated to receive on a continuous basis either 1 mg of 17beta - oestradiol orally combined with a daily intake of 100 mg progesterone ( group 1 ; n = 63 ) , or 50 microg of 17beta - oestradiol transdermally combined with a daily intake of 100 mg progesterone ( group 2 ; n = 68 ) , or triple dummy placebo ( group 3 ; n = 65 ) over a 6 - month period . IGF1 and P17936 levels were available for 133 women . RESULTS : Oral oestrogen significantly decreased DB01277 levels compared to placebo ( P = 0 . 04 ) and transdermal oestrogen ( P = 0 . 004 ) , whereas transdermal oestrogen had no effect on DB01277 levels compared to placebo ( P = 0 . 56 ) . As regards P17936 , no significant difference was detected between the three groups . CONCLUSIONS : Our data indicate that the route of oestrogen administration can influence DB01277 levels . DB01277 concentrations decreased significantly with oral oestrogen , whereas no significant change was observed with transdermal oestrogen at 6 months . The clinical relevance of these differential effects remains to be determined , particularly with regard to the risk for cardiovascular diseases .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"P15692 and serum withdrawal induced changes in the transcript profile in human endometrial endothelial cells . The changes in transcript profile induced by vascular endothelial growth factor ( P15692 ) and serum withdrawal in primary human endometrial endothelial cells ( ECs ) were investigated using microarrays , gene ontology and pathway analysis . P15692 altered the levels of transcripts involved in angiogenesis , cell survival , and apoptosis , including up - and downregulation of P31749 , Q92934 , MIF , and P17936 and O15123 , respectively . Serum deprivation induced downregulation of cell - cycle - related transcripts such as mitosis regulators Q12834 and SPC25 . Of the transcripts regulated by both P15692 and partial serum deprivation , remarkably 88 of 89 showed reciprocal regulation ( p < 1 x 10 (- 49 ) ) . These are predominantly cell - fate - associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts . Our results show that in addition to the known role of P15692 as an EC growth and survival promoter , it also regulates apoptosis - related messenger RNAs ( mRNAs ) , many of which were reciprocally regulated following serum withdrawal .",
"[ Pattern of abnormal skeletal development in girls with idiopathic precocious puberty and therapeutic effect of Chinese herbs for nourishing yin and purging fire ] . OBJECTIVE : To explore the pattern of abnormal skeletal development in girls with idiopathic precocious puberty ( IPP ) and the therapeutic effect of Chinese herbs for nourishing yin and purging fire ( CH ) . METHODS : Measurement of bone age , bone mineral content ( BMC ) and bone density ( BD ) were performed and levels of serum gla - protein ( BGP ) , insulin - like growth factor 1 ( DB01277 ) and insulin - like growth factor binding protein 3 ( P17936 ) were determined in girls with IPP at various stages of pubertal development . Data were compared with those collected from matched girls , and the correlativity between various parameters and the extent of the disease were analyzed to explore the pattern . Thirty - eight girls out of them were treated with CH and the therapeutic effect was observed . RESULTS : The bone age of the IPP girls was ahead of time obviously ( P < 0 . 05 ) , levels of BMC , BD and serum BGP , DB01277 were significantly higher than the levels in the healthy girls of matched age ( P < 0 . 05 ) . And the degree of these changes were markedly positive correlated with the severity of disease ( P < 0 . 05 ) . After being remitted with CH treatment , the advanced bone age was apparently alleviated , and above - mentioned abnormal criteria were lowered significantly ( P < 0 . 05 ) . CONCLUSION : The skeletal development of the girls with IPP was accelerated and the skeletal maturity were ahead of time , the more serious the condition of disease , the more obvious the acceleration and the advanced bone age . CH could decelerate skeletal development and delay the skeletal maturity of IPP patients .",
"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .",
"Relationship of plasma adiponectin with sex hormone and insulin - like growth factor levels . OBJECTIVE : Recent studies have suggested that a relationship between adiponectin and sex hormone , prolactin , and insulin - like growth factor levels could be important for breast cancer risk and insulin sensitivity . Therefore , we assessed the relationship of adiponectin with plasma concentrations of estrone ; estradiol ; estrone sulfate ; testosterone ; androstenedione ; dehydroepiandrosterone ( DB01708 ) ; DB05804 ( DHEAS ) ; sex hormone binding globulin ( P04278 ) ; prolactin ; insulin - like growth factor ( DB01277 ) ; its binding protein , IGF binding protein 3 ( P17936 ) ; c - peptide ; and IGF binding protein 1 ( P08833 ) among 360 postmenopausal women not taking postmenopausal hormones from the Nurses ' Health Study . RESEARCH METHODS AND PROCEDURES : Multivariate models were adjusted for physical activity , alcohol consumption , age at blood draw , age at first birth / parity , fasting status , and time of day of blood draw ; a separate model was additionally adjusted for BMI at blood draw . RESULTS : DB00286 were inversely associated with adiponectin levels ; however , except for free estradiol , these associations were substantially attenuated after adjustment for BMI . Free estradiol levels were 27 % lower among women in the top vs . bottom quartile of adiponectin levels . No consistent associations were observed for the androgens , prolactin , DB01277 , and P17936 . However , P04278 , c - peptide , and P08833 were strongly and independently associated with adiponectin levels ( r = 0 . 29 , - 0 . 30 , 0 . 24 , respectively ) . CONCLUSION : With the exceptions of P04278 , c - peptide , and P08833 , the studied analytes were modestly associated with adiponectin and the associations were , in large part , mediated by body fat .",
"Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK16___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .",
"The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve .",
"DB01277 , its binding protein 3 , and sex hormones in girls during puberty . The aim of the study was to estimate relationships between serum concentration of insulin - like growth factor 1 ( DB01277 ) , its binding protein ( P17936 ) , estradiol and testosterone in girls during puberty , taking into consideration gonadotropins level and nutritional status . Eighty - six girls aged 9 . 8 - 14 . 7 were examined . The girls were divided into three groups according to the pubertal stage . Body height , weight and thicknesses of skin folds were measured . Biochemical parameters were assessed using RIA method . It has been found that all investigated parameters are growing with pubertal development . There are significant positive correlations between DB01277 and testosterone , DB01277 and estradiol serum concentrations as well as between DB01277 serum concentration , BMI and sum of skin folds thicknesses . It has been also proved that there are positive correlations between P17936 and estradiol serum concentration as well as between P17936 and age , body height and body weight in girls during puberty .",
"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .",
"Monitoring the activation state of the insulin - like growth factor - 1 receptor and its interaction with protein tyrosine phosphatase 1B using bioluminescence resonance energy transfer . We have developed two bioluminescence resonance energy transfer ( BRET ) - based approaches to monitor 1 ) ligand - induced conformational changes within partially purified insulin - like growth factor - 1 ( DB01277 ) receptors ( P08069 ) and 2 ) P08069 interaction with a substrate - trapping mutant of protein tyrosine phosphatase 1B ( P18031 - D181A ) in living cells . In the first assay , human P08069 fused to Renilla reniformis luciferase ( Rluc ) or yellow fluorescent protein ( YFP ) were cotransfected in human embryonic kidney ( P29320 ) - 293 cells . The chimeric receptors were then partially purified by wheat germ lectin chromatography , and BRET measurements were performed in vitro . In the second assay , BRET measurements were performed on living P29320 - 293 cells cotransfected with P08069 - Rluc and YFP - P18031 - D181A . Ligand - induced conformational changes within the P08069 and interaction of the P08069 with P18031 could be detected as an energy transfer between Rluc and YFP . Dose - response experiments with DB01277 , IGF - 2 , and insulin demonstrated that the effects of these ligands on BRET correlate well with their known pharmacological properties toward the P08069 . Inhibition of P08069 autophosphorylation by the tyrphostin AG1024 ( 3 - bromo - 5 - t - butyl - 4 - hydroxy - benzylidenemalonitrile ) resulted in the inhibition of IGF1 - induced BRET signal between the P08069 and P18031 . In addition , an anti - P08069 antibody known to inhibit the biological effects of DB01277 inhibited ligand - induced BRET signal within the P08069 , as well as between P08069 and P18031 . This inhibition of BRET signal paralleled the inhibition of the ligand - induced autophosphorylation of the P08069 by this antibody . In conclusion , these BRET - based assays permit 1 ) the rapid evaluation of the effects of agonists or inhibitory molecules on P08069 activation and 2 ) the analysis of the regulation of P08069 - P18031 interaction in living cells .",
"P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .",
"[ Research advances on Q9UKQ2 expression and Q9UKQ2 - mediated tumor metastasis ] . A disintegrin - metalloproteinase 28 ( Q9UKQ2 ) is one of important members of ADAM family , that is involved in various biological events including cell adhesion , proteolysis , growth and metastasis of solid tumors and hematological malignancies . Studies have shown that Q9UKQ2 is highly expressed in several human tumors , such as lung , breast and bladder cancers , and chronic lymphocytic leukemia , and its tissue expression levels correlate with cancer metastasis . Q9UKQ2 - mediated cancer cell metastasis may be related with the cleavage of von Willebrand ' s factor ( P04275 ) , insulin - like growth factor binding protein - 3 ( P17936 ) and connective tissue growth factor ( P29279 ) , as well as the promoting Q14242 / P16109 - mediated cell adhesion . This review summarizes the basic and translational aspects of Q9UKQ2 biology that might stimulate the interest in Q9UKQ2 research and discovery of novel Q9UKQ2 targets , providing potential novel therapies for metastatic cancers .",
"Efficacy and safety of mecasermin rinfabate . There has been interest in using recombinant human ( rh ) insulin - like growth factor ( IGF ) - I ( rhIGF - I ) to treat short stature , either alone or in combination with its binding protein ( insulin - like growth factor binding protein [ IGFBP ] - 3 ) . P05019 has been shown to increase growth velocity in children with IGF deficiency , either as a result of growth hormone insensitivity syndrome ( GHIS ) or IGF gene deletion . However , there have been adverse events , particularly hypoglycaemia , reported with administration of unbound rhIGF - I . In addition , the serum half - life of unbound rhIGF - I is shorter when administered to patients with GHIS , who have low serum concentrations of its binding proteins P17936 and acid - labile subunit ( P35858 ) , than when administered to normal volunteers or to the patient with an P05019 gene deletion ( who had normal levels of P17936 ) . iPlex ( mecasermin rinfabate ) , an equimolar mixture of P05019 and its binding protein P17936 , was developed to prolong the half - life and to counteract acute adverse events ( particularly hypoglycaemia ) associated with administration of P05019 . Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders , it does appear that mecasermin rinfabate has a longer half - life in patients with GHIS than unbound P05019 , and fewer reports of adverse events ( including hypoglycaemia ) when administered to patients with diabetes .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Endocrine manifestations of chromosome 22q11 . 2 microdeletion syndrome . BACKGROUND : Endocrine abnormalities , including hypocalcemia , thyroid dysfunction , and short stature , are associated with chromosome 22q11 . 2 microdeletion syndrome . This study was undertaken to examine the frequencies and clinical features of endocrine abnormalities in patients with 22q11 . 2 microdeletion syndrome . METHODS : We analyzed 61 patients with 22q11 . 2 microdeletion syndrome diagnosed based on the verification of microdeletion by fluorescent in situ hybridization ( Q5TCZ1 ) using a probe of the DiGeorge syndrome critical region ( P54198 ) at 22q11 . 2 and a control probe , ARSA at 22q13 . Serum total calcium , phosphorus , and intact parathyroid hormone ( PTH ) levels were measured , thyroid function test was performed , and serum DB01277 and P17936 levels were also estimated . Height and weight of patients were compared with individual chronological ages . RESULTS : Hypocalcemia was found in 20 patients ( 32 . 8 % ) , and overt hypoparathyroidism in 8 ( 13 . 1 % ) . Two patients ( 3 . 3 % ) showed autoimmune thyroid diseases , 1 each with Graves ' disease and Hashimoto thyroiditis . Ten patients ( 16 . 4 % ) were below the third percentile in height , but the serum DB01277 level was normal in 9 out of these 10 patients . CONCLUSION : Our findings show that patients with chromosome 22q11 . 2 microdeletion syndrome present with variable endocrine manifestations and variable clinical phenotypes . In addition to Q5TCZ1 analysis , careful endocrine evaluations are required in patients with this microdeletion syndrome , particularly for those with hypoparathyroidism or thyroid dysfunction .",
"Anabolic effects of insulin - like growth factor in combination with insulin - like growth factor binding protein - 3 in severely burned adults . BACKGROUND : The purpose of this study was to determine the anabolic effects of recombinant human insulin - like growth factor - I ( rhIGF - 1 ) complexed with its principal binding protein DB01277 binding protein - 3 ( P17936 ) in severely burned adults . METHODS : Ten burned adults were studied consecutively after receiving saline ( pretreatment ) , then rhIGF - 1 / P17936 ( treatment ) for 5 days . Doses were 1 , 2 , and 4 mg / kg per day . DB09341 , electrolytes , hormones , and leg muscle protein metabolism were determined . Nine other studies were performed on similarly injured adults at comparable times to the treatment studies to control for time effects . RESULTS : Serum DB01277 and P17936 levels increased with all doses , but no incremental increases were found . Leg protein balance improved with rhIGF - 1 / P17936 , which was associated with an increase in muscle protein fractional synthetic rate . These effects were independent of time . All patients were euglycemic without electrolyte imbalances . CONCLUSION : Net protein synthesis in the isolated leg of severely burned adults improved with rhIGF - 1 / P17936 without development of glucose abnormalities .",
"DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .",
"Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5 - HT ligands . The brominated cyclodipeptides barettin ( cyclo [( 6 - bromo - 8 - entryptophan ) arginine ] ) and 8 , 9 - dihydrobarettin ( cyclo [( 6 - bromotryptophan ) arginine ] ) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose - dependent manner in concentrations ranging from 0 . 5 to 25 microM . To further establish the molecular target and mode of action of these compounds , we investigated their affinity to human serotonin receptors . The tryptophan residue in the barettins resembles that of endogenous serotonin [ 5 - hydroxytryptamine ] . A selection of human serotonin receptors , including representatives from all subfamilies ( 1 - 7 ) , were transfected into P29320 - 293 cells . Barettin selectively interacted with the serotonin receptors 5 - Q13049 , P28335 , and Q13639 at concentrations close to that of endogenous serotonin , with the corresponding Ki values being 1 . 93 , 0 . 34 , and 1 . 91 microM , respectively . 8 , 9 - Dihydrobarettin interacted exclusively with the P28335 receptor with a Ki value of 4 . 63 microM ; it failed to show affinity to 5 - Q13049 and Q13639 , indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins .",
"Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .",
"P01286 antagonists reduce the invasive and metastatic potential of human cancer cell lines in vitro . We investigated the effect of a P01286 antagonist , Q16674 - 602on the metastatic cascade in vitro of three human cancers , DBTRG - 05 glioblastoma , MDA - MB - 468 estrogen - independent breast , and ES - 2 clear cell ovarian cancer . P01286 receptors and their main splice variant , SV1 were detected on all three cell lines . After treatment with Q16674 - 602 , the cell viability decreased significantly , significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased . The attachment of cancer cells to fibronectin and matrigel was severely hindered . Wound - healing experiments demonstrated a reduced cellular motility in all three cell lines . The upregulation of caveolin - 1 and P12830 , and thepowerful downregulation of NF - kappaB and beta - catenin was detected . Our study suggests that the clinical application of highly potent P01286 antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK59___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain ."
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"___MASK85___",
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___MASK59___
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MH_train_383
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interacts_with DB01221?
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[
"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .",
"___MASK63___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK63___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Systematic meta - analyses and field synopsis of genetic association studies in schizophrenia : the SzGene database . In an effort to pinpoint potential genetic risk factors for schizophrenia , research groups worldwide have published over 1 , 000 genetic association studies with largely inconsistent results . To facilitate the interpretation of these findings , we have created a regularly updated online database of all published genetic association studies for schizophrenia ( ' SzGene ' ) . For all polymorphisms having genotype data available in at least four independent case - control samples , we systematically carried out random - effects meta - analyses using allelic contrasts . Across 118 meta - analyses , a total of 24 genetic variants in 16 different genes ( P02649 , P21964 , DAO , P21728 , P14416 , P21917 , Q96EV8 , P47870 , Q13224 , HP , P01584 , P42898 , O75051 , P31645 , P04637 and P17752 ) showed nominally significant effects with average summary odds ratios of approximately 1 . 23 . Seven of these variants had not been previously meta - analyzed . According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies , four of the significant results can be characterized as showing ' strong ' epidemiological credibility . Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia . As such , it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders .",
"Role of serotonin in the regulation of interferon - gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter - current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon - gamma ( P01579 ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time - dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 mRNA in the presence of elutriated monocytes . Monocyte - induced inhibition of P01579 production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 production in the presence of monocytes . We conclude that serotonergic P08908 receptors transduce signals that are required for NK cells to produce P01579 in response to P60568 .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .",
"WAY 100635 , a P08908 receptor antagonist , prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7 - chloro - kynurenic acid . The effect of WAY 100635 , a P08908 receptor antagonist , on the impairment of spatial learning caused by intrahippocampal administration of scopolamine , a cholinergic muscarinic receptor antagonist , or 7 - chloro - kynurenic acid , an antagonist at the glycine site associated with the DB01221 receptor complex , was studied in a two - platform spatial discrimination task . DB00747 ( 4 microg / microl ) or 7 - chloro - kynurenic acid ( 3 microg / microl ) , administered bilaterally into the P00915 region of the dorsal hippocampus 10 min before each training session , impaired choice accuracy with no effect on choice latency and errors of omission . Administered subcutaneously at 1 ( but not at 0 . 3 ) mg / kg 30 min before each training session , WAY 100635 did not modify the acquisition of spatial learning , but prevented the impairment of choice accuracy caused by intrahippocampal scopolamine or 7 - chloro - kynurenic acid . These findings suggest that blockade of P08908 receptors can compensate the loss of cholinergic or DB01221 - mediated excitatory input to pyramidal cells in the hippocampus . The mechanisms involved and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed .",
"Novel therapeutic strategies in major depression : focus on RNAi and ketamine . Major depression is a severe psychiatric syndrome with very high prevalence and - socioeconomic impact . Despite extensive research , its pathophysiology is poorly understood , yet several neurotransmitter systems and brain areas have been implicated . The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin ( 5 - hydroxytryptamine , 5 - HT ) and / or noradrenaline ( NA ) reuptake . These drugs evoke a series of neuronal adaptive mechanisms that limit their full clinical action , making necessary for many patients the use of augmentation strategies . In spite of such strategies , many depressed patients show limited or no improvement , which worsens their quality of life and increases the risk of suicide . Several novel observations in recent years have shaken the antidepressant field , by showing that depressed patients with severe treatment resistance can rapidly experience clinical remission . Hence , deep brain stimulation ( DBS ) of ventral anterior cingulate cortex ( Cg25 ) evokes rapid mood improvements in treatment - resistant patients . Likewise , single doses of the non - competitive N - methyl - D - aspartate ( DB01221 ) receptor antagonist ketamine evoke rapid and long - lasting ( up to 10 days ) antidepressant responses in treatment - resistant patients . On the other hand , new molecular strategies aimed at modulating the expression of certain genes show great potential in the antidepressant field . In particular , RNAi strategies have been used to evoke antidepressant - like effects in laboratory animals by knocking - down the expression of genes involved in antidepressant effects , such as the serotonin transporter ( P31645 ) or the P08908 autoreceptor . Here we review these novel strategies due to their potential impact in the identification of new targets and the further development of new antidepressant drugs .",
"Neuroprotective effects of serotonin 5 - HT 1A receptor activation against ischemic cell damage in gerbil hippocampus : Involvement of DB01221 receptor Q9UHB4 subunit and P23560 . It is known that the activation of 5 - hydroxytryptamine receptor type 1A ( 5HT ( 1A ) receptor ) may protect against brain damage induced by transient global ischemia . The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated . Given that serotonergic drugs may regulate N - methyl - d - aspartate ( DB01221 ) receptor function , which is implicated in events leading to ischemia - induced neuronal cell death , and also stimulate the expression of brain - derived neurotrophic factor ( P23560 ) , which is down - regulated in cerebral ischemia , we sought to determine the effects of the selective P08908 receptor agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , on the levels of DB01221 receptor Q9UHB4 subunit and P23560 in gerbil hippocampus after transient global cerebral ischemia . Pretreatment with 8 - OH - DPAT ( 1 mg / kg ) prevented the neuronal loss in P00915 subfield 72 h after ischemia and also the dramatic decrease in P23560 immunoreactivity observed in this area at an earlier time . DB01221 receptor Q9UHB4 levels in whole hippocampus were not affected 24 h after ischemia , but the levels of the subunit phosphorylated at the protein kinase A ( PKA ) site , pNR1 ( Ser897 ) , were significantly increased , and this increase was prevented by the same 8 - OH - DPAT dose , a probable consequence of the increased phosphatase 1 ( P50391 ) enzyme activity found in ischemic gerbils pretreated with the 5 - HT ( 1A ) receptor agonist . The results indicate that both Q9UHB4 subunit phosphorylation and the neurotrophin P23560 account , at least in part , for the neuroprotective effect of 8 - OH - DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of P08908 receptor activation in the search for neuroprotective strategies .",
"The action of 5 - HT on calcium - dependent potassium channels and on the spinal locomotor network in lamprey is mediated by P08908 - like receptors . 5 - HT has a powerful modulatory action on the firing properties of single neurons as well as on locomotor activity . In lamprey , 5 - HT increases the neuronal firing frequency in spinal neurons by reducing the conductance in Ca ( 2 +)- dependent K + channels ( KCa ) underlying the slow afterhyperpolarization ( sAHP ) , and it also lowers the burst frequency of the spinal locomotor network . To elucidate which type of 5 - HT receptor mediates these effects , different specific receptor agonists and antagonists were applied during intracellular current clamp recordings and during DB01221 - induced fictive locomotion in the lamprey spinal cord in vitro preparation . The P08908 receptor agonist 8 - OH - DPAT ( (+/-)- 8 - hydroxy - dipropylaminotetralin hydrobromide ) , the 5 - HT1 receptor agonist 5 - CT ( 5 - carboxyamidotryptamine maleate ) and the 5 - HT2 receptor agonist alpha - CH3 - 5 - HT ( alpha - methylserotonin maleate ) all reproduced the actions of 5 - HT at both the cellular and the network levels . The effects of all agonists were completely or partially blocked by the P08908 and 5 - HT2 receptor antagonist spiperone ( spiroperidol hydrochloride ) while selective 5 - HT2 receptor antagonists were ineffective . The selective P08908 receptor antagonist S (-)- UH301 ( S (-)- 5 - fluoro - 8 - hydroxy - dipropylaminotetralin hydrochloride ) also counteracted the effect of 5 - HT on the sAHP . 5 - Q9H205 and Q13639 receptor agonists and antagonists were without effects . The intracellular coupling mechanism was not sensitive to pertussis toxin nor to the DB02527 dependent protein kinase blocker ( Rp ) - cAMPS . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .",
"Functional identification of NR2 subunits contributing to DB01221 receptors on DB05875 receptor - expressing dorsal horn neurons . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers typically composed of two Q9UHB4 and two of four NR2 subunits : Q12879 - 2D . Mice lacking specific NR2 subunits show deficits in pain transmission yet subunit location in the spinal cord remains unclear . We have combined electrophysiological and pharmacological approaches to investigate the composition of functional DB01221 receptors expressed by lamina I , DB05875 receptor - expressing ( P25103 + ) neurons , as well as P25103 - neurons . Under low Mg2 + conditions ( 100 microM ) , the conductance of DB01221 receptors at - 90 mV ( g ( - 90 mV ) ) with Q12879 or Q13224 subunits ( Q12879 / B ) is low compared to conductance measured at the membrane potential where the inward current is maximal or maximal inward current ( MIC ) ( ratio of approximately 0 . 07 calculated from Kuner and Schoepfer , 1996 ) . For Q14957 or O15399 subunits ( Q14957 / D ) , the ratio is higher ( ratio approximately 0 . 4 ) . P25103 + and P25103 - neurons express DB01221 receptors that give ratios approximately 0 . 28 and 0 . 16 , respectively , suggesting both types of subunits are present in both populations of neurons , with P25103 + neurons expressing a higher percentage of Q14957 / D type DB01221 receptors . This was confirmed using EAB318 , an Q12879 / B preferring antagonist , and UBP141 , a mildly selective Q14957 / D antagonist to increase and decrease the g ( - 90 mV ) / g ( MIC ) ratios in both subpopulations of neurons .",
"Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression - 1 and nuclear - deformed epidermal autoregulatory factor by chronic stress . Chronic stress is known to affect brain areas involved in learning and emotional responses . These changes , thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress - related pathophysiologies . The serotonin - related transcription factors ( Q6P1N0 / Q6P1N0 ; five prime repressor element under dual repression / coiled - coil P06681 domain 1a , and O75398 / Deaf - 1 ; nuclear - deformed epidermal autoregulatory factor ) are two important regulators of the P08908 receptor . Using Western blotting and quantitative real - time polymerase chain reaction ( qPCR ) we examined the expression of mRNA and proteins for Q6P1N0 , O75398 , and the P08908 receptor in the prefrontal cortex ( P27918 ) of male rats exposed to chronic restraint stress ( CRS ; 6 h / day for 21 days ) . After 21 days of CRS , significant reductions in both Q6P1N0 mRNA and protein were observed in the P27918 ( 36 . 8 % and 32 % , respectively ; P < 0 . 001 ) , while the levels of both O75398 protein and mRNA did not change significantly . Consistent with reduced Q6P1N0 protein , P08908 receptor mRNA levels were equally upregulated in the P27918 , while protein levels actually declined , suggesting post - transcriptional receptor downregulation . The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Q6P1N0 and the P08908 receptor in the P27918 of the male rat while having no effect on O75398 . These results point to the importance of understanding the mechanism for the differential regulation of Q6P1N0 and O75398 in the P27918 as a basis for understanding the related effects of chronic stress on the serotonin system ( serotonin - related transcription factors ) and stress - related disorders like depression .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK20___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .",
"Neurophysiological analysis of circadian rhythm entrainment . We review recent studies in our laboratory that have investigated the neural mechanisms underlying photic entrainment of the mammalian circadian system . The results from studies of extracellular single - unit recordings and of photic induction of Fos - like immunoreactivity ( Fos - lir ) indicate that excitatory amino acid ( EAA ) transmission , and particularly activation of the N - methyl - D - aspartate ( DB01221 ) receptor subtype , is important for conveying photic information to suprachiasmatic nucleus ( SCN ) cells . We have also found that a subregion of the SCN still shows Fos - lir after blockade of EAA receptors , and we have evidence suggesting that these cells are innervated by a distinct subdivision of the retinal projection to the SCN . In addition , we have found that photic responses of cells in the intergeniculate leaflet ( which projects to the SCN ) and of SCN cells are modulated by serotonin ( 5 - HT ) via a receptor that resembles the P08908 subtype .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK13___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"DB09280 - ___MASK32___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Serotonin suppresses N - methyl - D - aspartate responses in acutely isolated spinal dorsal horn neurons of the rat . In acutely isolated spinal dorsal horn neurons of the rat , effects of serotonin ( 5 - hydroxytryptamine , 5 - HT ) on inward current induced by excitatory amino acids were studied under whole - cell voltage - clamp condition . 5 - HT suppressed the response to N - methyl - D - aspartate ( DB01221 ) , but not the response to kainate or quisqualate . This inhibitory effect of 5 - HT on DB01221 response was present at 5 - HT concentrations as low as 10 (- 15 ) M . Although the 5 - HT effect exhibited similar pharmacology to the P08908 - type receptors , it was not mimicked by increasing intracellular concentration of adenosine 3 ', 5 '- cyclic monophosphate that is the common second messenger for P08908 receptors in the mammalian central nervous system . Glycine strongly antagonized this inhibitory effect of 5 - HT , and 5 - HT reduced opening of DB01221 - gated single channels recorded from the outside - out membrane patch . These lines of evidence are consistent with a possibility that 5 - HT might directly modulate the DB01221 receptor - ion channel complex , either by interacting with the regulatory site ( s ) or by acting on a distinct site .",
"The role of spinal neurokinin - 1 and glutamate receptors in hyperalgesia and allodynia induced by prostaglandin E ( 2 ) or zymosan in the rat . Recent research has focused on prostaglandins in the central nervous system and their contribution to hyperalgesia and allodynia . This study sought to establish whether neurokinin - 1 ( NK - 1 ) receptors and glutamate receptors are involved in the hyperalgesic and allodynic effects of spinally administered prostaglandin E2 ( DB00917 ) in rats , and also to determine if the same receptors are involved the hyperalgesia induced by intraplantar administration of zymosan , an inflammatory agent which is known to evoke spinal DB00917 release . Spinal application of antagonists of the P25103 , the - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid ( AMPA ) / kainate glutamate or metabotropic glutamate receptor significantly attenuated the decrease in mechanical paw withdrawal response thresholds produced by either spinal administration of DB00917 or intraplantar administration of zymosan . The decrease in thermal paw withdrawal response latencies induced by DB00917 , but not by zymosan , was significantly attenuated by spinal administration of an N - methyl -- aspartate ( DB01221 ) receptor antagonist , an AMPA / kainate receptor antagonist , or a metabotropic glutamate receptor antagonist . Allodynia induced by DB00917 was significantly alleviated by antagonists of DB01221 or AMPA / kainate receptors . These results suggest that both DB00917 - induced and zymosan - induced mechanical hyperalgesia are mediated in part through activation of NK - 1 , AMPA / kainate and metabotropic glutamate receptors . DB00917 - induced , but not zymosan - induced , thermal hyperalgesia is mediated in part by activation of DB01221 , AMPA / kainate and metabotropic glutamate receptors . Activation of both DB01221 and AMPA / kainate receptors contribute to DB00917 - induced allodynia .",
"Effect of tandospirone , a serotonin - 1A receptor partial agonist , on information processing and locomotion in dizocilpine - treated rats . RATIONALE : Augmentation therapy with serotonin - 1A receptor ( P08908 ) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia . OBJECTIVE AND METHODS : The objective of the present study was to examine the effect of repeated administration of tandospirone ( 0 . 05 and 5 mg / kg ) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N - methyl - D - aspartate receptor antagonist MK - 801 , which has been used in animal models of schizophrenia . Furthermore , we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 ( 0 . 3 mg / kg ) , a P08908 receptor antagonist , and whether there is an interaction between haloperidol ( 0 . 1 mg / kg ; a dopamine - D2 receptor antagonist ) and tandospirone . RESULTS : Tandospirone at 5 mg / kg , but not 0 . 05 mg / kg , decreased locomotor activity in saline or MK - 801 - treated rats , which were not affected by co - treatment with WAY 100635 . DB00502 decreased locomotion both in saline and MK - 801 - treated animals , and this effect was not evident in the latter group receiving the higher dose of tandospirone . Tandospirone ( 5 mg / kg ) - induced disruption of sensorimotor gating in saline or MK - 801 - treated animals was reversed by WAY - 100635 , but not by haloperidol . CONCLUSIONS : These findings suggest that behavioural changes induced by tandospirone are not fully blocked by P08908 antagonists and that tandospirone ( 5 mg / kg ) potentiates the effect of MK - 801 . Overall , these findings point to an interaction between DB01221 and 5 - HT ( 1A ) receptors . Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems .",
"A serotonin - 1A receptor agonist and an N - methyl - D - aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model . The WAG / RIJ rats exhibit spontaneously occurring spike - wave discharges ( SWD ) accompanied by behavioural phenomena , with characteristics similar to the human absence type epilepsy . To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin - 1A ( P08908 ) receptor agonist 8 - hydroxy - 2 -( di - n - propylamino )- tetralin ( 8 - OH - DPAT ) and the N - methyl - D - aspartate ( DB01221 ) receptor antagonist (+)- 5 - methyl - 10 , 11 - dihydro - 5H - dibenzo [ a , d ] cyclohepten - 5 , 10 - imine maleate ( MK - 801 ) . Intracerebroventricular ( i . c . v . ) injection of 8 - OH - DPAT caused marked , dose dependent increase , MK - 801 a decrease in the cumulative duration and number of spike - wave discharges . Pretreatment with MK - 801 ( 10 microg / rat i . c . v . ) abolished the increase caused by 8 - OH - DPAT ( 20 microg / rat i . c . v . ) , but the decrease in SWD to MK - 801 was counterbalanced by 8 - OH - DPAT . These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy .",
"A possible mechanism of the nucleus accumbens and ventral pallidum P28222 receptors underlying the antidepressant action of ketamine : a PET study with macaques . DB01221 is a unique anesthetic reagent known to produce various psychotic symptoms . DB01221 has recently been reported to elicit a long - lasting antidepressant effect in patients with major depression . Although recent studies provide insight into the molecular mechanisms of the effects of ketamine , the antidepressant mechanism has not been fully elucidated . To understand the involvement of the brain serotonergic system in the actions of ketamine , we performed a positron emission tomography ( PET ) study on non - human primates . Four rhesus monkeys underwent PET studies with two serotonin ( 5 - HT ) - related PET radioligands , [( 11 ) C ] AZ10419369 and [( 11 ) C ] DASB , which are highly selective for the P28222 receptor and serotonin transporter ( P31645 ) , respectively . Voxel - based analysis using standardized brain images revealed that ketamine administration significantly increased P28222 receptor binding in the nucleus accumbens and ventral pallidum , whereas it significantly reduced P31645 binding in these brain regions . DB00574 , a 5 - HT releaser , significantly decreased P28222 receptor binding , but no additional effect was observed when it was administered with ketamine . Furthermore , pretreatment with 2 , 3 - dihydroxy - 6 - nitro - 7 - sulfamoylbenzo ( f ) quinoxaline ( NBQX ) , a potent antagonist of the glutamate α - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid ( AMPA ) receptor , blocked the action of ketamine on the P28222 receptor but not P31645 binding . This indicates the involvement of AMPA receptor activation in ketamine - induced alterations of P28222 receptor binding . Because NBQX is known to block the antidepressant effect of ketamine in rodents , alterations in the serotonergic neurotransmission , particularly upregulation of postsynaptic P28222 receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine .",
"Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .",
"Stimulation of the P08908 receptor selectively suppresses DB01221 receptor - mediated synaptic excitation in the rat visual cortex . We have previously found that stimulation of serotonin P08908 receptors inhibits the induction of long - term potentiation ( LTP ) in the rat visual cortex . In the present study , the selective P08908 receptor agonist 8 - hydroxy - 2 -( N , N - dipropylamino ) tetralin ( 8 - OH - DPAT ) significantly reduced N - methyl - d - aspartate ( DB01221 ) receptor - mediated synaptic responses recorded in Mg2 +- free medium in rat visual cortical slices . In addition , there was good correlation between the inhibitory effects of 8 - OH - DPAT on DB01221 responses and LTP . These results suggest that P08908 receptor stimulation inhibits the induction of LTP by suppressing DB01221 receptor - mediated synaptic excitation in the rat visual cortex .",
"Involvement of extracellular signal - regulated kinase module in HIV - mediated P01730 signals controlling activation of nuclear factor - kappa B and AP - 1 transcription factors . Although the molecular mechanisms by which the HIV - 1 triggers either T cell activation , anergy , or apoptosis remain poorly understood , it is well established that the interaction of HIV - 1 envelope glycoproteins with cell surface P01730 delivers signals to the target cell , resulting in activation of transcription factors such as NF - kappa B and AP - 1 . In this study , we report the first evidence indicating that kinases MEK - 1 ( Q96HU1 kinase / Erk kinase ) and P27361 ( extracellular signal - regulated kinase ) act as intermediates in the cascade of events that regulate NF - kappa B and AP - 1 activation upon HIV - 1 binding to cell surface P01730 . We found that CEM cells transfected with dominant negative forms of MEK - 1 or P27361 do not display NF - kappa B activation after HIV - 1 binding to P01730 . In contrast , NF - kappa B activation was observed in these cells after PMA stimulation . Although the different cell lines studied expressed similar amounts of P01730 and p56 ( lck ) , HIV - 1 replication and HIV - 1 - induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK - 1 or P27361 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK - 1 or wild - type P27361 . In light of recently published data , we propose that a positive signal initiated following oligomerization of P01730 by the virus is likely to involve a recruitment of active forms of p56 ( lck ) , P04049 , MEK - 1 , and P27361 , before AP - 1 and NF - kappa B activation .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK38___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"A pre - and postsynaptic modulatory action of 5 - HT and the 5 - Q13049 , 2C receptor agonist DOB on DB01221 - evoked responses in the rat medial prefrontal cortex . Intracellular recordings were made from pyramidal neurons in layers V and VI of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5 - Q13049 , 2C receptor agonist (-)- 1 - 2 , 5 - dimethoxy - 4 - bromophenol - 2 - aminopropane ( DOB ) and 5 - hydroxytryptamine ( 5 - HT ) on N - methyl - D - aspartate ( DB01221 ) - induced responses . Bath application of either DOB or 5 - HT [ in the presence of antagonists to P08908 , 5 - Q9H205 and gamma - aminobutytric acid ( GABA ) receptors ] produced a concentration - dependent biphasic modulation of the DB01221 responses . They facilitated and inhibited DB01221 responses at low ( </= 1 microM DOB and </= 50 microM 5 - HT ) and higher concentrations , respectively . Both the facilitating and inhibitory action were blocked by the highly selective 5 - Q13049 receptor antagonist R -(+)- alpha - ( 2 , 3 - dimethoxyphenil ) - 1 -[ 4 - fluorophenylethyl ]- 4 - piperidineme thanol ( M100907 ) and the 5 - HT2 receptor antagonist ketanserin , thus indicating that both facilitation and inhibition were mediated by the activation of the 5 - Q13049 receptor subtype . However , the facilitating , but not inhibitory , action of DOB showed a marked desensitization , suggesting that the facilitation and inhibition of DB01221 responses resulted from activation of different 5 - Q13049 receptor subtypes and / or signal - transduction pathways . Indeed , the selective PKC inhibitor chelerythrine and the Ca2 +/ P62158 - KII inhibitor KN - 93 prevented the facilitating and inhibitory action of DOB , respectively . We have generated several lines of evidence to indicate the following scenario . Low concentrations of DOB , at presynaptic nerve terminals , markedly enhance DB01221 - induced release of excitatory amino acids ( EAAs ) , which then act upon both DB01221 and non - DB01221 receptors to elicit inward current . The massive inward current masks the postsynaptic inhibitory action of DOB . At higher concentrations , DOB inhibits the release of EAAs and discloses the postsynaptic inhibitory action .",
"Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .",
"Assessment of DB01221 receptor activation in vivo by Fos induction after challenge with the direct DB01221 agonist ( tetrazol - 5 - yl ) glycine : effects of clozapine and haloperidol . Induction of Fos protein by the potent and direct DB01221 agonist ( tetrazol - 5 - yl ) glycine ( TZG ) was examined in mice . Effects of antipsychotic drugs were assessed on this in vivo index of DB01221 receptor activation . TZG induced the expression of Fos in a neuroanatomically selective manner , with the hippocampal formation showing the most robust response . In mice genetically altered to express low levels of the Q9UHB4 subunit of the DB01221 receptor , TZG - induced Fos was reduced markedly in comparison to the wild type controls . TZG - induced Fos was also blocked by the selective DB01221 antagonist MK - 801 . Pretreatment of mice with clozapine ( 3 and 10 mg / kg ) reduced TZG - induced Fos in the hippocampal formation but not in other brain regions . DB00502 at a dose of 0 . 5 mg / kg did not antagonize TZG induced Fos in any region . DB00502 at a dose of 1 . 0 mg / kg did attenuate the induction of Fos by TZG in the hippocampus but not in other brain regions . The relatively high dose ( 1 mg / kg ) of haloperidol required to block effects of TZG suggests that this action may not be related to the P14416 - blocking properties , since maximal D ( 2 ) receptor blockade was probably achieved by the 0 . 5 mg / kg dose of haloperidol . The antidepressant drug imipramine ( 10 or 20 mg / kg ) did not antagonize TZG induced Fos in any brain region . The data suggest that clozapine can reduce excessive activation of DB01221 receptors by TZG administration in vivo at doses relevant to the drugs ' actions in rodent models of antipsychotic activity . Whether or not this action of clozapine contributes to its therapeutic properties will require further study .",
"Characterization of serotonin - toxicity syndrome ( toxidrome ) elicited by 5 - hydroxy - l - tryptophan in clorgyline - pretreated rats . Patients are at high risk of developing serotonin - toxicity syndrome ( toxidrome ) when they take multiple serotonergic drugs , particularly co - administered with monoamine oxidase inhibitors or 5 - hydroxytryptamine ( 5 - HT ) reuptake blockers . The toxidrome can vary from mild to severe . The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5 - hydroxy - l - tryptophan ( 5 - HTP ) in clorgylinized rats . The severity was obtained by scoring behavioral signs including head shakes , penile erection , forepaw treading , hind limb abduction , Straub tail and tremor . It was found that 5 - HTP produced a dose - dependent increase in degrees of the toxidrome . Furthermore , correlation between the toxidrome and changes in body - core temperature ( delta Tcor ) was determined . There was hypothermia in the mild toxidrome ( delta Tcor < - 1 degrees C ) , high hyperthermia in the severe toxidrome ( delta Tcor > + 2 degrees C ) and a small change in T ( cor ) in the moderate toxidrome ( - 1 degrees C < delta Tcor < + 2 degrees C ) . Thus , delta Tcor in response to drugs can be used to estimate the severity of the toxidrome . The second attempt was to identify the receptors mediating those changes . P08908 receptors were involved in the hypothermic response while 5 - Q13049 and DB01221 receptors mediated head shakes , hyperthermia , forepaw treading and Straub tail . Lastly , antidotal effect of cyproheptadine and (+)- MK - 801 was examined . Both drugs blocked hyperthermia and death . However , the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced . These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5 - HT toxidrome .",
"A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .",
"Phosphorylation of DB00156 ( 495 ) regulates Ca ( 2 +)/ calmodulin - dependent endothelial nitric oxide synthase activity . The activity of the endothelial nitric oxide synthase ( P29474 ) can be regulated independently of an increase in Ca ( 2 +) by the phosphorylation of DB00133 ( 1177 ) but results only in a low nitric oxide ( NO ) output . In the present study , we assessed whether the agonist - induced ( Ca ( 2 +)- dependent , high - output ) activation of P29474 is associated with changes in the phosphorylation of DB00156 ( 495 ) in the calmodulin ( P62158 ) - binding domain . P29474 DB00156 ( 495 ) was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation . In the same cells , bradykinin enhanced the phosphorylation of DB00133 ( 1177 ) , which was maximal after 5 minutes , and abolished by the P62158 - dependent kinase II ( CaMKII ) inhibitor KN - 93 . Bradykinin also enhanced the association of CaMKII with P29474 . Phosphorylation of DB00156 ( 495 ) was attenuated by the protein kinase C ( PKC ) inhibitor Ro 31 - 8220 and after PKC downregulation using phorbol 12 - myristate 13 - acetate . The agonist - induced dephosphorylation of DB00156 ( 495 ) was completely Ca ( 2 +)- dependent and inhibited by the P50391 inhibitor calyculin A . Little P62158 was bound to P29474 immunoprecipitated from unstimulated cells , but the agonist - induced dephosphorylation of DB00156 ( 495 ) enhanced the association of P62158 . Mutation of DB00156 ( 495 ) to alanine increased P62158 binding to P29474 in the absence of cell stimulation , whereas the corresponding DB00128 ( 495 ) mutant bound almost no P62158 . Accordingly , NO production by the Ala ( 495 ) mutant was more sensitive to Ca ( 2 +)/ P62158 than the aspartate mutant . These results suggest that the dual phosphorylation of DB00133 ( 1177 ) and DB00156 ( 495 ) determines the activity of P29474 in agonist - stimulated endothelial cells . Moreover , the dephosphorylation of DB00156 ( 495 ) by P50391 precedes the phosphorylation of DB00133 ( 1177 ) by CaMKII . The full text of this article is available at http :// www . circresaha . org .",
"Dissociation between cognitive and motor / motivational deficits in the delayed matching to position test : effects of scopolamine , 8 - OH - DPAT and EAA antagonists . The effects of the muscarinic antagonists scopolamine HBr and MeBr , the P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , and the N - methyl - d - aspartate ( DB01221 ) antagonists MK - 801 and CGS - 19755 on performance of rats in a delayed matching - to - position task were examined . Pretreatment with scopolamine HBr ( 0 . 05 and 0 . 1 mg / kg ) , resulted in a delay - dependent decrease in the percentage of correct responses and discriminability ( log d ) , but had no effect on either the latency to complete trials , or the rate of trial completion during the fixed duration session . DB00747 MeBr ( 0 . 1 mg / kg ) did not impair percent correct or increase the response latency but did decrease the rate of trial completion . 8 - OH - DPAT ( up to 0 . 3 mg / kg ) , had no effect on percent correct , but did induce a small decrease in discriminability . The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion . Both MK - 801 ( 0 . 05 mg / kg ) and CGS 19755 ( 10 mg / kg ) induced a delay - independent impairment in percent correct , discriminability and a reduction in the rate of trial completion without affecting latency . A lower dose of CGS 19755 ( 5 . 0 mg / kg ) induced a slight impairment in discriminability without significantly affecting the other measures . Taken together , these results demonstrate some dissociation between drug - induced cognitive and motor / motivational deficits in the DMTP test . However , the data question the specificity of putative cognitive impairments reported in many previous studies with the P08908 agonist 8 - OH - DPAT .",
"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK65___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .",
"Role of nitric oxide in brain regions related to defensive reactions . DB00435 synthase ( NOS ) positive neurons are located in most brain areas related to defensive reactions , including the dorsolateral periaqueductal grey ( dlPAG ) . NOS inhibitors injected into this structure induce anxiolytic - like responses whereas NO donors promote flight reactions . Intra - dlPAG administration of carboxy - PTIO , a NO scavenger , or ODQ , a soluble guanylate cyclase inhibitor , produced anxiolytic - like effects on rats exposed to the elevated plus - maze ( EPM ) . A double - staining experiment using NADPHd histochemistry and c - Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG , paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus . Cat exposure also increased activation of NOS neurons in the medial amygdala , dorsal pre - mammillary nucleus and bed nucleus of stria terminalis . Local infusion into the dlPAG of a glutamate DB01221 - receptor antagonist ( AP7 ) or a benzodiazepine agonist ( midazolam ) completely prevented the flight reactions induced by intra - dlPAG administration of SIN - 1 , a NO donor . The responses were also inhibited by the 5 - Q13049 / C agonist DOI but not by a P08908 agonist . These results suggest a modulatory role for NO on brain areas related to defensive reactions , probably by interacting with glutamate , serotonin and / or GABA - mediated neurotransmission .",
"Lowering of body core temperature by exposure to a cold environment and by a P08908 agonist : effects on physiological and psychological variables and blood serotonin levels . The present study was designed to compare the effects of a pharmacologically induced decrease in body core temperature to the effects observed with lowering of body temperature by exposure to a cold environment . Our special interest was the involvement of 5 - HT in thermoregulatory responses . Sixty healthy male volunteers were randomly assigned to one of the following conditions : exposure to normal ambient temperature ( 28 degrees C ) and placebo , exposure to cold ambient temperature ( 5 degrees C ) and placebo , or normal ambient temperature and 10 mg of the partial P08908 agonist ipsapirone . As indicators of physiological responses to lowering of body temperature , tympanic temperature , skin temperature , P15941 , metabolic rate , and heart rate were monitored and saliva cortisol levels and peripheral 5 - HT concentrations were determined . In addition , ratings on ambient temperature , thermal discomfort , and feelings of irritability were obtained . While lowering of body core temperature was associated with marked counterregulations ( decrease of skin temperature , increase in P15941 and metabolic rate ) and feelings of discomfort , this was not observed with ipsapirone . An increase in cortisol levels was primarily observed in the ipsapirone group and was not reflected by respective changes in whole blood or platelet 5 - HT indicating that brain and platelet 5 - HT are not related .",
"Reduction of DB01221 - induced behaviour after acute and chronic administration of desipramine in mice . The mechanisms of the antinociceptive effect of desipramine ( DB01151 ) are only partly known . It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N - methyl - D - aspartic acid ( DB01221 ) receptor complex . In this study , the modulatory effect of DB01151 on the biting and scratching behaviour induced by intrathecal ( i . th . ) administration of DB01221 ( 0 . 25 nmol ) was investigated . Desipramine was administered acutely , either intrathecally ( 0 . 7 - 35 micrograms ) or intraperitoneally ( i . p . , 10 mg / kg ) , or chronically in the drinking water ( 0 . 15 g / l ) for 3 weeks . The DB01221 - induced behaviour was significantly reduced both after acute and chronic administration of DB01151 . Several studies have shown a functional upregulation of the P08908 receptor after chronic treatment with DB01151 . The activation of this receptor using the P08908 agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin hydrobromide ( 8 - OH - DPAT ) , leads to a reduction in DB01221 - induced behaviour . Using the P08908 antagonist NAN - 190 ( 10 micrograms , i . th . ) , the effect of chronic administration of DB01151 on the DB01221 - induced behaviour was reversed . However , NAN - 190 also increased DB01221 - induced behaviour in the control group , suggesting that a tonic inhibition of this behaviour , mediated by the P08908 receptor , may exist . These findings indicate that DB01151 may reduce glutaminergic transmission at the spinal DB01221 receptor . As this receptor is central in spinal nociceptive transmission , this could be one mechanism for the antinociceptive effect of DB01151 .",
"Gene - gene interaction analyses between DB01221 receptor subunit and dopamine receptor gene variants and clozapine response . AIMS : To investigate the possible association and gene - gene interaction effects of polymorphisms in DB01221 receptor subunit ( GRIN1 , Q12879 and Q13224 ) and dopamine receptor ( P21728 , P14416 and P35462 ) genes with clozapine response . MATERIALS & METHODS : GRIN1 rs11146020 ( G1001C ) , Q12879 GT - repeat and Q13224 rs10193895 ( G - 200T ) polymorphisms were tested for association in a Caucasian ( n = 183 ) and an African - American ( n = 49 ) sample using χ ( 2 ) and Q9UNW9 tests . Logistic regression and two - way Q9UNW9 were used to explore gene - gene interaction effects with dopamine receptor gene variants . RESULTS & CONCLUSION : This study does not support the involvement of the DB01221 receptor subunit gene polymorphisms in clozapine response . All tests for an association were negative . Gene - gene interaction analyses however yielded promising leads , including an observed effect between P21728 rs686 and P35462 Ser9Gly polymorphisms on clozapine response ( p = 0 . 002 ) .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK85___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK93___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Discriminative stimulus effects of ethanol in rats using a three - choice ethanol - midazolam - water discrimination . Three - choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other . This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma - aminobutyric acid type A ( GABAA ) receptor complex . As an extension to these studies , male Long - Evans rats were trained to discriminate midazolam ( 3 . 0 mg / kg , i . p . ) from ethanol ( 1 . 0 g / kg , i . g . ) from water ( 2 . 3 ml , i . g . ) in a three - lever , food reinforced task . Substitution tests were conducted following administration of GABAA - positive modulators , noncompetitive N - methyl - D - aspartate ( DB01221 ) antagonists , P28222 agonists and isopropanol . Among the GABAA - positive modulators , diazepam was the only drug that completely substituted for midazolam ; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution . The DB01221 antagonist dizocilpine substituted for ethanol , while phencyclidine showed no substitution for either ethanol or midazolam . The serotonin agonists tested also showed no substitution for either ethanol or midazolam . Isopropanol was the only other drug that completely substituted for ethanol . These data extend previous findings from an ethanol - pentobarbital - water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol - like effect .",
"Cyto - and receptor architecture of area 32 in human and macaque brains . Human area 32 plays crucial roles in emotion and memory consolidation . It has subgenual ( s32 ) , pregenual ( Q9H160 ) , dorsal , and midcingulate components . We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles . The macaque has areas s32 and Q9H160 . In s32 , layer IIIa / b neurons are larger than those of layer IIIc . This relationship is reversed in Q9H160 . Layer Va is thicker and Vb thinner in s32 . Area Q9H160 contains higher kainate , benzodiazepine ( BZ ) , and serotonin ( 5 - HT ) 1A but lower N - methyl - D - aspartate ( DB01221 ) and α2 receptor densities . Most differences were found in layers I , II , and VI . Together , these differences support the dual nature of macaque area 32 . Comparative analysis of human and macaque s32 and Q9H160 supports equivalences in cyto - and receptor architecture . Although there are differences in mean areal receptor densities , there are considerable similarities at the layer level . Laminar receptor distribution patterns in each area are comparable in the two species in layers III - Va for kainate , DB01221 , γ - aminobutyric acid ( GABA ) B , BZ , and P08908 receptors . Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and Q9H160 than to human Q9H160 . Thus , macaque 32 is more complex than hitherto known . Our data suggest a homologous neural architecture in anterior cingulate s32 and Q9H160 in human and macaque brains .",
"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .",
"Farnesyl diphosphate synthase : the art of compromise between substrate selectivity and stereoselectivity . Farnesyl diphosphate ( FPP ) synthase catalyzes the consecutive head - to - tail condensations of isopentenyl diphosphate ( IPP , P01031 ) with dimethylallyl diphosphate ( DMAPP , P01031 ) and geranyl diphosphate ( GPP , Q99622 ) to give ( E , E ) - FPP ( C15 ) . The enzyme belongs to a genetically distinct family of chain elongation enzymes that install E - double bonds during each addition of a five - carbon isoprene unit . Analysis of the Q99622 and C15 products from incubations with avian P14324 reveals that small amounts of neryl diphosphate ( Z - Q99622 ) and ( Z , E ) - FPP are formed along with the E - isomers during the P01031 --> Q99622 and Q99622 --> C15 reactions . Similar results were obtained for P14324 from Escherichia coli , Artemisia tridentata ( sage brush ) , Pyrococcus furiosus , and Methanobacter thermautotrophicus and for GPP and FPP synthesized in vivo by E . coli P14324 . When ( R ) -[ 2 - 2H ] IPP was a substrate for chain elongation , no deuterium was found in the chain elongation products . In contrast , the deuterium in ( S ) -[ 2 - 2H ] IPP was incorporated into all of the products . Thus , the pro - R hydrogen at P06681 of IPP is lost when the E - and Z - double bond isomers are formed . The synthesis of Z - double bond isomers by P14324 during chain elongation is unexpected for a highly evolved enzyme and probably reflects a compromise between optimizing double bond stereoselectivity and the need to exclude DMAPP from the IPP binding site .",
"Role of serotonin , gamma - aminobutyric acid , and glutamate in the behavioral thermoregulation of female tilapia during the prespawning phase . The role of hypothalamic neurotransmitter systems in behavioral thermoregulation was investigated in the prespawning female tilapia , Oreochromis mossambicus . Intrahypothalamic microinjection with serotonin ( 5 - HT , 3 microliters of 1 . 0 x 10 (- 6 ) M ) resulted in a significant increase in the selected temperature . This effect was mimicked by the agonist of P08908 , 1B , and 2C receptors , N - 3 - trifluoromethylphenyl piperazine . Intrahypothalamic microinjection of tilapia with gamma - aminobutyric acid ( GABA ) resulted in a biphasic effect of the temperature selection , whereas microinjection with muscimol , an agonist of GABAA receptor , had no effect on temperature selection . Both agonist and antagonist of glutamate ( DB00142 ) , N - methyl - D - aspartate ( DB01221 ) , and MK - 801 ( 1 . 0 x 10 (- 6 ) M ) , a noncompetitive blocker of DB01221 receptor , significantly decreased the preferred temperature . These results indicate that the hypothalamic 5 - HT , GABA , and DB00142 systems play a role in the temperature selection of prespawning female tilapia .",
"Inflammatory cells as source of tachykinin - induced mucus secretion in chronic bronchitis . Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease ( P48444 ) . Tachykinin - induced mucus secretion has been regarded as sensory nerve - dependent so far . We studied the distribution of tachykinin - mRNA and - peptide and its relation to NK - 1 subtype - positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells . RT - PCR demonstrated the expression of tachykinin - and NK - 1 - mRNA in human airway tissues . In situ hybridisation resulted in preprotachykinin ( PPT ) - A mRNA - signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands . NK - 1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT - A mRNA and tachykinin - positive cells . The present data directly demonstrate the presence of both PPT - A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to P25103 positive glandular myoepithelium . Our findings indicate that besides neurally released tachykinins , also inflammatory cell - derived tachykinins may lead to glandular secretion via P25103 stimulation . This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as P48444 or asthma .",
"Characterization of a novel effect of serotonin P08908 and 5 - Q13049 receptors : increasing cGMP levels in rat frontal cortex . Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years . Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens , the signaling pathways activated by these agents are unclear . Here it is shown that administration of serotonin ( 5 - hydroxytryptamine , 5 - HT ) increased cyclic guanosine monophosphate ( cGMP ) production in frontal cortical slices of rat brain . The effect of 5 - HT was greater than that of N - methyl - D - aspartate ( DB01221 ) , a stimulant of cGMP formation in the central nervous system . The 5 - HT ( 2A / 2C ) receptor phenethylamine agonist , 2 , 5 - dimethoxy - 4 - methylamphetamine ( DOM ) , increased cGMP content in the slices . Additionally 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( DPAT ) , a 5 -( HT1A / 7 ) receptor agonist also increased cGMP production . Stimulation of cGMP formation by DOM was prevented by a 5 - HT ( 2A / 2C ) receptor antagonist , pirenperone , as well as by a 5 - Q13049 receptor selective antagonist , MDL100907 . A P28335 receptor antagonist , SB242084 , did not block the effect of DOM . Stimulation of cGMP production by DPAT was blocked by the P08908 receptor antagonist , WAY100635 . Stimulation of cGMP formation by serotonin could be prevented by pirenperone or WAY100635 . In summary , activation of serotonin P08908 and 5 - Q13049 receptors increase brain cGMP levels .",
"Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 function in multiple ways . In particular , class 3 mutations such as p . Gly551Asp strongly decrease the time spent by P13569 in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p . Phe508del ) , the most frequent mutation among CF patients ( 70 - 90 % ) , destabilizes the P13569 protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug - like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco ™ ( also known as ___MASK32___ or VX - 770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 ) for the treatment of CF patients carrying at least one P13569 allele with the p . Gly551Asp mutation ( 2 - 5 % of all patients ) . In contrast , the corrector VX - 809 , which significantly improves p . Phe508del - P13569 trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p . Phe508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect .",
"Innovative approaches for the development of antidepressant drugs : current and future strategies . Depression is a highly debilitating disorder that has been estimated to affect up to 21 % of the world population . Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors ( SSRIs ) and serotonin and norepinephrine reuptake inhibitors ( SNRIs ) , there continue to be many unmet clinical needs with respect to both efficacy and side effects . These needs range from efficacy in treatment resistant patients , to improved onset , to reductions in side effects such as emesis or sexual dysfunction . To address these needs , there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas . There is tremendous diversity in the types of targets and approaches being taken . At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms ( P08908 , P28222 , P28221 , P28335 , alpha - 2A ) . At the other end of the spectrum are more novel targets , such as neurotrophins ( P23560 , IGF ) , based on recent findings that antidepressants induce neurogenesis . In between , there are many approaches that range from directly targeting serotonin receptors ( P28335 , P50406 ) to targeting the multiplicity of potential mechanisms associated with excitatory ( glutamate , DB01221 , Q14416 , P41594 ) or inhibitory amino acid systems ( GABA ) or peptidergic systems ( neurokinin 1 , DB05394 1 , melanin - concentrating hormone 1 , V1b ) . The present review addresses the most exciting approaches and reviews the localization , neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations .",
"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .",
"Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing ' s disease . A 75 - year - old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non - suppressibility to high - dose dexamethasone , responsiveness to P06850 , but not to ___MASK65___ , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 - PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT - PCR revealed abundant expressions of P01189 and SSTR ( - 1 , - 2 , - 5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion .",
"Acute heat stress induces edema and nitric oxide synthase upregulation and down - regulates mRNA levels of the Q05586 , Q12879 and Q13224 subunits in the rat hippocampus . The influence of heat stress on constitutive isoform of neuronal nitric oxide synthase ( P29474 ) and DB01221 receptor gene expression in hippocampus was examined in a rat model . Subjection of animals to 4 h heat stress at 38 degrees C resulted in a marked upregulation of P29474 in the hippocampus accompanied with a marked general expansion and edematous cell changes . On the other hand DB01221 receptor messenger RNA encoding Q05586 , Q12879 and Q13224 subunits showed a marked downregulation in the hippocampus of heat stressed rats compared to the controls . Our results show that upregulation of P29474 is instrumental in heat stress associated edema and cell injury . Furthermore , an increased production of NO as evident with upregulation of P29474 appears to be a key factor in the downregulation of DB01221 receptor gene expression in heat stress .",
"Activation of the P27361 / 2 signaling cascade by excitotoxic spinal cord injury . The role of the P27361 / 2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury ( SCI ) was examined . Specifically , phosphorylation of P27361 / 2 , activation of transcription factors NF - kB , P54762 - 1 , and CREB , and gene expression of the neurokinin - 1 receptor and DB01221 receptor subunits Q9UHB4 and NR - 2A were investigated . Excitotoxic injury was produced by intraspinal injection of quisqualic acid ( QUIS ) in male Sprague - Dawley rats . Western blots were used to evaluate phosphorylation and activation of P27361 / 2 and transcription factors using phospho - specific or total antibodies . Real - time PCR was used to evaluate gene expression of P25103 , NR - 1 , and NR - 2A . Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior . Excitotoxic spinal injury resulted in : ( 1 ) increased phosphorylation of P27361 / 2 ; ( 2 ) increased activation of NF - kB and phosphorylation of P54762 - 1 ; and ( 3 ) increased gene expression for the P25103 and Q9UHB4 and NR - 2A subunits of the DB01221 receptor . Blockade of the P29323 cascade with the MEK inhibitor PD98059 inhibited phosphorylation of P54762 - 1 , activation of NF - kB and gene expression of Q9UHB4 , NR - 2A and P25103 , and prevented the development of excessive grooming behavior . The results have shown that excitotoxic spinal injury leads to the injury - induced activation of the P29323 --> P54762 - 1 and NF - kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain . Blockade of this intracellular kinase cascade prevented the onset of injury - induced pain behavior ."
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[
"___MASK13___",
"___MASK20___",
"___MASK32___",
"___MASK38___",
"___MASK63___",
"___MASK65___",
"___MASK70___",
"___MASK85___",
"___MASK93___"
] |
___MASK32___
|
MH_train_384
|
interacts_with DB01169?
|
[
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK55___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"Involvement of peroxisome proliferator - activated receptor gamma in gonadal steroidogenesis and steroidogenic acute regulatory protein expression . Peroxisome proliferator - activated receptor ( Q07869 ) gamma belongs to the Q07869 family of nuclear transcription factors whose ligands , such as eicosanoids , fatty acids and prostaglandins , are known to affect gonadal function . Although several of these enhance the expression of the steroidogenic acute regulatory protein ( STAR ) and steroid production , the role of PPARgamma in regulating STAR - mediated steroidogenesis remains unclear . In the present study , we used ciglitazone to selectively activate PPARgamma and examine its role in STAR - mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA - 10 mouse Leydig tumour cells . Cotreatment with both dibutyryl - DB02527 and ciglitazone revealed a dose - dependent , significant increase in progesterone synthesis , Star promoter activity , Star mRNA and STAR protein relative to either compound alone . The overexpression of PPARgamma further increased Star - promoter activity . The ciglitazone - induced activity of the Star - promoter appears to be mediated through the DB02527 - response element half - sites located within its proximal 151 bp . Combined treatment with ciglitazone and dibutyryl - DB02527 significantly increased the expression and activity of transcriptional pathways impacted by the activator protein - 1 family member c - P05412 . The present study demonstrates that ciglitazone and dibutyryl - DB02527 synergistically enhance STAR expression in MA - 10 and KK1 cells . DB09201 - activated PPARgamma appears to increase the sensitivity of Leydig and granulosa cells to DB02527 stimulation , possibly via upregulation of c - P05412 expression .",
"Metallothionein prevention of arsenic trioxide - induced cardiac cell death is associated with its inhibition of mitogen - activated protein kinases activation in vitro and in vivo . Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent . The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress . Metallothionein ( MT ) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress - induced cardiac damage . To investigate whether and how MT protects against arsenic cardiotoxicity , MT - overexpressing H9c2 ( MT - H9c2 ) cardiac cells and transgenic ( MT - TG ) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide . Cardiac cell apoptosis was detected by molecular indices , including the cleavage of caspase 3 and caspase 12 , Bax / Bcl2 expression ratio , P35638 expression and / or confirmed by a terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling assay . DB01169 dose - and time - dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as P27361 / 2 , JNK and p38 , but not in MT - H9c2 cells . Importantly , the protective effect of MT on arsenic trioxide - induced apoptotic cell death was completely recaptured in the heart of MT - TG with a significant prevention of MAPKs activation . These results indicate that arsenic trioxide - upregulated MAPKs might play important role in arsenic trioxide - induced apoptotic cell death in cardiac cells both in vivo and in vitro , and MT ' s suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation . Therefore , selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity .",
"P04150 - mediated regulation of P14780 gene expression in human ovarian surface epithelial cells . OBJECTIVE : To obtain proof - of - concept that locally produced anti - inflammatory steroids suppress ovulation - associated extracellular matrix proteases in human ovarian surface epithelial ( OSE ) cells . DESIGN : Primary OSE cell cultures treated with interleukin - 1alpha ( IL - 1alpha ) ( 500 pg / mL ) as proxy for inflammation , with / without anti - inflammatory steroid ( cortisol or progesterone [ P ] , 0 . 01 - 1 . 0 microM ) . SETTING : Academic medical center . PATIENT ( S ) : Sixteen premenopausal women ( 29 - 46 years ) undergoing surgery for nonmalignant gynecological conditions . MAIN OUTCOME MEASURE ( S ) : Semiquantitative extracellular matrix protease gene expression profiling with verification by real - time quantitative reverse transcription polymerase chain reaction ( qRT - PCR ) and gelatinase zymography . RESULT ( S ) : Treatment with IL - 1alpha stimulated messenger RNA ( mRNA ) expression of several ovulation - associated matrix metalloproteinase genes by OSE cell cultures , including gelatinase B ( P14780 ) but not gelatinase A ( P08253 ) . The IL - 1alpha - stimulated P14780 mRNA production was suppressed by cortisol but not P . ___MASK81___ but not P also dose - dependently suppressed IL - 1alpha - stimulated P14780 gelatinase activity and this effect was blocked by the glucocorticoid receptor antagonist DB00834 . CONCLUSION ( S ) : In human OSE cells , stimulation of P14780 gene expression and proteolytic activity by IL - 1alpha is suppressed by anti - inflammatory cortisol through a glucocorticoid receptor - mediated mechanism . Because IL - 1alpha also generates cortisol formation in OSE by stimulating cortisone reductase activity , these results support a role for intracrine cortisol in minimizing proteolytic damage to the OSE at ovulation .",
"O75915 is required for arsenic trioxide induced apoptosis in HeLa and MCF - 7 cells via reactive oxygen species and mitochondria linked signal pathway . DB01169 , emerging as a standard therapy for refractory acute promyelocytic leukemia , induces apoptosis in a variety of malignant cell lines . O75915 , a novel retinoic acid - inducible gene , is known to be involved in apoptosis induced by various agents , for example , 12 - O - tetradecanoylphorbol 13 - acetate , N - 4 - hydroxy - phenyl - retinamide and arsenic trioxide . However , the molecular mechanisms underlying how O75915 gene is functionally involved in apoptosis remain largely unknown . Herein , our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF - 7 cells in a dose - dependent manner and paralleled with increased O75915 expression . O75915 expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide . Knockdown of O75915 attenuated arsenic trioxide induced apoptosis , and was accompanied by significantly reduced activity of caspase - 9 , enhanced Bad phosphorylation and inhibited Q02750 / 2 , P27361 / 2 and JNK phosphorylations . DB01169 induced loss of mitochondrial transmembrane potential was O75915 - dependent . These findings suggest that O75915 may serve as a pro - apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria - associated signal pathway .",
"Synergistic inhibition of colon carcinoma cell growth by Hedgehog - Gli1 inhibitor arsenic trioxide and phosphoinositide 3 - kinase inhibitor LY294002 . The Hedgehog ( Hh ) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis , but also in tumorigenesis . Aberrant Hh pathway activation has been reported in a variety of malignant tumors including colon carcinoma . Here , we sought to investigate the regulation of the Hh pathway transcription factor Gli1 by arsenic trioxide and phosphoinositide 3 - kinase ( PI3K ) inhibitor LY294002 in colon carcinoma cells . We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells , which was confirmed by quantitative real - time polymerase chain reaction and Western blots . Knocking down endogenous Gli1 reduced colon carcinoma cell viability through inducing cell apoptosis . Similarly , knocking down Gli2 using short interfering RNA impaired colon carcinoma cell growth in vitro . To elucidate the regulation of Gli1 expression , we found that both Gli inhibitor arsenic trioxide and PI3K inhibitor LY294002 significantly reduced Gli1 protein expression and colon carcinoma cell proliferation . DB01169 treatment also reduced Gli1 downstream target gene expression , such as Bcl2 and P24385 . More importantly , the inhibition of Hedgehog - Gli1 by arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor LY294002 in colon carcinoma cells . Our findings suggest that the Hh pathway transcription factor Gli1 is involved in the regulation of colon carcinoma cell viability . Inhibition of Hedgehog - Gli1 expression by arsenic trioxide and PI3K inhibitor synergistically reduces colon cancer cell proliferation , indicating that they could be used as an effective anti - colon cancer combination therapy .",
"DB00644 - regulated expression of Jun and P05412 target genes in gonadotropes requires a functional interaction between TCF / LEF family members and beta - catenin . DB00644 regulates gonadotrope function through a complex transcriptional network that includes three members of the immediate early gene family : Egr1 , Jun , and Atf3 . These DNA - binding proteins act alone or in pairs to confer hormonal responsiveness to Cga , Lhb , Fshb , and Gnrhr . Herein we suggest that the transcriptional response of Jun requires a functional interaction between the T - cell factor ( TCF ) / lymphoid enhancer factor ( LEF ) family of DNA - binding proteins and beta - catenin ( officially P35222 ) , a coactivator of TCF / LEF . Supporting data include demonstration that DB00644 increases activity of TOPflash , a TCF / LEF - dependent luciferase reporter , in LbetaT2 cells , a gonadotrope - derived cell line . Additional cotransfection experiments indicate that a dominant - negative form of Q9NQB0 ( TCFDN ) that binds DNA , but not beta - catenin , blocks DB00644 induction of TOPflash . Overexpression of O15169 , an inhibitor of beta - catenin , also reduces DB00644 stimulation of TOPflash . Transduction of LbetaT2 cells with TCFDN adenoviruses diminishes DB00644 stimulation of Jun mRNA without altering expression of Egr1 and Atf3 , two other immediate early genes that confer DB00644 responsiveness . Reduction of beta - catenin in LbetaT2 cells , through stable expression of short hairpin RNA , also selectively compromises DB00644 regulation of Jun expression and levels of P05412 protein . Finally , overexpression of TCFDN attenuates DB00644 regulation of Cga promoter activity , a known downstream target of P05412 . Together , these results indicate that DB00644 regulation of Jun transcription requires a functional interaction between TCF / LEF and beta - catenin and that alteration of either impacts expression of P05412 downstream targets such as Cga .",
"Dominant negative P13500 blocks human osteoclast differentiation . Human osteoclasts were differentiated using receptor activator of NFκB ligand ( O14788 ) and macrophage colony stimulating factor ( P09603 ) from colony forming unit - granulocyte macrophage ( CFU - GM ) precursors of the myeloid lineage grown from umbilical cord blood . Gene expression profiling using quantitative polymerase chain reaction ( Q - PCR ) showed more than 1 , 000 - fold induction of chemokine P13500 within 24 h of O14788 treatment . P13500 mRNA content exceeds that of other assayed chemokines ( P22362 , 3 , 4 , and 5 ) at all time points up to day 14 of treatment . P13500 induction preceded peak induction of calcium signaling activator calmodulin 1 ( P62158 ) and transcription factors P05412 and P01100 , which were at 3 days . Key osteoclast related transcription factors O95644 and Q13469 showed peak induction at 7 days , while marker genes for osteoclast function cathepsin K and tartrate resistance acid phosphatase ( TRAP ) were maximally induced at 14 days , corresponding with mature osteoclast function . To test whether the early and substantial peak in P13500 expression is part of human osteoclast differentiation events , a dominant negative inhibitor of P13500 ( 7ND ) was added simultaneously with O14788 and P09603 , resulting in blockade of P62158 , P05412 and Q13469 induction and strong inhibition of human osteoclast differentiation . These data show that a cascade of gene expression leading to osteoclast differentiation depends on intact early P13500 induction and signaling in human osteoclasts .",
"Antitumor activity of arsenic trioxide on retinoblastoma : cell differentiation and apoptosis depending on arsenic trioxide concentration . PURPOSE : DB01169 ( ATO ) targets multiple pathways in malignant cells , resulting in the promotion of differentiation or in the induction of apoptosis . The antitumor activity of ATO on retinoblastoma was investigated . METHODS : Human retinoblastoma cells were incubated with various ATO concentrations . The antiproliferative effect of ATO was evaluated by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay , and the effect of ATO on cell - cycle progression was validated by flow cytometry . At a low concentration , the ATO - induced differentiation of retinoblastoma cells was evaluated by neurofilament expression and extracellular signal - regulated kinase ( P29323 ) 1 / 2 activation , which was confirmed by the inhibition of P27361 / 2 . At a high concentration , ATO - induced H ( 2 ) O ( 2 ) production was investigated with the cell - permeable fluorescent dye 2 ' 7 '- dichlorofluorescein - diacetate , and the relationship of ATO - induced H ( 2 ) O ( 2 ) production with caspase - 3 - dependent apoptosis was validated by Western blot and 4 ' 6 - diamidino - 2 - phenolindole staining , which was confirmed by reactive oxygen species ( ROS ) inhibition . The effect of ATO on tumor formation was assessed with an orthotopic animal model of retinoblastoma . RESULTS : The antitumor activity of ATO in retinoblastoma was related to two main mechanisms , differentiation and apoptosis , which were determined by the level of ATO . At a low dose ( < or = 1 microM ) , ATO induced the differentiation of retinoblastoma cells through P27361 / 2 activation , whereas ROS generation by a high dose ( > or = 2 microM ) of ATO induced apoptosis in retinoblastoma cells . Moreover , ATO at low and high doses effectively inhibited tumor formation . CONCLUSIONS : These results suggest that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma .",
"Q99706 differentially signals downstream functions in human NK cells through distinct structural modules . Q99706 ( 2DL4 ) is a member of the killer cell Ig - like receptor ( P55040 ) family in human NK cells . It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells , but the mechanism for 2DL4 - mediated signaling remains unclear . In this study we characterized the signaling pathways stimulated by 2DL4 engagement . In a human NK - like cell line , KHYG - 1 , cross - linking of 2DL4 activated MAPKs including JNK , P29323 , and p38 . Furthermore , 2DL4 cross - linking resulted in phosphorylation of O15111 beta ( IKKbeta ) and the phosphorylation and degradation of P25963 , which indicate activation of the classical NF - kappaB pathway . Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes , including P01375 , P01579 , MIP1alpha , MIP1beta , and P10145 . Pharmacological inhibitors of JNK , Q02750 / 2 and p38 , blocked P01579 , P10145 , and MIP1alpha production , suggesting that MAPKs are regulating 2DL4 - mediated cytokine production in a nonredundant manner . Activation of both p38 and P29323 appear to be upstream of the stimulation of NF - kappaB . Mutation of a transmembrane arginine in 2DL4 to glycine ( R / G mutant ) abrogated FcepsilonRI - gamma association , as well as receptor - mediated cytolytic activity and calcium responses . Surprisingly , the R / G mutant still activated MAPKs and the NF - kappaB pathway and selectively stimulated the production of MIP1alpha , but not that of P01579 or P10145 . In conclusion , we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules : 1 ) through transmembrane association with FcepsilonRI - gamma ; and 2 ) through another receptor domain independent of the transmembrane arginine .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK13___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK13___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Cbl - b is a negative regulator of inflammatory cytokines produced by IgE - activated mast cells . c - Cbl and Cbl - b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow - derived mast cells from c - Cbl and Cbl - b - deficient mice it has recently been shown that Cbl - b is the dominant family member for negatively regulating signaling responses from high - affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl - b - deficient mice is the relatively higher levels of Cbl - b protein over c - Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c - Cbl and Cbl - b - deficient mice and find that loss of Cbl - b , but not c - Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl - b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl - b or c - Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl - b (-/-) mast cells compared with levels produced by c - Cbl (-/-) or wild - type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl - b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions .",
"Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .",
"AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 / MAPK , the PI3K / AKT / P42345 and the JAK / P40763 pathways . Here , we tested the efficacy of a P23458 / 2 - inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC - 1 ) , P07949 M918T ( MZ - CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC - 1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and / or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC - 1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC - 1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho - Y1062 P07949 levels , and P42345 effector phospho - S6 , while P23458 / 2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e . g . via JAK / phospho - P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK41___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK41___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK41___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK41___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"___MASK13___ inhibition effect on KITAsn822Lys - mediated signal transduction cascade . OBJECTIVE : Alterations in growth factor signaling pathways may be a frequent collaborating event in Q01196 - Q06455 - mediated leukemogenesis . Gain - of - function P10721 receptor mutations have been reported in adult AML patients , especially those with core binding factor leukemia ( CBFL ) . We have previously reported a new gain - of - function P10721 ( Asn822Lys ) mutation that is constitutively expressed in the Kasumi - 1 CBFL cell line , and has recently been described in two childhood AML patients . To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation , we investigated P10721 downstream signaling in the Kasumi - 1 cell line by means of ___MASK13___ ( Imatinib , Gleevec ) pharmacological inhibition . MATERIALS AND METHODS : We investigated P10721 ( Asn822Lys ) mutant - initiated signaling in Kasumi - 1 cell line , and characterized the inhibitory effect of the ___MASK13___ protein tyrosine kinase inhibitor on downstream signaling . RESULTS : The use of ___MASK13___ - mediated inhibition impaired the tyrosine phosphorylation of P10721 ( Asn822Lys ) and its association with the p85 subunit of phosphatidylinositol 3 '- kinase ( p85PI3K ) . The downstream constitutive phosphorylation of P45983 / 2 and P40763 was also significantly inhibited , but ___MASK13___ had no effect on the constitutive activation of Akt , thus suggesting that it is due to other signaling in Kasumi - 1 cells . ___MASK13___ inhibited the P10721 - mediated proliferation of Kasumi - 1 cells in a dose - dependent manner . CONCLUSIONS : These findings show the role of PI3K in P10721 ( Asn822Lys )- mediated constitutive activation through the Akt - independent downstream signaling pathway of JNK , and also demonstrate the mutant ' s susceptibility to ___MASK13___ , which may therefore have therapeutic potential in CBFL patients with susceptible P10721 mutations .",
"Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis - related genes peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) , CCAAT / enhancer binding protein - alpha ( C / EBP - α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis - related genes and P27361 / 2 activation in adipocytes .",
"Proangiogenesis action of the thyroid hormone analog 3 , 5 - diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (- 8 )- 10 (- 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3 , 5 - diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three - dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 )- agarose , as well as basic fibroblast growth factor ( b - FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three - dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b - FGF was blocked by PD 98059 , an inhibitor of the P27361 / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b - FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta3 , and are MAPK dependent .",
"SnoN / SkiL expression is modulated via arsenic trioxide - induced activation of the PI3K / AKT pathway in ovarian cancer cells . SnoN / SkiL ( TGFβ regulator ) is dysregulated in ovarian cancer , a disease associated with acquired drug - resistance . DB01169 ( As₂O₃ , used in treating APL ) induces SnoN to oppose the apoptotic response in ovarian cancer cells . We now report that As₂O₃ increases phosphorylation of P00533 / p66ShcA and P00533 degradation . As₂O₃ activates Src ( Y416 ) whose activity ( inhibited by Q99463 ) modulates P00533 activation , its interaction with Shc / Grb2 , and p - AKT . Inhibition of PI3K reduces SnoN and cell survival . Although P00533 or P28482 siRNA did not alter SnoN expression , As₂O₃ - induced cleaved PARP was reduced together with increased P98170 . Collectively , As₂O₃ mediates an initial rise in pY - Src ( 416 ) to regulate the PI3K / AKT pathway which increases SnoN and cell survival ; these early events may counter the cell death response associated with increased pY - P00533 / MAPK activation .",
"DB01169 phosphorylates c - Fos to transactivate P38936 ( P38936 / CIP1 ) expression . An infamous poison , arsenic also has been used as a drug for nearly 2400 years ; in recently years , arsenic has been effective in the treatment of acute promyelocytic leukemia . Increasing evidence suggests that opposite effects of arsenic trioxide ( ATO ) on tumors depend on its concentrations . For this reason , the mechanisms of action of the drug should be elucidated , and it should be used therapeutically only with extreme caution . Previously , we demonstrated the opposing effects of P27361 / 2 and JNK on P38936 ( P38936 / CIP1 ) ( P38936 ) expression in response to ATO in A431 cells . In addition , JNK phosphorylates c - Jun ( DB00133 ( 63 / 73 ) ) to recruit Q15583 / Q13547 to suppress P38936 gene expression . Presently , we demonstrated that a high concentration of ATO sustains P27361 / 2 phosphorylation , and increases c - Fos biosynthesis and stability , which enhances P38936 gene expression . Using site - directed mutagenesis , a DNA affinity precipitation assay , and functional assays , we demonstrated that phosphorylation of the C - terminus of c - Fos ( DB00156 ( 232 ) , DB00156 ( 325 ) , DB00156 ( 331 ) , and DB00133 ( 374 ) ) plays an important role in its binding to the P38936 promoter , and in conjunction with N - terminus phosphorylation of c - Fos ( DB00133 ( 70 ) ) to transactivate P38936 promoter expression . In conclusion , a high concentration of ATO can sustain P27361 / 2 activation to enhance c - Fos expression , then dimerize with dephosphorylated c - Jun ( DB00133 ( 63 / 73 ) ) and recruit p300 / CBP to the Sp1 sites ( - 84 /- 64 ) to activate P38936 gene expression in A431 cells .",
"DB01169 concentration determines the fate of Ewing ' s sarcoma family tumors and neuroblastoma cells in vitro . DB01169 ( As ( 2 ) O ( 3 ) ) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner . We assessed the effects of As ( 2 ) O ( 3 ) in CADO - ES Ewing ' s sarcoma ( ES ) , JK - GMS peripheral primitive neuroectodermal tumor ( PNET ) , and SH - SY5Y neuroblastoma cells , as they share common histogenetic backgrounds . As ( 2 ) O ( 3 ) at low concentrations ( 0 . 1 - 1 microM ) induced SH - SY5Y differentiation , and whereas PNET cells acquired a slightly differentiated phenotype , change was minimal in ES cells . P28482 ( P28482 ) was activated at low As ( 2 ) O ( 3 ) concentrations , and PD98059 , an inhibitor of MEK - 1 , blocked SH - SY5Y cell differentiation by As ( 2 ) O ( 3 ) . High concentrations ( 2 - 10 microM ) of As ( 2 ) O ( 3 ) induced the apoptosis in all three cell lines , and this was accompanied by the activation of c - jun N - terminal kinase . The generation of H ( 2 ) O ( 2 ) and activation of caspase 3 were identified as critical components of As ( 2 ) O ( 3 )- induced apoptosis in all of the above cell lines . P09038 enhanced As ( 2 ) O ( 3 )- induced apoptosis in JK - GMS cells . The overall effects of As ( 2 ) O ( 3 ) strongly suggest that it has therapeutic potential for the treatment of ES / PNET .",
"Oxidative stress - induced p53 activity is enhanced by a redox - sensitive Q96A56 SUMOylation . Tumor Protein p53 - Induced Nuclear Protein 1 ( Q96A56 ) is a tumor suppressor that modulates the p53 response to stress . Q96A56 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes . Q96A56 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development . In this work , we report that redox - dependent induction of p53 transcriptional activity is enhanced by the oxidative stress - induced SUMOylation of Q96A56 at lysine 113 . This SUMOylation is mediated by Q9Y6X2 and O00257 , two SUMO ligases especially related to the p53 activation upon DNA damage . Importantly , this modification is reversed by three P63165 - specific proteases Q9P0U3 , 2 and 6 . Moreover , Q96A56 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions . Q96A56 mutation at lysine 113 prevents the pro - apoptotic , antiproliferative and antioxidant effects of Q96A56 by impairing the p53 response on its target genes P38936 , Bax and PUMA . We conclude that Q96A56 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress .",
"In vitro and in vivo effects of the Q07869 agonists fenofibrate and retinoic acid in endometrial cancer . Fenofibrate , an agonist of Q07869 , in doses above 25 microM , inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells . We show that these effects are potentiated by retinoic acid , an agonist of the retinoid - Q9UBH6 . DNA content analysis shows that P55008 / S phase progression through the cell cycle is inhibited . Independent Component Analysis of gene microarray experiments demonstrated downregulation of P12004 D1 ( P24385 ) and associated changes in cell cycle gene expression . Expression of Q07869 mRNA was reduced by > 75 % using RNA - interference but this resulted in only minor changes in biological effects . A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth . CONCLUSION : The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro .",
"Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems . This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT - PCR . We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia . Twenty types of chromosomal abnormalities were detected in 42 % from all patients by commercially available multiplex RT - PCR for detecting 28 fusion genes and in 35 % by cytogenetic analysis including Q5TCZ1 analysis . The most common cytogenetic aberrations in acute myeloid leukemia patients was P29590 / PARA , followed by Q01196 / MGT8 and Q03164 , and in acute lymphoid leukemia patients was P11274 / P00519 , followed by P41212 / Q01196 and Q03164 gene rearrangement . Among the negative results for multiplex RT - PCR , clinically significant t ( 3 ; 3 )( q21 ; q26 . 2 ) , t ( 8 ; 14 )( q24 ; q32 ) and i ( 17 )( q10 ) were detected by conventional cytogenetics . The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies , and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems .",
"Lytic activity of P60568 and IL - 12 stimulated NK cells against Q9UKB1 osteosarcoma cell line . NK cells are CD16 , CD56 positive lymphocytes that spontaneously lyse tumor or virus infected cells . In this study we investigated whether P60568 and / or IL - 12 stimulated NK cells increased their lytic efficiency against Q9UKB1 osteosarcoma cell line . Our results demonstrate that both 18 hour and 5 day incubation times enhanced the lytic activity of human PBL against Q9UKB1 and K562 target cells and that IL - 12 appears to be more efficient than P60568 in augmenting NK cytotoxicity .",
"Synergism of Q9HC29 and Q96P20 activators promotes a unique transcriptional profile in murine dendritic cells . NLRs are cytoplasmic proteins that sense cellular stress and intracellular damage resulting from pathogen uptake . To date , the role of NLRs has been studied using combinations of NLR and TLR agonists , but the interplay between two different NLRs remains uncharacterized . In this study , we employed microarrays to investigate in DCs the regulation of gene transcription mediated by activation of Q9HC29 and Q96P20 pathways using P16444 and MSU . P16444 and MSU co - stimulation of murine BMDCs up - regulated the expression of genes encoding molecules for antigen presentation and co - stimulation ( MHC class II , P33681 , P42081 ) , integrins ( P05106 , P06756 ) , cytokines ( IL - 1α , IL - 1β , P05231 , P60568 , Q9NPF7 , IL - 12p40 ) , and chemokines ( P09341 , P19875 ) . Transcription of the cytokine genes induced by P16444 and MSU partially depended on Q9HC29 but was independent of Q96P20 . Finally , we showed that P27361 and c - P05412 activation increased upon P16444 and MSU co - stimulation . As a whole , the results indicate that two different NLR activators synergize at the transcriptional level , leading to unique differential expression of genes involved in the innate immune response .",
"DB01169 inhibits osteosarcoma cell invasiveness via MAPK signaling pathway . DB01169 ( As ( 2 ) O ( 3 ) ) is an active ingredient in traditional Chinese medicine . Recent studies showed that it causes apoptosis in several cancer cells . However , research of As ( 2 ) O ( 3 ) in osteosarcoma is sparse . In our present study , an inhibitory effect of As ( 2 ) O ( 3 ) on osteosarcoma cell adhesion and metastasis was observed with a cell adhesion , migration and invasion test . The impact of As ( 2 ) O ( 3 ) on the activities of P14780 and MAPK pathway - related downstream factors was analyzed by western blotting . Our results showed that As ( 2 ) O ( 3 ) significantly inhibited motility , migration and invasion in Q9UKB1 and MNNG cells in a concentration - dependent manner at concentrations ranging from 0 . 5 - 2 μM , and led to cytoskeletal rearrangements . As ( 2 ) O ( 3 ) exerted an inhibitory effect on the phosphorylation of P27361 / 2 and MEK , which are the members of the MAPK family . Additionally , treatment with As ( 2 ) O ( 3 ) in combination with inhibitors specific for MEK ( U0126 ) in Q9UKB1 and MNNG cells resulted in a marked inhibition of cell invasion and As ( 2 ) O ( 3 ) could significantly reduce PMA - induced invasion . In conclusion , we demonstrate the inhibitory effects of As ( 2 ) O ( 3 ) on the invasiveness of Q9UKB1 and MNNG cells , which may be due at least partly to inactivation of the MAPK signaling pathway .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK3___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Chronically increased ciliary neurotrophic factor and fibroblast growth factor - 2 expression after spinal contusion in rats . Demyelination and oligodendrocyte loss following spinal cord injury ( SCI ) are well documented . Recently , we showed oligodendrocyte progenitor cell ( OPC ) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders . We have since begun investigating potential mechanisms for this endogenous repair response . Here , we examined ciliary neurotrophic factor ( P26441 ) and fibroblast growth factor - 2 ( P09038 ) expression , because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders . We hypothesized that P26441 and P09038 would increase after SCI , especially in regions of enhanced oligogenesis . First , P26441 protein was quantified using Western blots , which revealed that P26441 protein continually rose through 28 days post injury ( dpi ) . Next , by using immunohistochemistry , we examined the spatiotemporal expression of P26441 in cross - sections spanning the injury site . P26441 immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords . Significantly increased P26441 was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls . By 28 dpi , P26441 expression was significantly higher along lesion borders compared with outlying spared tissue ; a similar distribution of phosphorylated P40763 , a transcription factor up - regulated by P26441 and to a lesser extent P09038 , was also detected . Because P26441 can potentiate P09038 expression , we examined the distribution of P09038 + cells . Significantly more P09038 + cells were noted along lesion borders at 7 and 28 dpi . Thus , both P26441 and P09038 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury - induced gliogenesis .",
"A metabolic prosurvival role for P29590 in breast cancer . Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression . However , the genetic cues modulating this metabolic switch remain largely undetermined . We identified a metabolic function for the promyelocytic leukemia ( P29590 ) gene , uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival . We found that P29590 acted as both a negative regulator of PPARγ coactivator 1A ( Q9UBK2 ) acetylation and a potent activator of Q07869 signaling and fatty acid oxidation . We further showed that P29590 promoted DB00171 production and inhibited anoikis . Importantly , P29590 expression allowed luminal filling in 3D basement membrane breast culture models , an effect that was reverted by the pharmacological inhibition of fatty acid oxidation . Additionally , immunohistochemical analysis of breast cancer biopsies revealed that P29590 was overexpressed in a subset of breast cancers and enriched in triple - negative cases . Indeed , P29590 expression in breast cancer correlated strikingly with reduced time to recurrence , a gene signature of poor prognosis , and activated Q07869 signaling . These findings have important therapeutic implications , as P29590 and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression , a potential future mode of cancer prevention and treatment .",
"Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : ___MASK75___ is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2 - mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK75___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK75___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Systematic review : diet - gene interactions and the risk of colorectal cancer . BACKGROUND : Diet contributes significantly to colorectal cancer ( CRC ) aetiology and may be potentially modifiable . AIM : To review diet - gene interactions , aiming to further the understanding of the underlying biological pathways in CRC development . METHODS : The PubMed and Medline were systematically searched for prospective studies in relation to diet , colorectal cancer and genetics . RESULTS : In a meta - analysis , no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found ( P - value for interaction 0 . 95 ) . We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC . High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype , whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC ( OR = 1 . 25 ; 95 % confidence interval ( CI ) : 0 . 92 - 2 . 01 ) compared with slow acetylators with low meat intake ( reference ) , P - value for interaction = 0 . 07 . Low meat intake in the studied populations may influence the result . Interactions between meat , cruciferous vegetables , fibres , calcium , vitamins , and alcohol and P08183 , P19838 , P09488 , P30711 , P24385 , P11473 , MGTM , P22301 and P37231 are suggested . CONCLUSIONS : A number of interactions between genetic variation and diet are suggested , but the findings need replication in independent , prospective , and well - characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached . When the above criteria are met , studies on diet - gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis .",
"Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6 . 1 - composed K - DB00171 channels expressed in neural stem cells . BACKGROUND AND PURPOSE : Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases . Iptakalim ( Ipt ) , a novel DB00171 - sensitive potassium ( K - DB00171 ) channel opener , has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro . However , it remains unknown whether Ipt could regulate the adult neurogenesis . METHODS AND RESULTS : Based on the finding that adult neural stem cells ( ANSCs ) in hippocampus expressed Kir6 . 1 / Q09428 - composed K - DB00171 channel , Kir6 . 1 heterozygotic ( Kir6 . 1 (+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis . We showed that administration of Ipt ( 10 mg / kg ) or fluoxetine ( Flx , 10 mg / kg ) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ ) of Kir6 . 1 (+/+) mice but failed to affect those of Kir6 . 1 (+/-) mice . Meanwhile , ANSCs in Kir6 . 1 (+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes . We further found that Kir6 . 1 (+/-) mice showed lower level of brain - derived neurotrophic factor ( P23560 ) in hippocampus compared with Kir6 . 1 (+/+) mice . Furthermore , Ipt increased the levels of P23560 and basic fibroblast growth factor ( P09038 ) throughout the hippocampus in Kir6 . 1 (+/+) mice but not in Kir6 . 1 (+/-) mice . Moreover , Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6 . 1 (+/+) mice . Notably , these effects were completely abolished in Kir6 . 1 (+/-) mice . CONCLUSIONS : Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6 . 1 - composed K - DB00171 channels , which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency , such as major depression .",
"Effects of leptin and adiponectin on proliferation and protein metabolism of porcine myoblasts . The aim of this study was to show the abundance of leptin and adiponectin receptors ( LEPR , Q96A54 , Q86V24 ) and to determine the direct effects of leptin and adiponectin on the in vitro growth of porcine skeletal muscle cells . Q96A54 and Q86V24 were abundant at mRNA and protein level in proliferating and differentiating myoblast cultures derived from semimembranosus and semitendinosus muscles of newborn piglets , whereas LEPR expression was close to the detection limit . Q15848 ( 10 , 20 , 40 μg / ml ) attenuated the proliferation of porcine myoblasts , measured as [ ( 3 ) H ] - thymidine incorporation and real - time monitoring of the cells in response to 24 - and 48 - h exposure , in a dose - dependent manner . This effect resulted from suppressed basic fibroblast growth factor ( P09038 ) - mediated stimulation of DNA synthesis in serum - free medium ( SFM ) containing P09038 . No effects of leptin ( 5 , 10 , 20 , 40 , 80 ng / ml ) on myoblast proliferation in SFM were detectable . Neither leptin nor adiponectin altered protein synthesis and degradation in differentiating porcine myoblasts cultured in SFM . The results on receptor abundance suggest that porcine skeletal muscle cells may be sensitive to adiponectin and leptin . However , except via inhibitory interaction of adiponectin with P09038 , these adipokines appear not to affect in vitro proliferation and protein metabolism of porcine muscle cells directly under serum - free culture conditions .",
"Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines . Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia , and prostate cancer . Although testosterone is the main androgen secreted from the testes , dihydrotestosterone ( DB02901 ) , a more potent androgen converted from testosterone by 5alpha - reductase isozymes , type I and II , is the major androgen in the prostate cells . The aim of this study is to investigate the cellular and molecular effects of dutasteride , a potent inhibitor of 5alpha - reductase type I and type II , in androgen - responsive ( LNCaP ) and androgen - unresponsive ( DU145 ) human prostate cancer ( PCa ) cell lines . The expression pattern of 190 genes , selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling , were analysed using a low density home - made oligoarray ( AndroChip 2 ) . Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested . AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed ( FC > or = +/- 1 . 5 ) . Eight of these genes , were overexpressed and three were underexpressed . Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen ( P14061 ; P37058 ; P19099 ) , androgen receptor and androgen receptor co - regulators ( AR ; P24385 ) , and signal transduction ( P04626 ; V - P62158 ; Q07889 ) whereas , underexpressed genes ( KLK3 ; P20151 ; Q15392 ) were androgen - regulated genes ( ARGs ) . No differentially expressed genes were scored in DU145 . Microarray data were confirmed by quantitative real - time PCR assay ( QRT - PCR ) . These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology .",
"Activation of the p38 MAPK / Akt / P27361 / 2 signal pathways is required for the protein stabilization of Q99741 and cyclin D1 in low - dose arsenite - induced cell proliferation . DB01169 ( ATO ) is a first - line anti - cancer agent for acute promyelocytic leukemia , and induces apoptosis in other solid cancer cell lines including breast cancer cells . However , as with arsenites found in drinking water and used as raw materials for wood preservatives , insecticides , and herbicides , low doses of ATO can induce carcinogenesis after long - term exposure . At 24 h after exposure , ATO ( 0 . 01 - 1 µM ) significantly increased cell proliferation and promoted cell cycle progression from the P55008 to S / G2 phases in the non - tumorigenic MCF10A breast epithelial cell line . The expression of 14 out of 96 cell - cycle - associated genes significantly increased , and seven of these genes including cell division cycle 6 ( Q99741 ) and cyclin D1 ( P24385 ) were closely related to cell cycle progression from P55008 to S phase . Low - dose ATO steadily increased gene transcript and protein levels of both Q99741 and cyclin D1 in a dose - and time - dependent manner . Low - dose ATO produced reactive oxygen species ( ROS ) , and activated the p38 MAPK , Akt , and P27361 / 2 pathways at different time points within 60 min . Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK , Akt , and P27361 / 2 decreased the ATO - increased expression of Q99741 protein . Inhibiting the activation of Akt and P27361 / 2 , but not p38 MAPK , decreased the ATO - induced expression of cyclin D1 protein . This study reports for the first time that p38 MAPK / Akt / P27361 / 2 activation is required for the protein stabilization of Q99741 in addition to cyclin D1 in ATO - induced cell proliferation and cell cycle modulation from P55008 to S phase .",
"DB01169 induces apoptosis through JNK and P29323 in human mesothelioma cells . Malignant mesothelioma is an aggressive tumor of serosal surfaces , which is refractory to current treatment options . DB01169 ( As2O3 ) is used clinically to treat acute promyelocytic leukemia , and also to inhibit proliferation of several solid tumors including hepatoma , esophageal , and gastric cancer in vitro . Here we found that As2O3 inhibited cell viability of a mesothelioma cell line , NCI - H2052 . As2O3 induced apoptosis of NCI - H2052 cells , which was accompanied by activation of c - Jun NH2 - terminal kinase ( JNK ) 1 / 2 , extracellular signal - regulated kinase ( P29323 ) 1 / 2 , and caspase - 3 . zVAD - fmk , a broad - spectrum caspase inhibitor , inhibited As2O3 - induced apoptosis and activation of caspase - 3 , but not that of P45983 / 2 and P27361 / 2 . Small interfering RNAs ( siRNAs ) targeting P45983 / 2 suppressed As2O3 - induced caspase - 3 activation and apoptosis , indicating that P45983 / 2 regulate As2O3 - induced apoptosis though caspase cascade . Furthermore , P45983 siRNA abrogated As2O3 - induced P45984 phosphorylation and P45984 siRNA abrogated As2O3 - induced P45983 phosphorylation , suggesting that P45983 and P45984 interact with each other . Moreover , P45983 siRNA , but not P45984 siRNA , abrogated As2O3 - induced P27361 / 2 phosphorylation . P45984 siRNA together with PD98059 , a specific MAPK / P29323 kinase inhibitor , suppressed As2O3 - induced apoptosis more significantly than P45984 siRNA alone . These results indicated that As2O3 induces apoptosis of NCI - H2052 cells mainly through P45983 / 2 activation , and that P27361 / 2 is involved in As2O3 - induced apoptosis when P45983 / 2 are inactivated .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK24___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"___MASK81___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK81___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .",
"P06401 membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine - induced matrix metalloproteinase 9 activity in vitro . Progesterone ( P4 ) and the progestin , 17α - hydroxyprogesterone caproate , are clinically used to prevent preterm births ( PTBs ) ; however , their mechanism of action remains unclear . Cytokine - induced matrix metalloproteinase 9 ( P14780 ) activity plays a key role in preterm premature rupture of the membranes and PTB . We demonstrated that the primary chorion cells and the HTR8 / SVneo cells ( cytotrophoblast cell line ) do not express the classical progesterone receptor ( P06401 ) but instead a novel progesterone receptor , progesterone receptor membrane component 1 ( O00264 ) , whose role remains unclear . Using HTR8 / SVneo cells in culture , we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate ( ___MASK41___ ) and dexamethasone ( DB00514 ) but not P4 or 17α - hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α - induced P14780 activity after a 24 - hour incubation period . The inhibitory effect of ___MASK41___ , but not DB00514 , was attenuated when O00264 expression was successfully reduced by O00264 small interfering RNA . Our findings highlight a possible novel role of O00264 in mediating the effects of ___MASK41___ and in modulating cytokine - induced P14780 activity in cytotrophoblast cells in vitro .",
"Low doses of natural killer T cells provide protection from acute graft - versus - host disease via an P05112 - dependent mechanism . P01730 (+) natural killer T ( NKT ) cells , along with P01730 (+) CD25 (+) regulatory T cells ( Tregs ) , are capable of controlling aberrant immune reactions . We explored the adoptive transfer of highly purified ( > 95 % ) P01730 (+) NKT cells in a murine model of allogeneic hematopoietic cell transplantation ( HCT ) . NKT cells follow a migration and proliferation pattern similar to that of conventional T cells ( Tcons ) , migrating initially to secondary lymphoid organs followed by infiltration of graft - versus - host disease ( GVHD ) target tissues . NKT cells persist for more than 100 days and do not cause significant morbidity or mortality . Doses of NKT cells as low as 1 . 0 × 10 ( 4 ) cells suppress GVHD caused by 5 . 0 × 10 ( 5 ) Tcons in an interleukin - 4 ( P05112 ) - dependent mechanism . Protective doses of NKT cells minimally affect Tcon proliferation , but cause significant reductions in interferon - γ ( IFN - γ ) and tumor necrosis factor - α ( P01375 - α ) production by donor Tcons and in skin , spleen , and gastrointestinal pathology . In addition , NKT cells do not impact the graft - versus - tumor ( GVT ) effect of Tcons against B - cell lymphoma - 1 ( P24385 ) tumors . These studies elucidate the biologic function of donor - type P01730 (+) NKT cells in suppressing GVHD in an allogeneic transplantation setting , demonstrating clinical potential in reducing GVHD in HCT .",
"Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma . Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia ( P29590 ) gene was significantly upregulated ( 2 . 5 - fold ) in cells positive to prominin - 1 antigen ( CD133 ) , a possible marker for cancer initiating cells . DB01169 ( As ( 2 ) O ( 3 ) ) is known to degrade P29590 protein and has been used for the treatment of patients with acute P29590 . In the present study , the effect of P29590 targeting therapy with As ( 2 ) O ( 3 ) and cytarabine ( DB00987 ) on Daoy medulloblastoma cell proliferation was investigated . Daoy cells were pretreated with As ( 2 ) O ( 3 ) for 6 weeks . The As ( 2 ) O ( 3 )- pretreated Daoy cells were cultured in medium containing DB00987 and cell viability was examined . Next , the As ( 2 ) O ( 3 )- pretreated Daoy cells were inoculated into the nude mouse brain and the effect of DB00987 on the tumor size was evaluated . A significant increase in chemosensitivity to DB00987 was observed in the As ( 2 ) O ( 3 )- pretreated Daoy cells in both in vitro and in vivo conditions . P29590 and P24385 ( cyclin D1 ) protein expression of Daoy medulloblastoma cells was downregulated by As ( 2 ) O ( 3 ) treatment . P29590 has been proposed as a novel therapeutic target to eradicate quiescent leukemia - initiating cells , and P29590 - expressing CD133 - positive cells are similarly a potential therapeutic target of treatment for medulloblastoma .",
"DB01169 inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells . DB01169 ( As2O3 ) has shown therapeutic effects in some leukemias and solid cancers . However , the molecular mechanisms of its anticancer efficacy have not been clearly elucidated , particularly in solid cancers . Our previous data showed that As2O3 induced apoptosis of human papillomavirus ( HPV ) 16 DNA - immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells . In the present study , we systemically examined the effects of As2O3 on five human cervical cancer cell lines and explored the possible molecular mechanisms . MTT assay showed that HPV - negative C33A cells were more sensitive to growth inhibition induced by As2O3 than HPV - positive cervical cancer cells , and HPV 18 - positive HeLa and C4 - I cells were more sensitive to As2O3 than HPV 16 - positive CaSki and SiHa cells . After As2O3 treatment , both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines . In contrast , p53 and Rb protein levels increased in all tested cell lines . P05412 protein expression decreased significantly in HeLa , CaSki and C33A cells with ELISA method . These results suggest that As2O3 is a potential anticancer drug for cervical cancer .",
"The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 - thickness , mid - small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c - Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 / CIP1 ) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt - beta - catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration .",
"Q9Y5V3 mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade . Understanding the molecular events that govern neural progenitor lineage commitment , mitotic arrest , and differentiation into functional progeny are germane to our understanding of neocortical development . Members of the family of bone morphogenetic proteins ( BMPs ) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation . We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that Q9Y5V3 is a mandatory component of the signaling cascade . Q9Y5V3 possesses the ability to bind and function with the TAK1 - Q15750 - P98170 complex facilitating the activation of p38 . Disruption of Q9Y5V3 or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure . The function of Q9Y5V3 is independent of Smad signaling , but the introduction of a dominant - negative Q99717 also rescues neural progenitor apoptosis , suggesting that both canonical and noncanonical pathways can converge and regulate BMP - mediated apoptosis . Collectively , these results establish Q9Y5V3 as an integral component in BMP signaling and clarify its role during neural progenitor development .",
"P03372 alpha mediates progestin - induced mammary tumor growth by interacting with progesterone receptors at the cyclin D1 / MYC promoters . Synthetic progesterone used in contraception drugs ( progestins ) can promote breast cancer growth , but the mechanisms involved are unknown . Moreover , it remains unclear whether cytoplasmic interactions between the progesterone receptor ( PR ) and estrogen receptor alpha ( ERα ) are required for PR activation . In this study , we used a murine progestin - dependent tumor to investigate the role of ERα in progestin - induced tumor cell proliferation . We found that treatment with the progestin medroxyprogesterone acetate ( ___MASK41___ ) induced the expression and activation of ERα , as well as rapid nuclear colocalization of activated ERα with PR . Treatment with the pure antiestrogen fulvestrant to block ERα disrupted the interaction of ERα and PR in vitro and induced the regression of ___MASK41___ - dependent tumor growth in vivo . ERα blockade also prevented an ___MASK41___ - induced increase in CYCLIN D1 ( P24385 ) and MYC expression . Chromatin immunoprecipitation studies showed that ___MASK41___ triggered binding of ERα and PR to the P24385 and MYC promoters . Interestingly , blockade or RNAi - mediated silencing of ERα inhibited ERα , but not PR binding to both regulatory sequences , indicating that an interaction between ERα and PR at these sites is necessary for ___MASK41___ - induced gene expression and cell proliferation . We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples . Together , our findings argued that ERα - PR association on target gene promoters is essential for progestin - induced cell proliferation .",
"DB01169 - mediated antiplatelet activity : pivotal role of the phospholipase C gamma 2 - protein kinase C - p38 MAPK cascade . DB01169 produces high rates of complete clinical remission in patients with relapsed / refractory acute promyelocytic leukemia . Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases . Few studies have examined the effects of arsenic trioxide on platelets , and the mechanisms underlying the signaling pathways remain obscure . The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation . DB01169 ( 5 micromol / L ) exhibited more potent activity at inhibiting collagen ( 1 microg / mL ) - induced platelet aggregation than other agonists . DB01169 ( 15 and 25 micromol / L ) inhibited collagen - induced platelet activation accompanied by [ Ca (+ 2 )] i mobilization , thromboxane A ( 2 ) ( TxA ( 2 ) ) formation , phospholipase C ( P98160 ) gamma 2 phosphorylation , and protein kinase C ( PKC ) activation . DB01169 ( 15 and 25 micromol / L ) did not significantly affect cyclic nucleotide - induced vasodilator - stimulated phosphoprotein phosphorylation . Moreover , arsenic trioxide markedly inhibited p38 mitogen - activated protein kinase ( MAPK ) but not P45983 / 2 or P28482 phosphorylation in washed platelets . DB01169 also markedly reduced hydroxyl radical ( OH (.) ) formation in the erythrocyte sedimentation rate ( P03372 ) study . The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the P98160 gamma 2 - PKC - p38 MAPK cascade , thereby leading to inhibition of [ Ca (+ 2 )] i or free radical formation , and finally the inhibition of platelet aggregation .",
"DB01169 ( ATO ) and Q02750 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells . Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras - mitogen - activated protein kinase ( MAPK ) can confer an aggressive , apoptosis - resistant phenotype to leukemia cells . In this study , we report that acute promyelocytic leukemia ( APL ) cells exploit the Ras - MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad , delaying arsenic trioxide ( ATO ) - induced apoptosis . Both in APL cell line NB4 and in APL primary blasts , the inhibition of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) and Bad phosphorylation by Q02750 inhibitors enhanced apoptosis in ATO - treated cells . We isolated an arsenic - resistant NB4 subline ( NB4 - As ( R ) ) , which showed stronger P27361 / 2 activity ( 2 . 7 - fold increase ) and Bad phosphorylation ( 2 . 4 - fold increase ) compared to parental NB4 cells in response to ATO treatment . Upon ATO exposure , both NB4 and NB4 - As ( R ) cell lines doubled protein levels of the death antagonist Bcl - xL , but the amount of free Bcl - xL that did not heterodimerize with Bad was 1 . 8 - fold greater in NB4 - As ( R ) than in the parental line . Q02750 inhibitors dephosphorylated Bad and inhibited the ATO - induced increase of Bcl - xL , overcoming ATO resistance in NB4 - As ( R ) . These results may provide a rationale to develop combined or sequential Q02750 inhibitors plus ATO therapy in this clinical setting .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK73___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Parathyroid hormone - responsive P84022 - related factor , Tmem119 , promotes osteoblast differentiation and interacts with the bone morphogenetic protein - Runx2 pathway . The mechanisms whereby the parathyroid hormone ( PTH ) exerts its anabolic action on bone are incompletely understood . We previously showed that inhibition of P27361 / 2 enhanced P84022 - induced bone anabolic action in osteoblasts . These findings suggested the hypothesis that changes in gene expression associated with the altered P84022 - induced signaling brought about by an P27361 / 2 inhibitor would identify novel bone anabolic factors in osteoblasts . We therefore performed a comparative DNA microarray analysis between empty vector - transfected mouse osteoblastic MC3T3 - E1 cells and PD98059 - treated stable P84022 - overexpressing MC3T3 - E1 cells . Among the novel factors , Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF - β . The levels of Tmem119 increased with time in cultures of MC3T3 - E1 cells and mouse mesenchymal ST - 2 cells committed to the osteoblast lineage by P12643 . PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3 - E1 cells . MC3T3 - E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2 , osteocalcin , alkaline phosphatase , and β - catenin , whereas Tmem119 augmented P12643 - induced Runx2 levels in mesenchymal cells . Tmem119 interacted with Runx2 , Q15797 , and Q99717 in C2C12 cells . In conclusion , we identified a P84022 - related factor , Tmem119 , that is induced by PTH and promotes differentiation in mouse osteoblastic cells . Tmem119 is an important molecule in the pathway downstream of PTH and P84022 signaling in osteoblasts .",
"TG - interacting factor transcriptionally induced by AKT / O43524 is a negative regulator that antagonizes arsenic trioxide - induced cancer cell apoptosis . DB01169 ( ATO ) is a multi - target drug approved by the Food and Drug Administration as the first - line chemotherapeutic agent for the treatment of acute promyelocytic leukemia . In addition , several clinical trials are being conducted with arsenic - based drugs for the treatment of other hematological malignancies and solid tumors . However , ATO ' s modest clinical efficacy on some cancers , and potential toxic effects on humans have been reported . Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue . Previously , we demonstrated that the JNK - induced complex formation of phosphorylated c - Jun and TG - interacting factor ( Q15583 ) antagonizes P29323 - induced cyclin - dependent kinase inhibitor P38936 ( P38936 ( P38936 / CIP1 ) ) expression and resultant apoptosis in response to ATO in A431 cells . Surprisingly , at low - concentrations ( 0 . 1 - 0 . 2 μM ) , ATO increased cellular proliferation , migration and invasion , involving Q15583 expression , however , at high - concentrations ( 5 - 20 μM ) , ATO induced cell apoptosis . Using a promoter analysis , Q15583 was transcriptionally regulated by ATO at the O43524 binding site ( - 1486 to - 1479bp ) via the c - Src / P00533 / AKT pathway . Stable overexpression of Q15583 promoted advancing the cell cycle into the S phase , and attenuated 20 μM ATO - induced apoptosis . Furthermore , blockage of the AKT pathway enhanced ATO - induced P38936 expression and resultant apoptosis in cancer cells , but overexpression of P31749 inhibited P38936 expression . Therefore , we suggest that Q15583 is transcriptionally regulated by the c - Src / P00533 / AKT pathway , which plays a role as a negative regulator in antagonizing ATO - induced P38936 expression and resultant apoptosis . Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO .",
"P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .",
"The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .",
"___MASK83___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK83___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK83___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK83___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK83___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"P28482 , but not P27361 , mediates acquired and \" de novo \" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .",
"Induction of graft - versus - leukemia ( GVL ) effect without graft - versus - host disease ( GVHD ) by pretransplant donor treatment with immunomodulators . Pretransplant donor treatment with immunomodulators such as complete Freund ' s adjuvant ( O75347 ) or oligodeoxynucleotide sequences expressing CpG motifs ( CpG ) , was applied in sublethally irradiated host mice inoculated with murine models of mammary carcinoma ( 4T1 ) or B cell leukemia ( P24385 ) . Spleen cells or P60568 activated splenocytes ( lymphokine activated killer [ Q96QP1 ] ) derived from donor mice treated with CpG emulsified in incomplete Freund ' s adjuvant ( IFA ) , ( CpG + IFA ) did not cause graft - versus - host disease ( GVHD ) , but were not efficient enough to induce a significant graft - versus - tumor ( GVT ) response against 4T1 cells . In contrast , an efficient graft - versus - leukemia ( GVL ) effect was evident in P24385 - bearing mice inoculated with spleen cells from donors pretreated with O75347 or CpG + IFA . Pretransplant donor treatment with O75347 prolonged survival to a median of 62 days with 3 of 27 mice remaining GVHD - and leukemia - free for > 200 days , compared to GVHD - related death of all mice inoculated with naïve cells ( median 17 days ) , or leukemia - related death of all mice inoculated with leukemia cells ( median of 27 days ) . Pretransplant donor treatment with CpG + IFA exerted a more efficient GVL effect with reduced GVHD resulting in 12 of 26 GVHD - and leukemia - free survivors for > 200 days . Our results suggest that it may be possible to prevent GVHD while sparing an efficient GVL effect by using pretransplant donor treatment with immunomodulators prior to allogeneic stem cell transplantation and / or donor lymphocyte infusions in hematologic malignancies .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta - cell selective and reversible . ___MASK75___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided ."
] |
[
"___MASK13___",
"___MASK24___",
"___MASK3___",
"___MASK41___",
"___MASK55___",
"___MASK73___",
"___MASK75___",
"___MASK81___",
"___MASK83___"
] |
___MASK75___
|
MH_train_385
|
interacts_with DB01088?
|
[
"Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of P04626 . We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity . Five of these genes failed to score in transformation assays ; however , novel recurring extracellular domain mutations of the receptor tyrosine kinase gene P04626 were potently oncogenic . These P04626 extracellular domain mutants were activated by two distinct mechanisms , characterized by elevated C - terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation . These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins , impacting cell motility . Survival of Ba / P13726 cells transformed to P08700 independence by the P04626 extracellular domain mutants was abrogated by treatment with small - molecule inhibitors of P04626 , raising the possibility that patients harboring such mutations could benefit from P04626 - directed therapy .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .",
"DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK93___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .",
"Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high - affinity ( KD = 36 +/- 3 nM ) and low - affinity ( KD = 2 . 1 +/- 0 . 8 microM ) prostacyclin ( DB01240 ) - receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [ 3H ] iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5 - 10 - fold increase in the number of both the low - and the high - affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5 - fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 - G2 - adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor .",
"Regulation of cyclooxygenase - 2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c - kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells . Emerging evidence has suggested the pivotal role of mast cells in a host defense against bacterial infection . In this paper , we report that bacterial lipopolysaccharide ( LPS ) is a potent enhancer of the cytokine - and IgE - dependent delayed responses of P08700 - dependent mouse bone marrow - derived cultured mast cells ( BMMC ) . LPS , although showing minimal effects , significantly augmented the c - kit ligand ( KL ) - or IgE - dependent expression of cyclooxygenase ( P36551 ) - 2 and the attendant delayed PGD2 generation , with P22301 and P05112 acting as potentiating and inhibitory cytokines , respectively . The P35354 - inducing activity of LPS was mimicked by exogenous P01584 . Assessment of endogenous cytokine induction revealed that P01584 expression was stimulated by either LPS or exogenous P01584 . P05231 expression occurred in parallel with P35354 expression . P22301 expression , which lagged behind P35354 expression , depended on exogenous P22301 , but not on LPS and P01584 . Thus , LPS and P01584 exhibited similar biological activities in terms of P35354 and endogenous cytokine expression . However , adding an antibody against the type I IL - 1 receptor to BMMC , which abrogated the effects of P01584 , failed to neutralize the effects of LPS . These results suggest that LPS activates BMMC through the signal transduction pathway shared with exogenous P01584 , rather than exerting its action indirectly via the production of endogenous P01584 .",
"___MASK50___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK50___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"[ Thrombocyte prostacyclin receptors in gestational hypertension and pre - eclampsia ] . OBJECTIVE : To determine prostacyclin ( DB01240 ) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome . METHODS : Radioligand binding studies with [ 3H ] - DB01088 were performed to measure receptor capacity ( Bmax ) and affinity ( Kd - 1 ) using platelet membranes from patients with preeclampsia , gestational hypertension or normal pregnancy . RESULTS : P43119 capacity did not differ between the patient groups . In contrast , P43119 affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy . A similar pattern was found in fetal growth ( normal pregnancy > gestational hypertension > preeclampsia ) . Furthermore , the rate of low Apgar scores and acidosis was increased in preeclampsia . CONCLUSIONS : In preeclampsia reduced platelet P43119 affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy , whereas these differences were less pronounced in gestational hypertension . This suggests a role of DB01240 and its receptor in gestational hypertension and in particular in preeclampsia .",
"Dopamine receptors D1 and D2 are related to observed maternal behavior . The dopamine pathway and especially the dopamine receptors 1 and 2 ( P21728 and P14416 ) are implicated in the regulation of mothering in rats . Evidence for this in humans is lacking . Here , we show that genetic variation in both P21728 and P14416 genes in a sample of 187 Caucasian mothers predicts variation in distinct maternal behaviors during a 30 - min mother - infant interaction at 6 months postpartum . Two P21728 single - nucleotide polymorphisms ( SNPs rs265981 and rs686 ) significantly associated with maternal orienting away from the infant ( P = 0 . 002 and P = 0 . 003 , respectively ) , as did P21728 haplotypes ( P = 0 . 03 ) . Two P14416 SNPs ( rs1799732 and rs6277 ) significantly associated with maternal infant - directed vocalizing ( P = 0 . 001 and P = 0 . 04 , respectively ) , as did P14416 haplotypes ( P = 0 . 01 ) . We present evidence for heterosis in P21728 where heterozygote mothers orient away from their infants significantly less than either homozygote group . Our findings provide important evidence that genetic variation in receptors critical for mothering in non - human species also affect human maternal behaviors . The findings also highlight the importance of exploring multiple dimensions of the complex human mothering phenotype .",
"[ Detection of a high - affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high - and a low - affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low - affinity binding sites disappear totally and the specific high - affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto ' s and Riedl ' s thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key - role of DB01240 in thyroid intermediary metabolism .",
"[ ___MASK5___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK5___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"P01236 : a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage . Recent studies have shown that the anterior pituitary hormone prolactin , together with various cytokines , plays an important role in maintaining normal immune responses . Although there is evidence that prolactin may be a significant immunotropic hormone that can counteract the immunosuppressive effects of drugs such as cyclosporine , morphine , or glucocorticoids , it remains unknown whether prolactin administration has any salutary effects on the depressed immune responses following severe hemorrhage . To study this , mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min , then adequately resuscitated and segregated into two groups . One group received saline - vehicle ( hem - SS ) ; animals in the other group were treated with prolactin ( hem - PRL ) ( 100 micrograms per 25 g BW , subcutaneously ) immediately before resuscitation . Two hours following saline or prolactin injection , splenocytes ( SPL ) were harvested and assessed for proliferative capacity ( PC ) and their ability to release P60568 and P08700 . Supernatant lymphokine levels were determined by bioassay . The proliferative capacity of the splenocytes , as well as their ability to release P60568 and P08700 , was significantly depressed in the vehicle - treated hemorrhaged animals , compared to shams . Treatment with prolactin restored the depressed splenocyte functions seen after severe hemorrhage . These results support the notion that the immunosuppression following hemorrhage and trauma may be mediated by hormones from the hypothalamic - pituitary - adrenal axis . Furthermore , our results suggest that the use of prolactin , which did not produce any adverse hemodynamic effects , represents a novel and safe immunomodulating hormone for the treatment of immunodepression following severe blood loss .",
"P01308 generates free radicals in human fibroblasts ex vivo by a protein kinase C - dependent mechanism , which is inhibited by pravastatin . P01308 can generate oxygen free radicals . Statins , P04035 inhibitors , exert a powerful antioxidant effect . The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects . In cultured skin fibroblasts from human volunteers exposed to high insulin concentration , either in the presence or in the absence of pravastatin , insulin induced translocation of the p47 ( phox ) subunit of NAD ( P ) H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta - dependent mechanism . The insulin - induced translocation of p47 ( phox ) was PKC delta dependent and attenuated by pravastatin , but independent of the activation of Akt and Rac1 . P01308 - induced Akt phosphorylation was increased by pravastatin and P27361 / 2 phosphorylation attenuated . The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts , ex vivo . It involves phosphatidylinositol 3 - kinase , PKC delta , and p47 ( phox ) translocation and promotes P27361 / 2 phosphorylation . ___MASK28___ inhibited radical oxygen species production by inhibiting PKC delta . These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome .",
"P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .",
"Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug - induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G - P04141 and P15692 . This stimulation was associated with drug - induced activation of NF - kappaB , AP - 1 , P05549 , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 - 2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 - 3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug - mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 / neu signaling ( Herceptin / ___MASK99___ ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug - stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth - stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .",
"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK8___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .",
"Control of vascular tube morphogenesis and maturation in 3D extracellular matrices by endothelial cells and pericytes . An important advance using in vitro EC tube morphogenesis and maturation models has been the development of systems using serum - free defined media . Using this approach , the growth factors and cytokines which are actually necessary for these events can be determined . The first model developed by our laboratory was such a system where we showed that phorbol ester was needed in order to promote survival and tube morphogenesis in 3D collagen matrices . Recently , we have developed a new system in which the hematopoietic stem cell cytokines , stem cell factor ( P21583 ) , interleukin - 3 ( P08700 ) , and stromal derived factor - 1α ( SDF - 1α ) were added in conjunction with P09038 to promote human EC tube morphogenesis in 3D collagen matrices under serum - free defined conditions . This new model using P21583 , P08700 , SDF - 1α , and P09038 also works well following the addition of pericytes where EC tube formation occurs , pericytes are recruited to the tubes , and vascular basement membrane matrix assembly occurs following EC - pericyte interactions . In this chapter , we describe several in vitro assay models that we routinely utilize to investigate the molecular requirements that are critical to EC tube formation and maturation events in 3D extracellular matrix environments .",
"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK94___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Expression of prostacyclin receptors in luteinizing hormone - releasing hormone immortalized neurons : role in the control of hormone secretion . PGs of the E series are involved in the control of P01148 secretion . The present experiments were conducted to clarify whether DB01240 ( prostacyclin ) might be also involved in such a control , using multiple methodological approaches on immortalized P01148 - secreting neurons . A RT - PCR procedure to detect mouse P43119 ( IP ) messenger RNA was first applied , and the results obtained showed the presence of a specific transcript in two cell lines of immortalized P01148 neurons ( GT1 - 1 and GN11 cell lines ) . Receptor binding assays on membrane preparations from GT1 - 1 cells showed the presence of a single specific and saturable class of binding sites ( Kd = 4 . 6 nM ; 10 , 000 sites / cell ) for [ 3H ] iloprost , a stable analog of DB01240 . Competition experiments showed that the binding sites labeled by [ 3H ] iloprost possess the pharmacological characteristics of IP receptors . In functional studies , DB01240 and its analogs , iloprost and cicaprost , were able to stimulate P01148 release from the GT1 - 1 cells with elevated potencies ( EC50 = 0 . 6 - 4 . 3 nM ) ; PGE1 was only slightly less active ( EC50 = 28 . 5 nM ) , whereas DB00917 , considered the major PG involved in P01148 secretion , was poorly effective ( EC50 = 921 nM ) . The relative potencies ( EC50 ) of these compounds in stimulating the intracellular accumulation of DB02527 were in line with their P01148 - releasing activities . In conclusion , these results indicate that immortalized P01148 - secreting neurons express IP receptors through which DB01240 may exert relevant effects on P01148 release .",
"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .",
"___MASK99___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK99___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .",
"DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .",
"___MASK28___ - induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . ___MASK28___ - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin - induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 function - blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin - induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin - enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 .",
"P35354 - derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up - regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK99___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK99___ is also being investigated as part of triplet drug regimens . ___MASK99___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"___MASK28___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .",
"Critical role of the interleukin 2 ( P60568 ) receptor gamma - chain - associated Jak3 in the P60568 - induced c - fos and c - myc , but not bcl - 2 , gene induction . The interleukin 2 receptor ( IL - 2R ) consists of three subunits , the IL - 2R alpha , IL - 2R beta c , and IL - 2R gamma c chains . Two Janus family protein tyrosine kinases ( PTKs ) , Jak1 and Jak3 , were shown to associate with IL - 2R beta c and IL - 2R gamma c , respectively , and their PTK activities are increased after P60568 stimulation . A Jak3 mutant with truncation of the C - terminal PTK domain lacks its intrinsic kinase activity but can still associate with IL - 2R gamma c . In a hematopoietic cell line , P08709 , that responds to either P60568 or P08700 , overexpression of this Jak3 mutant results in selective inhibition of the P60568 - induced activation of Jak1 / Jak3 PTKs and of cell proliferation . Of the three target nuclear protooncogenes of the P60568 signaling , c - fos and c - myc genes , but not the bcl - 2 gene , were found to be impaired . On the other hand , overexpression of the dominant negative form of the IL - 2R gamma c chain , which lacks most of its cytoplasmic domain , in P08709 cells resulted in the inhibition of all three protooncogenes . These results provide a further molecular basis for the critical role of Jak3 in P60568 signaling and also suggest a Jak PTK - independent signaling pathway ( s ) for the bcl - 2 gene induction by IL - 2R .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK11___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK88___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK8___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Two types of prostacyclin receptor coupling to stimulation of adenylate cyclase and phosphatidylinositol hydrolysis in a cultured mast cell line , BNu - 2cl3 cells . DB01240 ( DB01240 ) - mediated signal transduction was examined in interleukin 3 ( P08700 ) - dependent BNu - 2cl3 mast cells . DB01088 , a stable DB01240 analogue , induced the accumulation of intracellular DB02527 and IP3 , and an increase in the intracellular Ca2 + concentration . Pretreatment of the cells with a protein kinase C activator , 12 - O - tetradecanoyl phorbol 13 - acetate , suppressed the iloprost - induced IP3 accumulation and Ca2 + mobilization , but inversely potentiated the DB02527 accumulation , suggesting that neither of these signal transduction pathways of iloprosts is the result of a secondary effect of activation of the other . Removal of P08700 from the culture medium reduced the iloprost - induced IP3 accumulation and Ca2 + mobilization , while it had no effect on the iloprost - induced DB02527 accumulation at all . These results taken together suggest that BNu - 2cl3 cells express two types of P43119 ; one couples to stimulation of adenylate cyclase , its expression being independent of P08700 , while the other couples to phosphatidylinositol hydrolysis , its expression being dependent on P08700 .",
"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK5___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT - PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF - beta ) , macrophage colony - stimulating factor ( P09603 ) , oncostatin - M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL - 11 , IL - 12 and P05231 receptor ( IL - 6R ) . At the same time the expression of IL - 1 , P60568 , P08700 , P05231 , P29965 and IL - 2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro - and anti - inflammatory and other regulatory cytokines .",
"P01148 antagonist DB00050 reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia . BACKGROUND : Recent findings suggest that BPH has an inflammatory component . Clinical trials have documented that therapy with P01148 antagonist DB00050 causes a marked and prolonged improvement in LUTS in men with symptomatic BPH . We investigated the mechanism of action and effect of DB00050 in a rat model of BPH . METHODS : Adult male Wistar rats were used . BPH was induced in rats by subcutaneous injections of TE 2 mg / day for 4 weeks . Control animals received injections of corn oil . After induction of BPH , rats received depot DB00050 pamoate at the doses of 0 . 625 , 1 . 25 , and 12 . 5 mg / kg on days 1 and 22 and TE - control rats received vehicle injections . Whole prostates were weighed and processed for RNA and protein . Real - time RT - PCR assays for numerous inflammatory cytokines and growth factors were performed . Quantitative analyses of prostatic P01148 receptor , P01148 , androgen receptor ( AR ) and 5α - reductase 2 were done by real - time RT - PCR and immunoblotting ; serum DB02901 , LH , PSA , and DB01277 by immunoassays . RESULTS : mRNA levels for inflammatory cytokines IFN - γ , P08700 , P05112 , P05113 , P05231 , P10145 , P35225 , P40933 , and Q16552 and for growth factors P01133 , P09038 , FGF - 7 , P55075 , Q92915 , TGF - β1 , and P15692 were significantly reduced by DB00050 0 . 625 mg / kg ( P < 0 . 05 ) . Prostate weights were also significantly lowered by any dose of DB00050 . CONCLUSIONS : This study suggests that DB00050 reduces various inflammatory cytokines and growth factors in rat prostate and , at doses which do not induce castration levels of testosterone , can lower prostate weights . Our findings shed light on the mechanism of action of P01148 antagonists in BPH ."
] |
[
"___MASK11___",
"___MASK28___",
"___MASK50___",
"___MASK5___",
"___MASK88___",
"___MASK8___",
"___MASK93___",
"___MASK94___",
"___MASK99___"
] |
___MASK8___
|
MH_train_386
|
interacts_with DB00074?
|
[
"Human chromosome 10 loci map to three different sheep chromosomes . The interleukin 2 receptor ( P01589 ) , a human Chromosome ( Chr ) 10p locus , was mapped to sheep Chr 13q12 - q15 by in situ hybridization . Two loci from human Chr 10q , cytochrome P450 subfamily XVII ( P05093 ) and the tachykinin 2 receptor ( P21452 ) , were assigned to sheep Chrs 22q21 - q23 and 25q14 - q23 respectively . The assignment of P01589 allows the provisional assignment of the previously unassigned sheep syntenic group U15 to sheep Chr 13 . Sheep linkage group 5 is predicted to be located on sheep Chr 25 on the basis of the P21452 assignment .",
"Lactobacillus acidophilus L - 92 Cells Activate Expression of Immunomodulatory Genes in THP - 1 Cells . To understand the immunomodulatory effects of Lactobacillus acidophilus L - 92 cells suggested from our previous study of in vivo anti - allergy and anti - virus effects , host immune responses in macrophage - like THP - 1 cells after 4 h ( the early phase ) and 24 h ( the late phase ) of cocultivation with L - 92 cells were investigated by transcriptome analysis . In the early phase of L - 92 treatment , various transcription regulator genes , such as , NFkB1 , NFkB2 , P05412 , P31629 and Q01201 , and genes encoding chemokines and cytokines , such as P13236 , O14625 , P10147 and P01375 , were upregulated . Two transmembrane receptor genes , Q9NYK1 and P05362 , were also upregulated in the early phase of treatment . In contrast , many transmembrane receptor genes , such as P16871 , P33681 , Q9HC73 , P42081 , P06127 , HLA - DQA1 , P01589 , Q13261 and P15509 , and some cytokine genes , including P05231 , Q9NPF7 and O00626 , were significantly upregulated in the late phase after L - 92 exposure . Some genes encoding cytokines , such as P01583 , P01584 and P10145 , and the enzyme P14902 were upregulated at both the early and the late phases of treatment . These results suggest that probiotic L - 92 might promote Th1 and regulatory T - cell responses by activation of the MAPK signaling pathway , followed by the NOD - like receptor signaling pathway in THP - 1 cells .",
"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK93___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK25___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .",
"Induction therapy with interleukin - 2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function . PURPOSE : To determine the effectiveness of induction immunotherapy with interleukin - 2 receptor antagonists ( P01589 ) after intestinal transplantation ( IT ) . METHODS : A single - center , retrospective study was undertaken of all patients undergoing IT using existing medical records and database . Immunotherapy was either triple ( standard maintenance triple therapy [ SMTT ] ) or P01589 [ induction P01589 plus SMTTx ] or OKT3 [ induction antilymphocyte preparations plus SMTTx ] ) . Data was collected for the first 175 postoperative days . Outcomes included pretransplant renal function , posttransplant serum creatinine normalized to age ( nl - sCR ) , rejection ( P10323 ) , and survival . Standard statistical analysis was undertaken . RESULTS : There were no significant differences in the groups : triple ( n = 10 , median age 3 . 5 years , cGFR 106 +/- 44 mL / min ) , P01589 ( n = 13 , median age 3 . 2 years , cGFR 101 +/- 61 mL / min ) , OKT3 ( n = 4 , median age 7 . 7 years , cGFR 104 +/- 27 mL / min ) . nl - sCR was significantly ( P < . 01 ) lower in P01589 at most postoperative weeks . P01589 had significantly fewer rejection and infectious episodes than the other two groups . Three - year patient survival was 92 % in P01589 versus 50 % triple and OKT3 . CONCLUSIONS : P01589 immunotherapy after IT is associated with a lower incidence of renal dysfunction as compared with historical controls . Furthermore , P01589 therapy resulted in a lower incidence of rejection and improved survival . P01589 should be considered in select patients undergoing IT .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"___MASK64___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK64___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"___MASK57___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK57___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK27___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK27___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK27___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK27___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK27___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK27___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK27___ .",
"___MASK68___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"___MASK47___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK47___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK47___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"___MASK32___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK32___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK32___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK32___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .",
"Gene expression analysis of ELF - MF exposed human monocytes indicating the involvement of the alternative activation pathway . This study focused on the cell activating capacity of extremely low frequency magnetic fields ( ELF - MF ) on human umbilical cord blood - derived monocytes . Our results confirm the previous findings of cell activating capacity of ELF - MF ( 1 . 0 mT ) in human monocytes , which was detected as an increased ROS release . Furthermore , gene expression profiling ( whole - genome cDNA array Human Unigene RZPD - 2 ) was performed to achieve a comprehensive view of involved genes during the cell activation process after 45 min ELF - MF exposure . Our results indicate the alteration of 986 genes involved in metabolism , cellular physiological processes , signal transduction and immune response . Significant regulations could be analyzed for 5 genes ( expression > 2 - or < 0 . 5 - fold ) : Q13261 ( Interleukin 15 receptor , alpha chain ) , Q9UBC2 ( P00533 pathway substrate 15 - like 1 ) , Q9Y6K1 ( Hypothetical protein MGC16121 ) , Q9Y6K1 ( DNA ( cytosine - 5 ) methyltransferase 3 alpha ) , and one gene with no match to known genes , DKFZP586J1624 . Real - time RT - PCR analysis of the kinetic of the expression of Q13261 , and Q13651 during 45 min ELF - MF exposure indicates the regulation of cell activation via the alternative pathway , whereas the delayed gene expression of P01100 , P01589 and the melatonin synthesizing enzyme P46597 suggests the suppression of inflammatory processes . Accordingly , we suggest that ELF - MF activates human monocytes via the alternative pathway .",
"Non - HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients . Autoimmune Polyglandular Syndrome Type II ( APSII ) is characterized by the co - occurrence of clinical insufficiency of at least two endocrine glands . Although , HLA determinants of APSII predisposition have been identified , little attention has been paid to non - HLA genes . Here , we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co - occurrence of Autoimmune Thyroid Disease ( AITD ) and Type 1 Diabetes ( T1D ) and lower frequency of Addison ' s disease ( AD ) . We tested the high a priori possibility that well - established non - HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII , namely : ( 1 ) two T1D - associated SNPs , in P16410 and P01589 , suggest their involvement in T1D pathogenesis in this cohort ; ( 2 ) two SNPs in Q14765 and P40933 not previously associated to endocrinopathies , are possibly involved in co - occurrence of organ autoimmunity in APSII , and ; ( 3 ) one SNP in P01375 alpha showed association to APSII irrespective of AD . While this work was performed in a relatively small cohort , these results support the notion that the non - HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co - occurrence of multiple autoimmune endocrinopathies .",
"Human T - cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF - kappaB . Adult T - cell leukemia ( ATL ) is a highly aggressive T - cell malignancy caused by human T - cell leukemia virus type 1 ( HTLV - 1 ) . The activation of NF - kappaB by Tax has been reported to play a crucial role in HTLV - 1 - induced transformation . The HTLV - 1 bZIP factor ( P02008 ) , which is encoded by an mRNA of the opposite polarity of the viral genomic RNA , is involved in both T cell proliferation and suppression of Tax - mediated viral gene transcription , suggesting that P02008 cooperates closely with Tax . In the present study , we observed that P02008 specifically suppressed NF - kappaB - driven transcription mediated by p65 ( the classical pathway ) without inhibiting the alternative NF - kappaB signaling pathway . In an immunoprecipitation assay , P02008 bound to p65 and diminished the DNA binding capacity of p65 . In addition , P02008 induced p65 degradation through increasing the expression of the Q96JY6 gene , which encodes a ubiquitin E3 ligase for p65 . Finally , P02008 actually repressed the transcription of some classical NF - kappaB target genes , such as P10145 , P01589 , Q15306 , P19320 , and P15692 . Selective suppression of the classical NF - kappaB pathway by P02008 renders the alternative NF - kappaB pathway predominant after activation of NF - kappaB by Tax or other stimuli , which might be critical for oncogenesis .",
"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .",
"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK21___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .",
"DB00074 induction in patients receiving tacrolimus - based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine - based immunosuppression . However , its clinical utility in patients receiving tacrolimus - based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 ) , and 132 patients received tacrolimus without basiliximab ( TAC - No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 compared to TAC - IL - 2RA and TAC - No Groups ( 33 vs . 14 . 9 vs . 14 . 3 % , p < 0 . 001 ) . Inferior creatinine clearance was observed in dTAC - P01589 Group compared to TAC - P01589 and TAC - No Groups at months 1 ( 41 . 6 vs . 49 . 9 vs . 44 . 8 mL / min , p = 0 . 004 ) , 3 ( 49 . 8 vs . 57 . 2 vs . 53 . 5 mL / min , p = 0 . 017 ) , and 6 ( 53 . 1 vs . 61 . 8 vs . 57 . 0 mL / min , p = 0 . 001 ) . Patients who received basiliximab ( TAC - P01589 and dTAC - P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39 . 3 % , p = 0 . 009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction ."
] |
[
"___MASK21___",
"___MASK25___",
"___MASK27___",
"___MASK32___",
"___MASK47___",
"___MASK57___",
"___MASK64___",
"___MASK68___",
"___MASK93___"
] |
___MASK47___
|
MH_train_387
|
interacts_with DB06663?
|
[
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK49___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"Effects of chimeric somatostatin - dopamine molecules on human peripheral blood lymphocytes activation . O43521 23A761 , selective for somatostatin receptors subtypes 2 , 5 and the dopamine receptor subtype 2 , and O43521 23A757 with affinity for P30874 and DAR2 were studied on human PBL proliferation and activation . O43521 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen , while O43521 23A757 was more potent than specific P30874 and DAR2 agonists in suppressing antigen induced proliferation only . Both molecules displayed enhanced potency in suppressing IFNgamma and P05231 secretion compared with the SSTR and DAR2 analogs , while only O43521 23A761 was able to inhibit P60568 secretion and its effect is more potent than the control analogs . Furthermore O43521 23A761 inhibit cell progression into the S phase and then into the G2 / M , while O43521 23A757 inhibited bromodeoxyuridine incorporation only during the S phase . Both chimeric molecules resulted significantly more effective than the respective controls .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK93___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders . Methylphenidate ( ___MASK26___ ) reduces hyperactive - impulsive symptoms common in children with autism spectrum disorders ( ASDs ) , however , response and tolerability varies widely . We hypothesized monoaminergic gene variants may moderate ___MASK26___ effects in P51689 , as in typically developing children with attention - deficit / hyperactivity disorder . Genotype data were available for 64 children with P51689 and hyperactivity who were exposed to ___MASK26___ during a 1 - week safety / tolerability lead - in phase and 58 who went on to be randomized to placebo and three doses of ___MASK26___ during a 4 - week blinded , crossover study . Outcome measures included the Clinical Global Impression - Improvement ( CGI - I ) scale and the Aberrant Behavior Checklist ( ABC - hyperactivity index ) . A total of 14 subjects discontinued the study because of ___MASK26___ side effects . Subjects were genotyped for variants in P21728 - P21918 , P08913 , Q01959 , P31645 , P21397 and P27338 , and P21964 . Forty - nine percent of the sample met positive responder criteria . In this modest but relatively homogeneous sample , significant differences by P21728 ( P = 0 . 006 ) , P08913 ( P < 0 . 02 ) , P21964 ( P < 0 . 04 ) , P35462 ( P < 0 . 05 ) , P21917 ( P < 0 . 05 ) , Q01959 ( P < 0 . 05 ) and P31645 ( P < 0 . 05 ) genotypes were found for responders versus non - responders . Variants in P14416 ( P < 0 . 001 ) and P35462 ( P < 0 . 04 ) were associated with tolerability in the 14 subjects who discontinued the trial . For this first ___MASK26___ pharmacogenetic study in children with P51689 , multiple monoaminergic gene variants may help explain individual differences in ___MASK26___ ' s efficacy and tolerability .",
"Modulation of expression of somatostatin receptor subtypes in Graves ' ophthalmopathy orbits : relevance to novel analogs . Apart from evaluating orbital inflammation in Graves ' ophthalmopathy ( GO ) , somatostatin ( P61278 ) analogs have been proposed as a therapy , but recent trials were disappointing . We aimed to measure somatostatin receptor ( SSTR ) expression in orbital tissues ex vivo and determine whether the new broad - affinity analog DB06663 might be of therapeutic use . Orbital adipose / connective tissues from 29 GO patients and 10 normal individuals were analyzed . Transcripts were quantified using SYBR Green and a light cycler . In vitro models were used to investigate whether thyrotropin receptor activation ( as occurs via thyroid stimulating antibodies ) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and DB06663 in their modulation . The expression of P30872 was significantly higher in GO patients than normal controls ( P = 0 . 024 ) . Although differences in the expression of P30874 were not significant , 39 % of GO samples had levels above the 97th percentile of the controls . P32745 , - 4 , and - 5 were at or below the limit of detection ( LOD ) . The lymphocyte contribution was minimal , since CD3alpha transcripts were at the LOD . DB00024 receptor activation did not modulate SSTR expression . An in vitro model of adipogenesis indicated upregulation of P30872 and P30874 during differentiation . DB06663 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide . Ex vivo analysis of orbital tissues reveals upregulation of P30872 and - 2 in a group of GO patients . Adipogenesis , a process occurring in GO orbits , provides one possible explanation for some of the observed increase .",
"Filamin A in somatostatin and dopamine receptor regulation in pituitary and the role of DB02527 / PKA dependent phosphorylation . Molecular mechanisms underlying resistance of pituitary tumors to somatostatin ( SS ) and dopamine ( DA ) analogues treatment are not completely understood . Resistance has been associated with defective expression of functional somatostatin and dopamine receptors P30874 , P35346 , and P14416 , respectively . Recently , a role of cytoskeleton protein filamin A ( P21333 ) in P14416 and SSTR receptors expression and signaling in PRL - and GH - secreting tumors , respectively , has been demonstrated , first revealing a link between P21333 expression and responsiveness of pituitary tumors to pharmacological therapy . No molecular events underlying the reduction of P21333 levels in resistant tumors have been so far identified . P21333 can be phosphorylated by PKA on Ser2152 , with increased P21333 resistance to cleavage by calpain and conformational changes affecting P21333 regions involved in P30874 and P14416 binding and signal transduction . In this respect , the effect of DB02527 / PKA pathway in the regulation of P21333 stability and / or function by modulating its phosphorylation status could assume particular importance in pituitary , where DB02527 cascade plays a crucial role in pituitary cell functions and tumorigenesis . This review will discuss the role of P21333 in the regulation of the main GPCRs target of pharmacological treatment of pituitary tumors , that is , P30874 and P14416 , focusing on the effects of DB02527 / PKA - mediated P21333 phosphorylation on P21333 biological functions .",
"Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK93___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK26___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK26___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK26___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK26___ among adults with ADHD .",
"Correlation of monoclonal and polyclonal somatostatin receptor 5 antibodies in pancreatic neuroendocrine tumors . AIMS : To evaluate the frequency of somatostatin - receptor 5 ( SSTR 5 ) in pancreatic neuroendocrine tumors by using monoclonal and polyclonal antibodies . MATERIAL AND METHOD : we analyzed 66 proven pancreatic neuroendocrine tumors immunohistochemically with monoclonal ( clone UMB - 4 ) and polyclonal SSTR 5 - antibodies . Immunoreactive score ( P41252 ) and DAKO - score Her2 / neu were evaluated . RESULTS : Immunohistochemistry analysis demonstrated for the P41252 a significant higher staining of all specimen using the monoclonal antibodies ( P41252 P35346 poly vs P41252 SSTR 5 mono ; 20 . 0 % vs 30 . 3 % p < 0 . 001 ) by a correlation of 0 . 21 ; p = 0 . 04 . For the P04626 score there was also a significant higher staining in the monoclonal group ( Her2 SSTR 5 poly vs Her2 SSTR 5 mono ; 21 . 5 % vs 28 . 8 % p < 0 . 001 ) by a correlation of 0 . 20 ; p = 0 . 08 . CONCLUSION : Both antibodies are useful in staining of SSTR , although UMB - 4 demonstrated a 10 % higher SSTR 5 staining . Due to the previous underestimated expression rate of SSTR 5 , current standards in diagnostics and therapy should be reconsidered . The increasing usage of long - acting pansomatostatin receptor analogues will rise the adverse effects connected to P35346 binding .",
"Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .",
"P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .",
"___MASK47___ induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase - 5 ( O76074 ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1 - 20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin - 1 ( P10599 - 1 ) , hemeoxygenase - 1 ( P09601 ) and P15692 . ___MASK47___ induced P15692 and angiopoietin specific receptors such as P35968 , Tie - 1 and Tie - 2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 enzyme activity . ___MASK47___ below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . ___MASK47___ along with SnPP inhibited both P15692 and Q15389 ( Ang - 1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro - angiogenic factor .",
"Somatostatin activation of mitogen - activated protein kinase via somatostatin receptor 1 ( P30872 ) . Hormones and growth factors regulate cell growth via the mitogen - activated protein ( Q96HU1 ) kinase cascade . Here we examine the actions of the hormone somatostatin on the Q96HU1 kinase cascade through one of its two major receptor subtypes , the somatostatin receptor 1 ( P30872 ) stably expressed in CHO - P04264 cells . Somatostatin antagonizes the proliferative effects of fibroblast growth factor in CHO - P30872 cells via the P30872 receptor . However , in these cells , somatostatin robustly activates Q96HU1 kinase ( also called extracellular signal regulated kinase ; P29323 ) and augments fibroblast growth factor - stimulated P29323 activity . We show that the activation of P29323 via P30872 is pertussis toxin sensitive and requires the small G protein Ras , phosphatidylinositol 3 - kinase , the serine / threonine kinase P04049 , and the protein tyrosine phosphatase Q06124 . The activation of P29323 by P30872 increased the expression of the cyclin - dependent protein kinase inhibitor P38936 ( cip1 / P38936 ) . Previous studies have suggested that somatostatin - stimulated protein tyrosine phosphatase activity mediates the growth effects of somatostatin . Our data suggest that Q06124 stimulation by P30872 may mediate some of these effects through the activation of the Q96HU1 kinase cascade and the expression of P38936 ( cip1 / P38936 ) .",
"___MASK49___ in rheumatoid arthritis : studies with animal models . The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis . The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis . At the low doses used , methotrexate does not induce systemic immunosuppression . In methotrexate - treated rats , an improvement in P60568 synthesis is observed and increases in P60568 levels are expected to improve cell mediated immunity . Suppressor cells appear to be very sensitive to methotrexate . Macrophage function is modulated by methotrexate . All of these effects including the effects on joint destruction are probably due to inhibition of P00374 activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls . Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans .",
"___MASK94___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK94___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK94___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK94___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK94___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK94___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"Regeneration of insulin - producing pancreatic cells using a volatile bioactive compound and human teeth . Transplantation of insulin ( P01308 ) - secreting cells differentiated in vitro from stem cells promises a safer and easier treatment of severe diabetes mellitus . A volatile bioactive compound , hydrogen sulfide ( H2S ) , promotes cell differentiation ; human tooth - pulp stem cells undergo hepatic differentiation . The aim of this study is to develop a novel protocol using H2S to enhance pancreatic differentiation from the CD117 (+) cell fraction of human tooth pulp . During the differentiation , the cells were exposed to 0 . 1 ng ml (- 1 ) H2S . Immunocytochemistry , RT - PCR , determination of P01308 c - peptide content and flow cytometry of pancreatically related markers were carried out . Expression of WNT and the PI3K / AKT signaling pathway were also determined by PCR array . After differentiation , P01308 , glucagon ( P01275 ) , somatostatin ( P61278 ) and pancreatic polypeptide ( P01298 ) were positive when examined by immunofluorescence . P01308 and P01275 were also determined flow - cytometrically . Only the cells expressing P01308 increased after H2S exposure . The number of cells expressing P01275 was significantly decreased . Genes involved in canonical WNT and the WNT / calcium pathways were highly expressed after H2S exposure . H2S accelerated P01308 synthesis and secretion by regenerated P01308 - producing cells from human teeth . All signaling pathway functions of the PI3K - AKT pathway were extremely activated by H2S exposure . The matured P01308 - producing cells originating in human teeth were increased by H2S in order to control blood - glucose level .",
"Somatostatin ameliorates lipopolysaccharide - induced tight junction damage via the P29323 - MAPK pathway in Caco2 cells . Dysfunction of the epithelial barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut . Somatostatin ( P61278 ) has been demonstrated to reduce local and systemic inflammation reactions and maintain the integrity of the blood - brain barrier ( BBB ) . To determine the beneficial effect of P61278 on lipopolysaccharide ( LPS ) - induced damage of the tight junction ( TJ ) and its mechanisms , Caco2 cells pretreated with P61278 ( 1nM ) or MEK inhibitor U0126 ( 10μM ) were exposed to LPS . LPS significantly reduced the expression of TJ proteins in a dose - dependent way . LPS ( 100μg / ml ) greatly induced Caco2 monolayer barrier dysfunction by decreasing transepithelial resistance and increasing epithelial permeability . Pretreatment with P61278 effectively improved the barrier dysfunction of Caco2 cells . P61278 significantly increased the expression of TJ proteins occludin and ZO - 1 and inhibited the redistribution of TJ proteins due to LPS stimulation . Furthermore , P61278 decreased the LPS - induced phosphorylation of P27361 / 2 , and a selective MEK inhibitor markedly protected the barrier function against LPS disturbance by blocking the activation of the P29323 - MAPK pathway in Caco2 cells . Besides , LPS significantly increased the mRNA level of P35346 , which was partly inhibited by pretreatment with P61278 . In conclusion , the present study indicates that P61278 protects the Caco2 monolayer barrier against LPS - induced tight junction breakdown by down - regulating the activation of the P29323 - MAPK pathway and suppression the activation of P35346 .",
"ShRNA silencing glycogen synthase kinase - 3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK - 3β ) , a serine / threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK - 3β was aberrantly activated in pancreatic cancer . GSK - 3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl - 2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK - 3β knockdown group . In a xenograft tumor model , GSK - 3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK - 3β may become a promising therapeutic target for human pancreatic cancer .",
"Corynoxine , a natural autophagy enhancer , promotes the clearance of alpha - synuclein via Akt / P42345 pathway . Parkinson ' s disease ( PD ) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates ( namely Lewy bodies ) in dopaminergic neurons in the substantia nigra region of the brain . P37840 ( α - syn ) is the major component of Lewy bodies in PD patients , and impairment of the autophagy - lysosomal system has been linked to its accumulation . In our previous study , we identified an oxindole alkaloid Corynoxine B ( Cory B ) , isolated from Uncaria rhynchophylla ( Miq . ) Jacks ( Gouteng in Chinese ) , as a Q14457 - dependent autophagy inducer . In this work , we show that Cory , an enantiomer of Cory B , also induces autophagy in different neuronal cell lines , including N2a and SHSY - 5Y cells , which is paralleled with increased lysosomal enzyme cathepsin D . In vivo , Cory promotes the formation of autophagosomes in the fat bodies of Drosophila . By inducing autophagy , Cory promotes the clearance of wild - type and A53T α - syn in inducible PC12 cells . Interestingly , different from its enantiomer Cory B , Cory induces autophagy through the Akt / P42345 pathway as evidenced by the reduction in the levels of phospho - Akt , phospho - P42345 and phospho - P08133 S6 Kinase . Collectively , our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine , which may have potential application in the prevention or treatment of PD .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK37___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK37___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK37___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"Inhibitory effect of somatostatin - 14 and some analogues on human natural killer cell activity . The effect of somatostatin - 14 ( P61278 ) and the P61278 analogues P52788 and RC160 on human natural killer ( NK ) activity mediated by large granular lymphocytes ( LGL ) , as well as on P60568 - and / or anti - CD16 monoclonal antibody ( mAb ) - induced activation of these cells , was investigated . The NK activity of LGL was studied by the release of 51Cr by the erythroleukemia - derived cell line K562 , whereas 51Cr release by the P815 murine mastocytoma - derived cell line , for which lysis was redirected by the use of an anti - CD16 mAb , was used to study the cytolytic potential of these cells . P60568 was used at the final concentration of 100 IU and was incubated overnight with LGL . P61278 and the analogues , added to these systems at final doses ranging from 10 (- 12 ) to 10 (- 5 ) M , were inhibitory of the NK cell activity to K562 , with a dose - response curve starting from 10 (- 8 ) M and reaching a significant level at 10 (- 6 ) M . On the contrary , no effect was observed on the redirected killing assay to P815 and on the P60568 - induced activation of NK cells . These results provide additional evidence for the immunomodulatory action of somatostatin .",
"Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .",
"DB06663 , a multiple somatostatin receptor subtypes ligand , reduces cell viability in non - functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion . Somatostatin ( SRIF ) analogs have been employed in medical therapy of non - functioning pituitary adenomas ( DB04552 ) , with contrasting results . Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor ( P15692 ) secretion and action , and that P15692 expression may be related to pituitary tumor growth . The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on P15692 secretion and cell proliferation in human DB04552 primary cultures . We assessed the expression of SRIF receptors ( P30872 - 5 ) , the in vitro effects on P15692 secretion , and on cell viability of SRIF and of the stable SRIF analog pasireotide ( DB06663 ) , which activates P30872 , 2 , 3 , and 5 . Twenty - five DB04552 were examined by RT - PCR for expression of alpha - subunit , SSTR , P15692 , and P15692 receptors 1 ( P15692 - Q96GN5 ) and 2 ( P15692 - R2 ) . Primary cultures were tested with SRIF and with pasireotide . All DB04552 samples expressed alpha - sub , P15692 and P17948 and 2 , while SSTR expression pattern was highly variable . Two different groups were identified according to P15692 secretion inhibition by SRIF . P15692 secretion and cell viability were reduced by SRIF and pasireotide in the ' responder ' group , but not in the ' non - responder ' group , including DB04552 expressing P35346 . SRIF and pasireotide completely blocked forskolin - induced P15692 secretion . In addition , SRIF and pasireotide completely abrogated the promoting effects of P15692 on DB04552 cell viability . Our data demonstrate that pasireotide can inhibit DB04552 cell viability by inhibiting P15692 secretion , and suggest that the multireceptor - SSTR agonist pasireotide might be useful in medical therapy of selected DB04552 .",
"Effect of DB06663 ( pasireotide ) on corticotropic cells : action in dogs with Cushing ' s disease . DB06663 ( pasireotide ) is a multiligand somatostatin ( SRIF ) analog able to bind to somatostatin receptor ( SSTR ) subtypes 1 , 2 , 3 and 5 , and trigger antisecretory and antiproliferative signaling cascades . Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing ' s disease in a spontaneous manner , due to adrenocorticotropic hormone ( DB01285 ) - producing pituitary adenomas . Different levels of expression of P30874 and P35346 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells . The objective of this study was to evaluate whether DB06663 controls both tumor cell growth and hormone synthesis , therefore controlling the disease . DB06663 was tested in dogs suffering from Cushing ' s disease ( 10 animals were treated continuously during 6 months , and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2 - month rest period ) . A significant decrease in DB01285 , urinary cortisol creatinine ratio , adenoma size ( magnetic nuclear resonance ) and improvement of clinical signs were obtained , without side effects . AtT20 cells treated with DB06663 suppressed pro - opiomelanocortin ( P01189 ) promoter activity through P30874 , via the G ( i ) α - subunit , and reduced P22736 / Nurr1 transcriptional activity . We conclude that DB06663 , in addition to its well - described antisecretory effects , inhibits , as shown in AtT20 cells , DB01285 synthesis at the P01189 transcriptional level , an effect mediated mainly through P30874 , and limits tumor growth . The controlled Cushing ' s disease in the dogs that received the treatment indicates that DB06663 has a potential therapeutic use in humans suffering from Cushing ' s disease .",
"Effect of chronic ___MASK47___ treatment on the prostate of C57Bl / 6 mice . ___MASK47___ is a potent and selective inhibitor of phosphodiesterase - 5 ( O76074 ) and is considered first - line therapy for erectile dysfunction . Nowadays , ___MASK47___ is used extensively throughout the world on patients with pulmonary hypertension . However , few studies have evaluated the possible side effects of chronic ___MASK47___ treatment on the male reproductive system , specifically in the prostate . In the present study , it was demonstrated via morphological and ultrastructural analysis that chronic treatment with ___MASK47___ induced an enhancement of the glandular activity of the prostate . In addition , mice treated with ___MASK47___ showed a significant increase in testosterone serum levels . However , no statistically significant differences were observed in nitric oxide serum levels , or in sGC , P29474 , PSA and TGF - β prostatic expression . In conclusion , the present study suggests that chronic use of ___MASK47___ does not cause evident prostatic damage , and therefore , can be used pharmacologically to treat a variety of disorders .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK54___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"[ New medical treatments in Cushing disease ] . The standard treatment of Cushing disease is surgery . Radiotherapy and steroïdogenesis inhibitors are second - line treatments . The new multi - ligand somatostatin analogs , such as DB06663 , having a much higher affinity with several receptors of somatostatin ( P30872 , 3 , and 5 ) than octreotid ( mostly a P30874 receptor ) have been synthetized . Some studies have shown that P35346 is predominantly expressed in corticotroph pituitary adenomas and that DB06663 has more efficacy than octreotid in the treatment of Cushing disease . It has been suggested that the thiazolinidinediones , P37231 agonists , might also be useful in the treatment of this disease , but studies are still limited and give conflicting results . In a recent study conducted on dogs , Castillo et al have shown that the retinoïds give encouraging results and might open a new pathway in the treatment of Cushing disease . But further studies , especially on humans , are necessary before conclusions can be reached . Labeur and his team have contributed a study on the use of gamma - interferon on murine pituitary cells and on human and murine corticotroph pituitary adenoma cells , and they have evidenced a 20 to 60 % decrease in the production of DB01285 in 5 cases out of 7 in the tumoral cells treated -- versus the non - treated ones . Eventually , Pivonello and his team have confirmed the D2 dopaminergic receptor expression in corticotroph pituitary cells , mainly in the intermediary zone . Thus they have suggested that the dopaminergic agonists -- such as cabergoline - could be used in corticotroph pituitary adenomas derivated from the intermediary zone .",
"Brucine suppresses colon cancer cells growth via mediating P35968 signalling pathway . Angiogenesis plays an important role in colon cancer development . This study aimed to demonstrate the effect of brucine on tumour angiogenesis and its mechanism of action . The anti - angiogenic effect was evaluated on the chicken chorioallantoic membrane ( P62158 ) model and tube formation . The mechanism was demonstrated through detecting mRNA and protein expressions of P35968 ( P35968 ) , PKCα , PLCγ and Raf1 by reverse transcription - polymerase chain reaction ( RT - PCR ) and Western blot ( WB ) , as well as expressions of P15692 and PKCβ and P42345 by ELISA and WB . The results showed that brucine significantly reduced angiogenesis of P62158 and tube formation , inhibited the P15692 secretion and P42345 expression in LoVo cell and down - regulated the mRNA and phosphorylation protein expressions of P35968 , PKCα , PLCγ and Raf1 . In addition , the effects of brucine on P35968 kinase activity , viability of LoVo cell and gene knockdown cell were detected with the Lance ™ assay , WST - 1 assay and instantaneous siRNA . Compared to that of normal LoVo cells , the inhibition on proliferation of knockdown cells by brucine decreased significantly . These results suggest that brucine could inhibit angiogenesis and be a useful therapeutic candidate for colon cancer intervention .",
"Distinct patterns of neuropeptide gene expression in the lateral hypothalamic area and arcuate nucleus are associated with dehydration - induced anorexia . We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration - associated anorexia . In situ hybridization and hormone analyses of anorexic and paired food - restricted rats revealed two distinct profiles . First , both groups had the characteristic gene expression and endocrine signatures usually associated with starvation : increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus ( Q5SW96 ) ; increased circulating glucocorticoid but reduced leptin and insulin . Dehydrated animals are strongly anorexic despite these attributes , showing that the output of leptin - and insulin - sensitive Q5SW96 neurons that ordinarily stimulate eating must be inhibited . The second pattern occurred only in anorexic animals and had two components : ( 1 ) reduced corticotropin - releasing hormone ( P06850 ) mRNA in the neuroendocrine paraventricular nucleus ( PVH ) and ( 2 ) increased P06850 and neurotensin mRNAs in the lateral hypothalamic ( LHA ) and retrochiasmatic areas . However , neither corticosterone nor suppressed PVH P06850 gene expression is required for anorexia after dehydration because PVH P06850 mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls . We also showed that LHA P06850 mRNA was strongly correlated with the intensity of anorexia , increased LHA P06850 gene expression preceded the onset of anorexia , and dehydrated adrenalectomized animals ( which also develop anorexia ) had elevated LHA P06850 gene expression with a distribution pattern similar to intact animals . Finally , we identified specific efferents from the P06850 - containing region of the LHA to the PVH , thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the Q5SW96 and the LHA . Together , these observations suggest that P06850 and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects .",
"Effects of vasoactive intestinal peptide ( P01282 ) and somatostatin ( P61278 ) on lipoprotein receptor expression by A431 tumor cells . A variety of tumor cells have been shown to express lipoprotein receptors . Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells . We investigated the effects of vasoactive intestinal peptide ( P01282 ) and somatostatin - 14 ( P61278 - 14 ) on the binding of 111Indium - labeled lipoproteins [ ( 111 ) In - low density lipoprotein ( ( 111 ) In - LDL ) , ( 111 ) In - high density lipoprotein ( ( 111 ) In - HDL ) and ( 111 ) In - very low density lipoprotein ( ( 111 ) In - VLDL ) ] onto the epidermoid mammary carcinoma cell line A431 . Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL , HDL and VLDL expressed by A431 cells , respectively . P01282 increased significantly the binding capacity for ( 111 ) In - LDL on A431 cells . The P01282 - induced increase of ( 111 ) In - LDL binding sites was inhibited by P61278 - 14 . Furthermore , P61278 - 14 inhibited P01282 - induced 3H - thymidine incorporation and adenosine 3 '- 5 ' cyclic monophosphate ( DB02527 ) formation in A431 cells with IC50 values in the range of 5 - 7 nM . However , P61278 - 14 showed no effect on dibutyryl - DB02527 - induced increase of ( 111 ) In - LDL binding sites expressed on A431 cells . In contrast to ( 111 ) In - LDL binding , no effects of P01282 or P61278 - 14 on HDL or VLDL binding to A431 tumor cells were found . Our results suggest a direct effect of P01282 and P61278 - 14 on LDL - binding onto tumor cells . The complex interactions between P01282 and P61278 - 14 on P01130 expression of tumor cells may play a role in tumor cell lipid metabolism .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK94___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"___MASK37___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"P01308 - like growth factor pathway genes and blood concentrations , dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin - like growth factor 1 ( DB01277 ) . Several single nucleotide polymorphisms ( SNPs ) have been weakly associated with circulating concentrations of DB01277 and IGF binding protein 3 ( P17936 ) , but none of these SNPs was associated with risk of prostate cancer . We examined whether an association between 16 SNPs associated with circulating DB01277 or P17936 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5 , 253 cases and 4 , 963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . The BPC3 includes nested case - control studies within large North - American and European cohorts . Per - allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake , which was expressed as the percentage of energy derived from total , animal , dairy or plant protein sources , using conditional logistic regression models . Total , animal , dairy and plant protein intakes were significantly positively associated with blood DB01277 ( p < 0 . 01 ) , but not with P17936 concentrations ( p > 0 . 10 ) or with risk of prostate cancer ( p > 0 . 20 ) . After adjusting for multiple testing , the SNP - prostate cancer associations did not differ by intakes of protein , although two interactions by intake of plant protein were of marginal statistical significance [ P35346 ( somatostatin receptor 5 ) - rs197056 ( uncorrected p for interaction , 0 . 001 ) ; P35346 - rs197057 ( uncorrected p for interaction , 0 . 002 ) ] . We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .",
"Expression of somatostatin receptors in human melanoma cell lines : effect of two different somatostatin analogues , octreotide and DB06663 , on cell proliferation . Somatostatin analogues ( SAs ) are potential anticancer agents . This study was designed to investigate the expression of somatostatin receptors ( SSTRs ) in melanoma cells and the effect of two SAs on cell proliferation and viability . Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and DB06663 . Expression of P30872 , P30874 , P32745 and P35346 was assessed by real - time polymerase chain reaction . Proliferation , viability and cell death were assessed using standard assays . Inhibition was modelled by mixed - effect regression . Melanoma cells expressed one or more SSTR . Both SAs inhibited proliferation of most melanoma cell lines , but inhibition was < 50 % . Neither SA affected cell viability or induced cell death . The results suggest that melanoma cell lines express SSTRs . The SAs investigated , under the conditions used in this study , did not , however , significantly inhibit melanoma growth or induce cell death . Novel SAs , combination therapy with SAs and their anti - angiogenic properties should be further investigated .",
"Modulation by cytokines of glucocorticoid action . Glucocorticoids ( GC ) are potent modulators of the inflammatory response . Their effects serve to down - regulate the inflammatory response and are mediated by genomic pathways that follow the interaction with specific receptors ( glucocorticoid receptors , GR ) . Interleukin ( IL ) - 1 , P60568 , and P05231 are able to increase GC secretion by enhancing synthesis and release of P06850 and DB01285 . Cytokine effects upon steroidogenesis also occur at the adrenal level . The role of cytokines as modulators of GR has received scarce attention . IL - 1 has been shown to up - regulate GR mRNA expression in hypothalamic P06850 secreting cells . On the other hand , macrophage migration inhibitory factor ( MIF ) , a T - cell product inducible by inflammatory substances including other cytokines , counterregulates GC action within the immune system . Besides immunocytes and neurons , bone cells are a sensitive target for GC and cytokines . We have found that P60568 and P05231 up - regulate remarkably the number of GR binding sites and the expression of GR mRNA in peripheral blood mononuclear cells and in osteoblast - like Saos - 2 cells . Available data suggest that inflammatory cytokines have both direct and indirect effects on GC action at the target level . Autocrine - induced transcription of GR in immunocytes and / or osteoblasts could be a mechanism that restrains excess cytokine production .",
"Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK94___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"Ca2 + regulates hormone secretion and proopiomelanocortin gene expression in melanotrope cells via the calmodulin and the protein kinase C pathways . The mechanism by which Ca2 + regulates proopiomelanocortin ( P01189 ) - derived peptide secretion and P01189 mRNA levels was investigated in primary cultures of porcine intermediate lobe ( IL ) cells maintained in serum - free medium . P01189 gene expression was evaluated by the dot blot hybridization assay with a 32P - labeled DNA probe complementary to the full - length sequence of porcine P01189 mRNA . Treatment of IL cells for 24 h with the calmodulin ( P62158 ) antagonists W7 and W13 reduced P01189 mRNA levels by a maximum of 50 % in a dose - dependent manner ( ED50 approximately 10 (- 8 ) M ) . Accumulation of alpha - melanocyte - stimulating hormone ( alpha - MSH ) in the medium was also depressed by 50 % after 8 h of treatment . The role of protein kinase C ( PKC ) was investigated by depleting the IL cell PKC content with phorbol ester treatment . Phorbol 12 - myristate 13 - acetate ( PMA ) at 5 X 10 (- 8 ) M induced a rapid translocation of cytoplasmic PKC activity toward the membrane . After 12 h of PMA treatment , PKC activity was undetectable in either the cytoplasmic or the particulate fractions . The same dose of PMA induced a time - dependent decrease in P01189 mRNA levels ( 50 % inhibition after 24 h ) . The same effect was seen with the phorbol ester phorbol 12 , 13 - dibutyrate at 5 X 10 (- 8 ) M , whereas the inactive phorbol ester 4 alpha - phorbol at 5 X 10 (- 8 ) M was without effect after 24 h of treatment . PMA treatment had a biphasic effect on alpha - MSH secretion . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Fluvoxamine exerts anorexic effect in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m - chlorophenylpiperazine ( mCPP ) and fenfluramine . We previously reported that fluvoxamine , a selective serotonin reuptake inhibitor , together with pharmacological inactivation of P28335 receptors exert feeding suppression through activation of P28222 receptors in mice . Here , we report that fluvoxamine exerted anorexic effects in P28335 receptor mutant mice with heterozygous mutation of beta - endorphin gene ( 2CREnd mice ) , whereas fluvoxamine had no effect on food intake in age - matched wild - type mice and P28335 receptor mutant mice , which are associated with decreases in hypothalamic proopiomelanocortin ( P01189 ) expression . mCPP suppressed food intake in P28335 receptor mutant mice , 2CREnd mice and age - matched wild - type mice . These results suggest that fluvoxamine - induced feeding suppression requires a perturbation of P28335 receptor and beta - endorphin signalling plus functional hypothalamic P01189 activity , whereas mCPP - induced feeding suppression does not always require functional P28335 receptor , beta - endorphin , and P01189 activity in mice .",
"DB00428 - induced increase in cholesterol ester transfer protein ( P11597 ) and its reversal by insulin in transgenic mice expressing human P11597 . High plasma triacylglycerol and low high - density lipoprotein levels are risk factors for cardiovascular disease in diabetes . Plasma high - density lipoprotein levels are regulated by cholesterol ester transfer protein ( P11597 ) . The regulation of P11597 under diabetic conditions is not clear , and this is due to a lack of appropriate models . We used transgenic mice expressing human P11597 to study the regulation of this protein under type - 1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes . Mice expressing human P11597 under the control of its natural flanking region and age - matched littermates not expressing this protein were made diabetic by injecting streptozotocin , and the reversal of diabetes was assessed by injecting insulin . The plasma total cholesterol , low - density lipoprotein - cholesterol , and triacylglycerol concentrations were elevated , whereas high - density lipoprotein - cholesterol concentrations were reduced after the onset of diabetes . P01308 injection partially recovered this effect . The plasma cholesterol ester transfer activity , P11597 mass , and hepatic P11597 mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration . There was a strong correlation between high - density lipoprotein - cholesterol concentrations and cholesterol ester transfer activity . These results suggest that an increase in P11597 under diabetic conditions might be a major factor responsible for increased incidence of diabetes - induced atherosclerosis .",
"P30872 and P35346 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors . The effectiveness of the long acting somatostatin analogues like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells . The immunohistochemical method performed on surgically removed tumors searches the expression of receptors at the level of receptor protein and gives us insight into receptor ' s cellular localization . The aim of study was to assess the presence of all the 5 subtypes of SSTR 1 - 5 ( including 2A and 2B SSTR isoforms ) in surgically treated human neuroendocrine tumors ( NETs ) to establish which receptor subtype is the dominant form of somatostatin receptor in particular tumor and thus to be able to predict which somatostatin analog will be effective in NETs treatment . 18 samples of neuroendocrine tumors ( surgically excised tumors or biopsies ) were immunostained with specific antibodies . Expression of SSTR was scored semiquantitatively . Only strong or moderate immunostaining was considered as positive reaction . The summarized expression pattern of SSTR in the investigated neuroendocrine tumors in our material was : SSTR 1 > SSTR 5 > SSTR 3 > SSTR 2A > SSTR 2B . The receptors were distributed mainly in the area of cells cytoplasm with a few specimens showing only membranous or mixed : membranous -- cytoplasmic localization . The observed pattern suggests that apart from octreotide and lanreotide , newly synthesized multiligand analogs such as DB06663 , KE 108 or SSTR 1 and SSTR 5 selective analogs could be effective in NETs treatment .",
"___MASK47___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin - dependent kinase ( CDK ) inhibitor . Cushing disease caused by adrenocorticotropin ( DB01285 ) - secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes , hypertension , osteoporosis , central obesity , cardiovascular morbidity , and increased mortality . There is no effective pituitary targeted pharmacotherapy for Cushing disease . Here , we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene ( O95997 / securin ) targeted to the adenohypophyseal proopiomelanocortin ( P01189 ) lineage , which recapitulated early features pathognomonic of corticotroph adenomas , including corticotroph expansion and partial glucocorticoid resistance . Adult Tg : Pomc - Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up - regulation , as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease . Early development of corticotroph pathologies in Tg : Pomc - Pttg embryos facilitated drug testing in vivo . We identified a pharmacologic P24941 / cyclin E inhibitor , R - roscovitine ( seliciclib ; CYC202 ) , which specifically reversed corticotroph expansion in live Tg : Pomc - Pttg embryos . We further validated that orally administered R - roscovitine suppresses DB01285 and corticosterone levels , and also restrained tumor growth in a mouse model of DB01285 - secreting pituitary adenomas . Molecular analyses in vitro and in vivo showed that R - roscovitine suppresses DB01285 expression , induces corticotroph tumor cell senescence and cell cycle exit by up - regulating p27 , P38936 and p57 , and downregulates cyclin E expression . The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK74___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK78___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Inhibition of the tumour necrosis factor - alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs . Several autocrine soluble factors , including macrophage inflammatory protein - 1α and tumour necrosis factor - alpha ( P01375 - α ) , promote the survival and growth of multiple myeloma ( MM ) cells . We hypothesised that inhibition of the P01375 - α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines . In the present study , a P01375 - α - neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells . In addition , combination treatment with the P01375 - α - neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor κB ( NF - κB ) p65 nuclear translocation and mammalian target of rapamycin ( P42345 ) activation and upregulated the expression of Bax and Bim . Treatment of Q5SW96 - 77 cells with the NF - κB inhibitor dimethyl fumarate or the P42345 inhibitor rapamycin suppressed NF - κB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan . Furthermore , infliximab , a monoclonal antibody against P01375 - α , also enhanced the cytotoxic effect of anticancer drugs in Q5SW96 - 77 cells . These results indicated that P01375 - α - neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the P01375 receptor / P42345 / NF - κB pathways . The inhibition of P01375 - α may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients .",
"Somatostatin modulates PI3K - Akt , P29474 and NHE activity in the ciliary epithelium . Somatostatin ( P61278 ) is a biologically active peptide produced in neuroendocrine cells . In the present study , we provide evidence of pro - P61278 and P61278 receptor ( P30872 and 2A ) mRNA expression in ocular ciliary epithelium ( CE ) . P61278 or P61278 - like immunoreactivity was detected by radioimmunoassay in tissue extract from ciliary processes and in aqueous humor . The distinct immunolabeling of CE with P61278 and proprotein convertases PC1 and P16519 antibodies suggested a tissue and cell - specific processing of pro - P61278 . P61278 ( 10 (- 8 ) to 10 (- 4 ) M ) added exogenously to the CE , elicited the following effects : ( i ) a dose - dependent attenuation of Na +/ H +- exchanger ( NHE ) activity ; ( ii ) up to a two - fold increase phosphorylation of p - Akt - Ser473 and of p - P29474 - Ser617 , and ( iii ) lack of response on intracellular cyclic GMP production . LY294002 , a PI3K - inhibitor , blocked P61278 - induced p - Akt - Ser473 and partially p - P29474 - Ser617 , however , it did not reverse P61278 - induced NHE attenuation . Collectively , these results suggested involvement of P61278 in multiple intracellular signaling pathways in the CE .",
"Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune - mediated arthritis . OBJECTIVE : Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties . However , it is not known which of the 5 somatostatin receptor subtypes ( SSTRs 1 - 5 ) is involved in these actions . The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide ( DB06663 ) in a mouse model of antigen - induced arthritis ( AIA ) . METHODS : Studies were performed in P30874 - deficient mice ( P30874 (-/-) ) and their wild - type littermates ( P30874 (+/+) ) . The expression of P30872 , SSTR2A , P32745 , and P35346 in dorsal root ganglia was examined by immunohistochemistry . RESULTS : Untreated P30874 (-/-) mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in P30874 (+/+) mice . In wild - type mice , both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone . In P30874 (-/-) mice , the antiinflammatory effects of both octreotide and pasireotide were completely abrogated . Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions . In addition , both octreotide and pasireotide reduced inflammatory hyperalgesia . The antinociceptive actions of octreotide were abolished in P30874 (-/-) mice , but those of pasireotide were retained . In dorsal root ganglia of naive wild - type mice , only P30872 and SSTR2A , but not P32745 or P35346 , were detected in a subset of small - and medium - diameter neurons . CONCLUSION : Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the P30874 receptor . In addition , we identified the P30872 receptor as a novel pharmacologic target for somatostatin - mediated peripheral analgesia in inflammatory pain .",
"Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .",
"Reliability and discriminant validity of P04626 gene quantification and chromosome 17 aneusomy analysis by real - time PCR in primary breast cancer . There is an increasing demand for the evaluation of P04626 status in breast cancer . In this study , sections from fixed tissues and triton extracts of tissue homogenates were obtained from 163 malignant breast tumors and analyzed in parallel using immunohistochemistry combined with fluorescence in situ hybridization , as gold standard tests , and an ELISA test ( c - erbB2 / c - neu Rapid Format ELISA , Oncogene Research Products , USA ) . Tumor DNA was employed to evaluate two quantitative PCR methods : the P04626 / neu DNA Quantification Kit ( Roche Diagnostics GmbH , Germany ) , which uses the gastrin chromosome 17 reference gene , and our recently developed Oncolab qPCR assay , where both a chromosome 17 gene ( somatostatin receptor type II ( P30874 ) ) and a non - chromosome 17 reference gene ( glyceraldehyde - 3 - phosphate deshydrogenase ( P04406 ) ) were used to detect an increase in P04626 gene copy number and to evaluate the aneusomy of chromosome 17 , respectively . By IHC / Q5TCZ1 and ELISA , P04626 was overexpressed in 27 ( 16 . 6 % ) and 24 ( 14 . 7 % ) samples , respectively . With the Roche and Oncolab qPCR assays , 29 ( 17 . 8 % ) samples showed a ratio of P04626 / gastrin > or = 2 . 0 and 26 ( 16 . 0 % ) showed a ratio of P04626 / P30874 > or = 2 . 0 , respectively . In samples presenting P04626 / P30874 < 2 . 0 and P04626 / P04406 > or = 2 . 0 , which was indicative of a chromosome 17 polysomy , we observed a modest increase in P04626 protein expression . Complete agreement between the four methods for P04626 status determination was obtained for 154 ( 94 . 5 % ) samples . Overall , these results demonstrate that quantitative PCR is a reliable method for analyzing P04626 status and chromosome 17 polysomy .",
"Somatostatin receptor expression in adrenocortical tumors and effect of a new somatostatin analog DB06663 on hormone secretion in vitro and in ex vivo adrenal cells . BACKGROUND : Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion , cell proliferation , and apoptosis by 5 somatostatin receptors ( P30872 - 5 ) . The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and / or secretion of growth factors and growth - promoting hormones . AIM : Very little information is available on the effect of somatostatin analogs on adrenal tumors , so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog ( DB06663 ) on hormone secretion and cell viability in adrenal cells . MATERIAL / SUBJECTS AND METHODS : SSTR expression was analyzed by real - time PCR in 13 adrenocortical carcinomas ( ACC ) , 24 aldosterone - producing adenomas ( APA ) , 11 cortisol - producing adenomas ( P15085 ) , and 7 normal adrenals ( NA ) , and verified by immunohistochemistry ( IHC ) in 14 samples . The effect of DB06663 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay , and its effect on viability in H295R and SW13 using the MTT test . RESULTS : P30872 and P30874 mRNA was expressed in 100 % of adrenal tumors . Compared to NA , ACC revealed an increase in almost all SSTR , while only some APA over - expressed P32745 and P30872 . P15085 expressed SSTR similar to NA . IHC confirmed the mRNA expression data . At nanomolar concentrations , DB06663 inhibited hormone secretion in primary adrenal cultures and H295R cells , but had no evident effect on cell viability . CONCLUSIONS : The evidence of SSTR over - expression ( particularly in ACC ) and of hormone secretion being inhibited by DB06663 suggests a potential therapeutic role for this broad - spectrum somatostatin analog in adrenal tumors .",
"Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .",
"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK74___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .",
"Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy . The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors ( GEP - NETs ) have increased in the past 20 years . GEP - NETs are heterogeneous tumors , in terms of clinical and biological features , that originate from the pancreas or the intestinal tract . Some GEP - NETs grow very slowly , some grow rapidly and do not cause symptoms , and others cause hormone hypersecretion and associated symptoms . Most GEP - NETs overexpress receptors for somatostatins . Somatostatins inhibit the release of many hormones and other secretory proteins ; their effects are mediated by G protein - coupled receptors that are expressed in a tissue - specific manner . Most GEP - NETs overexpress the somatostatin receptor P30874 ; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone - related symptoms and also have antitumor effects . Long - acting formulations of somatostatin analogues stabilize tumor growth over long periods . The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP - NETs . Peptide receptor radiotherapy has significant antitumor effects , increasing overall survival times of patients with tumors that express a high density of SSTRs , particularly P30874 and P35346 . The multi - receptor somatostatin analogue DB06663 ( pasireotide ) and chimeric molecules that bind P30874 and the dopamine receptor D2 are also being developed to treat patients with GEP - NETs . Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways , such as mammalian target of rapamycin ( P42345 ) and vascular endothelial growth factor , might be the most effective therapeutics for GEP - NETs .",
"[ Methylation profiling of human atherosclerotic plaques ] . Somatic mutation theory of atherogenesis proved by alterations at the DNA level such as \" loss of heterozygosity \" and microsatellite instability in atherosclerotic plaque is complemented by the date of epigenetic variability of genetic loci involved in the pathological process . However , only recently large - scale analysis of epigenetic modifications in the human genome became possible . For the first time quantitative microarray - based methylation profiling of 1505 CpG - sites across 807 genes was performed in atherosclerotic aorta and carotid artery wall lesions using the GoldenGate Methylation Cancer Panel I ( \" Illumina \" , USA ) . One hundred and three ( 7 % ) CpG - sites in 90 ( 11 % ) genes were differentially methylated between tissue samples . The most pronounced differences in DNA methylation levels were registered for a site which is located in CpG - island of imprinted gene H19 . By comparing 90 genes that were differentially methylated between tissue samples in our study , 10 genes ( P05362 , P09488 , P08833 , P01189 , P02647 , P18510 , P01308 , P01374 , P08254 , P35442 ) were overlapped with data in Human Genome Epidemiology Network ( HuGENet ) , in which they were identified as candidates for cardiovascular disease continuum .",
"Inhibitory effects of DB06663 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo . DB01285 ( DB01285 ) production by pituitary corticotroph adenomas is the main cause of Cushing ' s disease . A drug that targets pituitary DB01285 - secreting adenomas would aid treatment of Cushing ' s disease . DB00104 , a somatostatin receptor type 2 ( P30874 ) - preferring somatostatin analogue , has no effect on DB01285 secretion in patients with Cushing ' s disease . The multiligand DB06663 ( pasireotide ) displays a much higher affinity for P30872 and P35346 than octreotide and suppresses DB01285 secretion in cultures of human corticotroph tumors to a greater extent than octreotide . In the present in vitro and in vivo study , we determined the effect of DB06663 on DB01285 production and cell proliferation of AtT - 20 corticotroph tumor cells . DB06663 decreased proopiomelanocortin ( P01189 ) mRNA levels in AtT - 20 cells and DB01285 levels in the culture medium of these cells , suggesting that DB06663 suppresses DB01285 synthesis and secretion in corticotroph tumor cells . DB06663 also decreased cell proliferation and both cyclic adenosine monophosphate response element - binding protein and Akt phosphorylation in AtT - 20 cells . P35346 knockdown inhibited the DB06663 - induced decreases in cell proliferation . Fluorescence - activated cell sorting analyses revealed that DB06663 did not attenuate cell cycle progression . Tumor weight in mice xenografted with AtT - 20 cells and treated with DB06663 was significantly lower than in AtT - 20 - xenografted control mice . DB06663 also significantly decreased plasma DB01285 levels , and P01189 and pituitary tumor transforming gene mRNA levels in the tumor cells . Thus , DB06663 inhibits DB01285 production and corticotroph tumor cell proliferation in vitro and in vivo .",
"Chemical development of intracellular protein heterodimerizers . Cell activation initiated by receptor ligands or oncogenes triggers complex and convoluted intracellular signaling . Techniques initiating signals at defined starting points and cellular locations are attractive to elucidate the output of selected pathways . Here , we present the development and validation of a protein heterodimerization system based on small molecules cross - linking fusion proteins derived from HaloTags and P60880 - tags . Chemical dimerizers of HaloTag and P60880 - tag ( HaXS ) show excellent selectivity and have been optimized for intracellular reactivity . HaXS force protein - protein interactions and can translocate proteins to various cellular compartments . Due to the covalent nature of the HaloTag - HaXS - P60880 - tag complex , intracellular dimerization can be easily monitored . First applications include protein targeting to cytoskeleton , to the plasma membrane , to lysosomes , the initiation of the PI3K / P42345 pathway , and multiplexed protein complex formation in combination with the rapamycin dimerization system .",
"DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response ."
] |
[
"___MASK26___",
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"___MASK49___",
"___MASK54___",
"___MASK74___",
"___MASK78___",
"___MASK93___",
"___MASK94___"
] |
___MASK74___
|
MH_train_388
|
interacts_with DB01248?
|
[
"Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing . Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer ( PCa ) . We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia ( BPH ) samples using the pyrosequencing ( PSQ ) method to identify genes with diagnostic and prognostic potential . P10826 , HIN1 , P10415 , P09211 , P30279 , Q86T13 , P25054 , RASSF1A , P08183 , P52952 , P55290 , Q14117 , P35354 , P24530 , MAL , P50479 , HLAa , P03372 and TIG1 were highly methylated in PCa compared to BPH ( p < 0 . 001 ) , while P36952 , CDH1 , Q15672 , P53355 , P10828 , P43121 , O94813 , CDKN2a and SFN were not . P10826 methylation above 21 % completely distinguished PCa Separation based on methylation level of SFN , O94813 and P36952 distinguished low and high Gleason score cancers , e . g . SFN and P36952 together correctly classified 81 % and 77 % of high and low Gleason score cancers respectively . Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study . Increasing age was positively associated with gene methylation ( p < 0 . 0001 ) . Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like P10826 , HIN1 , P10415 , P25054 and P09211 is warranted for diagnostic potential and SFN , O94813 and P36952 for prognostic potential .",
"P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . DB01248 dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .",
"The P10415 antagonist ABT - 199 triggers apoptosis , and augments ibrutinib and idelalisib mediated cytotoxicity in P61073 Wild - type and P61073 WHIM mutated Waldenstrom macroglobulinaemia cells .",
"chFRP5 - ZZ - PE38 , a large IgG - toxin immunoconjugate outperforms the corresponding smaller FRP5 ( Fv )- P25101 immunotoxin in eradicating ErbB2 - expressing tumor xenografts . As therapeutics , antibodies can be used \" un - armed \" or as immunoconjugates to direct cytotoxic moieties to tumor cells . Immunoconjugates are made by attaching chemotherapy drugs , radioisotopes or toxins to the antibody . Small recombinant antibody fragments fused to cytotoxic moieties , termed recombinant immunotoxins are also being developed as an additional approach for a targeted cancer therapy . Key parameters in determining the therapeutic potential of such targeted therapies are target specificity , affinity , stability and size . With regard to treating solid tumors , tumor penetration ( which is inversely proportional to size ) is currently regarded as the prime factor for efficacy , while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent . When comparing recombinant immunotoxins and antibody - toxin immunoconjugates that target ErbB2 / P04626 , here we found that a bivalent antibody - toxin immunoconjugate ( 200 kDa ) was superior to the corresponding recombinant monovalent immunotoxin ( 69 kDa ) in killing ErbB2 - expressing tumor cells in culture and as xenografts in nude mice , suggesting that higher avidity and longer residence time may outweigh tumor penetration . Our study suggests that the re - valuation of currently neglected , large IgG - effector molecule conjugates for anti - cancer therapy may be justified .",
"Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line , 1 . 1B4 . BACKGROUND : Molecular mechanisms of toxicity and cell damage were investigated in the novel human beta cell line , 1 . 1B4 , after exposure to proinflammatory cytokines - IL - 1β , IFN - γ , P01375 - α . METHODS : MTT assay , insulin radioimmunoassay , glucokinase assay , real time reverse transcription PCR , western blotting , nitrite assay , caspase assay and comet assay were used to investigate mechanisms of cytokine toxicity . RESULTS : Viability of 1 . 1B4 cells decreased after 18h cytokine exposure . Cytokines significantly reduced cellular insulin content and impaired insulin secretion induced by glucose , alanine , DB00761 , elevated Ca ( 2 +) , P0C6A0 or forskolin . P35557 enzyme activity , regulation of intracellular Ca ( 2 +) and PDX1 protein expression were significantly reduced by cytokines . mRNA expression of genes involved in secretory function - P01308 , GCK , P16519 and P17302 was downregulated in cytokine treated 1 . 1B4 cells . Upregulation of transcription of genes involved in antioxidant defence - P04179 and P07203 was observed , suggesting involvement of oxidative stress . Cytokines also upregulated transcriptions of P19838 and P42224 , which was accompanied by a significant increase in NOS2 transcription and accumulation of nitrite in culture medium , implicating nitrosative stress . Oxidative and nitrosative stresses induced apoptosis was evident from increased % tail DNA , DNA fragmentation , caspase 3 / 7 activity , apoptotic cells and lower P10415 protein expression . CONCLUSIONS : This study delineates molecular mechanisms of cytokine toxicity in 1 . 1B4 cells , which agree with earlier observations using human islets and rodent beta cells . GENERAL SIGNIFICANCE : This study emphasizes the potential usefulness of this cell line as a human beta cell model for research investigating autoimmune destruction of pancreatic beta cells .",
"Q16696 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1 - induced DNA damage . Q16696 ( Q16696 ) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 ( AFB1 ) . Our previous study suggested that Q16696 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells ( BEAS - 2B ) . However , the role of Q16696 in AFB1 - induced DNA damage is unclear . Using BEAS - 2B cells that stably express Q16696 ( B - 2A13 ) , P05177 ( B - 1A2 ) , and P11509 ( B - 2A6 ) , we compared their effects in AFB1 - induced DNA adducts , DNA damage , and cell cycle changes . BEAS - 2B cells that were transfected with vector ( B - vector ) were used as a control . The results showed that AFB1 ( 5 - 80 nM ) dose - and time - dependently induced DNA damage in B - 2A13 cells . AFB1 at 10 and 80nM significantly augmented this effect in B - 2A13 and B - 1A2 cells , respectively . B - 2A6 cells showed no obvious DNA damage , similar to B - vector cells and the vehicle control . Similarly , compared with B - vector , B - 1A2 or B - 2A6 cells , B - 2A13 cells showed more sensitivity in AFB1 - induced γ P16104 expression , DNA adduct 8 - hydroxy - deoxyguanosine formation , and S - phase cell - cycle arrest . Furthermore , AFB1 activated the proteins related to DNA damage responses , such as Q13315 , ATR , Chk2 , p53 , P38398 , and P16104 , rather than the proteins related to DNA repair . These effects could be almost completely inhibited by 100 μM nicotine ( a substrate of Q16696 ) or 1 μM 8 - methoxypsoralen ( DB00553 ; an inhibitor of CYP enzyme ) . Collectively , these findings suggest that Q16696 plays an important role in low - concentration AFB1 - induced DNA damage , possibly linking environmental airborne AFB1 to genetic injury in human respiratory system .",
"Drug insight : Use of docetaxel in prostate and urothelial cancers . Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies , with two taxanes now in clinical use . Their mechanism of action against tumor cells is by alteration of microtubule dynamics , which causes cell - cycle arrest during mitosis . DB01248 binds to the microtubules with a higher affinity than paclitaxel , and over a broader range of cell - cycle activities . It has also been shown to promote apoptosis via P10415 phosphorylation . In hormone - refractory prostate cancer , docetaxel has been studied as both a single agent and in combination with estramustine , and in different treatment schedules , with demonstrated efficacy . Two phase III trials have confirmed a survival benefit , making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer . In urothelial cancer , docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens . A phase III trial comparing docetaxel and cisplatin to methotrexate , vinblastine , doxorubicin , and cisplatin was inferior when evaluating response rates and overall survival . More recent phase II trials combining docetaxel with two additional agents have shown promise , but confirmatory trials are needed .",
"Predictive factors for response to docetaxel in human breast cancers . DB01248 has come into wide use recently for the treatment of breast cancer in neoadjuvant , adjuvant and metastatic settings . DB01248 binds to beta - tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization , resulting in elevated levels of microtubule formation . During metaphase , defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest , culminating in apoptosis . However , docetaxel is not effective for all breast cancers . For example , in metastatic settings , the response rate to docetaxel reportedly ranges from 30 to 50 % . It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment . Currently it is impossible to identify , before the initiation of therapy , the patients for whom docetaxel will be effective . Various biological parameters have been studied clinically for their ability to predict response to docetaxel , such as parameters related to : ( 1 ) efflux ( p - glycoprotein ) and metabolism ( P08684 ) ; ( 2 ) beta - tubulin ( somatic mutation of beta - tubulin and changes in beta - tubulin isotypes levels ) ; ( 3 ) cell cycle ( P04626 , P38398 and Aurora - A ) ; and ( 4 ) apoptosis ( p53 , P10415 and thioredoxin ) . More recently , gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel . In the present paper , clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field .",
"MYC directs transcription of Q07820 and P06730 genes to control sensitivity of gastric cancer cells toward HDAC inhibitors . Histone deacetylases ( HDACs ) control fundamental physiological processes such as proliferation and differentiation . HDAC inhibitors ( HDACi ) induce cell cycle arrest and apoptosis of tumor cells . Therefore , they represent promising cancer therapeutics that appear particularly useful in combination therapies . Although HDACi are tested in current clinical trials , the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood . To gain insight into pathways that limit HDACi efficacy in gastric cancer , we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid ( DB02546 ) . We report that higher expression levels of the anti - apoptotic P10415 family members Q07820 and BCL ( XL ) were detectable in cells with high inhibitory concentration 50 ( IC ( 50 ) ) values for DB02546 . Using RNAi , we show that Q07820 and BCL ( XL ) lower the efficacy of DB02546 . To find strategies to interfere with Q07820 and BCL ( XL ) expression , we investigated molecular regulation of both proteins . We show that specific siRNAs against c - MYC as well as pharmacological inhibition of this cancer - relevant transcription factor reduced Q07820 and BCL ( XL ) expression . Subsequently , we observed an increase in DB02546 efficacy . Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors . Whereas c - MYC controls transcription of Q07820 directly , regulation of BCL ( XL ) was due to c - MYC ' s capability to regulate the P06730 gene , which encodes a rate - limiting factor of eukaryotic translation . Our data reveal a new molecular mechanism for how c - MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c - MYC in gastric cancer .",
"Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha - emitting radioisotope astatine - 211 conjugated to anti - P04626 / neu diabodies . PURPOSE : Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle . Small , engineered antitumor antibody fragments are capable of rapid , highly specific tumor targeting in immunodeficient mouse models . We hypothesized that the P13671 . 5 diabody , a noncovalent anti - P04626 single - chain Fv dimer , would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short - lived alpha - emitting radioisotope ( 211 ) At . EXPERIMENTAL DESIGN : Immunodeficient nude mice bearing established P04626 / neu - positive MDA - MB - 361 / DYT2 tumors treated with N - succinimidyl N -( 4 -[( 211 ) At ] astatophenethyl ) succinamate ( ( 211 ) At - O75563 ) - P13671 . 5 diabody . Additional cohorts of mice were treated with ( 211 ) At - O75563 T84 . 66 diabody targeting the carcinoembryonic antigen or ( 211 ) At - O75563 on a diabody specific for the Müllerian inhibiting substance type II receptor , which is minimally expressed on this tumor cell line . RESULTS : A single i . v . injection of ( 211 ) At - O75563 P13671 . 5 diabody led to a 30 - day delay in tumor growth when a 20 muCi dose was administered and a 57 - day delay in tumor growth ( 60 % tumor - free after 1 year ) when a 45 muCi dose was used . Treatment of mice bearing the same tumors with ( 211 ) At - O75563 T84 . 66 diabody at the same doses led to a delay in tumor growth , but no complete responses , likely due to substantially lower expression of this antigen on the MDA - MB - 361 / DYT2 tumors . In contrast , a dose of 20 muCi of ( 211 ) At - O75563 on the anti - Müllerian - inhibiting substance type II receptor diabody did not affect tumor growth rate , demonstrating specificity of the therapeutic effect . CONCLUSIONS : These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful , short - lived alpha - emitting radioisotopes .",
"P04626 interacts with P16070 to up - regulate P61073 via epigenetic silencing of microRNA - 139 in gastric cancer cells . BACKGROUND & AIMS : Human epidermal growth factor receptor 2 ( P04626 ) ( neu / P04626 ) is overexpressed on many types of cancer cells , including gastric cancer cells ; P04626 overexpression has been associated with metastasis and poor prognosis . We investigated the mechanisms by which P04626 regulates cell migration and invasion . METHODS : P04626 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody , trastuzumab . We identified proteins that interact with P04626 or microRNAs ( miRNAs ) involved in P04626 signaling . We used various software programs to identify miRNAs that regulate factors in the P04626 signaling pathway . We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients . RESULTS : We found that P16070 binds directly to P04626 , which up - regulates the expression of metastasis - associated protein - 1 , induces deacetylation of histone H3 lysine 9 , and suppresses transcription of microRNA139 ( miR - 139 ) to inhibit expression of its target gene , P61073 ( P61073 ) . Knockdown of P04626 and P16070 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice . Lymph node metastasis was associated with high levels of P04626 , P16070 , and P61073 , and reduced levels of miR - 139 in human metastatic gastric tumors . Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and / or DNA methyltransferase resulted in up - regulation of miR - 139 . CONCLUSIONS : P04626 interaction with P16070 up - regulates P61073 by inhibiting expression of miR - 139 , at the epigenetic level , in gastric cancer cells . These findings indicate how P04626 signaling might promote gastric tumor progression and metastasis .",
"P10242 suppresses differentiation and apoptosis of human breast cancer cells . INTRODUCTION : P10242 is highly expressed in estrogen receptor positive ( ER + ve ) breast tumours and tumour cell lines . We recently demonstrated that P10242 is essential for the proliferation of ER + ve breast cancer cells , and have now investigated its role in mammary epithelial differentiation . METHODS : MCF - 7 breast cancer cells were treated with sodium butyrate , vitamin E succinate or 12 - O - tetradecanoylphorbol - 13 - acetate to induce differentiation as measured by Nile Red staining of lipid droplets and β - casein expression . The non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 , was induced to differentiate with lactogenic hormones . P10242 levels were manipulated by inducible lentiviral shRNA - mediated knockdown and retroviral overexpression . RESULTS : We found that P10242 expression decreases following chemically - induced differentiation of the human breast cancer cell line MCF - 7 , and hormonally - induced differentiation of a non - tumorigenic murine mammary epithelial cell ( Q9NRJ3 ) line , P13500 . We also found that shRNA - mediated P10242 knockdown initiated differentiation of breast cancer cells , and greatly sensitised them to the differentiative and pro - apoptotic effects of differentiation - inducing agents ( DIAs ) . Sensitisation to the pro - apoptotic effects DIAs is mediated by decreased expression of P10415 , which we show here is a direct P10242 target in breast cancer cells . Conversely , enforced expression of P10242 resulted in the cells remaining in an undifferentiated state , with concomitant suppression of apoptosis , in the presence of DIAs . CONCLUSIONS : Taken together , these data imply that P10242 function is critical in regulating the balance between proliferation , differentiation , and apoptosis in MECs . Moreover , our findings suggest P10242 may be a viable therapeutic target in breast cancer and suggest specific approaches for exploiting this possibility .",
"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .",
"___MASK99___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK99___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Phase I trial of oral P42345 inhibitor everolimus in combination with trastuzumab and vinorelbine in pre - treated patients with P04626 - overexpressing metastatic breast cancer . To determine the feasible dose and schedule for everolimus , an oral P42345 inhibitor , combined with vinorelbine and trastuzumab for patients with P04626 - overexpressing metastatic breast cancer pretreated with trastuzumab . In this phase Ib multicenter , Bayesian dose - escalation study , 50 patients received everolimus 5 mg / day , 20 mg / week , or 30 mg / week plus vinorelbine ( 25 mg / m² on day 1 and 8 every 3 weeks ) and trastuzumab ( 2 mg / kg weekly ) . Endpoints included end - of - cycle - 1 dose - limiting toxicity ( DLT ) rate ( primary endpoint ) , safety , relative dose intensity , overall response rate ( ORR ) , and pharmacokinetics . Grade 3 / 4 neutropenia was the most common end - of - cycle - 1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg / day and 30 mg / week cohorts , respectively . Other end - of - cycle - 1 DLTs included single cases of febrile neutropenia , grade 3 stomatitis with concomitant fatigue , grade 2 stomatitis , grade 3 anorexia , and grade 2 acneiform dermatitis , all in the 5 - mg / day cohort . Based on the recorded DLTs and global safety , everolimus 5 mg / day and 30 mg / week were chosen as the optimal dose levels for the daily and weekly arms . Forty - seven patients were evaluable for efficacy . ORR was 19 . 1 % , with a disease control rate of 83 . 0 % and median progression - free survival of 30 . 7 weeks . No drug interaction was observed between everolimus and vinorelbine . ___MASK90___ combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with P04626 - overexpressing metastatic breast cancer that progressed on trastuzumab ( NCT00426530 ) .",
"P01308 - like growth factor - I controls P38398 gene expression through activation of transcription factor Sp1 . The insulin - like growth factors ( IGFs ) have a central role in mammary gland growth and differentiation as well as in breast cancer development . The P38398 gene encodes a pleiotropic protein that functions as a transcription factor . Germline P38398 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms . Several lines of evidence led us to hypothesize that there is a functional interaction between the P38398 and P05019 systems relevant to breast cancer biology . The present study tested the notion that P38398 gene expression is regulated by the P05019 signaling pathway . Results of Western immunoblotting and RT - PCR analyses show that P05019 stimulates P38398 protein and mRNA levels . Transient transfection experiments using P38398 promoter - luciferase reporter constructs reveal that P05019 enhances P38398 promoter activity , suggesting that the effect of P05019 is mediated at the transcriptional level . In addition , we provide evidence that the Sp1 zinc - finger protein is directly involved in P38398 gene transactivation . Combined , our data suggests that , at least part of the biological actions of P05019 in mammary gland cells may be mediated through P38398 . Dysregulated P38398 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis .",
"DB06809 and P27487 modulate mobilization , engraftment , and survival of hematopoietic stem and progenitor cells mediated by the P48061 / P48061 - P61073 axis . The chemokine stromal cell - derived factor - 1 ( P48061 / P48061 ) and its receptor , P61073 , are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem ( HSCs ) and progenitor ( HPCs ) cells . Modulation of this ligand - receptor interaction may be of clinical utility . We now report that : ( 1 ) the CC chemokine , macrophage inflammatory protein - 1alpha ( MIP - 1alpha / P10147 ) synergizes with DB06809 ( an antagonist of the binding of P48061 / P48061 to P61073 ) to rapidly mobilize HPCs to the blood of mice ; moreover , the combination of granulocyte colony - stimulating factor ( DB00099 ) with DB06809 and MIP - 1alpha / P10147 , given in a specific sequence , mobilizes the greatest number of HPCs compared to any combination of two of these mobilizing agents ; ( 2 ) pretreatment of recipient mice with Diprotin A , an inhibitor of P27487 / Dipeptidylpeptidase IV ( DPPIV ) , enhances the competitive HSCs repopulating capacity of untreated donor cells ; ( 3 ) the survival - enhancing effects of P48061 / P48061 on HPCs subjected in vitro to delayed addition of growth factors ( GFs ) are mediated in part through the cell cycle - related proteins P38936 ( cip1 / waf1 ) ( as assessed using P38936 ( cip1 / waf1 ) -/- and +/+ mice ) and Mad2 ( using Mad2 +/- and +/+ mice ) ; and ( 4 ) deletion of P27487 / DPPIV on mouse bone marrow cells increases the survival - enhancing effects of P48061 / P48061 on HPCs . These results demonstrate the means to increase the mobilization of HPCs , the engrafting capability of HSCs , and responsiveness of HPCs to the survival - enhancing activity of P48061 / P48061 , effects that may be of practical value .",
"Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom . The present study was aimed to investigate the cognitive enhancing and anti - oxidant activities of Inonotus obliquus ( Chaga ) against scopolamine - induced experimental amnesia . Methanolic extract of Chaga ( Q9NRJ3 ) at 50 and 100 mg kg (- 1 ) doses were administered orally for 7 days to amnesic mice . Learning and memory was assessed by passive avoidance task ( PAT ) and Morris water maze ( MWM ) test . Tacrine ( ___MASK18___ , 10 mg kg ( - 1 ) , orally ( p . o ) ) used as a reference drug . To elucidate the mechanism of the cognitive enhancing activity of Q9NRJ3 , the activities of acetylcholinesterase ( P22303 ) , anti - oxidant enzymes , the levels of acetylcholine ( ACh ) and nitrite of mice brain homogenates were evaluated . Q9NRJ3 treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms . Further , Q9NRJ3 significantly reduced the oxidative - nitritive stress , as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner . In addition , Q9NRJ3 treatment significantly decreased the P22303 activity in both the salt and detergent - soluble fraction of brain homogenates . Further , treatment with Q9NRJ3 restored the levels of ACh as did ___MASK18___ . Thus , the significant cognitive enhancement observed in mice after Q9NRJ3 administration is closely related to higher brain anti - oxidant properties and inhibition of P22303 activity . These findings stress the critical impact of Chaga , a medicinal mushroom , on the higher brain functions like learning and memory .",
"Combination therapy with anti - ErbB3 monoclonal antibodies and P00533 TKIs potently inhibits non - small cell lung cancer . Personalized therapy of advanced non - small cell lung cancer ( NSCLC ) has been improved by the introduction of P00533 tyrosine kinase inhibitors ( TKIs ) , gefitinib and erlotinib . P00533 TKIs induce dramatic objective responses and increase survival in patients bearing sensitizing mutations in the P00533 intracytoplasmic tyrosine kinase domain . However , virtually all patients develop resistance , and this is responsible for disease relapse . Hence several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable to sensitize resistant cells to P00533 TKIs . Recent studies have suggested that upregulation of another member of the P00533 receptor family , namely ErbB3 is involved in drug resistance , through increased phosphorylation of its intracytoplasmic domain and activation of PI3K / AKT signaling . In this paper we first show , by using a set of malignant pleural effusion derived cell cultures ( MPEDCC ) from patients with lung adenocarcinoma , that surface ErbB3 expression correlates with increased AKT phosphorylation . Antibodies against ErbB3 , namely A3 , which we previously demonstrated to induce receptor internalization and degradation , inhibit growth and induce apoptosis only in cells overexpressing surface ErbB3 . Furthermore , combination of anti - ErbB3 antibodies with P00533 TKIs synergistically affect cell proliferation in vitro , cause cell cycle arrest , up - regulate P38936 expression and inhibit tumor growth in mouse xenografts . Importantly , potentiation of gefitinib by anti - ErbB3 antibodies occurs both in de novo and in ab initio resistant cells . Anti - ErbB3 mAbs strongly synergize also with the dual P00533 and P04626 inhibitor lapatinib . Our results suggest that combination treatment with P00533 TKI and antibodies against ErbB3 should be a promising approach to pursue in the clinic .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK48___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK48___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK48___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK48___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK48___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK48___ increased the protein expression of hepatic P05181 and ___MASK48___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK48___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK48___ and RFP - induced hepatotoxicity .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK90___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Purinergic receptor - mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine - rich repeat phosphatase , calcineurin , protein phosphatase 2A , and P60484 phosphatases . Akt is an important oncoprotein , and data suggest a critical role for nuclear Akt in cancer development . We have previously described a rapid ( 3 - 5 min ) and Q99572 - dependent depletion of nuclear phosphorylated Akt ( pAkt ) and effects on downstream targets , and here we studied mechanisms behind the pAkt depletion . We show that cholesterol - lowering drugs , statins , or extracellular DB00171 , induced a complex and coordinated response in insulin - stimulated A549 cells leading to depletion of nuclear pAkt . It involved protein / lipid phosphatases P60484 , pleckstrin homology domain leucine - rich repeat phosphatase ( O60346 and - 2 ) , protein phosphatase 2A ( PP2A ) , and calcineurin . We employed immunocytology , immunoprecipitation , and proximity ligation assay techniques and show that O60346 and calcineurin translocated to the nucleus and formed complexes with Akt within 3 min . Also P60484 translocated to the nucleus and then co - localized with pAkt close to the nuclear membrane . An inhibitor of the scaffolding immunophilin FK506 - binding protein 51 ( FKBP51 ) and calcineurin , FK506 , prevented depletion of nuclear pAkt . Furthermore , okadaic acid , an inhibitor of PP2A , prevented the nuclear pAkt depletion . Chemical inhibition and siRNA indicated that O60346 , PP2A , and P60484 were required for a robust depletion of nuclear pAkt , and in prostate cancer cells lacking P60484 , transfection of P60484 restored the statin - induced pAkt depletion . The activation of protein and lipid phosphatases was paralleled by a rapid proliferating cell nuclear antigen ( P12004 ) translocation to the nucleus , a P12004 - P38936 ( cip1 ) complex formation , and cyclin D1 degradation . We conclude that these effects reflect a signaling pathway for rapid depletion of pAkt that may stop the cell cycle .",
"A multimarker model to predict outcome in tamoxifen - treated breast cancer patients . PURPOSE : This study was designed to produce a model to predict outcome in tamoxifen - treated breast cancer patients based on clinicopathologic features and multiple molecular markers . EXPERIMENTAL DESIGN : This was a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen for whom standard clinicopathologic data and tumor tissue microarrays were available . Nine molecular markers were studied by semiquantitative immunohistochemistry and / or fluorescence in situ hybridization . Cox proportional hazards analysis was used to determine the contributions of each variable to disease - specific and overall survival , and machine learning was used to produce a model to predict patient outcome . RESULTS : On a univariate basis , the following features were significantly associated with worse survival : high pathologic tumor or nodal class , histologic grade , epidermal growth factor receptor , P04626 , MYC , or P04637 ; absent estrogen receptor ( ER ) or progesterone receptor ; and low P10415 . P24385 and P46527 did not reach statistical significance . On a multivariate basis , nodal class , ER , and MYC were statistically significant as independent factors for survival . However , the benefit of ER - positive status was moderated by P10415 , P04626 , and progesterone receptor . P10415 and P04637 also interacted as an independent risk factor . A kernel partial least squares polynomial model was developed with an area under the receiver operating characteristic curve of 0 . 90 . CONCLUSIONS : Our data show the predictive value of P10415 , P04626 , MYC , and P04637 in addition to the standard hormone receptors and clinicopathologic features , and they show the importance of conditional interpretation of certain molecular markers . Our multimarker predictive model performed significantly better than standard guidelines .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK18___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK18___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK18___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK18___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK18___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"___MASK90___ enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro - apoptotic and cell - cycle - progression regulatory proteins . DB06769 is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed / refractory multiple myeloma ( MM ) . ___MASK90___ , an mammalian target of rapamycin ( P42345 ) inhibitor , is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers . We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines ( RPMI8226 and MM1 . S ) and primary MM cells . Our results demonstrated a synergistic effect of these drugs , which was effective for both p53 - wild - type and p - 53 - deleted MM cells , but was minimal in mononuclear cells from a healthy donor . Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin - V / PI staining , caspase - 3 degradation , and PARP cleavage . Cell death was associated with the up - regulation of the pro - apoptotic protein Bax and the down - regulation of the anti - apoptotic proteins Mcl - 1 and survivin . The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the P42345 pathway , p70s6k , and 4EBP - 1 , as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1 . S cells . P38936 was also down - regulated upon treatment with the two drugs , suggesting a mechanism of sensitization through the release of cell cycle arrest . Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine , and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and P42345 inhibitors in future clinical practice .",
"Q9UBP4 maintains the PANC - 1 human pancreatic tumor cells in a dedifferentiated state . Pancreatic cancer ( PaCa ) is the fourth leading cause of cancer deaths in Western societies , with pancreatic ductal adenocarcinomas ( PDACs ) accounting for > 90 % of such cases . PDAC is a heterogeneous disease that includes a subset showing overexpression of the secreted glycoprotein Q9UBP4 ( Q9UBP4 ) , a protein shown to be downregulated in various cancers of different tissues . The biological function of Q9UBP4 in this subset was studied using the Q9UBP4 expressing PANC - 1 cell line as a model for PDACs . The influence of Q9UBP4 overexpression and knockdown on cellular differentiation and proliferation of PANC - 1 was investigated . Confocal microscopy showed that Q9UBP4 was expressed in a fraction of PANC - 1 cells . While lentiviral - mediated overexpression of Q9UBP4 did not alter cellular proliferation , knockdown of Q9UBP4 resulted in significant reduction of cellular proliferation and concomitant induction of cell cycle inhibitors P42772 ( p15INK4b ) , P38936 ( p21CIP1 ) and P46527 ( p27KIP1 ) . In parallel , pancreatic epithelial cell differentiation markers P04746 , Q9UNI1 , P17538 , P01275 , P16278 and P01308 were significantly upregulated . PANC - 1 cells differentiated using exendin - 4 showed analogous induction of cell cycle inhibitors and differentiation markers . Thus , we conclude that Q9UBP4 is required to maintain a highly dedifferentiated and consequently proliferative state in PANC - 1 , indicating a similar function in the Q9UBP4 overexpressing subset of PDACs . Therefore , Q9UBP4 represents a potential target for the treatment of Q9UBP4 - positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation .",
"Autocrine and paracrine roles of P15692 / P35968 and P49767 / P35916 signaling in angiosarcomas of the scalp and face . Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons . To clarify its characteristic features and cell cycle kinetics , we quantitatively evaluated the expression of cell cycle - related molecules and vascular endothelial growth factors using immunohistochemical staining , for comparison with 2 benign vascular tumors of the skin , the capillary hemangioma and the cavernous hemangioma . Cell proliferation , determined with reference to the Ki - 67 labeling index , was highest in angiosarcomas and lowest in cavernous hemangiomas ( angiosarcomas versus capillary hemangioma , P = . 014 ; capillary hemangioma versus cavernous hemangiomas , P = 1 . 4 x 10 (- 4 ) ) . Similar differences were also found in cyclin A , cyclin E , and P38936 ( Waf1 ) expression . Expressions of cyclin D1 and p16 ( INK4A ) were also significantly higher in angiosarcoma than in cavernous hemangioma . Expressions of these 5 proteins showed significant positive correlations with Ki - 67 labeling indices ( Spearman rho = 0 . 91 - 0 . 43 ) . Expression levels of vascular endothelial growth factor and its receptor , P35968 , were highest in angiosarcomas . P49767 expression in angiosarcomas was significantly higher than in cavernous hemangiomas , and its receptor P35916 expression was highest in angiosarcomas . Furthermore , significant positive correlations of these protein expression with Ki - 67 labeling indices were noted ( Spearman rho = 0 . 88 - 0 . 40 ) . Among them , P35916 showed the highest correlation coefficient . These results suggest that not only P35968 - mediated signal but also P35916 - mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK20___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK20___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"___MASK58___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK58___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"___MASK26___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Exome - level comparison of primary well - differentiated neuroendocrine tumors and their cell lines . Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors ( NET ) and have been instrumental in the design of clinical trials targeting the PI3K / AKT / P42345 pathways , P15692 inhibitors , and somatostatin analogues . It remains unknown , however , whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines . Four bronchopulmonary NET ( BP - NET ) - NCI - H720 , NCI - H727 , NCI - H835 , and UMC11 - and two pancreatic neuroendocrine tumors ( panNET ) - BON - 1 and QGP1 - were cultured . DNA was isolated , and exome sequencing was done . GATK and EXCAVATOR were used for bioinformatic analysis . We detected a total of 1 , 764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP - NET and 4 . 3 per Mb in panNET cell lines , including 52 mutated COSMIC cancer genes in these cell lines , such as P04637 , P38398 , P06400 , P49815 , P46531 , Q09472 , GNAS , P35968 , Q15831 , and P25054 but not P46100 , Q9UER7 , nor O00255 . Our data suggest that mutation rate , the pattern of copy number variations , and the mutational spectra in the BP - NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP - NET . Likewise , mutation rate and pattern including the absence of mutations in P46100 / Q9UER7 , O00255 , and P25490 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET . These results suggest that results from experiments with BP - NET and panNET cell lines need to be interpreted with caution .",
"Effects of maternal smoking on the placental expression of genes related to angiogenesis and apoptosis during the first trimester . OBJECTIVE : Maternal cigarette smoking is reportedly associated with miscarriage , fetal growth restriction and placental abruption , and is paradoxically associated with a decreased risk of developing preeclampsia . In the present study , we investigated the gene expression levels of villous tissues in early gestation . We compared the expression levels of the genes related to angiogenesis and apoptosis in the villous tissues obtained from smoking and non - smoking pregnant women . MATERIALS AND METHODS : We collected villous tissue samples from 57 women requesting surgical termination due to non - medical reasons at 6 - 8 weeks of gestation . The maternal cigarette smoking status was evaluated by the level of serum cotinine and patients were divided into active smokers and non - smokers by the serum cotinine level . The placental levels of P15692 , P49763 , P17948 , Q16665 , P04637 , Q07812 and P10415 mRNA were quantified by real time PCR . RESULTS : The gene expression level of P49763 and Q16665 in the active smoker group was significantly higher than that in the non - smoker group . We did not observe any significant differences in the P15692 or P17948 expression between the groups . In active smoker group , the gene expression levels of P04637 and Q07812 were significantly higher than those in the non - smoker group . The ratio of Q07812 / P10415 mRNA in the active smoker group was significantly higher than that in the non - smoker group . CONCLUSIONS : Our findings revealed that smoking might affect the placenta during early pregnancy . Maternal cigarette smoking in early pregnancy may be associated with villus hypoxia , which may influence angiogenesis and apoptosis .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK38___ GITS , Diaprel MR ) . One daily dose of ___MASK38___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"Ubiquitin - dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen . We previously reported that acetaminophen ( DB00316 , 4 - hydroxyacetanilide ) caused apoptosis of P13671 glioma cells . Therefore , we hypothesized that the level of p53 , which usually stimulates apoptosis , might be increased after DB00316 exposure . However , DB00316 exposure for 24 h markedly decreased the p53 content and its downstream target P38936 in a concentration - dependent manner . Reduction of p53 was not accompanied by a decrease in p53 mRNA in P13671 glioma cells , suggesting that p53 was mainly affected at the protein level . Unexpectedly , DB00316 stimulated phosphorylation of p53 at Ser15 , Ser20 , and Ser37 , which usually elevates p53 content . However , phosphorylation of these residues did not prevent DB00316 - induced decrease in p53 . The p53 reduction was independent from the level of phospho - Akt , which is known to promote p53 degradation . Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 ( mdm2 ) and ubiquitin were bound to p53 during its degradation . Lactacystin and N - benzoyloxycarbonyl ( Z ) - DB00149 - DB00149 - leucinal ( MG132 ) , inhibitors of proteasomal proteolysis , prevented the decrease , supporting the proteasomal degradation of p53 upon DB00316 exposure . Pretreatment with chlormethiazole , an inhibitor of ethanol - inducible P05181 , significantly lowered the P05181 enzyme activity and the rate of DB00316 - induced cell death while it prevented the reduction of p53 and P38936 in P13671 glioma cells . A nontoxic analog of DB00316 , 3 - hydroxyacetanilde , did not reduce p53 and P38936 contents in P13671 glioma cells and LLC - P30613 porcine kidney cells . Taken together , our results show that DB00316 or its reactive metabolite ( s ) can directly reduce the p53 content through mdm2 - mediated ubiquitin conjugation , despite phosphorylation of p53 at its N terminus .",
"Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .",
"___MASK96___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy ."
] |
[
"___MASK18___",
"___MASK20___",
"___MASK26___",
"___MASK38___",
"___MASK48___",
"___MASK58___",
"___MASK90___",
"___MASK96___",
"___MASK99___"
] |
___MASK20___
|
MH_train_389
|
interacts_with DB00918?
|
[
"___MASK77___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK85___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Dose finding , placebo - controlled study of oral almotriptan in the acute treatment of migraine . OBJECTIVE : To assess the efficacy and tolerability of oral almotriptan , a selective serotonin receptor ( P28222 / 1D ) agonist , when used at different doses in the treatment of acute migraine . METHODS : This was a placebo controlled , double - blind , parallel - group , dose - finding study . Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2 , 6 . 25 , 12 . 5 , or 25 mg at the onset of moderate or severe pain . Patients graded pain intensity on a 4 - point verbal scale from 0 ( no pain ) to 3 ( severe pain ) and recorded adverse events . The primary efficacy variable was headache response at 2 hours . Data were analyzed on an intent - to - treat basis . RESULTS : Nine hundred and three patients were randomized , and 742 were included in the evaluation of the efficacy and tolerability . Headache response at 2 hours was 32 . 5 % with placebo , and 30 % , 56 . 3 % , 58 . 5 % , and 66 . 5 % with almotriptan 2 , 6 . 25 , 12 . 5 , and 25 mg doses ( p < 0 . 05 for 6 . 25 , 12 . 5 , and 25 mg vs placebo ) . A dose - dependent decrease in the incidence of migraine - associated symptoms and the need for escape medication was observed . The incidence of adverse events with the almotriptan 2 - mg , 6 . 25 - mg , and 12 . 5 - mg groups was comparable to that with the placebo group . CONCLUSION : DB00918 12 . 5 mg demonstrated the most favorable ratio between efficacy and tolerability , offering equivalent efficacy and better tolerability compared with the 25 mg dose . The minimum effective dose of almotriptan was 6 . 25 mg .",
"Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA - protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 , P30939 , P28223 , P46098 , and P50406 ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full - length GR verified most of the predicted DNA - protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .",
"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .",
"DB00918 : a novel P28222 / D agonist for the symptomatic treatment of migraine . Currently available oral triptans are not ideal , at least for 20 - 30 % of migraine patients , due to either response failure or adverse events . DB00918 is a novel selective P28222 / D receptor agonist exhibiting the highest bioavailability among triptans , both outside and within a migraine attack . The tolerability of the therapeutic oral dose of almotriptan , 12 . 5 mg , is similar to that of placebo , with a remarkably low incidence of chest symptoms . At this dose , efficacy parameters remain comparable to those of sumatriptan 100 mg , while the recurrence rate is in the lower range . This balanced profile makes almotriptan 12 . 5 mg a good choice for the symptomatic treatment of the typical migraine patient .",
"[ ___MASK53___ sodium ( Photofrin - II ) ] . ___MASK53___ sodium ( ___MASK53___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK53___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK35___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK36___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .",
"Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .",
"DB00918 for the acute treatment of adolescent migraine . IMPORTANCE OF THE FIELD : Migraine is a common problem affecting 10 - 20 % of adolescents . Its treatment has three fundamental components : bio - behavioral interventions , preventive measures , and acute drug therapy . In June 2009 , the US FDA approved almotriptan , a P28222 / 1D receptor agonist , for the acute treatment of migraine in adolescents aged 12 - 17 years -- the first ' DB00669 ' to be approved for adolescents . AREAS COVERED IN THIS REVIEW : This review will provide an overview of migraine in adolescents focusing on epidemiology , pathophysiology , classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan . WHAT THE READER WILL GAIN : Given its recent FDA approval , it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent , almotriptan . TAKE HOME MESSAGE : DB00918 is a safe , effective , and approved agent for the acute treatment of migraine headache in adolescents .",
"The role of endothelium - derived hyperpolarizing factor and cyclooxygenase pathways in the inhibitory serotonergic response to the pressor effect elicited by sympathetic stimulation in chronic sarpogrelate treated rats . We have demonstrated that the antagonism of 5 - HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by P28221 and P34969 activation . The aim of this work was to determine mechanisms involved in the 5 - hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5 - HT2 receptor blocker . The blockade of 5 - HT2 receptors was induced by orally sarpogrelate treatment ( 30 mg / kg / day ) . Two weeks later , animals were anaesthetized and pithed . A bolus injection of 1H -[ 1 , 2 , 4 ] oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) ( 10 µg / kg ) , a guanylyl cyclase inhibitor , or indomethacin ( 2mg / kg ) , a non - selective P36551 inhibitor , prior to the infusion of ( 2S ) (+)- 5 -( 1 , 3 , 5 - trimethylpyrazol - 4 - yl )- 2 -( dimethylamino ) tetralin , AS - 19 ( 5 µg / kg / min ) were not able to abolish its inhibitory action . However , i . v . administration of glibenclamide ( 20mg / kg ) , a blocker of DB00171 - sensitive K (+) channels , completely reversed AS - 19 sympathoinhibitory action . The inhibitory effect of 2 -[ 5 -[ 3 -( 4 - methylsulfonylamino ) benzyl - 1 , 2 , 4 - oxadiazol - 5 - yl ]- 1H - indol - 3 - yl ] ethanamine , L - 694 , 247 ( 5 µg / kg / min ) was abolished by indomethacin , whereas pretreatment with ODQ had no effect . DB04743 ( 3mg / kg ) , a P35354 inhibitor , completely reversed the inhibitory action of L - 694 , 247 , whereas 1 - [ [ 4 , 5 - bis ( 4 - methoxyphenyl )- 2 - thiazolyl ] carbonyl ] - 4 - methylpiperazine hydrochloride ( FR122047 ) ( 3mg / kg ) , a P23219 inhibitor , partially blocked this action . The sympathoinhibition by 5 - HT ( 20 µg / kg / min ) could not be elicited after i . v . treatment with indomethacin plus glibenclamide . In conclusion , these results suggest that in chronic sarpogrelate - treated rats , the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via P34969 and P28221 receptor activation is mediated by KATP channel - mediated smooth muscle hyperpolarization and the P36551 pathway , respectively .",
"Safety profile of almotriptan , a new antimigraine agent . Effects on central nervous system , renal function and respiratory dynamics . DB00918 ( 3 - [ 2 -( dimethylamino ) ethyl ] - 5 -( pyrrolidin - 1 - ylsulfonylmethyl )- 1H - indole , CAS 154323 - 57 - 6 ) is a new P28222 / 1D agonist whose clinical efficacy has been demonstrated in Phase III clinical trials . This study aimed to evaluate the safety of almotriptan with respect to the central nervous system , renal function and respiratory dynamics using preclinical animal models . The results indicate that almotriptan does not cross the blood - brain barrier , since no effects on / interaction with spontaneous locomotor activity , hexobarbital - induced sleeping time , caffeine - induced increase of spontaneous locomotor activity , or hypothermia ( caused by stimulation of central P28221 receptors ) was observed following treatment . DB00918 had a mild antiemetic effect and a slight , transient diuretic effect in dogs , although the latter effect is probably of no clinical relevance . In addition , no effect on the respiratory system of conscious guinea pigs was observed following almotriptan treatment . These results indicate that almotriptan has a favourable safety profile with respect to the central nervous , renal and respiratory systems .",
"Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 / 1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69 . 1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first - pass metabolism ( 18 . 7 - 79 . 6 % ) . The elimination half - life was short and ranged between 0 . 7 and 3 h . The main route of elimination of almotriptan was urine with 75 . 6 % and 80 . 4 % of the dose recovered over a 168 - h period in rats and dogs , respectively . The gamma - aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N - oxide metabolite were the main metabolites in dog .",
"[ 5 - hydroxytryptamine ( serotonin ) receptors -- nomenclature and classification of types and subtypes ] . 5 - HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes . At present 15 receptor subtypes of three groups has been recognized . The 5 - HT1 subfamily of receptors contains subtypes P08908 , P28222 , P28221 , P28566 , and P30939 ; activation of all of them results in the inhibition of adenylylcyclase . The subfamily of 5 - HT2 contains subtypes 5 - Q13049 , P41595 , and P28335 ; their activation leads to the stimulation of P98160 . Finally , subfamily of miscellaneous 5 - HT receptors contains subtypes 5 - Q9H205 , Q13639 , 5 - HT5 , P50406 , and P34969 ; some of them has been cloned , however , our knowledge on their function is still minimal . 5 - HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease . 5 - HT plays an important role in depression ; to cure this disease , drugs which increase levels of this neurotransmitter are used . A new drug group called Selective Serotonin Reuptake Inhibitors ( SSRI ) has been recently discovered . These drugs block the reuptake of 5 - HT into nerve endings . There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential .",
"DB00918 is an effective and well - tolerated treatment for migraine pain : results of a randomized , double - blind , placebo - controlled clinical trial . DB00918 is a novel and specific serotonin P28222 / 1D agonist for the acute treatment of migraine . This randomized , single - dose , double - blind , multicentre , study assessed the efficacy and safety of oral almotriptan ( 12 . 5 mg and 25 mg ) in patients with migraine , and compared it with the standard treatment ( sumatriptan 100 mg ) and placebo . A total of 668 patients treated one migraine attack of moderate or severe intensity with study medication . The primary efficacy assessment was migraine pain relief , improvement from severe or moderate pain to mild or no pain , at 2 h after treatment . Response rates , stratified for variation in baseline pain levels , for both almotriptan doses were equivalent to sumatriptan and significantly better than placebo . Other efficacy assessments confirmed the equivalence of the almotriptan groups with the sumatriptan group . DB00918 12 . 5 mg was as well tolerated as placebo ( P = 0 . 493 ) and significantly better tolerated than sumatriptan ( P < 0 . 001 ) , in terms of the overall incidence of adverse events . There was no statistically significant difference in the incidence of adverse events between almotriptan 25 mg and sumatriptan 100 mg ( P = 0 . 376 ) . The results from this large clinical study indicate that the new , specific P28222 / 1D agonist , almotriptan , is an effective and well - tolerated treatment for migraine pain .",
"Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post - mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH - risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha1 - adrenergic , alpha2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 , P28221 , 5 - Q13049 , and P28335 receptors ) . ___MASK91___ was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 , P28221 , and 5 - Q13049 ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0 . 087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"___MASK91___ binding to human and rat dopamine and 5 - HT receptors . ___MASK91___ ( ___MASK91___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK91___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK91___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK91___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers . OBJECTIVE : To assess the interaction between almotriptan , a P28222 / 1D - receptor agonist used to treat migraine , and verapamil , an agent for migraine prophylaxis . METHODS : Twelve healthy volunteers received the following treatments in a crossover design : ( 1 ) 120 - mg sustained - release verapamil tablet twice daily for 7 days and one 12 . 5 - mg almotriptan tablet on day 7 and ( 2 ) one 12 . 5 - mg almotriptan tablet alone on day 7 . Serial plasma and urine samples were obtained on day 7 . DB00918 plasma concentrations were determined by liquid chromatography - tandem mass spectrometry ; urine samples were analyzed by ultraviolet HPLC . Safety measures included blood pressure and pulse measurements , electrocardiography , and adverse event monitoring . Statistical comparisons of pharmacokinetic parameters and vital sign data were made by Q9UNW9 . RESULTS : Mean almotriptan peak concentration and area under the plasma concentration - time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone . The magnitudes of these differences were approximately 20 % . Renal clearance was unaffected by verapamil coadministration . No significant effects of treatment on blood pressure or pulse were detected , with the exception of sitting systolic blood pressure at 2 hours after administration . However , the difference in mean change from baseline at this time point was only 8 mm Hg . CONCLUSIONS : Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of P08684 to almotriptan metabolism . This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK80___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"How does almotriptan compare with other triptans ? A review of data from placebo - controlled clinical trials . DB00918 , the new selective P28222 / 1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain - free . DB00918 12 . 5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12 . 5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12 . 5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan ' s consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK28___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .",
"Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK60___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice ."
] |
[
"___MASK28___",
"___MASK35___",
"___MASK36___",
"___MASK53___",
"___MASK60___",
"___MASK77___",
"___MASK80___",
"___MASK85___",
"___MASK91___"
] |
___MASK85___
|
MH_train_390
|
interacts_with DB02701?
|
[
"DB02701 inhibits alkylating agent - induced apoptotic neurodegeneration in the developing rat brain . BACKGROUND : Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system ( CNS ) . Administration of single dose of thiotepa in 7 - d postnatal ( Q0GE19 ) rat triggers activation of apoptotic cascade and widespread neuronal death . The present study was aimed to elucidate whether nicotinamide may prevent thiotepa - induced neurodegeneration in the developing rat brain . METHODOLOGY / PRINCIPAL FINDINGS : Neuronal cell death induced by thiotepa was associated with the induction of Bax , release of cytochrome - c from mitochondria into the cytosol , activation of caspase - 3 and cleavage of poly ( ADP - ribose ) polymerase ( P09874 ) . Post - treatment of developing rats with nicotinamide suppressed thiotepa - induced upregulation of Bax , reduced cytochrome - c release into the cytosol and reduced expression of activated caspase - 3 and cleavage of P09874 . Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus ; post - treatment with nicotinamide reduced the number of dead cells in these brain regions . Terminal deoxynucleotidyl transferase ( TdT ) - mediated dUTP nick end - labeling ( TUNEL ) and immunohistochemical analysis of caspase - 3 show that thiotepa - induced cell death is apoptotic and that it is inhibited by nicotinamide treatment . CONCLUSION : DB02701 ( Nic ) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat . These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants .",
"N - methyl - 2 - pyridone - 5 - carboxamide : a novel uremic toxin ? BACKGROUND : N - methyl - 2 - pyridone - 5 - carboxamide ( 2PY ) is one of the end products of nicotinamide - adenine dinucleotide ( NAD ) degradation . We recently found that serum 2PY concentrations in chronic renal failure ( CRF ) patients were enhanced to the values , which are potentially toxic . The aim of this study was to determine whether 2PY is an inhibitor of poly ( ADP - ribose ) polymerase , the nuclear enzyme that is highly involved in variety of physiologic events , including regulation of DNA replication and DNA repair . METHODS : High - performance liquid chromatography ( HPLC ) was used to determine 2PY and other NAD catabolite concentrations in serum of : nondialyzed patients ; patients chronically hemodialyzed ; patients after kidney transplantation ; and healthy individuals ( control group ) . Moreover , the effect of nicotinamide and 2PY on poly ( ADP - ribose ) polymerase ( P09874 ) in vitro was studied . RESULTS : The serum nicotinamide , 2PY , and 4PY ( N - methyl - 4 - pyridone - 3 - carboxamide ) concentrations are many times elevated in nondialyzed CRF patients when compared with controls . The direct correlations were found between serum 2PY ( as well as 4PY and nicotinamide ) concentrations and serum creatinine concentration , and negative correlations between serum concentrations of these compounds and creatinine clearance . The concentration of 2PY decreases considerably after hemodialysis ( HD ) session , but elevates back 48 hours later . It permanently declines after kidney transplantation . DB02701 and 2PY significantly inhibit P09874 activity in vitro . CONCLUSIONS : Increased serum 2PY concentration , along with a deterioration of kidney function and its toxic properties ( significant inhibition of P09874 by 2PY ) , suggest that it could be a novel uremic toxin .",
"P09874 ( P09874 ) activation and NAD (+) in DNA repair and cell death . DB02701 adenine dinucleotide , NAD (+) , is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis , the tricarboxylic acid cycle ( TCA ) and mitochondrial respiration . These processes consume and produce both oxidative and reduced forms of NAD ( NAD (+) and DB00157 ) . NAD (+) is also important for ADP ( ribosyl ) ation reactions mediated by the ADP - ribosyltransferase enzymes ( ARTDs ) or deacetylation reactions catalyzed by the sirtuins ( SIRTs ) which use NAD (+) as a substrate . In this review , we highlight the significance of NAD (+) catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs . We summarize the current findings on the involvement of P09874 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by P09874 activation and energy depletion . By sharing the same substrate , the activities of ARTDs and SIRTs are tightly linked , are dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology , inflammatory diseases and ischaemia / reperfusion .",
"Role of nicotinamide in DNA damage , mutagenesis , and DNA repair . DB02701 is a water - soluble amide form of niacin ( nicotinic acid or vitamin B3 ) . Both niacin and nicotinamide are widely available in plant and animal foods , and niacin can also be endogenously synthesized in the liver from dietary tryptophan . DB02701 is also commercially available in vitamin supplements and in a range of cosmetic , hair , and skin preparations . DB02701 is the primary precursor of nicotinamide adenine dinucleotide ( NAD (+) ) , an essential coenzyme in DB00171 production and the sole substrate of the nuclear enzyme poly - ADP - ribose polymerase - 1 ( P09874 ) . Numerous in vitro and in vivo studies have clearly shown that P09874 and NAD (+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation . This paper will examine the role of nicotinamide in the protection from carcinogenesis , DNA repair , and maintenance of genomic stability .",
"Preventing NAD (+) depletion protects neurons against excitotoxicity : bioenergetic effects of mild mitochondrial uncoupling and caloric restriction . Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity , which involves energy depletion . By examining bioenergetic changes induced by glutamate , we found that the cellular nicotinamide adenine dinucleotide ( NAD (+) ) level is a critical determinant of neuronal survival . The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain . 2 , 4 - dinitrophenol ( DNP ) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons , which accelerates oxidation of NAD ( P ) H to NAD (+) in mitochondria . The NAD (+)- dependent histone deacetylase sirtulin 1 ( Q96EB6 ) and glucose transporter 1 ( P11166 ) mRNA are upregulated mouse brain under caloric restriction . To examine whether NAD (+) mediates neuroprotective effects , nicotinamide , a precursor of NAD (+) and inhibitor of Q96EB6 and poly ( ADP - ribose ) polymerase 1 ( P09874 ) ( two NAD (+)- dependent enzymes ) , was employed . DB02701 attenuated excitotoxic death and preserved cellular NAD (+) levels to support Q96EB6 and PARP 1 activities . Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress .",
"DB02701 deficiency in human lymphocytes prevents the [ 3H ] thymidine - induced adaptive response for the repair of X - ray - induced chromosomal damage . Human lymphocytes treated with [ 3H ] thymidine ( [ 3H ] dThd ) become refractory to the induction of chromosomal aberrations by subsequent doses of X rays . This adaptive response to [ 3H ] dThd does not occur in the presence of 3 - aminobenzamide ( 3AB ) . 3AB inhibits the synthesis of poly ( ADP - ribose ) by the enzyme adenosine diphosphate ribosyl transferase ( P09874 ) , which requires NAD as a substrate . 3AB also prevents chromosomal repair , as measured in X - ray dose - fractionation studies . Because 3AB might interfere with metabolic reactions other than those mediated by P09874 , experiments were carried out to see if the adaptive response was also inhibited in nicotinamide - free medium , which prevents poly ( ADP - ribosyl ) ation by depleting cellular NAD . The experiments show that the incorporation of [ 3H ] dThd has no effect on the induction of chromosomal aberrations by subsequent doses of X rays if the cells are cultured in nicotinamide - free medium . DB02701 deficiency mimics the effects of 3AB on both the adaptive response and chromosome repair . The results indicate that P09874 activity itself , and not other metabolic processes affected by inhibitors of this enzyme , plays an essential role in the adaptive response .",
"Endothelial sirtuin 1 deficiency perpetrates nephrosclerosis through downregulation of matrix metalloproteinase - 14 : relevance to fibrosis of vascular senescence . Sirtuin 1 ( Q96EB6 ) depletion in vascular endothelial cells mediates endothelial dysfunction and premature senescence in diverse cardiovascular and renal diseases . However , the molecular mechanisms underlying these pathologic effects remain unclear . Here , we examined the phenotype of a mouse model of vascular senescence created by genetically ablating exon 4 of Sirt1 in endothelial cells ( Sirt1 ( endo -/-) ) . Under basal conditions , Sirt1 ( endo -/-) mice showed impaired endothelium - dependent vasorelaxation and angiogenesis , and fibrosis occurred spontaneously at low levels at an early age . In contrast , induction of nephrotoxic stress ( acute and chronic folic acid - induced nephropathy ) in Sirt1 ( endo -/-) mice resulted in robust acute renal functional deterioration followed by an exaggerated fibrotic response compared with control animals . Additional studies identified matrix metalloproteinase - 14 ( P50281 ) as a target of Q96EB6 . In the kidneys of Sirt1 ( endo -/-) mice , impaired angiogenesis , reduced matrilytic activity , and retention of the profibrotic cleavage substrates tissue transglutaminase and endoglin accompanied P50281 suppression . Furthermore , restoration of P50281 expression in Q96EB6 - depeleted mice improved angiogenic and matrilytic functions of the endothelium , prevented renal dysfunction , and attenuated nephrosclerosis . Our findings establish a novel mechanistic molecular link between endothelial Q96EB6 depletion , downregulation of P50281 , and the development of nephrosclerosis .",
"Presence of functionally active protease - activated receptors 1 and 2 in myenteric glia . Protease - activated receptors ( PARs ) belong to the family of membrane receptors coupled to G - proteins ; their presence is reported in a wide variety of cells . The object of this study was to demonstrate the presence of P25116 and P55085 in myenteric glia of the guinea pig , and to elucidate the cellular mechanisms that are triggered upon receptor activation . Thrombin and P25116 agonist peptide ( P09874 ) activate P25116 with a maximum mean +/- SEM change in intracellular calcium concentration with respect to basal level ( Delta [ Ca2 +] i ) of 183 +/- 18 nm and 169 +/- 6 nm , respectively . Trypsin and P55085 agonist peptide ( Q9UGN5 ) activate P55085 with a maximum Delta [ Ca2 +] i of 364 +/- 28 nm and 239 +/- 19 nm , respectively . Inhibition of phospholipase C by U73312 ( 1 microm ) decreased the Delta [ Ca2 +] i due to P25116 activation from 167 +/- 10 nm to 87 +/- 6 nm . The P55085 - mediated Delta [ Ca2 +] i decreased from 193 +/- 10 nm to 124 +/- 8 nm when phospholipase C activity was inhibited . Blockade of sphingosine kinase with dimethylsphingosine ( 1 microm ) decreased the Delta [ Ca2 +] i due to P55085 activation from 149 +/- 19 nm to 67 +/- 1 nm , but did not influence the P25116 - mediated Delta [ Ca2 +] i . P25116 and P55085 were localized in myenteric glia by immunolabeling . Our results indicate that P25116 and P55085 are present in myenteric glia of the guinea pig , and their activation leads to increases in intracellular calcium via different signal transduction mechanisms that involve activation of phospholipase C and sphingosine kinase .",
"MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in P01308 - 1 pancreatic beta - cells . DB02701 has been reported to induce differentiation of precursor / stem cells toward a beta - cell phenotype , increase islet regeneration , and enhance insulin biosynthesis . Exposure of P01308 - 1 beta - cells to elevated glucose leads to reduced insulin gene transcription , and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 ( P52945 ) and mammalian homologue of avian MafA / l - Maf ( MafA ) . DB02701 and other low - potency poly ( ADP - ribose ) polymerase ( PARP ) inhibitors were thus tested for their ability to restore insulin promoter activity . The low - potency PARP inhibitors nicotinamide , 3 - aminobenzamide , or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose . In contrast , the potent P09874 inhibitors PJ34 or DB04335 - 1001 had no effect on promoter activity . Antioxidants , including DB06151 , lipoic acid , or quercetin , only minimally induced the insulin promoter . Site - directed mutations of the human insulin promoter mapped the low - potency PARP inhibitor response to the C1 element , which serves as a MafA binding site . P01308 - 1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels . Low - potency PARP inhibitors restored MafA mRNA and protein levels , but they had no affect on P52945 protein levels or binding activity . Increased MafA expression by low - potency PARP inhibitors was independent of increased MafA protein or mRNA stability . These data suggest that low - potency PARP inhibitors increase insulin biosynthesis , in part , through a mechanism involving increased MafA gene transcription .",
"P43490 regulates cell survival through autophagy in cardiomyocytes . DB02701 adenine dinucleotide ( NAD (+) ) acts as a transfer molecule for electrons , thereby acting as a key cofactor for energy production . NAD (+) also serves as a substrate for cellular enzymes , including poly ( ADPribose ) polymerase ( PARP ) - 1 and Sirt1 . Activation of P09874 by DNA damage depletes the cellular pool of NAD (+) , leading to necrotic cell death . NAD (+) in the nucleus enhances the activity of Sirt1 , thereby modulating transcription . NAD (+) is either synthesized de novo from amino acids , namely tryptophan and aspartic acid , or resynthesized from NAD (+) metabolites , such as nicotinamide ( NAM ) , through the salvage pathway . NAM phosphoribosyltransferase ( P43490 ) is a rate - limiting enzyme in the NAD (+) salvage pathway . We have recently demonstrated that P43490 is an important regulator of NAD (+) and autophagy in cardiomyocytes . Here we discuss the role of P43490 in regulating autophagy and potential mechanisms by which NAD (+) regulates autophagy in the heart .",
"Menstrual cycle - dependent febrile episode mediated by sequence - specific repression of poly ( ADP - ribose ) polymerase - 1 on the transcription of the human serotonin receptor 1A gene . The serotonin receptor 1A ( encoded by the P08908 gene ) plays a critical role in serotonergic transmission and was linked with many human diseases . A 33 - year - old woman with rare menstrual cycle - dependent fever showed abnormal estrogen profile and responded well to the P08908 agonist buspirone , suggesting that her fevers were allied to estrogen - related P08908 deficiency . We identified an adenine deletion 480 - bases upstream of the translation start site ( i . e . , - 480delA ) of P08908 in this patient . To determine the underlying mechanism of - 480delA - mediated P08908 deficiency , we first showed that P08908 - 480 region can be bound by multiple nuclear protein ( s ) . We then identified poly ( ADP - ribose ) polymerase ( P09874 ) as one of the proteins that binds to P08908 - 480 region . Using P09874 overexpression and knockdown , our data demonstrated that P09874 represses P08908 transcription . Furthermore , P08908 - 480delA promoter possesses increased interaction with P09874 and caused an additional reduction in transcription . Finally , 17β - estradiol administration further reduced transcription associated with the mutant promoter . Altogether , these data suggest that estrogen - induced hyperactivity of P08908 mutant promoter causes the reduction of P08908 mRNA and leads to the disruption of P08908 - mediate hypothermic regulation . This is the first report of P08908 mutation underlying menstrual cycle - dependent febrile episodes , and implies that similar \" febrile episode \" cases may also result from the dysfunction of serotonin transmission .",
"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK57___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .",
"Accumulation of poly ( ADP - ribose ) polymerase inhibitors in children with chronic renal failure . DB02701 , N - methyl - 2 - pyridone - 5 - carboxamide ( Met2PY ) and N - methyl - 4 - pyridone - 3 - carboxamide ( Met4PY ) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide ( NAD ) that can potentially inhibit poly ( ADP - ribose ) polymerase 1 ( P09874 ; DNA repair enzyme ) . Our research was aimed at establishing whether chronic renal failure ( CRF ) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit P09874 activity . DB02701 , Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children . The effect of these NAD metabolites on P09874 activity was studied in vitro . We found that plasma concentration of all NAD metabolites ( nicotinamide , Met2PY , Met4PY ) in children with CRF could reach the concentration of 2 , 30 and 10 microM as compared to 0 . 2 , 1 and 0 . 5 microM , respectively , in healthy children . The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF . We found that Met2PY , Met4PY and nicotinamide inhibited in vitro P09874 activity with IC50 values of 2 . 1 , 0 . 18 and 0 . 12 mM , respectively . Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of P09874 activity . NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults .",
"DB02701 uncouples hormone - dependent chromatin remodeling from transcription complex assembly . Sirtuins , homologs of the yeast SIR2 family , are protein deacetylases that require nicotinamide adenosine dinucleotide as cofactor . To determine whether the sirtuin family of deacetylases is involved in progesterone receptor ( PR ) - mediated transcription , the effect of sirtuin inhibitor , nicotinamide ( NAM ) , was monitored in T47D breast cancer cells . NAM suppressed hormone - dependent activation of PR - regulated genes in a dose - dependent manner . Surprisingly , NAM - mediated inhibition of PR - mediated transcription occurs independently of Q96EB6 and P09874 . Chromatin immunoprecipitation experiments did not show that PR binding nor that of the coactivators CBP and SRC3 was compromised . Consistent with the recruitment of the P51532 chromatin remodeling complex , promoter chromatin remodeling still occurs despite NAM inhibition of PR transactivation . Rather , we show that this inhibition of transcription is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter . These results show that NAM uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital NAM - regulated steps required for promoter chromatin remodeling and basal transcription complex communication .",
"Genome - wide methylation profiling of schizophrenia . Schizophrenia is one of the major psychiatric disorders . It is a disorder of complex inheritance , involving both heritable and environmental factors . DNA methylation is an inheritable epigenetic modification that stably alters gene expression . We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution . We have performed 26 high - resolution genome - wide methylation array analyses to determine the methylation status of 27 , 627 CpG islands and compared the data between patients and healthy controls . Methylation profiles of DNAs were analyzed in six pools : 220 schizophrenia patients ; 220 age - matched healthy controls ; 110 female schizophrenia patients ; 110 age - matched healthy females ; 110 male schizophrenia patients ; 110 age - matched healthy males . We also investigated the methylation status of 20 individual patient DNA samples ( eight females and 12 males . We found significant differences in the methylation profile between schizophrenia and control DNA pools . We found new candidate genes that principally participate in apoptosis , synaptic transmission and nervous system development ( P47869 , Q9HAP6 , P42574 ) . Methylation profiles differed between the genders . In females , the most important genes participate in apoptosis and synaptic transmission ( P98170 , O14764 , P01178 , P08729 ) , whereas in the males , the implicated genes in the molecular pathology of the disease were Q8IY37 , P36507 , Q9H6D8 and O14908 . Data from the individual methylation analyses confirmed , the gender - specific pools results . Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients . The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis .",
"___MASK51___ attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells . BACKGROUND & AIMS : Activation of hepatic stellate cells ( P19526 ) and transdifferentiation to myofibroblasts following liver injury is the main culprit for hepatic fibrosis . Myofibroblasts show increased proliferation , migration , contraction , and production of extracellular matrix ( Q13201 ) . In vitro , P04035 inhibitors ( statins ) inhibit proliferation and induce apoptosis of myofibroblastic P19526 . To investigate the antifibrotic effects of atorvastatin in vivo we used bile duct ligated rats ( BDL ) . METHODS : BDL rats were treated with atorvastatin ( 15 mg / kg / d ) immediately after ligation ( prophylactically ) or in on - going fibrosis ( therapeutically ) . Fibrosis was assessed by hydroxyproline content and Sirius - red staining . The activation of P19526 was investigated by analysis of alphaSMA expression . mRNA levels of cytokines and procollagen were analyzed by RT - PCR , and P08253 activity by zymography . Proliferation was assessed by expression of cathepsins ( B and D ) , proliferating cell nuclear antigen ( P12004 ) , and Ki67 - staining . Apoptosis was characterized by caspase - 3 activity , cleavage of P09874 , and TUNEL assay . Hepatic inflammation was investigated by serum parameters and liver histology . RESULTS : Prophylactic and early therapy with atorvastatin significantly attenuated fibrosis and P19526 activation . Later therapy lacked significant effects on fibrosis but reduced profibrotic cytokine expression and led to a more quiescent state of P19526 with less proliferation and apoptosis , while hepatic inflammation did not change . CONCLUSIONS : This study shows that very early atorvastatin treatment inhibits P19526 activation and fibrosis in the BDL model in vivo , while late treatment reduces P19526 turnover and activity . Our findings underline that long - term studies in humans are warranted .",
"Poly ( ADP - ribose ) metabolism in X - irradiated Chinese hamster cells : its relation to repair of potentially lethal damage . DB02701 - adenine dinucleotide ( NAD + ) is the substrate used by cells in poly ( ADP - ribose ) synthesis . X - irradiation of log - phase Chinese hamster cells caused a rapid decrease in NAD + levels which was linearly dependent on radiation dose . The activity of ADP - ribosyl transferase ( P09874 ) also increased linearly with radiation dose . The decrease of NAD + was slower , and the increase in P09874 activity was less pronounced , in a radiation sensitive line , V79 - AL162 / S - 10 . An inhibitor of P09874 , m - aminobenzamide , largely prevented the depletion of cellular NAD + and reduced the rate at which P09874 activity disappeared during post - irradiation incubation . Post - irradiation treatment with hypertonic buffer or with medium containing D2O -- which inhibit repair of radiation - induced potentially lethal damage -- enhanced the depletion of NAD + and prevented the reduction in P09874 activity following irradiation . The characteristics of the effects of treatment with hypertonic buffer on NAD + metabolism were qualitatively similar to the effects that such treatment has on radiation - induced cell killing . These results suggest that poly ( ADP - ribose ) synthesis after irradiation plays a role in the repair of potentially lethal damage .",
"DBC1 / Q8N163 and Q8IX12 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor . Deleted in breast cancer 1 ( DBC1 , Q8N163 , Q8N163 ) is a large , predominantly nuclear , multidomain protein that modulates gene expression by inhibiting several epigenetic modifiers , including the deacetylases Q96EB6 and O15379 , and the methyltransferase O43463 . DBC1 shares many highly conserved protein domains with its paralog cell cycle and apoptosis regulator 1 ( Q8IX12 , CARP - 1 ) . In this study , we examined the full - length sequential and structural properties of DBC1 and Q8IX12 from multiple species and correlated these properties with evolution . Our data shows that the conserved domains shared between DBC1 and Q8IX12 have similar domain structures , as well as similar patterns of predicted disorder in less - conserved intrinsically disordered regions . Our analysis indicates similarities between DBC1 , Q8IX12 , and the nematode protein lateral signaling target 3 ( G3V0H7 ) , suggesting that DBC1 and Q8IX12 may have evolved from G3V0H7 . Our data also suggests that DBC1 emerged later in evolution than Q8IX12 . DBC1 contains regions that show less conservation across species as compared to the same regions in Q8IX12 , suggesting a continuously evolving scenario for DBC1 . Overall , this study provides insight into the structure and evolution of DBC1 and Q8IX12 , which may impact future studies on the biological functions of these proteins .",
"Radiosensitizing effects of nicotinamide on a C3H mouse mammary adenocarcinoma . A study on per os drug administration . DB02701 is an inhibitor of adenosine diphosphate ribosyl transferase ( P09874 ) which is involved in the mechanism of DNA repair after high doses of ionizing radiation . C3H mice with transplanted mammary adenocarcinomas were treated with low doses of nicotinamide , 10 mg / kg , 5 days a week , and in combination with ionizing radiation , 30 Gy , using different drug dose schedules . Mice given nicotinamide in combination with irradiation took a longer time to reach a tumor volume of 1 , 000 mm3 and a higher complete response rate ( i . e . defined as total disappearance of the tumor for at least 7 days ) than those given radiation alone . This was true whether nicotinamide was given daily from one week before tumor transplantation until the animal was killed or from transplantation day until day of irradiation . In addition , nicotinamide given per os at a dose between the recommended maximum daily allowance for human subjects ( 20 mg / 70 kg ) , and the therapeutic allowance ( 1 g - 12 g daily ) 5 days a week for 9 weeks , showed a radiosensitizing effect without any histologically detectable damage to the normal tissues of the mouse , including bone marrow , intestine and the liver .",
"___MASK49___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK49___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK49___ is a promising pharmacological tool in the treatment of renal edema .",
"DB02701 pre - treatment ameliorates NAD ( H ) hyperoxidation and improves neuronal function after severe hypoxia . Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling ( between NAD (+) and DB00157 ) immediately after reoxygenation , resulting in DB00157 hyperoxidation . We test whether the addition of nicotinamide ( to enhance NAD (+) levels ) or P09874 inhibition ( to prevent consumption of NAD (+) ) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices . After severe , prolonged hypoxia ( maintained for 3min after spreading depression ) there was hyperoxidation of DB00157 following reoxygenation , an increased soluble NAD (+)/ DB00157 ratio , loss of neuronal field excitatory post - synaptic potential ( fEPSP ) and decreased DB00171 content . DB02701 incubation ( 5mM ) 2h prior to hypoxia significantly increased total NAD ( H ) content , improved neuronal recovery , enhanced DB00171 content , and prevented DB00157 hyperoxidation . The nicotinamide - induced increase in total soluble NAD ( H ) was more significant in the cytosolic compartment than within mitochondria . Prolonged incubation with PJ - 34 ( > 1h ) led to enhanced baseline DB00157 fluorescence prior to hypoxia , as well as improved neuronal recovery , DB00157 hyperoxidation and DB00171 content on recovery from severe hypoxia and reoxygenation . In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ - 34 prior to hypoxia improved recovery of neuronal function , enhanced DB00157 reduction and DB00171 content , but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation .",
"DB02701 treatment reduces the levels of histone H3K4 trimethylation in the promoter of the mper1 circadian clock gene and blocks the ability of dexamethasone to induce the acute response . Circadian rhythms , which measure time on a scale of 24h , are generated by one of the most ubiquitous endogenous mechanisms , the circadian clock . Q96EB6 , a class III histone deacetylase , and P09874 , a poly ( ADP - ribose ) polymerase , are two NAD (+)- dependent enzymes that have been shown to be involved in the regulation of the clock . Here we present evidence that the metabolite nicotinamide , an inhibitor of Q96EB6 , P09874 and mono ( ADP - ribosyl ) transferases , blocks the ability of dexamethasone to induce the acute response of the circadian clock gene , mper1 , while it concomitantly reduces the levels of histone H3 trimethylation of lysine 4 ( H3K4me3 ) in the mper1 promoter . Moreover , application of alternative inhibitors of Q96EB6 and ADP - ribosylation did not lead to similar results . Therefore , inhibition of these enzymes does not seem to be the mode by which NAM exerts these effects . These results suggest the presence of a novel mechanism , not previously documented , by which NAM can alter gene expression levels via changes in the histone H3K4 trimethylation state .",
"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .",
"DB02701 rescues human embryonic stem cell - derived neuroectoderm from parthanatic cell death . Abundant cell death is observed when human embryonic stem cells ( hESCs ) undergo neuralization , a critical first step for future cell - based therapies addressing neurodegeneration . Using hESC neuralization as an in vitro model of human development , we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death . We found that poly ( ADP - ribose ) polymerase - 1 ( P09874 ) / apoptosis - inducing factor ( O95831 ) - mediated cell death ( parthanatos ) is a dominant mechanism responsible for cell loss during hESC neuralization . The demise of neural progenitor cells , at least in part , is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions . Under such conditions , P09874 overactivation triggered cell death through the mitochondrial - nuclear translocation of O95831 . Blocking P09874 activity with small hairpin RNA interference or nicotinamide dramatically enhanced hESC neuralization , providing optimal survival of the developing neuroepithelium . Because nicotinamide is a physiological metabolite , our results raise the possibility that neural stem / progenitor cell survival in vivo requires a metabolic niche . We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine .",
"O60603 and poly ( ADP - ribose ) polymerase 1 promote central nervous system neuroinflammation in progressive EAE . Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing - remitting disease ( RRMS ) and is followed by a progressive phase ( SPMS ) . The progressive phase causes the greatest disability and has no effective therapy , but the processes that drive SPMS are mostly unknown . Here we found higher serum concentrations of 15alpha - hydroxicholestene ( 15 - HC ) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis ( EAE ) but not in patients with RRMS . In mice , 15 - HC activated microglia , macrophages and astrocytes through a pathway involving O60603 ( O60603 ) and poly ( ADP - ribose ) polymerase 1 ( P09874 ) . P09874 activity was higher in monocytes of patients with SPMS , and P09874 inhibition suppressed the progression of EAE . Thus , the O60603 - P09874 pathway is a potential new therapeutic target in SPMS .",
"DB02701 sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors enhance the effect of DNA alkylating agents on BRCA1 ‑ and P51587 - deficient cell lines . The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide ( NAM ) on breast cancer cells with different P38398 expression or function , such as BRCA1 ‑ deficient MDA - MB - 436 cells , low expression P38398 MCF - 7 cells , and the P38398 wild ‑ type MDA - MB - 231 cells , to demonstrate its effects as a chemo ‑ or radiosensitizing agent . PARP activity was analyzed in MDA - MB - 436 , MCF - 7 and MDA - MB - 231 breast cancer cells subjected or not to NAM . Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence . Crystal violet assays were used to test growth inhibition and the chemo ‑ and radiosensitization effects of NAM were investigated using clonogenic assays . Significant differences among data sets were determined using two - tailed Q9UNW9 and Bonferroni tests . We demonstrated that NAM reduces PARP activity in vitro , and in cells subjected or not to DNA damage , it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA - MB - 436 and MCF - 7 cells . Downregulation of P09874 with siRNA led to modest growth inhibition , which was further increased by cisplatin . DB02701 also induced radiosensitization in MDA - MB - 436 and MDA - MB - 231 cells . In conclusion , NAM may be used as a chemo ‑ or radiosensitizing agent regardless of the P38398 status in breast cancer .",
"DB00853 : mechanisms of action , repair and resistance . Glioblastoma multiforme is the most common aggressive adult primary tumour of the central nervous system . Treatment includes surgery , radiotherapy and adjuvant temozolomide ( DB00853 ) chemotherapy . DB00853 is an alkylating agent prodrug , delivering a methyl group to purine bases of DNA ( O6 - guanine ; N7 - guanine and N3 - adenine ) . The primary cytotoxic lesion , O6 - methylguanine ( O6 - MeG ) can be removed by methylguanine methyltransferase ( P16455 ; direct repair ) in tumours expressing this protein , or tolerated in mismatch repair - deficient ( P22897 - ) tumours . Thus P16455 or P22897 deficiency confers resistance to DB00853 . Inherent - and acquired resistance to DB00853 present major obstacles to successful treatment . Strategies devised to thwart resistance and enhance response to DB00853 , including inhibition of DNA repair mechanisms which contribute to DB00853 resistance , are under clinical evaluation . Depletion of P16455 prior to alkylating agent chemotherapy prevents O6 - MeG repair ; thus , P16455 pseudosubstrates O6 - benzylguanine and lomeguatrib are able to sensitise tumours to DB00853 . Disruption of base excision repair ( BER ) results in persistence of potentially lethal N7 - and N3 - purine lesions contributing significantly to DB00853 cytoxicity particularly when O6 - MeG adducts are repaired or tolerated . Several small molecule inhibitors of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , a critical BER protein are yielding promising results clinically , both in combination with DB00853 and as single agent chemotherapy in patients whose tumours possess homologous recombination DNA repair defects . Another validated , but as yet preclinical protein target , mandatory to BER is abasic ( AP ) endonuclease - 1 ( P27695 ) ; in preclinical tests , P27695 inhibition potentiates DB00853 activity . An alternative strategy is synthesis of a molecule , evoking an irrepairable cytotoxic O6 - G lesion . Preliminary efforts to achieve this goal are described .",
"Regulation of rat haptoglobin gene expression is coordinated by the nuclear matrix . Using computer stress - induced duplex destabilization ( SIDD ) analysis and binding experiments , we identified a S / MAR element ( - 599 /- 200 bp ) ( Hp - S / MAR ) adjacent to the cis - element ( - 165 /- 56 bp ) in the rat haptoglobin gene . We examined its functional interactions with the lamins and lamin - associated proteins in the basal state and during acute - phase ( AP ) response - induced increased transcription . Colocalization , electrophoretic mobility shift assay ( EMSA ) , and re - electrophoresis of nucleoprotein complexes , South - Western and Western blot analysis and coimmunoprecipitation experiments revealed that the lamins , P09874 , P17676 , and Hp - S / MAR assembled higher order complexes through direct lamin - Hp - S / MAR and probably P09874 - Hp - S / MAR interactions although P17676 did not bind to the Hp - S / MAR but established direct interaction with P09874 . The transition from constitutive to increased haptoglobin gene transcription during the AP response was associated with quantitative and qualitative changes in Hp - S / MAR - protein interactions , respectively , observed as increased association of the lamin ( s ) with the Hp - S / MAR and as the appearance of a 90 kDa Hp - S / MAR - binding protein . Also , during the AP response the contact between P17676 and P09874 established in the basal state was lost . DNA chromatography with the haptoglobin cis - element and Western blot analysis suggests that P09874 was a coactivator during constitutive and elevated transcription . The results show that the lamin components of the nuclear matrix form a network of functional , dynamic protein - protein and protein - Hp - S / MAR associations with multiple partners , and underline the involvement of P09874 in the regulation of haptoglobin gene transcription . We concluded that the interplay of these interactions fine tunes haptoglobin gene expression to meet the changing requirements of liver cells .",
"A nuclear poly ( ADP - ribose )- dependent signalosome confers DNA damage - induced O15111 activation . Upon genotoxic stresses , cells activate IkappaB kinases ( IKKs ) and the transcription factor NF - kappaB to modulate apoptotic responses . The P63165 ligase Q8N2W9 and the kinase ataxia talengiectasia mutated ( Q13315 ) have been implicated to SUMOylate and phosphorylate nuclear IKKgamma ( Q9Y6K9 ) in a consecutive mode of action , which in turn results in activation of cytoplasmic IKK holocomplexes . However , the nuclear signals and scaffold structures that initiate IKKgamma recruitment and activation are unknown . Here , we show that poly ( ADP - ribose )- polymerase - 1 ( P09874 ) is the DNA proximal regulator , which senses DNA strand breaks and , through poly ( ADP - ribose ) ( PAR ) synthesis , assembles IKKgamma , Q8N2W9 , and Q13315 in a dynamic manner . Signalosome formation involves direct protein - protein interactions and binding to ADP - ribose polymers through PAR binding motifs ( PARBM ) . Activated P09874 and a PARBM in Q8N2W9 are required to trigger IKKgamma SUMOylation , which in turn permits IKK and NF - kappaB activation , as well as NF - kappaB - regulated resistance to apoptosis .",
"Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .",
"Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects . Neural tube defects ( NTDs ) are a common cause of disability or death of new - borns , but the aetiology and genetic background of this disease are still poorly understood . Therefore , it was decided to determine the conditions for the identification of several polymorphisms and to perform a preliminary study on Polish NTD patients and their parents . According to the results of this study , the genetic predisposition to NTD can be correlated with the 677TT genotype in the P42898 gene , 677CT / 1298AC haplotype ( the P42898 gene ) , 2756G allele in the Q99707 gene , 66AG variant and minisatellite sequence with 5 or 10 repeats in intron 6 of the Q9UBK8 gene . The 530GG and TIVS7 - 2 / TIVS7 - 2 genotypes in the T gene could also be considered as a risk factor for NTD . The analysis also revealed no correlation between neurulation disturbances and A4956G and A1186G mutations in the P38398 gene and the 844ins68bp in P35520 gene . Although a correlation was found of some molecular markers with NTD , an additional examination should be conducted on more numerous groups to obtain statistically significant results .",
"Perinatal asphyxia : CNS development and deficits with delayed onset . Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted . The primary insult relates to the duration of the period lacking oxygenation , leading to death if not re - established . Re - oxygenation leads to a secondary insult , related to a cascade of biochemical events required for restoring proper function . Perinatal asphyxia interferes with neonatal development , resulting in long - term deficits associated to mental and neurological diseases with delayed clinical onset , by mechanisms not yet clarified . In the experimental scenario , the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy . Asphyxia induces transcriptional activation of pro - inflammatory factors , in tandem with P09874 overactivation , and pharmacologically induced P09874 inhibition also down - regulates the expression of proinflammatory cytokines . DB02701 has been proposed as a suitable P09874 inhibitor . Its effect has been studied in an experimental model of global hypoxia in rats . In that model , the insult is induced by immersing rat fetus into a water bath for various periods of time . Following asphyxia , the pups are delivered , treated , and nursed by surrogate dams , pending further experiments . DB02701 rapidly distributes into the brain following systemic administration , reaching steady state concentrations sufficient to inhibit P09874 activity for several hours , preventing several of the long - term consequences of perinatal asphyxia , supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles .",
"Inhibition of P09874 by olaparib ( AZD2281 ) increases the radiosensitivity of a lung tumor xenograft . P09874 is a critical enzyme in the repair of DNA strand breaks . Inhibition of P09874 increases the effectiveness of radiation in killing tumor cells . However , although the mechanism ( s ) are well understood for these radiosensitizing effects in vitro , the underlying mechanism ( s ) in vivo are less clear . DB02701 , a drug structurally related to the first generation P09874 inhibitor , 3 - aminobenzamide , reduces tumor hypoxia by preventing transient cessations in tumor blood flow , thus improving tumor oxygenation and sensitivity to radiotherapy . Here , we investigate whether olaparib , a potent P09874 inhibitor , enhances radiotherapy , not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non - small cell lung carcinoma ( NSCLC ) . In irradiated Calu - 6 and A549 cells , olaparib enhanced the cytotoxic effects of radiation ( sensitizer enhancement ratio at 10 % survival = 1 . 5 and 1 . 3 ) and DNA double - strand breaks persisted for at least 24 hours after treatment . Combination treatment of Calu - 6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression ( P = 0 . 007 ) relative to radiotherapy alone . To determine whether this radiosensitization was solely due to effects on DNA repair , we used a dorsal window chamber model to establish the drug / radiation effects on vessel dynamics . DB09074 alone , when given as single or multiple daily doses , or in combination with fractionated radiotherapy , increased the perfusion of tumor blood vessels . Furthermore , an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide . This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK63___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK63___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"Effects of hyperthermia and nicotinamide on DNA repair synthesis , ADP - ribosyl transferase activity , NAD + and DB00171 pools , and cytotoxicity in gamma - irradiated human mononuclear leukocytes . Effects of hyperthermia and nicotinamide on ADP - ribosyl transferase activity ( P09874 ) , unscheduled DNA synthesis ( UDS ) , NAD +- and DB00171 - pools and cytotoxicity were investigated in gamma - irradiated human mononuclear leukocytes . A significant decrease in radiation - induced UDS after heat treatment for 45 min was found . DB02701 increased the UDS levels in irradiated cells , but no effect of hyperthermia on these increased UDS values was observed . In the presence of 2 mM nicotinamide radiation - induced P09874 activity was reduced to about 50 per cent . However , hyperthermia for 45 min was found to have no effect on the enzyme activity for temperatures below 46 degrees C . DB02701 increased the NAD + pool in unirradiated cells . Damaging the cells with gamma - radiation leads to a severe depletion of the NAD + pool . The NAD + pool is restored , however , if the cells repair for 5 h at 37 degrees C . When radiation - damaged cells were treated with hyperthermia , exogenously supplied nicotinamide could not be converted to NAD + in sufficient amounts to prevent NAD + depletion . These data indicate that the radiosensitizing effect of heat and nicotinamide could both be explained by effects on the enzyme P09874 , i . e . nicotinamide by directly blocking the enzyme and hyperthermia by limiting the co - substrate ( NAD + ) .",
"[ Treatment of type 1 diabetes mellitus revealed below 7 years of age in the Diabetes Center of Silesia , Poland ] . INTRODUCTION : Frequency of type 1 diabetes mellitus diagnosis in young children increases . Within this group , such factors as limited cooperation , little acceptance of multiple injections and other typical patterns of behavior can strongly influence the insulin management outcome . AIM OF THE STUDY : The objective of the study was to provide information regarding metabolic control in young diabetes patients . MATERIAL AND METHODS : Charts of 58 children with T1DM , all subjects under control of our Department , that were aged at onset ( 1998 - 2003 ) below 7 years ( mean 4 . 05 +/- 1 . 6 ) were studied retrospectively . HbA1c , total , bolus and basal daily insulin requirement ( P30518 ) , weight , height , severe hypoglycaemia and diabetic ketoacidosis ( DKA ) were analyzed till April 2006 in 2 - year intervals . P01308 therapy model was also taken into consideration . RESULTS : Mean HbA1c was 7 . 2 +/- 1 . 2 % for all children for the whole studied period and did not alter significantly between analyzed intervals . Most common treatment model at diabetes onset was the therapy with premixed insulin ( Mix ) ( 67 % ) and after 4 and 6 years - continuous subcutaneous insulin infusion ( CSII ) ( 50 % and 75 % respectively ) . A tendency for a better metabolic control was observed at multiple daily injections and CSII than at Mix . Change of the weight or height percentile channel was not revealed . Bolus and basal P30518 increased in the first observation interval . Afterwards they stabilized respectively at 0 . 35 - 0 . 42 U / kg / 24 h and 0 . 35 - 0 . 39 U / kg / 24 h . Severe hypoglycaemia occurred 6 . 72 / 100 patient - years . CONCLUSION : P01308 therapy aimed at maintaining long - term good metabolic control is possible to achieve and is safe in young diabetic children .",
"P01308 resistance and angiotensin converting enzyme polymorphism in Japanese hypertensive subjects . P00797 - angiotensin system activity has been shown to affect insulin sensitivity . However , the relationship between I / D polymorphism and insulin resistance is controversial . Therefore , we examined the relationship between the P12821 genotype and insulin sensitivity in 51 Japanese hypertensive patients using the glucose clamp technique . The P12821 genotype distribution in the hypertensive subjects was : 7 subjects with DD , 20 subjects with ID , and 24 subjects with II . P01308 sensitivity in terms of the glucose disposal rate was not significantly different among the three P12821 genotypes , although there was a tendency for insulin sensitivity to decrease in the order of II , ID and DD , DD being the lowest . These findings are contrary to previous reports that insulin sensitivity was increased in normotensive subjects with the DD genotype who were Caucasian or African - American . There might be a difference due to race and whether the subjects are hypertensive or obese . We concluded that insulin sensitivity was not different among the P12821 genotypes in the Japanese hypertensive subjects , supporting a previous report on the Chinese population . To date , insulin sensitivity has not been found to differ with P12821 genotypes in the oriental population .",
"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .",
"Plasticity of the central nervous system ( CNS ) following perinatal asphyxia : does nicotinamide provide neuroprotection ? We have investigated the idea that nicotinamide , a non - selective inhibitor of the sentinel enzyme Poly ( ADP - ribose ) polymerase - I ( P09874 ) , provides neuroprotection against the long - term neurological changes induced by perinatal asphyxia . Perinatal asphyxia was induced in vivo by immersing foetuses - containing uterine horns removed from ready - to - deliver rats into a water bath for 20 min . Sibling caesarean - delivered pups were used as controls . The effect of perinatal asphyxia on neurocircuitry development was studied in vitro with organotypic cultures from substantia nigra , neostriatum and neocortex , platted on a coverslip 3 days after birth . After approximately one month in vitro ( DIV 25 ) , the cultures were treated for immunocytochemistry to characterise neuronal phenotype with markers against the N - methyl - D - aspartate receptor subunit 1 ( Q9UHB4 ) , the dopamine pacemaker enzyme tyrosine hydroxylase ( TH ) , and nitric oxide synthase ( NOS ) , the enzyme regulating the bioavailability of NO . DB02701 ( 0 . 8 mmol / kg , i . p . ) or saline was administered to asphyctic and caesarean - delivered pups 24 , 48 and 72 h after birth . It was found that nicotinamide treatment prevented the effect of perinatal asphyxia on several neuronal parameters , including TH - and NOS - positive neurite atrophy and NOS - positive neuronal loss ; supporting the idea that nicotinamide constitutes a therapeutic alternative for the effects produced by sustained energy - failure conditions , as occurring during perinatal asphyxia .",
"DB02701 : a potential addition to the anti - psoriatic weaponry . Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern . Increased expression of adhesion molecules , prominent neutrophil accumulation , and increased production of nitric oxide are characteristics of this disorder . Moreover , histamine and proteases are supposed to participate in the pathogenesis of psoriasis . DB02701 is an inhibitor of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) that , through enhancement of nuclear kappa B - mediated transcription , plays a pivotal role in the expression of inflammatory cytokines , chemokines , adhesion molecules , and inflammatory mediators . Through interaction with P28907 and inhibition of IL - 1 , IL - 12 , and P01375 production , nicotinamide produces a mild TH2 bias . DB02701 is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release . It inhibits nitric oxide synthase mRNA induction and suppresses antigen - induced lymphocyte transformation . DB02701 increases the biosynthesis of ceramides , which upon degradation produce sphingosine . DB03203 inhibits protein kinase C ( PKC ) and decreases basal cell proliferation dependent on PKC . Taken together , it can be reasoned that nicotinamide could be a useful addition to anti - psoriatic armamentarium . The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen - induced arthritis . DB02701 decreased the methotrexate - induced hepatotoxicity . The above combinations may prove to have a powerful anti - psoriatic effect as well . As PARP inhibitors could exert anti - retroviral effect , nicotinamide could also be of special value in the treatment of HIV - infected psoriatics .",
"Attenuation of bromobenzene - induced hepatotoxicity by poly ( ADP - ribose ) polymerase inhibitors . Inhibitors of the nuclear enzyme poly -( ADP - ribose ) polymerase ( PARP ) have been demonstrated to attenuate pathophysiological conditions associated with toxicant - induced oxidative stress . This investigation evaluates DB02701 ( NIC ) , a non - specific PARP inhibitor , and 6 ( 5 )- Phenanthridinone ( Phen ) , a specific P09874 inhibitor , for their efficacy in blocking or attenuating bromobenzene ( BB ) induced hepatocellular toxicity . Male ICR mice were treated with an intraperitoneal injection of bromobenzene , followed by concomitant treatment with NIC or with NIC at 0 . 5 , 1 and 2 hours after BB treatment , or with concomitant treatment of Phen at 10 mg / ml , 20 mg / ml , or 40 mg / ml solution concentration . Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3 . 5 - fold increase in serum alanine transferase ( ALT ) compared to controls . Mice treated with 3 injections of NIC ( at 0 . 5 , 1 and 2 hours ) after BB treatment demonstrated a 90 % reduction in serum ALT at 24 hours after BB treatment ( p < 0 . 05 ) . Mice with concomitant BB and Phen treatment demonstrated a 75 % reduction in ALT at 24 hours after treatment ( p < 0 . 05 ) . Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups . Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups . The P09874 inhibitors evaluated in this investigation produce clinically significant attenuation of BB - induced liver injury in male ICR mice .",
"Protective effect of nicotinamide against poly ( ADP - ribose ) polymerase - 1 - mediated astrocyte death depends on its transporter - mediated uptake . AIM : Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a DNA repair enzyme , and its excessive activation , following ischemia , trauma , etc . , depletes cellular nicotinamide adenine dinucleotide ( NAD (+) ) as a substrate and eventually leads to brain cell death . DB02701 , an NAD (+) precursor and a P09874 inhibitor , is known to prevent P09874 - triggered cell death , but there is no available information on the mechanisms involved in its transport . Here we clarified the transport characteristics of nicotinamide in primary cultured mouse astrocytes . MAIN METHODS : Uptake characteristics of [( 14 ) C ] nicotinamide were assessed by a conventional method with primary cultured mouse astrocytes . Cell viability and P09874 activity were determined with intracellular LDH activity and immunocytochemical detection of PAR accumulation , respectively . KEY FINDINGS : P09874 activation was induced by treatment of astrocytes with N - methyl - N '- nitro - N - nitrosoguanidine ( MNNG ) , an alkylating agent . MNNG - triggered astrocyte death and PAR accumulation were completely inhibited by treatment with nicotinamide as with DPQ ( 3 , 4 - dihydro - 5 -( 4 -( 1 - piperidinyl ) butoxy )- 1 ( 2H )- isoquinolinone ) , a second generation PARP inhibitor . The uptake of [( 14 ) C ] nicotinamide was time - , temperature - , concentration - and pH - dependent , and was inhibited and stimulated by co - and pre - treatment with N - methylnicotinamide , a representative substrate of an organic cation transport system , respectively . Co - treatment of astrocytes with nicotinamide and N - methylnicotinamide resulted in a decrease in PAR accumulation and absolute prevention of cell death . SIGNIFICANCE : These findings suggest that nicotinamide has a protective effect against P09874 - induced astrocyte death and that its transporter - mediated uptake , which is extracellular pH - sensitive and common to N - methylnicotinamide , is critical for prevention of P09874 - triggered cell death .",
"Establishment of an immortalized P09874 -/- murine endothelial cell line : a new tool to study P09874 mediated endothelial cell dysfunction . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays a critical role in endothelial cell dysfunction associated with various pathophysiological conditions . To elucidate P09874 pathways involved in endothelial cell dysfunction , it is essential to establish \" in vitro \" experimental models using isolated endothelial cells . So far , two approaches have been used : primary endothelial cells from P09874 -/- mice which have a limited life - span , being a major handicap if large quantities of cells are required ; and pharmacological inhibition of PARP in P09874 +/+ endothelial cell lines , which is not specific for P09874 and would have biological effects different that genetic inhibition . To overcome these limitations , we have established an immortalized P09874 -/- endothelial cell line ( HYKO6 ) by transfection of primary cells with a plasmid containing the SV40 genome and selected on the basis of morphological and phenotypical features . The HYKO6 cell line exhibited endothelial characteristics , such as constitutive expression of CD105 , CD31 , P13598 , P19320 , and P04275 and formation of capillary - like structures ( CLS ) on Matrigel surface . However , expression of P05362 antigen is lost in the HYKO6 cells . After P01375 treatment , HYKO6 cells exhibited increased expression of P16581 and P19320 . Likewise , NF - kappaB - dependent transcriptional activation was increased in the HYKO6 cell line in response to P01375 at a level similar to that found for primary P09874 -/- cells . This cell line should provide , for the first time , a valuable tool to study P09874 pathways in endothelial cell dysfunction .",
"P25116 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy . Genetic variations of the protease - activated receptor - 1 ( P25116 ) have been associated with platelet receptor density and linked to thrombin receptor - activating peptide ( TRAP ) - induced phenotypes of platelet aggregation and P16109 expression . We investigated whether the P25116 intervening sequence - 14 A > T dimorphism influences platelet procoagulant activity . We also determined whether the Q9H244 antagonist clopidogrel could offset any observed functional polymorphism of the P25116 receptor by inhibiting Q9H244 - mediated amplification of TRAP - induced responses . We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP - induced platelet aggregation and markers of procoagulant activity . Platelet responses were measured at baseline , 4 h post clopidogrel 300 mg , and 10 and 28 days following clopidogrel 75 mg daily . Each patient was genotyped for the P25116 intervening sequence - 14 A / T dimorphism . Increased platelet aggregation and procoagulant responses were observed with P25116 A allele homozygotes . DB00758 significantly inhibited these platelet responses regardless of P25116 genotype , but did not offset the hyper - reactivity associated with the A / A homozygotes . We conclude that a common sequence variation within the P25116 gene influences TRAP - induced platelet procoagulant activity as well as aggregation . Higher platelet reactivity associated with P25116 IVSn - 14 A allele homozygotes persists despite clopidogrel therapy . These individuals may be at higher risk of thromboembolic events and may require additional anti - platelet medication .",
"p53 - , Q96EB6 - , and P09874 - independent downregulation of p21WAF1 expression in nicotinamide - treated cells . DB02701 at mM concentration is a potent inhibitor of certain key molecules involved in cell survival , such as Q96EB6 and P09874 , and affects cell survival in various conditions in vivo and in vitro . However , the effect of an acute treatment of nicotinamide on gene expression has rarely been closely examined . In our study , the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53 - negative or Q96EB6 - knockdown cells indicating gene regulation not mediated by p53 or Q96EB6 . Meanwhile , in the nicotinamide - treated cells , Sp1 activity and protein level was substantially reduced due to increased proteasome - mediated degradation . Our results indicate that nicotinamide treatment attenuates p21WAF1 expression through Sp1 downregulation , and suggest a possible involvement of nicotinamide metabolism in cellular gene expression .",
"Changes in the response of the Q9HBH0 - 1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP - ribosyl transferase . The effect of inhibitors of nuclear ADP - ribosyl transferase ( P09874 ) on the cytotoxicity of melphalan ( DB01042 ) in the Q9HBH0 - 1 tumour in vivo was investigated . A large single dose of nicotinamide ( 1000 mg kg - 1 ) enhanced the tumour cell killing by DB01042 as measured by tumour cell survival . This enhancement was maximum when nicotinamide was administered within 1 h before injecting the DB01042 . When given at this time , the nicotinamide had a dose - modifying effect on all DB01042 doses tested , giving rise to a mean enhancement ratio ( ER ) of 2 . 2 . DB02701 did not appear to inhibit the recovery from DB01042 induced potentially lethal damage . DB01042 ( 6 mg kg - 1 ) produced a transient drop in mouse body temperature . This effect was both increased and prolonged by nicotinamide . In addition the inhibitor also delayed the clearance of DB01042 from the plasma of C3H mice , such that the half - life of the chemotherapeutic agent was extended from 41 min to 143 min . The effect of combining DB01042 with nicotinamide doses below 1000 mg kg - 1 was also investigated . The results showed that as the nicotinamide dose was decreased , the enhancement of the effects on body temperature , pharmacokinetics and white blood cell counts were reduced . However , a concomitant loss in the enhancement of tumour cell killing was also observed . Similar results were obtained using 3 - aminobenzamide , a more efficient inhibitor of P09874 .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK59___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Activation of the P47900 receptor induces apoptosis and inhibits proliferation of prostate cancer cells . G protein - coupled receptors , the largest cell surface receptor family , have emerged as critical players in cell death and survival . High gene expression level of the G ( q )- coupled P2Y ( 1 ) nucleotide receptor in PC - 3 prostate cancer cells was demonstrated using real - time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy . A selective P2Y ( 1 ) receptor agonist , the ADP analogue MRS2365 , concentration - dependently induced intracellular calcium mobilization ( EC ( 50 ) 5 . 28nM ) , which was diminished by P2Y ( 1 ) receptor - selective antagonist MRS2500 . P2Y ( 1 ) receptor activation by MRS2365 induced apoptosis in assays of P42574 , LDH release , and annexin - V staining . The pro - apoptotic effect of MRS2365 was blocked by MRS2500 , P2Y ( 1 ) siRNA , and an inhibitor of the Q96HU1 kinase pathway PD98059 . MRS2365 significantly inhibited the proliferation of PC - 3 cells , examined using a MTT assay . Thus , activation of the P2Y ( 1 ) receptor induced cell death and inhibited growth of human prostatic carcinoma PC - 3 cells . Activation of the P2Y ( 1 ) receptor should be a novel and promising therapeutic strategy for prostate cancer .",
"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK80___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .",
"Poly ( ADP - ribose ) polymerase - 1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22 - 28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD + ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 overactivation may ensue , depleting cells of NAD + and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 expression and that administration of a P09874 inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty - four percent of control pups developed high - grade NEC ( grades 3 - 4 ) , whereas only 7 % of pups receiving nicotinamide developed high - grade NEC . DB02701 treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 overactivation in NEC may drive mucosal cell death in this disease and that P09874 may be a novel therapeutic target in NEC .",
"Further studies on the hypothesis of P09874 inhibition as a strategy for lessening the long - term effects produced by perinatal asphyxia : effects of nicotinamide and theophylline on P09874 activity in brain and peripheral tissue : nicotinamide and theophylline on P09874 activity . DB09140 interruption leads to death when re - oxygenation is not promptly re - established . Re - oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis . The effects observed long after perinatal asphyxia ( PA ) have been explained by over - expression of sentinel proteins , such as poly ( ADP - ribose ) polymerase - 1 ( P09874 ) , competing for NAD (+) during re - oxygenation , leading to the idea that sentinel protein inhibition constitutes a therapeutic strategy . We studied the effects of nicotinamide and theophylline on P09874 activity assayed in brain and peripheral ( heart ) rat tissue 1 - 24 h after birth , as well as on changes in behaviour and monoamine neurotransmission in adult rats . PA was induced by immersing rat foetuses into a water bath for 0 or 21 min . After resuscitation , the pups were treated with nicotinamide ( 0 . 8 mmol / kg , i . p . ) , theophylline ( 0 . 14 mmol / kg , i . p . ) or saline ( 0 . 9 % NaCl ) and nurtured by surrogate dams , pending behavioural and microdialysis experiments , or euthanised after birth for assaying P09874 activity . To estimate the in vivo distribution of a single dose of nicotinamide or theophylline into brain and peripheral compartment , a series of animals were implanted with microdialysis probes , one into the brain and other subcutaneously , 1 h after birth , assaying the drugs with a HPLC - UV system . DB02701 , but not theophylline prevented the long - term effects induced by PA . Only nicotinamide produced a consistent decrease in P09874 activity in brain and heart , whether assayed in control or asphyxia - exposed pups . The present results support the idea that the long - term effects induced by PA imply P09874 over - activation .",
"Genetic polymorphisms associated with ___MASK1___ - induced neurotoxicity . BACKGROUND : Encephalopathy is a rare drug toxicity of fluorouracil therapy . Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes , thymidylate synthase and dihydropyrimidine dehydrogenase . METHODS : Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5 - fluorouracil - based chemotherapy presented with acute mental change and hyperammonemia . To evaluate the genetic background of the fluorouracil - associated hyperammonemic encephalopathy , analysis of the polymorphisms of the P04818 , Q12882 and P42898 genes was performed . RESULTS : The patients revealed to be P04818 suppressors showing homogenous deletion of 6 bp in the 3 '- UTR and 3RC / 3RC genotype in the promoter enhancer region ( TSER ) , respectively . CONCLUSION : Genetic polymorphisms of the P04818 gene would contribute to the 5 - fluorouracil - associated hyperammonemic encephalopathy . The prospective validation of the clinical implication of P04818 gene polymorphisms is warranted .",
"NAD + and nicotinamide : sex differences in cerebral ischemia . BACKGROUND : Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes . While caspase - dependent mechanisms predominate in the female brain , caspase - independent cell death induced by the activation of poly ( ADP - ribose ) polymerase ( PARP ) predominates in the male brain . P09874 gene deletion decreases infarction volume in the male brain , but paradoxically increases damage in P09874 knockout females . PURPOSE : This study examined stroke - induced changes in NAD + , a key energy molecule involved in P09874 activation in both sexes . METHODS : Mice were subjected to middle cerebral artery occlusion and NAD + levels were assessed . P42574 activity and nuclear translocation were assessed 6h after ischemia . In additional cohorts , DB02701 ( 500 mg / kg i . p . ) a precursor of NAD + or vehicle was administered and infarction volume was measured 24h after ischemia . RESULTS : Males have higher baseline NAD + levels than females . Significant stroke - induced NAD + depletion occurred in males and ovariectomized females but not in intact females . P09874 deletion prevented the stroke - induced loss in NAD + in males , but worsened NAD + loss in P09874 deficient females . Preventing NAD + loss with nicotinamide reduced infarct in wild - type males and P09874 knockout mice of both sexes , with no effect in WT females . P42574 activity was significantly increased in P09874 knockout females compared to males and wild - type females , this was reversed with nicotinamide . CONCLUSIONS : Sex differences exist in baseline and stroke - induced NAD + levels . DB02701 protected males and PARP knockout mice , but had minimal effects in the wild - type female brain . This may be secondary to differences in energy metabolism between the sexes .",
"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK68___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK80___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK25___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK57___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK1___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK1___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK1___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .",
"Cellular mechanisms of the hemostatic effects of desmopressin ( DB00035 ) . The synthetic analog of vasopressin desmopressin ( DB00035 ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . DB00035 induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of DB00035 on FVIII plasma levels remains to be elucidated . The hemostatic effect of DB00035 likely involves additional cellular effects that remain to be discovered .",
"Crosslinked electrospun P32926 nanofibrous membranes : elucidation of their physicochemical , physicomechanical and molecular disposition . The effects of modifying electrospun poly ( vinyl alcohol ) ( P32926 ) nanofibers through crosslinking using glutaraldehyde ( GA ) are explored in this paper . Various concentrations of P32926 solutions containing model drugs rifampicin ( Q9HBH0 ) and isoniazid ( DB00951 ) were electrospun and thereafter crosslinked using GA vapors . P32926 nanofibers demonstrated high drug entrapment efficiency of 98 . 77 % ± 1 . 384 % and 95 . 07 % ± 1 . 988 % for the DB00951 - and Q9HBH0 - loaded P32926 nanofibers , respectively . The surface morphology , molecular vibrational transitions , tensile attributes and in vitro drug release were characterized and supported by in silico molecular mechanics simulations . Results indicated that crosslinking caused a significant reduction in the rate of drug release where 81 . 11 % ± 2 . 35 % of DB00951 and 59 . 31 % ± 2 . 57 % of Q9HBH0 were released after 12 h . Tensile properties such as the ultimate strength and Young ' s modulus increased after crosslinking , caused by crosslinks forming between P32926 nanofibers as was revealed through scanning electron microscopy analysis . Fourier Transform infrared analysis was conducted to further support the mode of crosslinking . Additionally , image processing analysis was carried out to quantify the effect of formulation variables on the morphology of nanofibers . Furthermore , the effect of GA - induced crosslinking and addition of drugs on the performance of electrospun fibers was further elucidated and conceptualized using a molecular mechanics assisted model building and energy refinement approach via molecular mechanics energy relationships by exploring the spatial disposition of energy - minimized molecular structures of the polymer , crosslinker and the drugs .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK25___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK25___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis ."
] |
[
"___MASK1___",
"___MASK25___",
"___MASK49___",
"___MASK51___",
"___MASK57___",
"___MASK59___",
"___MASK63___",
"___MASK68___",
"___MASK80___"
] |
___MASK51___
|
MH_train_391
|
interacts_with DB04835?
|
[
"DB04835 , a P51681 coreceptor antagonist that blocks entry of human immunodeficiency virus type 1 . Inhibition of the human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor is an encouraging new approach to pharmacotherapy against HIV . The HIV - 1 strain makes use of either the P51681 or the P61073 coreceptor to gain access into host P01730 + cells . DB04835 , the first HIV - 1 P51681 coreceptor antagonist , blocks entry of HIV - 1 . This recently approved drug has demonstrated clinically significant decreases in plasma concentrations of HIV - 1 RNA and increases in P01730 + cell counts ; however , it is indicated only for use as salvage therapy . Drug resistance is a concern , as is selective pressure on viral coreceptor use , because viral coreceptor targets may switch as disease progresses . In addition , before maraviroc therapy can be started , costly assays are required to determine the host ' s viral coreceptor tropism . Emerging therapies targeting P61073 , the other HIV coreceptor , have shown promise in decreasing plasma concentrations of HIV - 1 RNA . Long - term studies with both targets are required to explore the critical issues of efficacy and immunologic safety , as the function of these coreceptors is linked to host chemokine pathways .",
"What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation ___MASK45___ ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .",
"DB04835 . DB04835 , first in a new pharmacological class of antiretroviral agents known as P51681 antagonists , has been approved by the U . S . Food and Drug Administration for the treatment of HIV - infected adult patients who are infected with only P51681 - tropic HIV - 1 virus and who have HIV - 1 strains resistant to multiple antiretroviral agents . DB04835 has demonstrated in vitro activity against a wide range of P51681 tropic clinical isolates , including those resistant to the four currently existing drug classes of antiretroviral agents . In the two pivotal phase III studies , MOTIVATE - 1 and - 2 , maraviroc , in combination with optimized background therapy ( OBT ) , demonstrated superior virologic and immunologic treatment outcomes than OBT alone in treatment - experienced patients infected with P51681 - tropic HIV - 1 . In these studies , maraviroc also demonstrated acceptable safety and tolerability profiles with adverse events and discontinuation rates in general comparable to those noted in the placebo arms .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK75___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK75___ .",
"A novel bivalent HIV - 1 entry inhibitor reveals fundamental differences in P51681 - μ - opioid receptor interactions between human astroglia and microglia . OBJECTIVE : We explored whether the opiate , morphine , affects the actions of maraviroc , as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist , naltrexone , on HIV - 1 entry in primary human glia . METHODS : HIV - 1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV - 1 transactivator protein Tat . The effect of maraviroc and the bivalent ligand with or without morphine on P51681 surface expression and cytokine release was also explored . RESULTS : DB04835 inhibits HIV - 1 entry into glial cells , whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry . We also demonstrate that the maraviroc - containing bivalent ligand better inhibits R5 - tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine . Importantly , the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine . Exposure to maraviroc decreased the release of pro - inflammatory cytokines and restricted HIV - 1 - dependent increases in P51681 expression in both astrocytes and microglia , whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia . The P51681 - μ - opioid receptor ( MOR ) stoichiometric ratio varied among the two cell types with P51681 expressed at much higher levels than MOR in microglia , which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia . CONCLUSION : A novel bivalent compound reveals fundamental differences in P51681 - MOR interactions and HIV - 1 infectivity among glia , and has unique therapeutic potential in opiate abuse - HIV interactive comorbidity .",
"In vitro phenotypic susceptibility of HIV - 2 clinical isolates to P51681 inhibitors . HIV - 2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors , to a fusion inhibitor , and to some of the protease inhibitors . DB04835 is the first drug of the new anti - P51681 drug class and is effective only on P51681 - tropic ( R5 ) HIV - 1 . No previous studies concerning HIV - 2 susceptibility to maraviroc have been reported yet . We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell ( PBMC ) model . We analyzed the maraviroc susceptibility of 13 R5 HIV - 2 , 2 X4R5 ( dual ) HIV - 2 , and 2 P61073 - tropic ( X4 ) HIV - 2 clinical isolates . We also tested , with the same protocol , 1 X4 HIV - 1 and 4 R5 HIV - 1 clinical isolates . For the R5 HIV - 2 clinical isolates , the 50 % effective concentration ( EC ( 50 ) ) for maraviroc was 0 . 80 nM ( interquartile range [ IQR ] , 0 . 48 to 1 . 39 nM ) , similar to that observed for the R5 HIV - 1 isolates . The median maximum percentage of inhibition in the R5 HIV - 2 isolates was 93 % ( IQR , 84 to 98 % ) , similar to that observed in the R5 HIV - 1 isolates . As expected , both X4 HIV - 1 and HIV - 2 were highly resistant to maraviroc . Our study showed for the first time that maraviroc is active in vitro against R5 HIV - 2 . The new tools we developed will allow identification of HIV - 2 - infected patients eligible for P51681 inhibitor use and management of virological failure when receiving a maraviroc - based regimen .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK20___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Granulocyte - macrophage colony stimulating factor up - regulates P32246 in human neutrophils . Neutrophils ( polymorphonuclear leukocytes ; PMN ) are phagocytic cells instrumental in the clearance of infectious pathogens . Human PMN are commonly thought to respond primarily to chemokines from the CXC family . However , recent findings suggest that under specific cytokine activation conditions , PMN can also respond to some CC chemokines . In this study , the effect of GM - P04141 , a well - characterized PMN priming and maturation factor , on CC - chemokine receptor ( CCR ) expression in PMN was investigated . Constitutive expression of P32246 and P51677 mRNA in PMN was detected by ribonuclease protection assay . Following incubation of PMN with GM - P04141 ( 0 . 01 - 10 ng / ml ; 6 h ) P32246 mRNA expression was rapidly ( approximately 1 h ) up - regulated . In contrast , no significant induction of P41597 , P51677 , CCR4 , or P51681 mRNA was observed . P32246 protein was also up - regulated by GM - P04141 stimulation . GM - P04141 - induced up - regulation of P32246 showed functional consequences because GM - P04141 - treated PMN , but not control cells , responded to the CC chemokines macrophage inflammatory protein - 1alpha , monocyte chemoattractant protein - 3 , and RANTES in assays of chemotactic migration and intracellular calcium mobilization . These results suggest that PMN activated by the proinflammatory cytokine GM - P04141 can change their receptor expression pattern and become responsive to CC chemokines .",
"Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV - 1 ) is the predominant mode of infection world - wide . To better understand sexual transmission of HIV - 1 in women we have analysed virus co - receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA - DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV - 1 infection . P61073 was expressed at marginally higher levels than P51681 on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV - 1 following sexual contact can not be explained solely on the expression of chemokine co - receptors by T lymphocyte subsets .",
"Structure and dynamics of the gp120 V3 loop that confers noncompetitive resistance in R5 HIV - 1 ( JR - FL ) to maraviroc . DB04835 , an ( HIV - 1 ) entry inhibitor , binds to P51681 and efficiently prevents R5 human immunodeficiency virus type 1 ( HIV - 1 ) from using P51681 as a coreceptor for entry into P01730 (+) cells . However , HIV - 1 can elude maraviroc by using the drug - bound form of P51681 as a coreceptor . This property is known as noncompetitive resistance . HIV - 1 ( V3 - M5 ) derived from HIV - 1 ( JR - FLan ) is a noncompetitive - resistant virus that contains five mutations ( I304V / F312W / T314A / E317D / I318V ) in the gp120 V3 loop alone . To obtain genetic and structural insights into maraviroc resistance in HIV - 1 , we performed here mutagenesis and computer - assisted structural study . A series of site - directed mutagenesis experiments demonstrated that combinations of V3 mutations are required for HIV - 1 ( JR - FLan ) to replicate in the presence of 1 µM maraviroc , and that a T199K mutation in the P06681 region increases viral fitness in combination with V3 mutations . Molecular dynamic ( MD ) simulations of the gp120 outer domain V3 loop with or without the five mutations showed that the V3 mutations induced ( i ) changes in V3 configuration on the gp120 outer domain , ( ii ) reduction of an anti - parallel β - sheet in the V3 stem region , ( iii ) reduction in fluctuations of the V3 tip and stem regions , and ( iv ) a shift of the fluctuation site at the V3 base region . These results suggest that the HIV - 1 gp120 V3 mutations that confer maraviroc resistance alter structure and dynamics of the V3 loop on the gp120 outer domain , and enable interactions between gp120 and the drug - bound form of P51681 .",
"Host factors mediating HIV - 1 replication . Human immunodeficiency virus type 1 ( HIV - 1 ) infection is the leading cause of death worldwide in adults attributable to infectious diseases . Although the majority of infections are in sub - Saharan Africa and Southeast Asia , HIV - 1 is also a major health concern in most countries throughout the globe . While current antiretroviral treatments are generally effective , particularly in combination therapy , limitations exist due to drug resistance occurring among the drug classes . Traditionally , HIV - 1 drugs have targeted viral proteins , which are mutable targets . As cellular genes mutate relatively infrequently , host proteins may prove to be more durable targets than viral proteins . HIV - 1 replication is dependent upon cellular proteins that perform essential roles during the viral life cycle . DB04835 is the first FDA - approved antiretroviral drug to target a cellular factor , HIV - 1 coreceptor P51681 , and serves to intercept viral - host protein - protein interactions mediating entry . Recent large - scale siRNA and shRNA screens have revealed over 1000 candidate host factors that potentially support HIV - 1 replication , and have implicated new pathways in the viral life cycle . These host proteins and cellular pathways may represent important targets for future therapeutic discoveries . This review discusses critical cellular factors that facilitate the successive steps in HIV - 1 replication .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"P51681 antibodies HGS004 and HGS101 preferentially inhibit drug - bound P51681 infection and restore drug sensitivity of DB04835 - resistant HIV - 1 in primary cells . R5 HIV - 1 strains resistant to the P51681 antagonist DB04835 ( MVC ) can use drug - bound P51681 . We demonstrate that MVC - resistant HIV - 1 exhibits delayed kinetics of coreceptor engagement and fusion during drug - bound versus free P51681 infection of cell lines . Antibodies directed against the second extracellular loop ( ECL2 ) of P51681 had greater antiviral activity against MVC - bound compared to MVC - free P51681 infection . However , in PBMCs , only ECL2 P51681 antibodies HGS004 and HGS101 , but not 2D7 , inhibited infection by MVC resistant HIV - 1 more potently with MVC - bound than with free P51681 . In addition , HGS004 and HGS101 , but not 2D7 , restored the antiviral activity of MVC against resistant virus in PBMCs . In flow cytometric studies , P51681 binding by the O14964 mAbs , but not by 2D7 , was increased when PBMCs were treated with MVC , suggesting MVC increases exposure of the relevant epitope . Thus , HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance .",
"Multipotent stem / progenitor cells in human biliary tree give rise to hepatocytes , cholangiocytes , and pancreatic islets . Multipotent stem / progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato - pancreatic common duct , cystic duct , and hilum . They express endodermal transcription factors ( e . g . , Sox9 , Q9H6I2 , Q9Y261 , PDX1 , HES1 , Q9Y4Z2 , Q92786 ) intranuclearly , stem / progenitor surface markers ( EpCAM , P13591 , CD133 , P61073 ) , and sometimes weakly adult liver , bile duct , and pancreatic genes ( albumin , cystic fibrosis transmembrane conductance regulator [ P13569 ] , and insulin ) . They clonogenically expand on plastic and in serum - free medium , tailored for endodermal progenitors , remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈ 36 hours and slowing to one every 2 - 3 days . Transfer into distinct culture conditions , each comprised of a specific mix of hormones and matrix components , yields either cords of hepatocytes ( express albumin , P08684 , and transferrin ) , branching ducts of cholangiocytes ( expressing anion exchanger - 2 - P04920 and P13569 ) , or regulatable C - peptide secreting neoislet - like clusters ( expressing glucagon , insulin ) and accompanied by changes in gene expression correlating with the adult fate . Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes , whereas if into fat pads of streptozocin - induced diabetic mice , results in functional islets secreting glucose - regulatable human C - peptide . CONCLUSION : The phenotypes and availability from all age donors suggest that these stem / progenitors have considerable potential for regenerative therapies of liver , bile duct , and pancreatic diseases including diabetes .",
"Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice . Guidelines state that the P51681 - inhibitor DB04835 should be prescribed to patients infected with R5 - tropic HIV - 1 only . Therefore , viral tropism needs to be assessed phenotypically or genotypically . Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4 - tropic variants . Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co - receptor usage in routine clinical practice . Samples from therapy - naive and therapy - experienced patients were collected for routine tropism testing at three European clinical centres . Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells . Q14624 - V3 was amplified in a triplicate nested RT - PCR procedure and sequenced . Co - receptor usage was predicted using the Geno2Pheno ( [ coreceptor ] ) algorithm and analysed with a false - positive rate ( P21462 ) of 5 . 75 % , 10 % , or an P21462 of 20 % and according to the current European guidelines on the clinical management of HIV - 1 tropism testing . A total of 266 sequences were obtained from 101 patient samples . Discordance in tropism prediction for the triplicates was observed in ten samples using an P21462 of 10 % . Triplicate testing resulted in a 16 . 7 % increase in X4 - predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for DB04835 treatment . In conclusion , triplicate genotypic tropism testing increases X4 tropism detection in individual cases , which may prove to be pivotal when P51681 - inhibitor therapy is applied .",
"Glioblastoma : synergy of growth promotion between P13501 and P25103 can be thwarted by blocking P13501 with miraviroc , an FDA approved anti - HIV drug and blocking P25103 with aprepitant , an FDA approved anti - nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti - HIV drug , maraviroc , inhibits human P51681 ' s ligand from binding , and hence blocks P51681 stimulation . The anti - nausea drug aprepitant blocks DB05875 signaling at P25103 . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 and P25103 , through intermediaries , phosphorylate and thereby activate P27361 / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 . Phosphorylated P51681 exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non - cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well - designed trial of the proposed combination in the treatment of glioblastoma .",
"Discordance rates between Trofile test and short - term virological response to maraviroc . Enhanced sensitivity Trofile ( ES - Trofile ) is the most frequently used technique to assay HIV tropism . A clinical approach to predict P51681 - antagonists efficacy , based on the virological response to a short - term maraviroc exposure ( DB04835 Clinical Test , Q8IVS2 ) , has been recently reported . We compared the results of ES - Trofile with Q8IVS2 in 47 HIV - infected patients , and a global discordance around 15 % was observed between the phenotypic method and the clinical approach . Discordance results were mainly found in patients with an ES - Trofile reported as dual / mixed . These provocative results might have important clinical implications and should be considered in order to accurately prescribe treatment with P51681 antagonists .",
"___MASK17___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK17___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Regulation of cell cycle proteins by chemokine receptors : A novel pathway in human immunodeficiency virus neuropathogenesis ? In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus ( HIV ) , the authors have been studying the effect of chemokines on the CDK / P06400 / Q01094 pathway -- which is involved in neuronal apoptosis and differentiation . First , they have asked whether P61073 , the specific receptor for the chemokine P48061 and X4 - using gp120s , can regulate P06400 and Q01094 activity in cultures of differentiated rat neurons . Although P51677 and P51681 are known to mediate infection of microglia by HIV - 1 , recent evidence indicate that P61073 also play important roles in HIV - induced neuronal injury , and dual - tropic isolates that use P61073 to infect macrophages have recently been reported . The authors have focused on two specific brain areas in which P61073 is physiologically relevant , i . e . , the cerebellum and the hippocampus . So far , the data indicate that changes in the nuclear and cytosolic levels of P06400 , which result in the functional loss of this protein , are associated with apoptosis in these neurons , and that SDF - 1alpha and gp120IIIB affect this pathway . A summary of the findings are presented .",
"___MASK95___ : kinetic and dynamic profile in the treatment of pain . ___MASK95___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK95___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK95___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK95___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced P22301 expression . Biomaterial scaffolds are central to many tissue engineering strategies as they create a space for tissue growth and provide a support for cell adhesion and migration . However , biomaterial implantation results in unavoidable injury resulting in an inflammatory response , which can impair integration with the host and tissue regeneration . Toward the goal of reducing inflammation , we investigated the hypothesis that a lentiviral gene therapy - based approach to localized and sustained P22301 expression at a scaffold could modulate the number , relative proportions , and cytokine production of infiltrating leukocyte populations . Flow cytometry was used to quantify infiltration of six leukocyte populations for 21 days following implantation of P00747 scaffolds into intraperitoneal fat . Leukocytes with innate immune functions ( i . e . , macrophages , dendritic cells , neutrophils ) were most prevalent at early time points , while T lymphocytes became prevalent by day 14 . Reporter gene delivery indicated that transgene expression persisted at the scaffold for up to 28 days and macrophages were the most common leukocyte transduced , while transduced dendritic cells expressed the greatest levels of transgene . P22301 delivery decreased leukocyte infiltration by 50 % relative to controls , increased macrophage P22301 expression , and decreased macrophage , dendritic cell , and P01730 T cell IFN - γ expression . Thus , P22301 gene delivery significantly decreased inflammation following scaffold implant into the intraperitoneal fat , in part by modulating cytokine expression of infiltrating leukocytes .",
"Two - year safety and virologic efficacy of maraviroc in treatment - experienced patients with P51681 - tropic HIV - 1 infection : 96 - week combined analysis of MOTIVATE 1 and 2 . BACKGROUND : DB04835 , the first approved P51681 antagonist , demonstrated 48 - week safety and virologic efficacy in P51681 - tropic HIV - infected , treatment - experienced patients ; however , critical longer - term safety and durability of responses are unknown . METHODS : Two - year follow - up of 2 prospective , randomized , blinded studies of maraviroc once daily or twice daily , or placebo in treatment - experienced patients with R5 - tropic HIV - 1 receiving an optimized background regimen . Unblinding occurred after the week - 48 visit of the last enrolled patient . Safety and virologic parameters were assessed through week 96 . RESULTS : One thousand forty - nine patients were randomized and received study drugs . HIV - 1 RNA was < 50 copies per milliliter at week 96 in 39 % and 41 % of patients receiving maraviroc every day or twice a day , respectively . Among patients with HIV - 1 RNA < 50 copies per milliliter at week 48 , 81 % and 87 % of patients receiving maraviroc every day or twice a day , respectively , maintained this response at week 96 . At week 96 , median P01730 + T - cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day , respectively . Exposure - adjusted rates of adverse events were similar with maraviroc or placebo . No new or unexpected events were observed after week 48 . CONCLUSIONS : DB04835 - containing antiretroviral regimens maintained durable responses in treatment - experienced patients with R5 HIV - 1 through 96 weeks of treatment with a safety profile similar to placebo .",
"Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis - infected mice is modulated by interferon - gamma . Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions . Here , we evaluated the expression of chemokines and chemokine receptors and their regulation by P01579 in the course of Paracoccidioides brasiliensis ( Pb ) infection in mice . We found an association between KC and MIP - 1alpha ( P10147 ) production and neutrophil infiltration in the lungs of Pb - infected mice during the early acute phase of infection . High levels of RANTES / P13501 , P13500 / P13500 , P02778 / P02778 , and Mig / Q07325 simultaneously with mononuclear cell infiltration in the lungs was found . In the absence of P01579 ( GKO mice ) we observed increased production of KC and MIP - 1alpha and chronic neutrophilia . Moreover , we found a change in the chemokine receptor profiles expressed by wild - type ( WT ) versus GKO animals . Increased expression of P49682 and P51681 , and low levels of P51677 and CCR4 were observed in the lungs of Pb - infected WT mice , whereas the opposite effect was observed in the lungs of GKO mice . Consistent with these results , infected cells from WT mice preferentially migrated in response to P02778 ( P49682 ligand ) , while those from GKO mice migrated in response to eotaxin / P51671 ( P51677 ligand ) . These results suggest that P01579 modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb - infected mice .",
"The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK45___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .",
"[ At what time and with which combinations should maraviroc be indicated in the new antiretroviral treatment scenario ? ] . DB04835 is a selective and slowly reversible antagonist of the P51681 co - receptor which has shown to have powerful antiviral activity , in vitro , against a wide range of HIV clinical isolates , including strains multi - resistant to 4 classes of pre - existing antiretroviral drugs . DB04835 is active against HIV populations that only use the P51681 coreceptor to enter the cell and has not demonstrated significant activity in the treatment of viral populations that use the P61073 co - receptor . The mechanism of action of maraviroc , non - competitive with other antiretroviral drugs , and the absence of crossed resistance with the rest of their families , has led to DB04835 being a drug available for use in rescue antiretroviral treatment . However , the excellent tolerance of maraviroc compared to the placebo in phase III clinical trials , its safety and its favourable pharmacological interactions profile with other drugs commonly used in HIV infected patients with comorbidity brings to light other scenarios in which DB04835 could be useful .",
"Reviews of anti - infective agents : maraviroc : the first of a new class of antiretroviral agents . DB04835 is the first US Food and Drug Administration - approved drug from a new class of antiretroviral agents that targets a host protein , the chemokine receptor P51681 , rather than a viral target . Binding of maraviroc to this cell - surface protein results in blocking human immunodeficiency virus type 1 ( HIV - 1 ) attachment to the coreceptor and prevents the virus from entering P01730 + cells . In this review , we include the details of the discoveries that led to the development of this drug . The drug ' s pharmacology , including pharmacokinetics and drug interactions , is discussed , as are the clinical efficacy studies that led to licensure . HIV - 1 mechanisms of resistance to maraviroc , assays to determine viral coreceptor use ( tropism ) , drug safety , and clinical use of maraviroc are discussed at length .",
"The use of intraallelic variability for testing neutrality and estimating population growth rate . To better understand the forces affecting individual alleles , we introduce a method for finding the joint distribution of the frequency of a neutral allele and the extent of variability at closely linked marker loci ( the intraallelic variability ) . We model three types of intraallelic variability : ( a ) the number of nonrecombinants at a linked biallelic marker locus , ( b ) the length of a conserved haplotype , and ( c ) the number of mutations at a linked marker locus . If the population growth rate is known , the joint distribution provides the basis for a test of neutrality by testing whether the observed level of intraallelic variability is consistent with the observed allele frequency . If the population growth rate is unknown but neutrality can be assumed , the joint distribution provides the likelihood of the growth rate and leads to a maximum - likelihood estimate . We apply the method to data from published data sets for four loci in humans . We conclude that the Delta32 allele at P51681 and a disease - associated allele at P40692 arose recently and have been subject to strong selection . Alleles at PAH appear to be neutral and we estimate the recent growth rate of the European population to be approximately 0 . 027 per generation with a support interval of ( 0 . 017 - 0 . 037 ) . Four of the relatively common alleles at P13569 also appear to be neutral but DeltaF508 appears to be significantly advantageous to heterozygous carriers .",
"Allosteric model of maraviroc binding to CC chemokine receptor 5 ( P51681 ) . DB04835 is a nonpeptidic small molecule human immunodeficiency virus type 1 ( HIV - 1 ) entry inhibitor that has just entered the therapeutic arsenal for the treatment of patients . We recently demonstrated that maraviroc binding to the HIV - 1 coreceptor , CC chemokine receptor 5 ( P51681 ) , prevents it from binding the chemokine P10147 and the viral envelope glycoprotein gp120 by an allosteric mechanism . However , incomplete knowledge of ligand - binding sites and the lack of P51681 crystal structures have hampered an in - depth molecular understanding of how the inhibitor works . Here , we addressed these issues by combining site - directed mutagenesis ( SDM ) with homology modeling and docking . Six crystal structures of G - protein - coupled receptors were compared for their suitability for P51681 modeling . All P51681 models had equally good geometry , but that built from the recently reported dimeric structure of the other HIV - 1 coreceptor P61073 bound to the peptide CVX15 ( Protein Data Bank code 3OE0 ) best agreed with the SDM data and discriminated P51681 from non - P51681 binders in a virtual screening approach . SDM and automated docking predicted that maraviroc inserts deeply in P51681 transmembrane cavity where it can occupy three different binding sites , whereas P10147 and gp120 lie on distinct yet overlapped regions of the P51681 extracellular loop 2 . Data suggesting that the transmembrane cavity remains accessible for maraviroc in P10147 - bound and gp120 - bound P51681 help explain our previous observation that the inhibitor enhances dissociation of preformed ligand - P51681 complexes . Finally , we identified residues in the predicted P51681 dimer interface that are mandatory for gp120 binding , suggesting that receptor dimerization might represent a target for new P51681 entry inhibitors .",
"Hepatic safety and tolerability in the maraviroc clinical development program . DB04835 is the first P51681 antagonist to be approved for the treatment of HIV - 1 infection . It is generally well tolerated , with a similar side - effect profile to placebo in controlled studies . Many agents used to treat HIV disease are associated with the potential for hepatotoxicity . The hepatic effects of maraviroc were analyzed across all Pfizer - sponsored maraviroc clinical trials , in which 2350 volunteers received maraviroc . Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1 / 2a studies of up to 28 - day duration , they demonstrated no dose relationship or association with hyperbilirubinemia . In the four phase 2b / 3 studies in antiretroviral - naive and antiretroviral - experienced patients , there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96 . The findings were similar in patients coinfected with hepatitis B and / or C virus , although the number of coinfected patients was small . No patient met the strict definition for Hy ' s Law . Two participants reported severe hepatotoxicity and although other potential causes were present , the contribution of maraviroc to these events could not be excluded . This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied .",
"[ Methods for determining viral tropism : genotype and phenotype tests ] . The recent approval of the first P51681 antagonist , DB04835 ( MVC , Celsentri ) , with specific antiviral activity against R5 - tropic virus variants has generated the need for studies to determine the viral tropism in all those patient candidates for starting treatment with this new drug . Although genotyping methods appear to be the most useful tool due to its speed and simplicity , in the case of viral tropism , phenotyping techniques are currently considered the most reliable . In the last few years , different phenotyping assays have been developed to determine the use of the co - receptor . However , the Trofile phenotype assay is currently the one most used for the determination of tropism , since it is the only one that has been clinically validated . Given that the presence of X4 - tropic variants in the viral population has been associated with virological failure to MVC , the main challenge of both genotyping and phenotyping tools is to optimise their sensitivity for detecting X4 - tropic variants present in a minority of the viral population . At the same time , the correlation between genotyping / phenotyping methods is being evaluated to determine whether genotyping tools can be useful to make therapeutic decisions .",
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK75___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK75___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK44___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Essential role for retinoic acid in the promotion of P01730 (+) T cell effector responses via retinoic acid receptor alpha . DB00162 and its metabolite , retinoic acid ( RA ) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells . Here we showed RA was also required to elicit proinflammatory P01730 (+) helper T cell responses to infection and mucosal vaccination . P10276 ( RARα ) was the critical mediator of these effects . Antagonism of RAR signaling and deficiency in RARα ( Rara (-/-) ) resulted in a cell - autonomous P01730 (+) T cell activation defect , which impaired intermediate signaling events , including calcium mobilization . Altogether , these findings reveal a fundamental role for the RA - RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses .",
"DB04835 . DB04835 is a specific , slowly reversible , noncompetitive , small - molecule antagonist of the P51681 chemokine receptor , which also serves as an HIV - 1 coreceptor . By acting as an antagonist at the P51681 coreceptor , maraviroc inhibits HIV - 1 from entering host cells . Clinical data for maraviroc are available from two large , well designed , ongoing phase IIb / III trials ( MOTIVATE - 1 and MOTIVATE - 2 ) conducted in patients infected with R5 - tropic HIV - 1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and / or were triple - class resistant . According to 24 - week interim results of the MOTIVATE - 1 and - 2 trials , a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg ( depending on optimised background therapy [ OBT ] ) twice daily plus OBT compared with placebo plus OBT . This significant difference was maintained at 48 weeks in MOTIVATE - 1 . In the MOTIVATE - 1 and - 2 trials , a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV - 1 RNA level < 400 and < 50 copies / mL compared with those receiving placebo plus OBT . In addition , the P01730 + cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT . The 48 - week results of MOTIVATE - 1 also report a significant difference in favour of maraviroc for all these endpoints . In general , maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment - experienced patients infected with R5 - tropic HIV - 1 .",
"Deep sequencing to infer HIV - 1 co - receptor usage : application to three clinical trials of maraviroc in treatment - experienced patients . BACKGROUND : The DB04835 versus Optimized Therapy in Viremic Antiretroviral Treatment - Experienced Patients ( MOTIVATE ) studies compared maraviroc versus placebo in treatment - experienced patients with P51681 - using ( R5 ) human immunodeficiency virus type 1 ( HIV - 1 ) , screened using the original Trofile assay . A subset with non - R5 HIV infection entered the A4001029 trial . We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials . METHODS : V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche / 454 GS - FLX to a depth of > 3000 sequences / sample . Samples were considered non - R5 if ≥ 2 % of their viral population scored greater than or equal to - 4 . 75 or ≤ 3 . 5 using the PSSM ( x4 / R5 ) or geno2pheno algorithms , respectively . RESULTS : Deep sequencing identified more than twice as many maraviroc recipients as having non - R5 HIV , compared with the original Trofile . With use of genotyping , we determined that 49 % of maraviroc recipients with R5 HIV at screening had a week 48 viral load < 50 copies / mL versus 26 % of recipients with non - R5 . Corresponding percentages were 46 % and 23 % with screening by Trofile . In cases in which screening assays differed , median week 8 log₁₀ copies / mL viral load decrease favored 454 . Other parameters predicted by genotyping included likelihood of changing to non - R5 tropism . CONCLUSIONS : This large study establishes deep V3 sequencing as a promising tool for identifying treatment - experienced individuals who could benefit from P51681 - antagonist - containing regimens .",
"[ Pharmacokinetics , interactions and mechanism of action of maraviroc ] . DB04835 ( MVC , Celsentri ) is an allosteric and reversible inhibitor of the P51681 chemokine coreceptor . MVC is the first marketed P51681 antagonist and the only oral entry inhibitor approved so far for the treatment of HIV infection . It has been approved for adults with previous antiretroviral exposure . MVC exclusively inhibits the replication of R5 - tropic HIV - 1 variants after binding to the transmembrane P51681 receptor cavity . MVC is rapidly absorbed following oral administration , and plasma T ( max ) is achieved within 0 . 5 - 4 hours after a 300 mg dose . Renal clearance is approximately 10 - 12 L / h . MVC is a substrate of the cytochrome P450 isoenzyme 3A4 ; therefore dose adjustments are required when co - administrated with other drugs that induce or inhibit P08684 . In addition , MVC dose adjustments are advised in patients with renal failure ( CLcr < 80 ml / min ) only if they receive P08684 inhibitors .",
"A microsimulation of the cost - effectiveness of maraviroc for antiretroviral treatment - experienced HIV - infected individuals . PURPOSE : DB04835 ( MVC ) is the first approved P51681 antagonist . The aim of this study was to explore the cost - effectiveness of MVC in treatment - experienced or treatment - resistant HIV - infected adults . METHODS : The validated HIV microsimulation model ARAMIS was used to predict clinical and economic outcomes of treating patients with optimized background therapy ( OBT ) alone , as compared to a strategy of testing for the patient ' s viral tropism and treating with OBT with or without ( +/- ) MVC in a cohort corresponding to the MOTIVATE screening cohort . RESULTS : Compared to treatment with OBT alone , a treatment strategy of OBT +/- MVC ( twice daily ) according to tropism test result was predicted to increase P01730 + cell count after 5 years ( from mean 249 to 360 cells / microL ) , undiscounted life expectancy ( 7 . 6 to 8 . 9 years ) , and quality - adjusted life years ( QALYs ; from 4 . 99 to 5 . 71 ) for an additional $ 40 , 500 , giving an incremental cost - effectiveness ratio of $ 56 , 400 per QALY gained . The result was relatively insensitive to alternative clinical and cost assumptions within reasonable ranges , but for individuals with HIV susceptible to only two or fewer components of OBT , the Q03060 decreased to $ 52 , 000 per QALY gained . CONCLUSION : MVC is cost - effective , especially among individuals with few remaining options for active antiretroviral therapy .",
"Development and application of a simple LC - MS method for the determination of plasma maraviroc concentrations . DB04835 is an orally available antagonist of the P51681 chemokine receptor , which acts as a human immunodeficiency virus type 1 ( HIV - 1 ) coreceptor . Binding of maraviroc to this receptor blocks HIV - 1 attachment to the coreceptor and prevents HIV - 1 from entering host cells . DB04835 does not require intracellular processing to exert this activity . Drug interaction studies have shown changes in maraviroc exposure when given with other anti - HIV medications , and thus quantification of maraviroc in human plasma is important to manage drug interactions and to evaluate the relationship between plasma concentrations and treatment response . We developed a conventional LC - MS method for determining plasma maraviroc concentrations , validated by estimating precision and accuracy for inter - and intraday analysis in the concentration range of 0 . 011 - 2 . 188 µg / ml . The calibration curve was linear within this range . The average accuracy ranged from 92 . 7 % to 99 . 7 % , while the relative standard deviations of both inter - and intraday assays were less than 7 . 1 % . Recovery of maraviroc exceeded 86 . 7 % . Our LC - MS method provides a conventional , accurate and precise way to determine the maraviroc concentration in human plasma . This method enables dose adjustment based on monitoring plasma maraviroc concentrations and permits management of drug interactions and toxicity .",
"DB04835 is able to inhibit dual - R5 viruses in a dual / mixed HIV - 1 - infected patient . OBJECTIVES : DB04835 is the first licensed chemokine co - receptor 5 ( P51681 ) co - receptor antagonist in clinical practice . It is currently being used in patients harbouring exclusively P51681 - tropic virus . The objective of the study was to investigate the impact of maraviroc on viruses with different co - receptor preferences in a patient with a dual / mixed ( D / M ) infection . METHODS : We present a case report of an HIV - 1 patient infected with a D / M virus population . Co - receptor tropism was determined by phenotypic and genotypic tests . Biological clones from pre - and post - maraviroc therapy were generated . Tropism of these infectious clones was investigated in U373 - MAGI cells expressing P01730 + P51681 + or P01730 + P61073 + . DB04835 susceptibility and viral replication were determined using donor peripheral blood mononuclear cells ( PBMCs ) . RESULTS : In - depth clonal genotypic analysis revealed the presence of both R5 - tropic variants and X4 - tropic viruses before the start of maraviroc . During maraviroc therapy all R5 - predicted viruses were suppressed . Phenotypic analyses revealed that all biological clones before maraviroc therapy could infect both P51681 - and P61073 - bearing U373 - MAGI cells , demonstrating dual tropism . The baseline biological clones preferentially infected the P51681 cell line and were fully susceptible to maraviroc in PBMCs ( dual - R5 ) . In contrast , during maraviroc therapy the dual - R5 - tropic viruses were replaced by more X4 - tropic viruses ( dual - X4 ) , which could not be inhibited by maraviroc . CONCLUSIONS : This case report demonstrates that dual - tropic viruses , capable of using both co - receptors in phenotypic assays , can be inhibited by maraviroc if they have a P51681 co - receptor preference in vivo .",
"Safety profile of maraviroc in patients coinfected with HIV - 1 and hepatitis B or C included in the maraviroc expanded access program . OBJECTIVE : To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV - 1 coinfected with hepatitis B virus ( HBV ) or hepatitis C virus ( HCV ) . METHODS : This was a multicenter , noncomparative , open - label , expanded access program ( EAP ) initiated in February 2007 . Patients with P51681 - tropic HIV - 1 and HIV - 1 RNA ≥ 1000 copies / mL on their current treatment received maraviroc 300 mg ( 150 mg with protease inhibitors ) twice daily with optimized background therapy ( OBT ) , which could include the newer agents raltegravir , etravirine , and darunavir . The adverse event ( AE ) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2 , where the OBT did not include these agents . RESULTS : A total of 1 , 032 patients were enrolled : 51 HIV / HBV coinfected ; 149 HIV / HCV coinfected , 9 HIV / HBV / HCV coinfected , and 823 HIV - 1 monoinfected . Most ( 76 % ) received at least 1 newer agent . Overall AE frequency was comparable across coinfection groups ( 63 % - 72 % ) . Hepatobiliary events were more common in HIV / HCV coinfection than in HIV monoinfection or HIV / HBV coinfection ( 10 . 0 , 4 . 8 , and 3 . 1 per 100 patient - years , respectively ) . Across all coinfection groups , there was a trend toward lower exposure - adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies . Grade 3 / 4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm . CONCLUSION : DB04835 plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV - 1 - infected patients coinfected with HBV or HCV .",
"Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .",
"Maternal - fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques . Single - dose nevirapine ( DB00238 ) is effective in reducing mother - to - child transmission ( MTCT ) of HIV ; however , the subsequent development of drug resistance is problematic . The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to DB00238 in a single - dose strategy . Four pregnant macaques received an oral dose of maraviroc 2 h before delivery , and both infant and maternal plasma maraviroc concentrations and P51681 receptor occupancy on P01730 (+) lymphocytes were measured over time . Maximum plasma maraviroc concentrations were found at delivery ( 2 - h - postintrapartum dose ) in both the mothers and infants , with median concentrations of 974 ng / ml ( range , 86 to 2 , 830 ng / ml ) and 22 ng / ml ( range , 4 to 99 ng / ml ) , respectively . DB04835 was detected in the plasma of mothers up to 48 h after dosing but only as long as 3 . 5 h in the infants . The median fetal - maternal area under the concentration - time curve ( AUC ) ratio was 0 . 009 ( range , 0 . 000 to 0 . 015 ) . DB04835 receptor occupancy data showed evidence of unprotected P51681 receptors on P01730 (+) cells in the mothers 24 to 48 h after dosing . Extremely low P51681 expression on P01730 (+) cells of newborn macaques prevented determination of receptor occupancy in the infants . In rhesus macaques , maraviroc was poorly transferred across the placenta and was quickly cleared from the infants ' blood . The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV .",
"HIV - 1 resistance to maraviroc conferred by a P01730 binding site mutation in the envelope glycoprotein gp120 . DB04835 ( MVC ) is a P51681 antagonist that inhibits HIV - 1 entry by binding to the coreceptor and inducing structural alterations in the extracellular loops . In this study , we isolated MVC - resistant variants from an HIV - 1 primary isolate that arose after 21 weeks of tissue culture passage in the presence of inhibitor . gp120 sequences from passage control and MVC - resistant cultures were cloned into NL4 - 3 via yeast - based recombination followed by sequencing and drug susceptibility testing . Using 140 clones , three mutations were linked to MVC resistance , but none appeared in the V3 loop as was the case with previous HIV - 1 strains resistant to P51681 antagonists . Rather , resistance was dependent upon a single mutation in the C4 region of gp120 . Chimeric clones bearing this N425K mutation replicated at high MVC concentrations and displayed significant shifts in 50 % inhibitory concentrations ( IC ( 50 ) s ) , characteristic of resistance to all other antiretroviral drugs but not typical of MVC resistance . Previous reports on MVC resistance describe an ability to use a drug - bound form of the receptor , leading to reduction in maximal drug inhibition . In contrast , our structural models on K425 gp120 suggest that this resistant mutation impacts P01730 interactions and highlights a novel pathway for MVC resistance .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK82___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"DB04835 versus efavirenz , both in combination with zidovudine - lamivudine , for the treatment of antiretroviral - naive subjects with P51681 - tropic HIV - 1 infection . BACKGROUND : The MERIT ( DB04835 versus Efavirenz in Treatment - Naive Patients ) study compared maraviroc and efavirenz , both with zidovudine - lamivudine , in antiretroviral - naive patients with R5 human immunodeficiency virus type 1 ( HIV - 1 ) infection . METHODS : Patients screened for R5 HIV - 1 were randomized to receive efavirenz ( 600 mg once daily ) or maraviroc ( 300 mg once or twice daily ) with zidovudine - lamivudine . Coprimary end points were proportions of patients with a viral load < 400 and < 50 copies / mL at week 48 ; the noninferiority of maraviroc was assessed . RESULTS : The once - daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria . In the primary 48 - week analysis ( n = 721 ) , maraviroc was noninferior for < 400 copies / mL ( 70 . 6 % for maraviroc vs 73 . 1 % for efavirenz ) but not for < 50 copies / mL ( 65 . 3 % vs 69 . 3 % ) at a threshold of - 10 % . More maraviroc patients discontinued for lack of efficacy ( 11 . 9 % vs 4 . 2 % ) , but fewer discontinued for adverse events ( 4 . 2 % vs 13 . 6 % ) . In a post hoc reanalysis excluding 107 patients ( 15 % ) with non - R5 screening virus by the current , more sensitive tropism assay , the lower bound of the 1 - sided 97 . 5 % confidence interval for the difference between treatment groups was above - 10 % for each end point . CONCLUSIONS : Twice - daily maraviroc was not noninferior to efavirenz at < 50 copies / mL in the primary analysis . However , 15 % of patients would have been ineligible for inclusion by a more sensitive screening assay . Their retrospective exclusion resulted in similar response rates in both arms Trial registration . ClinicalTrials . gov identifier : ( NCT00098293 ) .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK87___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc , an inhibitor of HIV - 1 entry via the P51681 co - receptor . An effective vaginal microbicide could reduce human immunodeficiency virus type 1 ( HIV - 1 ) transmission to women . Among microbicide candidates in clinical development is DB04835 ( MVC ) , a small - molecule drug that binds the P51681 co - receptor and impedes HIV - 1 entry into cells . Delivered systemically , MVC reduces viral load in HIV - 1 - infected individuals , but its ability to prevent transmission is untested . We have now evaluated MVC as a vaginal microbicide with use of a stringent model that involves challenge of rhesus macaques with a high - dose of a P51681 - using virus , SHIV - 162P3 . Gel - formulated , prescription - grade MVC provided dose - dependent protection , half - maximally at 0 . 5 mM ( 0 . 25 mg / mL ) . The duration of protection was transient ; the longer the delay between MVC application and virus challenge , the less protection ( half life of approximately 4 h ) . As expected , MVC neither protected against challenge with a P61073 - using virus , SHIV - KU1 , nor exacerbated postinfection viremia . These findings validate MVC development as a vaginal microbicide for women and should guide clinical programs .",
"Inhibition of thrombin activity by prothrombin activation fragment 1 . 2 . P00734 is the precursor of thrombin , the central enzyme in coagulation . P00734 is activated in vivo by the prothrombinase complex to form fragment 1 . 2 and thrombin . Fragment 1 . 2 has an amino - terminal gla domain and two kringle domains . The second kringle domain ( kringle 2 ) binds to the exosite II on thrombin . Nascent thrombin generated on platelet surface remains non - covalently bound to fragment 1 . 2 by kringle 2 - exosite II interaction . To determine whether this interaction can modulate coagulant activity of thrombin , we labeled thrombin at the active site with fluorescein - DB00120 - Pro - DB00125 chloromethylketone and monitored the fluorescence changes upon ligand binding . Anionic phospholipid - bound fragment 1 . 2 and fragment 2 bound to P21462 - thrombin and induced changes in the active site with half maximal effects at 7 . 2 microM and 8 . 8 microM , respectively . We also tested the effect of anionic phospholipid - bound fragment 1 . 2 ( 0 - 10 microM ) on thrombin clotting activity . Phospholipid - bound fragment 1 . 2 inhibited fibrinogen clotting in a concentration - dependent manner but had no significant effect on amidolytic activity towards S2238 , suggesting a competitive inhibition of the fibrinogen binding site . Furthermore , fragment 1 . 2 inhibited P21462 - thrombin binding to platelet . Consistent with these findings fragment 1 . 2 inhibited thrombin - induced aggregation of gel filtered platelets in a concentration - dependant manner . These results suggest that the membrane - bound prothrombin fragment 1 . 2 may play a role in hemostasis by down regulating the procoagulant activity of newly formed thrombin .",
"[ Clinical pharmacokinetic of maraviroc ] . DB04835 ( MVC , UK - 427 , 857 ) is the first member of a new class , the P51681 antagonists . By an original mechanism of action , maraviroc binds to the P51681 receptor in order to prevent HIV from binding and entering human cells . DB04835 ( Celsentri ) is an orally administered drug available as 150 and 300 mg film - coated tablets . The current approved daily dosage of maraviroc is 300 mg bid in combination with other antiretroviral medications . DB04835 plasma exposure is not dose proportional . After a rapid ( but moderate ) intestinal absorption , several inactive oxidized metabolites are produced via cytochrome P450 3A4 pathway . According to this liver metabolism , dosage adjustments are required when maraviroc is administered in combination with cytochrome P450 inhibitors or inducers . The potential for drug - drug interactions and the well - defined relationship between plasma concentrations and virological response suggest the usefulness of Therapeutic Drug Monitoring of maraviroc in HIV - infected patients .",
"[ Mechanisms of resistance and failure of treatment with maraviroc ] . DB04835 ( MVC ) is a new antagonist of the P51681 coreceptor and is the first antiviral compound available that has a cell factor essential for HIV entry as a target . The information available from clinical studies with MVC suggests that the main cause of therapeutic failure is , more than the tropism change , the rapid selection of pre - existing strains with an affinity for P61073 , not detected by the reference test . A recently developed tropism test with an improved sensitivity will help to detect the minority , but clinically significant , presence of strains that use P61073 . Evidence of resistance to MVC has been shown in vivo in some patients . The mechanism of this resistance appears to be related to changes in gp120 and mainly in the V3 region which enables the virus to recognise the P51681 - co - receptor bound to the MVC molecule . From a practical point of view , standardised tests are currently unavailable to assess susceptibility to MVC , although in dose - response phenotype tests a maximum percentage inhibition ( MPI ) < 95 % would be indicative of resistance to the compound . Similarly , although some mutations associated with resistance in V3 , and other zones of gp120 , have been described , this preliminary information suggests different resistance patterns and at the moment , we do not know the canonical mutations to be able to establish genotyping algorithms .",
"Multifaceted mechanisms of HIV inhibition and resistance to P51681 inhibitors PSC - RANTES and DB04835 . Small - molecule P51681 antagonists , such as maraviroc ( MVC ) , likely block HIV - 1 through an allosteric , noncompetitive inhibition mechanism , whereas inhibition by agonists such as PSC - RANTES is less defined and may involve receptor removal by cell surface downregulation , competitive inhibition by occluding the HIV - 1 envelope binding , and / or allosteric effects by altering P51681 conformation . We explored the inhibitory mechanisms of maraviroc and PSC - RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors . Intrinsic PSC - RANTES - resistant virus ( YA versus RT ) or those selected in PSC - RANTES treated macaques ( M584 versus P09131 - 4 ) only displayed resistance in multiple - cycle assays or with a P51681 mutant that can not be downregulated . In single - cycle assays , these HIV - 1 clones displayed equal sensitivity to PSC - RANTES inhibition , suggesting effective receptor downregulation . Prolonged PSC - RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration ( substrate ) could saturate the receptors and overcome PSC - RANTES inhibition . In contrast , resistance to MVC was observed with the MVC - resistant HIV - 1 ( R3 versus S2 ) in both multiple - and single - cycle assays and with altered virus concentrations , which is indicative of allosteric inhibition . MVC could also mediate inhibition and possibly resistance through competitive mechanisms .",
"P10275 negatively influences the expression of chemokine receptors ( P61073 , P32246 ) and ligand - mediated migration in prostate cancer DU - 145 . We previously reported that androgen receptor ( AR ) plays a role in the regulation of adhesion to the extracellular matrix and invasion of human prostate cancer cells by influencing the expression of specific integrin subunits . It is now considered that chemokines play a significant role in organ - selective cancer metastasis . In this study , we hypothesized that AR may influence the expression of these chemokine receptors and cell function . The mRNA expression of chemokine receptors in human prostate cancer cell line DU - 145 and DU - 145 cells expressing AR ( DU - 145 / AR ) was investigated by RT - PCR . DU - 145 cells selectively expressed P61073 and P32246 mRNA at high levels compared with DU - 145 / AR cells . DU - 145 showed vigorous migratory responses to its ligand P48061 ( also called stromal - derived factor - 1alpha , SDF - 1alpha ) and P10147 ( also called macrophage inflammatory protein - 1 , MIP - 1alpha ) . In contrast , neither P48061 nor P10147 affected the migration of DU - 145 / AR cells . These results indicate that expression of AR down - regulates the migratory responses of human prostate cancer cells via chemokine and its receptor systems .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK57___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .",
"[ Secondary effects of treatment with maraviroc and other P51681 antagonists . Potential impact of the P51681 blocker ] . DB04835 is the first inhibitor of P51681 co - receptors to be marketed as an antiretroviral . The pre - clinical studies and phase III trials have shown that it has a very favourable safety profile . No characteristic adverse effect of maraviroc has been identified . Unlike with aplaviroc , where its clinical development was stopped due to serious hepatoxicity , no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co - infected by hepatotropic virus . Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients treated with maraviroc . In a study on naive patients , maraviroc produced nonsignificant changes in total cholesterol , LDL , HDL and triglycerides . Although P51681 co - receptors play a role in the immune response of the body , it has not been shown whether individuals homozygote for its deletion ( delta - 32 mutation ) have an increased risk of serious infections , with the possible exception of encephalitis due to the West Nile virus . However , long - term follow up is required on patients treated with to be able to rule out any increased susceptibility to infections or neoplasms .",
"Investigating hypothetical products from noncoding frames ( HyPNoFs ) . Hypothetical Products from Noncoding Frames ( i . e . , HyPNoFs ) are hypothetical , not - coded proteins , translated from alternate reading frames ( i . e . , coding + 1 and coding + 2 ) of cDNAs . HyPNoFs of P01730 , PKC , oncostatin , bcl - 2 proto - oncogene , tumor suppressor p53 , cystic fibrosis transmembrane regulator ( P13569 ) , and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS - Q99884 data bank . Homology searchers carried out revealed that hypothetical products ( i . e . , HyPNoFs ) may share high similarity with real protein products actually coded . Sequence similarity of hypothetical products to real proteins is sometimes very high , suggesting common conformational features , according to the Sander and Schneider cutoff value . This finding supports the hypothesis that eukaryotic DNA , currently considered to be monocistronic , might occasionally have polycistronic regions , carrying different protein messages on overlapping frames . As yet , polycistronic genes have been observed in viral genomes only . The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy , rather than a present feature of the genome in eukaryotes . These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes ' evolution and to investigate structure - function relationships of protein and DNA sequences ."
] |
[
"___MASK17___",
"___MASK20___",
"___MASK44___",
"___MASK45___",
"___MASK57___",
"___MASK75___",
"___MASK82___",
"___MASK87___",
"___MASK95___"
] |
___MASK57___
|
MH_train_392
|
interacts_with DB06695?
|
[
"Pharmacogenetics and future strategies in treating hyperglycaemia in diabetes . This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes : metformin , sulphonylureas and thiazolidinediones . Currently , metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in O75051 transporters might affect metformin response . An aetiological approach has identified monogenic patients with diabetes due to TCF1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas , and Q14654 or Q09428 mutations in which sulphonylureas can be used in place of insulin treatment . In Type 2 diabetes sulphonylurea response has been shown to be associated with variants Q9NQB0 associated with type 2 diabetes risk . For thiazolidinediones , focus has been on PPARgamma variants although with no consistent result . Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies . Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required . Establishing such cohorts is a priority in diabetes pharmacogenetics research .",
"An antibody from a patient with ranitidine - induced thrombocytopenia recognizes a site on glycoprotein IX that is a favored target for drug - induced antibodies . Although thrombocytopenia associated with the use of histamine H2 receptor ( P25021 ) antagonists has been described , a drug - dependent , platelet - reactive antibody has not previously been identified in such cases . We studied serum from a patient who developed acute , severe thrombocytopenia after exposure to the H2 receptor antagonist , ranitidine , and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations . In flow cytometric and immunoprecipitation studies , the antibody was shown to be specific for the glycoprotein Ib / IX complex ( GPIb / IX ) . From the pattern of monoclonal antibody ( MoAb ) inhibition and the reactions of antibody with Chinese hamster ovary ( CHO ) cells transfected with P14770 and GPIbbeta , we found that the patient ' s antibody is specific for an epitope on P14770 close to , or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine , drugs structurally unrelated to ranitidine . These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on P14770 may be a common target for drug - induced antibodies . Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism ( s ) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity .",
"The role of genetics in the risk of thromboembolism : prothrombin 20210A and oral contraceptive therapy . PURPOSE : To provide an overview of the prothrombin 20210A mutation , its effects on the incidence of venous thromboembolism ( VTE ) in users of oral contraceptive therapy ( O75051 ) , and screening recommendations for the primary care practice setting . DATA SOURCES : Several databases , including MEDLINE , EMBASE , BIOSIS , Cochrane Library , and SciSearch , were searched for articles published between 1996 and 2003 . An integrative review of studies addressing prothrombin 20210A was done using available case - series and case - control studies . No randomized controlled trials on prothrombin 20210A were available in the literature from the years searched . CONCLUSIONS : P00734 20210A increases the risk of developing a VTE for those who carry the genetic mutation . The presence of either concomitant circumstantial factors ( e . g . , surgery or immobilization ) or a combination of genetic factors ( e . g . , factor V Leiden and prothrombin 20210A ) raises the frequency of VTEs to an even greater extent . The risk increases exponentially in users of O75051 . Screening guidelines for the use of O75051 in prothrombin 20210A carriers remain unclear due to the paucity of empirical evidence related to the topic . IMPLICATIONS Q9NZC7 PRACTICE : Practitioners caring for a prothrombin 20210A carrier should maintain a high degree of suspicion with even vague signs or symptoms of a possible VTE . Practitioners should consider completing a full diagnostic workup for VTE on that patient , particularly if that patient is taking O75051 . Until evidence becomes available as to the best anticoagulation practice after an initial or recurrent VTE in a prothrombin 20210A carrier , standard treatment guidelines for anticoagulation should be followed .",
"NSA9 , a human prothrombin kringle - 2 - derived peptide , acts as an inhibitor of kringle - 2 - induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer ' s and Parkinson ' s , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle - 2 increase levels of NO and the mRNA expression of P35228 , IL - 1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle - 2 derived peptide NSA9 inhibits NO release and the production of pro - inflammatory cytokines such as IL - 1beta , P01375 , and P05231 in LPS - activated EOC2 microglia . In this study , we investigated the anti - inflammatory effects of NSA9 in human prothrombin - and kringle - 2 - stimulated EOC2 microglia . Treatment with 20 - 100 muM of NSA9 attenuated both prothrombin - and kringle - 2 - induced microglial activation . NO production induced by MAPKs and NF - kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF - kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle - 2 .",
"Interpretation of point - of - care INR results in patients treated with dabigatran . BACKGROUND : Point - of - care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . DB06695 , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point - of - care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature + point - of - care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2 - to 4 - fold with the point - of - care device compared with laboratory measures across the plasma dabigatran concentration range 50 - 1400 ng / mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60 - 275 ng / mL ) , whole blood point - of - care INR values increased from 1 . 7 to 4 . 0 , versus 1 . 1 to 1 . 5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr . point - of - care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran .",
"Effect of zymogen domains and active site occupation on activation of prothrombin by P04275 - binding protein . P00734 is conformationally activated by P04275 - binding protein ( vWbp ) from Staphylococcus aureus through insertion of the NH ( 2 )- terminal residues of vWbp into the prothrombin catalytic domain . The rate of prothrombin activation by vWbp ( 1 - 263 ) is controlled by a hysteretic kinetic mechanism initiated by substrate binding . The present study evaluates activation of prothrombin by full - length vWbp ( 1 - 474 ) through activity progress curve analysis . Additional interactions from the COOH - terminal half of vWbp ( 1 - 474 ) strengthened the initial binding of vWbp to prothrombin , resulting in higher activity and an ∼ 100 - fold enhancement in affinity . The affinities of vWbp ( 1 - 263 ) or vWbp ( 1 - 474 ) were compared by equilibrium binding to the prothrombin derivatives prethrombin 1 , prethrombin 2 , thrombin , meizothrombin , and meizothrombin ( des - fragment 1 ) and their corresponding active site - blocked analogs . Loss of fragment 1 in prethrombin 1 enhanced affinity for both vWbp ( 1 - 263 ) and vWbp ( 1 - 474 ) , with a 30 - 45 % increase in Gibbs free energy , implicating a regulatory role for fragment 1 in the activation mechanism . Active site labeling of all prothrombin derivatives with D - DB00120 - Pro - DB00125 - chloromethyl ketone , analogous to irreversible binding of a substrate , decreased their K ( D ) values for vWbp into the subnanomolar range , reflecting the dependence of the activating conformational change on substrate binding . The results suggest a role for prothrombin domains in the pathophysiological activation of prothrombin by vWbp , and may reveal a function for autocatalysis of the vWbp · prothrombin complexes during initiation of blood coagulation .",
"Bernard - Soulier syndrome ( hemorrhagiparous thrombocytic dystrophy ) . Bernard - Soulier syndrome ( BSS ) , also known as Hemorrhagiparous thrombocytic dystrophy , is a hereditary bleeding disorder affecting the megakaryocyte / platelet lineage and characterized by bleeding tendency , giant blood platelets and low platelet counts . This syndrome is extremely rare as only approximately 100 cases have been reported in the literature . Clinical manifestations usually include purpura , epistaxis , menorrhagia , gingival and gastrointestinal bleeding . The syndrome is transmitted as an autosomal recessive trait . The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb - V - IX complex , a platelet - restricted multisubunit receptor required for normal primary hemostasis . The GPIb - V - IX complex binds P04275 , allowing platelet adhesion and platelet plug formation at sites of vascular injury . Genes coding for the four subunits of the receptor , GPIBA , GPIBB , P40197 and P14770 , map to chromosomes 17p12 , 22q11 . 2 , 3q29 , and 3q21 , respectively . Defects have been identified in GPIBA , GPIBB , and P14770 but not in P40197 . Diagnosis is based on a prolonged skin bleeding time , the presence of a small number of very large platelets ( macrothrombocytopenia ) , defective ristocetin - induced platelet agglutination and low or absent expression of the GPIb - V - IX complex . P00734 consumption is markedly reduced . The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses , trauma and surgical procedures . Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion .",
"Evidence of an Epigenetic Modification in Cell - cycle Arrest Caused by the Use of Ultra - highly - diluted Gonolobus Condurango Extract . OBJECTIVES : Whether the ultra - highly - diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation / deacetylation of histones has not been explored . Therefore , in this study , we pointedly checked if the homeopathically - diluted anti - cancer remedy Condurango 30C ( ethanolic extract of Gonolobus condurango diluted 10 (- 60 ) times ) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis - a - vis the succussed alcohol ( placebo ) control . METHODS : We checked the activity of different signal proteins ( like P38936 ( WAF ) , p53 , Akt , P40763 ) related to deacetylation , cell growth and differentiation by western blotting and analyzed cell - cycle arrest , if any , by fluorescence activated cell sorting . After viability assays had been performed with Condurango 30C and with a placebo , the activities of histone de - acetylase ( HDAC ) enzymes 1 and 2 were measured colorimetrically . RESULTS : While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced Q92769 activity quite strikingly , it apparently did not alter the Q13547 enzyme ; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity . Data on P38936 ( WAF ) , p53 , Akt , and P40763 activities and a cell - cycle analysis revealed a reduction in DNA synthesis and P55008 - phase cell - cycle arrest when Condurango 30C was used at a 2 % dose . CONCLUSION : Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells , which the placebo was unable to do .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK84___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK84___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK6___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Inhibition of prothrombin kringle - 2 - induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo . P00734 kringle - 2 ( pKr - 2 ) , a domain of prothrombin , can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation . However , the chemical products that inhibit pKr - 2 - induced inflammatory activities in the brain are still not well known . The present study investigated whether minocycline , a semisynthetic tetracycline derivative , could inhibit pKr - 2 - induced microglial activation and prevent the loss of nigral dopaminergic ( DA ) neurons in vivo . To address this question , rats were administered a unilateral injection of pKr - 2 in the substantia nigra in the presence or absence of minocycline . Our results show that pKr - 2 induces the production of proinflammatory cytokines , such as tumor necrosis factor - α ( P01375 - α ) and interleukin - 1β ( IL - 1β ) , and inducible nitric oxide synthase from the activated microglia . In parallel , 7 days after pKr - 2 injection , tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons . This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor - α , interleukin - 1β , and nitric oxide synthase . These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr - 2 - induced microglial activation .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK50___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK50___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK50___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK50___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK50___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK31___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .",
"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .",
"Cellular mechanisms of the hemostatic effects of desmopressin ( ___MASK49___ ) . The synthetic analog of vasopressin desmopressin ( ___MASK49___ ) is widely used for the treatment of patients with von Willebrand disease ( VWD ) , hemophilia A , several platelet disorders , and uremic bleeding . ___MASK49___ induces an increase in plasma levels of P04275 ( P04275 ) , coagulation factor VIII ( FVIII ) , and tissue plasminogen activator ( t - PA ) . It also has a vasodilatory action . In spite of its extensive clinical use , its cellular mechanism of action remains incompletely understood . Its effect on P04275 and t - PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium , via activation of endothelial vasopressin P30518 receptor and DB02527 - mediated signaling . This leads to exocytosis from Weibel Palade bodies where both P04275 and t - PA are stored , as well as to nitric oxide ( NO ) production via activation of endothelial NO synthase . The mechanism of action of ___MASK49___ on FVIII plasma levels remains to be elucidated . The hemostatic effect of ___MASK49___ likely involves additional cellular effects that remain to be discovered .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK96___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK3___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"___MASK33___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .",
"___MASK17___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Integrin alpha5 - induced P00533 activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway . We have previously shown that prothrombin , a blood coagulation factor , can cause an inhibition of DNA synthesis in normal rat hepatocytes . To explore the mechanisms of this prothrombin action , we examined its effects on the activation of fibronectin receptor integrin alpha5 , since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures . We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor ( P00533 ) , leading to P00533 tyrosine phosphorylation at tyrosine residues DB00135 - 845 and DB00135 - 1173 . P00533 tyrosine phosphorylation triggered phosphorylation of its down - stream target Shc and the activation of the c - Jun N - terminal kinase ( JNK ) pathway . P00734 also induced hepatocyte apoptosis , a change in cell shape and activation of caspase 3 pathway . The JNK pathway is most likely involved in prothrombin - induced hepatocyte apoptosis , because pre - treatment of hepatocytes with JNK kinase inhibitor II ( SP600125 ) antagonized these prothrombin actions . The data suggest that integrin - related P00533 activation by prothrombin can induce cell growth inhibition and apoptosis via an P00533 - JNK signaling pathway .",
"Effects of G - P04141 on systemic inflammation , coagulation and platelet activation in patients with acute myocardial infarction . INTRODUCTION : In the prospective , randomised , double - blind , placebo - controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells ( REVIVAL ) - 2 trial patients with acute myocardial infarction ( AMI ) and successful mechanical reperfusion received granulocyte - colony stimulating factor ( DB00099 , 10 μg / kg KG s . c . ) or placebo for 5 days . Aim of this substudy was to assess the impact of G - P04141 on systemic inflammatory and procoagulant responses and platelet activation . METHODS AND RESULTS : Before and five days after DB00099 ( n = 56 ) or placebo ( n = 58 ) circulating cytokine concentrations of interleukin ( IL ) - 1ß , P05231 , P10145 , P22301 , IL - 12 and Tumor - Necrosis Factor - α ( P01375 - α were measured . P00734 fragment F1 + 2 and Tissue Factor activity served as a measure for activated coagulation . Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor ( O95456 ) , P16109 and P29965 by flow cytometry . Administration of G - P04141 was associated with elevated P01375 - α and CRP concentrations compared to the placebo group after 5 days . Other cytokines ( IL - 1ß , P05231 , P10145 , P22301 , IL - 12 ) were comparable after treatment with G - P21583 or placebo . Similarly , circulating prothrombin fragments F1 + 2 , TF activity and platelet activation did not differ in both groups . CONCLUSION : Treatment with G - P04141 in patients with AMI was associated with enhanced proinflammatory P01375 - α and CRP levels but no activation of coagulation ."
] |
[
"___MASK17___",
"___MASK31___",
"___MASK33___",
"___MASK3___",
"___MASK49___",
"___MASK50___",
"___MASK6___",
"___MASK84___",
"___MASK96___"
] |
___MASK6___
|
MH_train_393
|
interacts_with DB08865?
|
[
"Circulating hepatocyte growth factor as an independent prognostic factor of disseminated intravascular coagulation . BACKGROUND : P14210 ( P14210 ) , a pleiotropic factor regulating development and wound healing , is secreted as inactive pro - P14210 and is converted into active P14210 by coagulation serine proteases . P08581 overexpression can cause massive venous thrombi , and factor Xa is reported to release soluble P14210 from granulocytes . We hypothesized that a hypercoagulable condition , such as disseminated intravascular coagulation ( DIC ) , may increase circulating P14210 through active cleavage by coagulation serine proteases . METHODS : In 172 DIC - suspected patients , plasma levels of total and active P14210 , thrombin - antithrombin complex ( TAT ) , plasmin - antiplasmin complex ( PAP ) , and interleukin ( IL ) - 6 were measured by ELISA . Active P14210 release in granulocytes was examined in patients with and without overt - DIC . P14210 - induced tissue factor expression in peripheral monocytes was measured by flow cytometry . RESULTS : Circulating levels of total and active P14210 correlated well with coagulopathy severity , including DIC score , D - dimer , TAT and PAP levels . P14210 positively correlated with P05231 and absolute neutrophil count . In contrast to the cancer group , P14210 levels were significantly increased in accordance with increased DIC scores in non - cancer group . Elevated circulating P14210 was an independent prognostic marker in the non - cancer group , while P14210 level failed to predict mortality in the cancer group . Amounts of P14210 released from stimulated granulocytes were not significantly different between overt - DIC and no overt - DIC patients . P14210 potentiated endotoxin - induced tissue factor expression of monocytes in vitro . CONCLUSION : These findings suggest that circulating P14210 is a potential laboratory marker reflecting coagulation activity and DIC prognosis in non - cancer patients and that P14210 may play a role in a vicious cycle of hypercoagulability .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK87___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK54___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK54___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK54___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK19___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK19___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK19___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK19___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Modulation of c - MET proto - oncogene ( P08581 ) mRNA abundance by cytokines and hormones : evidence for rapid decay of the 8 kb c - MET transcript . The c - MET proto - oncogene product is a transmembrane tyrosine kinase receptor which was recently shown to transmit an array of important cellular responses induced by Hepatocyte Growth Factor ( P14210 ) . These biological effects include induction of mitogenesis , motogenesis , morphogenesis , metastogenesis and anti - tumor activity on a variety of epithelial cells . All of these processes are known to be associated with normal and abnormal tissue growth and development . The 190 kDa c - MET protein is encoded by a major transcript of 8 kilobases ( kb ) , which is reported to be expressed predominantly in epithelial tissues . The expression pattern of c - MET mRNA and protein are drastically modified in many tumor tissues and cell lines . Currently , no information is available on the molecular mechanisms that regulate c - MET mRNA level . In the present communication , we report for the first time that the inflammatory cytokines such as P01583 , P05231 and P01375 , as well as TGF - beta 1 , P01133 , P14210 and the steroidal hormones ( estrogen , progesterone , tamoxifen and dexamethasone ) markedly influence the steady - state levels of the 8 kb c - MET mRNA in human carcinoma cell lines derived from human tissues such as ovary , breast and endometrium . We demonstrate that c - MET receptor protein is present at high levels in primary tumors of human ovaries ( clear cell carcinomas ) . We present evidence that the 8 kb c - MET mRNA undergoes rapid degradation with a half - life of less than 30 min and that this decay can be quickly inhibited by cycloheximide . Our results suggest that the expression of the c - met proto - oncogene resembles that of an immediate early response gene .",
"STK / Q04912 receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the P08581 family . STK / Q04912 tyrosine kinase , a member of the hepatocyte growth factor ( P14210 ) receptor family , is a receptor for macrophage - stimulating protein ( MSP ) . To examine the STK / Q04912 signalling pathway , we generated STK / Q04912 transfectants showing opposite features in growth . STK / Q04912 - expressing Ba / P13726 pro - B cells ( BaF / STK ) exhibited MSP - dependent growth , whereas STK / Q04912 - expressing mouse erythroleukaemia cells ( P61006 / STK ) displayed MSP - induced apoptosis . This apoptosis was accompanied by the prolonged activation of c - Jun N - terminal kinase ( JNK ) , which has recently been implicated in the initiation of apoptosis . Co - immunoprecipitation analyses showed that autophosphorylated STK / Q04912 associated with P98160 - gamma , P13 - kinase , Shc and Grb2 in both transfectants . However , major tyrosine - phosphorylated proteins , p61 and p65 , specifically associated with STK / Q04912 in P61006 / STK cells . Mutations at two C - terminal tyrosine residues , Y1330 and Y1337 , in the counterpart of the multifunctional docking site of the P08581 abolished both MSP - induced growth and apoptosis . Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site . These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis . Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase .",
"___MASK36___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"17 ___MASK42___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .",
"A Hepatocyte Growth Factor ( P14210 ) / receptor autocrine loop regulates constitutive self - renewal of human periodontal ligament cells but reduces sensitivity to exogenous P14210 . BACKGROUND : In addition to its prominent role in liver regeneration , hepatocyte growth factor ( P14210 ) is now generally thought to be produced by mesenchymal cells to promote the regeneration of epithelial tissue by a paracrine mechanism . However , it is not known how or if P14210 could be involved in the regeneration of periodontal tissues . The purpose of this study was to characterize the ability of normal human periodontal ligament ( PDL ) cells to produce or respond to P14210 . METHODS : PDL cells derived from healthy young volunteers were used from passages four through 10 . P14210 receptors were detected both by immunocytochemical staining and Western - blotting analysis . Both DNA synthesis ( by bromo - deoxyuridine [ BrdU ] - incorporation ) and secreted P14210 were quantified by enzyme - linked immunosorbent assays . Mitogen - activated protein kinase ( MAPK ) phosphorylation was also analyzed by Western blot . RESULTS : Despite the immunocytochemical demonstration of P08581 protein in the cytoplasm and on the plasma membrane of PDL cells , exogenous recombinant human P14210 did not exert the mitogenic effects expected . As reported for other mesenchymal cells , PDL cells were found to secrete P14210 . Treatments with neutralizing anti - P14210 antibody significantly suppressed constitutive PDL cell proliferation and sustained the receptor protein at higher levels than in non - treated cells . Under these conditions , exogenous P14210 rapidly phosphorylated extracellular signal - regulated kinase ( P29323 ) , an action linked to the cell proliferation and downregulation of cell - surface receptors . CONCLUSIONS : Unlike other known mesenchymal or epithelial cells , these findings suggest that normal PDL cells from young donors possess a constitutive P14210 / receptor autocrine loop that normally regulates their replacement self - proliferation but reduces sensitivity to exogenously applied P14210 by acute receptor downregulation .",
"P14210 and P04626 / neu downregulate expression of apoptosis - inducing factor in non - small cell lung cancer . Our previous study showed that patients with advanced stages of non - small cell lung cancer ( NSCLC ) were frequently detected with upregulation of hepatocyte growth factor ( P14210 ) . In vitro , P14210 reduced expression of apoptosis - inducing factor ( O95831 ) and cisplatin sensitivity in NSCLC cells . The effect of P14210 was via P08581 ( c - MET ) and the downstream effector , focal adhesion kinase ( Q05397 ) . In this study , we determined the prognostic value of O95831 in NSCLC patients . O95831 expression was determined by immunohistochemistry and immunoblotting . Our data show that O95831 expression was associated with better prognosis . Expression of O95831 inversely correlated with that of positive NSCLC markers , e . g . , dihydrodiol dehydrogenase ( Q04828 ) , c - MET , short oncostatin M receptor ( OSMRs ) , matrix metalloproteinase ( MMP ) - 1 , and P04626 / neu , which were closely associated with drug resistance , tumor recurrence , metastasis and poor prognosis . Noteworthy , silence of P04626 / neu gene expression increases O95831 level and drug sensitivity . Addition of P14210 inhibits O95831 expression in P04626 / neu - silenced cells . These results suggested that both P14210 and P04626 / neu affect drug resistance by regulating O95831 expression in NSCLC .",
"___MASK69___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK69___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .",
"Gab1 but not Grb2 mediates tumor progression in DB00134 overexpressing colorectal cancer cells . P08581 ( DB00134 ) plays an important role in the progression of multiple cancer types . The overexpression of DB00134 in DLD - 1 colon carcinoma cells with kirsten rat sarcoma oncogene homolog ( P01116 ) oncogene activation resulted in enhanced subcutaneous and orthotopic tumor growth rate and increased metastatic potential . To elucidate the mechanism of this effect , we stably expressed kinase - inactive DB00134 ( K1110A ) , Src homology 2 ( SH2 ) - binding domain - inactive DB00134 ( Y1349 / 1356F ) , growth factor receptor - bound protein 2 ( Grb2 ) non - binding DB00134 ( N1358H ) and mutant receptors with ability to selectively recruit signaling proteins Grb2 , src homology domain c - terminal adaptor homolog ( Shc ) , phospholipase c - gamma ( PLCgamma ) and p85 phosphatidyl inositol 3 kinase . As subcutaneous implants , DLD - 1 cells that expressed the majority of these receptor constructs failed to recapitulate the tumor growth - enhancing effect of the wild - type DB00134 receptor . The Grb2 - and Shc - recruiting DB00134 mutants demonstrated slight but consistent tumor - suppressive activity , whereas the expression of N1358H mutant stimulated tumor growth rate comparable with the wild - type receptor . This suggests that direct Grb2 / Shc binding does not contribute to the tumor progression activity of DB00134 receptor . The tumors expressing Grb2 - and Shc - recruiting DB00134 receptors demonstrated a marked loss in Grb2 - associated adaptor protein 1 ( Gab1 ) protein levels , which was not observed in the cell lines , consistent with a post - translationally regulated process . Moreover , a moderate level of Gab1 overexpression stimulated tumor growth . The findings suggest a delicate balance for intact Y1349 / 1356 SH2 - binding domain to mediate the tumor progression activity of the coactivated DB00134 - rat sarcoma oncogene homolog ( DB01367 ) pathways . Selectivity for specific adaptor protein involvement may be the key that determines the tissue - and cell - type specificity of DB00134 - mediated tumorigenicity in human cancers .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK94___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"___MASK50___ increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : ___MASK50___ is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . ___MASK50___ and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : ___MASK50___ increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"P08581 tyrosine kinase met is a substrate of the receptor protein - tyrosine phosphatase Q12913 . The receptor protein - tyrosine phosphatase ( PTP ) Q12913 ( CD148 / PTP - eta ) has been implicated in the regulation of cell growth , differentiation , and transformation , and most recently has been identified as a potential tumor suppressor gene mutated in colon , lung , and breast cancers . We have generated constructs comprising the cytoplasmic segment of Q12913 fused to the maltose - binding protein to identify potential substrates and thereby suggest a physiological function for Q12913 . We have shown that the substrate - trapping mutant form of Q12913 interacted with a small subset of tyrosine - phosphorylated proteins from lysates of the human breast tumor cell lines MDA - MB - 231 , T - 47D , and T - 47D / DB00134 and have identified the hepatocyte growth factor / scatter factor receptor DB00134 , the adapter protein Gab1 , and the junctional component O60716 as potential substrates . Following ligand stimulation , phosphorylation of specific tyrosyl residues in DB00134 induces mitogenic , motogenic , and morphogenic responses . When co - expressed in 293 cells , the full - length substrate - trapping mutant form of Q12913 formed a stable complex with the chimeric receptor colony stimulating factor 1 ( P04141 ) - DB00134 and wild type Q12913 dephosphorylated P04141 - DB00134 . Furthermore , we observed that Q12913 preferentially dephosphorylated a Gab1 binding site ( DB00135 ( 1349 ) ) and a COOH - terminal tyrosine implicated in morphogenesis ( DB00135 ( 1365 ) ) , whereas tyrosine residues in the activation loop of DB00134 ( DB00135 ( 1230 ) , DB00135 ( 1234 ) , and DB00135 ( 1235 ) ) were not preferred targets of the PTP . The ability of Q12913 preferentially to dephosphorylate particular tyrosine residues that are required for DB00134 - induced signaling suggests that Q12913 may function in controlling the specificity of signals induced by this PTK , rather than as a simple \" off - switch \" to counteract PTK activity .",
"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK4___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .",
"P14210 triggers distinct mechanisms of Q9NR80 and Tiam1 activation to induce endothelial barrier enhancement . Previous reports described an important role of hepatocyte growth factor ( P14210 ) in mitigation of pulmonary endothelial barrier dysfunction and cell injury induced by pathologic agonists and mechanical forces . P14210 protective effects have been associated with Rac - GTPase signaling pathway activated by Rac - specific guanine nucleotide exchange factor Tiam1 and leading to enhancement of intercellular adherens junctions . This study tested involvement of a novel Rac - specific activator , Q9NR80 , in endothelial barrier enhancement by P14210 and investigated a mechanism of P14210 - induced Q9NR80 activation . Si - RNA - based knockdown of Tiam1 and Q9NR80 had an additive effect on attenuation of P14210 - induced Rac activation and endothelial cell ( EC ) barrier enhancement . Tiam1 and Q9NR80 activation was abolished by pharmacologic inhibitors of P08581 and P19957 - kinase . In contrast to Tiam1 , Q9NR80 interacted with P25054 and associated with microtubule fraction upon P14210 stimulation . EC treatment by low dose DB08313 to inhibit peripheral microtubule dynamics partially attenuated P14210 - induced Q9NR80 peripheral translocation , but had negligible effect on Tiam1 translocation . These effects were associated with attenuation of P14210 - induced barrier enhancement in EC pretreated with low ND dose and activation of Rac and its cytoskeletal effectors PAK1 and cortactin . These data demonstrate , that in addition to microtubule - independent Tiam1 activation , P14210 engages additional microtubule - and P25054 - dependent pathway of Q9NR80 activation . These mechanisms may complement each other to provide the fine tuning of Rac signaling and endothelial barrier enhancement in response to various agonists .",
"Protein Tyrosine Phosphatase 1B ( P18031 ) deficiency accelerates hepatic regeneration in mice . Protein tyrosine phosphatase 1B ( P18031 ) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors and modulate the intensity of their signaling cascades . Because liver regeneration involves tyrosine phosphorylation - mediated signaling , we investigated the role of P18031 in this process by performing partial hepatectomy in wild - type ( P18031 (+/+) ) and P18031 - deficient ( P18031 (-/-) ) mice . The expression of P12004 and cyclins D1 and E ( cell proliferation markers ) was enhanced in P18031 (-/-) regenerating livers , in parallel with 5 '- bromo - 2 '- deoxyuridine incorporation . Phosphorylation of P45983 / 2 and P40763 , early triggers of hepatic regeneration in response to P01375 - α and P05231 , was accelerated in P18031 (-/-) mice compared with P18031 (+/+) mice . These phosphorylations were increased in P18031 (-/-) hepatocytes or by silencing P18031 in wild - type cells and decreased further after the addition of recombinant P18031 . Enhanced P01133 - and P08581 - mediated signaling was observed in regenerating livers lacking P18031 and in P01133 - or P14210 - stimulated P18031 (-/-) hepatocytes . Moreover , P18031 (-/-) mice displayed a more rapid increase in intrahepatic lipid accumulation than P18031 (+/+) control mice . Late responses to partial hepatectomy revealed additional divergences because stress - mediated signaling was attenuated at 24 to 96 hours in P18031 (-/-) mice compared with P18031 (+/+) mice . Finally , P18031 deficiency also improves hepatic regeneration in mice fed a high - fat diet . These results suggest that pharmacological inhibition of P18031 would improve liver regeneration in patients with acute or chronic liver injury .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"DB08865 for the treatment of patients with advanced non - small cell lung cancer . DB08865 is a potent small - molecule inhibitor of Q9UM73 ( anaplastic lymphoma kinase ; Q9UM73 ) and hepatocyte growth factor receptor ( P08581 , proto - oncogene c - DB00134 ) . A range of tumors , including subsets of non - small cell lung cancer ( NSCLC ) , anaplastic large cell lymphoma and inflammatory myofibroblastic tumors harbor an Q9UM73 rearrangement that leads to oncogenic activation of Q9UM73 . DB08865 has demonstrated preclinical and clinical activity against such malignancies through inhibition of Q9UM73 , and patients harboring Q9UM73 - rearranged NSCLC have demonstrated high response rates and prolonged progression - free survival in phase I and II studies . In August 2011 , crizotinib was approved for the treatment of advanced Q9UM73 - positive NSCLC ."
] |
[
"___MASK19___",
"___MASK36___",
"___MASK42___",
"___MASK4___",
"___MASK50___",
"___MASK54___",
"___MASK69___",
"___MASK87___",
"___MASK94___"
] |
___MASK69___
|
MH_train_394
|
interacts_with DB00773?
|
[
"DNA damage and S phase arrest induced by Ochratoxin A in human embryonic kidney cells ( P29320 293 ) . Ochratoxin A ( OTA ) is a ubiquitous mycotoxin with potential nephrotoxic , hepatotoxic and immunotoxic effects . The mechanisms underlying the nephrotoxicity of OTA remain obscure . To investigate DNA damage and the changes of the cell cycle distribution induced by OTA , human embryonic kidney cells ( P29320 293 cells ) were incubated with various concentrations of OTA for 24h in vitro . The results indicated that OTA treatment led to the production of reactive oxygen species ( ROS ) and to a decrease of the mitochondrial membrane potential ( ΔΨm ) . OTA - induced DNA damage in P29320 293 cells was evidenced by DNA comet tails formation and increased expression of γ - P16104 . In addition , OTA could induce cell cycle arrest at the S phase in P29320 293 cells . The expression of key cell cycle regulatory factors that were critical to the S phase , including cyclin A2 , cyclin E1 , and P24941 , were further detected . The expression of cyclin A2 , cyclin E1 , and P24941 were significantly decreased by OTA treatment at both the mRNA and protein levels . The apoptosis of P29320 293 cells after OTA treatment was observed using Hoechst 33342 staining . The results confirmed that OTA did induce apoptosis in P29320 293 cells . In conclusion , our results provided new insights into the molecular mechanisms by which OTA might promote nephrotoxicity .",
"Combinatorial antitumor effect of HDAC and the PI3K - Akt - P42345 pathway inhibition in a Pten defecient model of prostate cancer . Increased expression of histone deacetylases ( HDACs ) and activation of the PI3K - Akt - mTORC1 pathway are common aberrations in prostate cancer ( PCa ) . For this reason , inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa . Previous reports demonstrated that HDAC inhibitors ( HDACi ) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor ( AR ) . In this study we utilized the AR negative PCa cell line and observed that re - expression of AR ( PC3 - AR ) results in greater levels of apoptosis when treated with the pan - DACi , DB06603 ( PAN ) . PAN mediated apoptosis in PC3 and PC3 - AR cells was associated with increased levels of double strand DNA breaks , indicated by p - ɣ P16104 . Further , PAN treatment in PC3 - AR cells resulted in moderate attenuation of the Q13315 - Akt - P29323 DNA damage response pathway . For this reason , we combined PAN with the dual PI3K - P42345 inhibitor , BEZ235 . Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein Q13315 and significantly increased anti - tumor activity compared to each single treatment . Overall , superior anti - tumor activity with combination of PAN with BEZ235 was independent of AR status . These findings suggest that this therapeutic strategy should be further developed in clinical trials .",
"Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites .",
"Biological effects of alpha particle radiation exposure on human monocytic cells . Radon ( ( 222 ) Rn ) gas produces decay progeny that emits high energy alpha ( α )- particles . Epidemiological studies have shown that exposure to ( 222 ) Rn is linked with elevated risk of developing lung cancer , however clear mechanisms leading to such effects have not been delineated . Cytokines play a critical role in inflammation and their dysregulated production often contributes to disease pathogenesis . In this study , Bio - plex multiplex technology was employed to investigate modulations of 27 pro - inflammatory cytokines following exposure of human monocytic cells to 1 . 5 Gy of α - particle radiation . Concurrently , DNA damage was assessed by examining the formation of phosphorylated H2A histone family X ( γ - P16104 ) sites . Of the 27 cytokines assessed , 4 cytokines were shown to be statistically downregulated by ∼ 2 fold relative to the untreated controls and included the interleukin ( IL ) family of proteins ( P60568 , P40933 and Q16552 ) and macrophage inflammatory protein 1 beta ( MIP - 1b ) . Interferon - inducible protein - 12 ( IP - 12 ) , vascular endothelial growth factor and regulated on activation normal T cell expressed and secreted ( RANTES ) were shown to be high expressors and upregulated . Cells irradiated with α - particles ranging from 0 . 27 to 2 . 14 Gy showed statistically significant , dose - dependant increases in γ - P16104 formation . These data suggest that α - particle radiation causes dysregulation in the production of a number of pro - inflammatory cytokines and results in significant DNA damage .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK39___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"___MASK23___ block of cloned human T - type voltage - gated calcium channels . ___MASK23___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK55___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , a Korean traditional medicine . We investigated the anti - angiogenic effects of the water extract of HangAmDan ( WEHAD ) , which is a crude extract of nine Korean medicinal substances of animal and plant origin . In human umbilical vein endothelial cells , WEHAD significantly inhibited P09038 - induced proliferation , adhesion , migration , and capillary tube formation . We used an antibody array to perform an analysis of signaling proteins , which showed up - regulated expression of various proteins including Q06609 , P43351 , and p73 , and down - regulated expression of pFAK . Blood vessel formation in a chick chorioallantoic membrane ( P62158 ) treated with WEHAD was markedly reduced in length compared with a PBS - treated control group . These results suggest that inhibition of angiogenesis by WEHAD may be the mechanism of action for the anti - cancer effects of HAD .",
"Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II . Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid - borne P11388 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide ( DB00773 ) . This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both P43351 + repair - proficient strains and rad52 mutants that are defective in the repair of double - stranded breaks . These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II , and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent .",
"Tyrosine phosphorylation enhances P43351 - mediated annealing by modulating its DNA binding . P43351 protein has an important role in homology - directed DNA repair by mediating Q06609 nucleoprotein filament formation on single - stranded DNA ( ssDNA ) protected by replication protein - A ( RPA ) and annealing of RPA - coated ssDNA . In human , cellular response to DNA damage includes phosphorylation of P43351 by c - P00519 kinase at tyrosine 104 . To address how this phosphorylation modulates P43351 function , we used an amber suppressor technology to substitute tyrosine 104 with chemically stable phosphotyrosine analogue ( p - Carboxymethyl - L - phenylalanine , pCMF ) . The P43351 ( Y104pCMF ) retained ssDNA - binding activity characteristic of unmodified P43351 but showed lower affinity for double - stranded DNA ( dsDNA ) binding . Single - molecule analyses revealed that P43351 ( Y104pCMF ) specifically targets and wraps ssDNA . While P43351 ( Y104pCMF ) is confined to ssDNA region , unmodified P43351 readily diffuses into dsDNA region . The Y104pCMF substitution also increased the ssDNA annealing rate and allowed overcoming the inhibitory effect of dsDNA . We propose that phosphorylation at Y104 enhances ssDNA annealing activity of P43351 by attenuating dsDNA binding . Implications of phosphorylation - mediated activation of P43351 annealing activity are discussed .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK21___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"Cytoplasmic - nuclear shuttling of P62942 - rapamycin - associated protein is involved in rapamycin - sensitive signaling and translation initiation . Translation initiation is one of the key events regulated in response to mitogenic stimulation and nutrient availability , tightly coupled to mammalian cell cycle progression and growth . P62942 - rapamycin - associated protein ( P42345 ; also named P42345 or P42345 ) , a member of the ataxia telangiectasia mutated ( Q13315 ) - related kinase family , governs a rapamycin - sensitive membrane - to - cytoplasm signaling cascade that modulates translation initiation via P08133 S6 kinase ( P08133 ( s6k ) ) and P06730 binding protein 1 ( Q13541 ) . Our studies reported here reveal a surprising regulatory mechanism of this signaling , which involves cytoplasmic - nuclear shuttling of P42345 . By using leptomycin B ( LMB ) , a specific inhibitor of nuclear export receptor Crm1 , we show that P42345 is a cytoplasmic - nuclear shuttling protein . Inhibition of P42345 nuclear export by LMB coincides with diminished P08133 ( s6k ) activation and Q13541 phosphorylation . Further investigation by altering P42345 ' s nuclear shuttling activity with exogenous nuclear import and export signals has yielded results that are consistent with a direct link between nuclear shuttling of P42345 and mitogenic stimulation of P08133 ( s6k ) activation and Q13541 phosphorylation . Furthermore , by using a reporter system , we provide evidence suggesting that nuclear shuttling of P42345 regulates mitogen - stimulated rapamycin - sensitive translation initiation . These findings uncover a function for the nucleus in the direct regulation of the protein synthesis machinery via extracellular signals .",
"Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .",
"P00441 acts as a nuclear transcription factor to regulate oxidative stress resistance . P00441 ( Sod1 ) has been known for nearly half a century for catalysis of superoxide to hydrogen peroxide . Here we report a new Sod1 function in oxidative signalling : in response to elevated endogenous and exogenous reactive oxygen species ( ROS ) , Sod1 rapidly relocates into the nucleus , which is important for maintaining genomic stability . Interestingly , H2O2 is sufficient to promote Sod1 nuclear localization , indicating that it is responding to general ROS rather than Sod1 substrate superoxide . ROS signalling is mediated by Mec1 / Q13315 and its effector Dun1 / Cds1 kinase , through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60 , 99 . In the nucleus , Sod1 binds to promoters and regulates the expression of oxidative resistance and repair genes . Altogether , our study unravels an unorthodox function of Sod1 as a transcription factor and elucidates the regulatory mechanism for its localization .",
"Synergism between bosutinib ( ___MASK33___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Chronic myeloid leukemia . Progress has been made in understanding P11274 - P00519 - positive leukemias . A new transcript ( p230BCR - P00519 ) has been characterized that is associated with Ph - positive chronic neutrophilic leukemia . The Q13315 protein appears to be a regulator of P00519 activity in response to irradiation damage . Pathways linking P11274 - P00519 to the BCL - 2 family of proteins may be active in Philadelphia - positive cells and inhibit apoptosis . The 62 - kD protein constitutively phosphorylated in chronic myeloid leukemia progenitors has been cloned . Ph - negative long - term culture - initiating cells are detectable in many chronic myeloid leukemia patients . The combination of interferon alfa and cytarabine appears to be superior to interferon alfa alone . Autografting with in vivo - purged stem cells may induce prolonged remissions . Specific inhibitors of the P11274 - P00519 tyrosine kinase are becoming available .",
"Effects of short - and long - term risperidone treatment on prolactin levels in children with autism . BACKGROUND : The effects of short - and long - term risperidone treatment on serum prolactin were assessed in children and adolescents with autism . METHODS : Patients with autism ( N = 101 , 5 - 17 years of age ) were randomized to an 8 - week trial of risperidone or placebo and 63 then took part in a 4 - month open - label follow - up phase . Serum samples were obtained at Baseline and Week - 8 ( N = 78 ) , and at 6 - month ( N = 43 ) and 22 - month ( N = 30 ) follow - up . Serum prolactin was determined by immunoradiometric assay ; dopamine type - 2 receptor ( P14416 ) polymorphisms were genotyped . RESULTS : Baseline prolactin levels were similar in the risperidone ( N = 42 ) and placebo ( N = 36 ) groups ( 9 . 3 +/- 7 . 5 and 9 . 3 +/- 7 . 6 ng / ml , respectively ) . After 8 weeks of risperidone , prolactin increased to 39 . 0 +/- 19 . 2 ng / ml , compared with 10 . 1 +/- 8 . 8 ng / ml for placebo ( p < . 0001 ) . P01236 levels were also significantly increased at 6 months ( 32 . 4 +/- 17 . 8 ng / ml ; N = 43 , p < . 0001 ) and at 22 months ( N = 30 , 25 . 3 +/- 15 . 6 ng / ml , p < . 0001 ) . P01236 levels were not associated with adverse effects and P14416 alleles ( Taq1A , - 141C Ins / Del , C957T ) did not significantly influence baseline levels or risperidone - induced increases in prolactin . CONCLUSIONS : ___MASK75___ treatment was associated with two - to four - fold mean increases in serum prolactin in children with autism . Although risperidone - induced increases tended to diminish with time , further research on the consequences of long - term prolactin elevations in children and adolescents is needed .",
"Analysis of DNA recombination and repair proteins in living cells by photobleaching microscopy . DNA double strand break repair through homologous recombination has been shown biochemically to require the coordinated action of the P43351 group of proteins , including the DNA strand exchange protein Rad51 . We have started to develop experimental tools to investigate the close cooperation of homologous recombination proteins in living cells , where proteins operate in the context of chromatin and in the presence of other nuclear processes . This chapter describes in detail methods to establish cell lines stably expressing green fluorescent protein - tagged recombination proteins and photobleaching techniques to investigate the behavior of the proteins with the use of live cell video microscopy . Fluorescence recovery after photobleaching ( P42345 ) , fluorescence loss after photobleaching ( FLIP ) , and their combination in the same cell are useful techniques to gain insights into the dynamic behavior of the recombination proteins . Parameters such as diffusion rates and mobile versus immobile fractions before and after DNA damage induction can be obtained . In addition , residence times of recombination proteins at sites of DNA damage can be determined . Through the application of P42345 and FLIP it is possible to establish whether proteins are present in the same multiprotein complex , whether this is affected by DNA damage induction , and whether proteins dynamically associate with and dissociate from sites of DNA damage .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Signaling by retinol and its serum binding protein . DB00162 , retinol , circulates in blood bound to retinol - binding protein ( P02753 ) which , in turn , associates with transthyretin ( P02766 ) to form a retinol - P02753 - P02766 ternary complex . At some tissues , retinol - bound ( holo - ) P02753 is recognized by a membrane protein termed Q9BX79 , which transports retinol from extracellular P02753 into cells and , concomitantly , activates a O60674 / P40763 / 5 signaling cascade that culminates in induction of P35610 target genes . Q9BX79 - mediated retinol transport and cell signaling are critically inter - dependent , and they both require the presence of cellular retinol - binding protein 1 ( P09455 ) , an intracellular retinol acceptor , as well as a retinol - metabolizing enzyme such as lecithin : retinol acyltransferase ( O95237 ) . Q9BX79 thus functions as a \" cytokine signaling transporter \" which couples vitamin A homeostasis and metabolism to cell signaling , thereby regulating gene transcription . Recent studies provided molecular level insights into the mode of action of this unique protein .",
"Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft . Neurofibromatosis type 1 ( P21359 ) patients are prone to the development of malignant tumors , the most common being Malignant Peripheral Nerve Sheath Tumor ( MPNST ) . P21359 - MPNST patients have an overall poor survival due to systemic metastasis . Currently , the management of MPNSTs includes surgery and radiation ; however , conventional chemotherapy is not very effective , underscoring the need for effective biologically - targeted therapies . Recently , the P21359 gene product , neurofibromin , was shown to negatively regulate the phosphoinositide - 3 - kinase ( PI3K ) / Protein Kinase - B ( Akt ) / mammalian Target Of ___MASK87___ ( P42345 ) pathway , with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of P42345 activity . We developed and characterized a human P21359 - MPNST explant grown subcutaneously in NOD - SCID mice , to evaluate the effect of the P42345 inhibitor rapamycin . We demonstrate that rapamycin significantly inhibited human P21359 - MPNST P42345 pathway activation and explant growth in vivo at doses as low as 1 . 0 mg / kg / day , without systemic toxicities . While rapamycin was effective at reducing P21359 - MPNST proliferation and angiogenesis , with decreased CyclinD1 and P15692 respectively , there was no increase in tumor apoptosis . ___MASK87___ effectively decreased activation of S6 downstream of P42345 , but there was accompanied increased Akt activation . This study demonstrates the therapeutic potential and limitations of rapamycin in P21359 - associated , and likely sporadic , MPNSTs .",
"mRNA expression , functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray . AIM : To understand the local pathophysiological alterations and gene ontology - based functional classification of colonic biopsies into inflammatory and neoplastic diseases . METHODS : Total RNA was extracted from frozen biopsies and amplified by T7 - method . Expression profile was evaluated by Atlas Glass 1K microarrays . After microarray quality control , applicable data were available from 10 adenomas , 6 colorectal adenocarcinomas ( CRCs ) , and 6 inflammatory bowel diseases ( IBDs ) . Multivariate statistical and cell functional analyses were performed . Real - time RT - PCR and immunohistochemistry were used for validation . RESULTS : Discriminant analysis of selected genes , could correctly reclassify all 22 samples using 4 parameters ( heat shock transcription factor - 1 , bystin - like , calgranulin - A , O14798 ) . Q9UKU7 samples were characterized by overregulated chemokine ( C - X - C motif ) ligand 13 , replication protein A1 , Q15723 and downregulated Q9Y4K3 , P10415 - interacting killer genes . In adenomas upregulation of Q9Y4K3 , replication protein A1 , Q15723 and underexpression of P10415 - associated X protein , calgranulin - A genes were found . CRC cases had significantly increased epidermal growth factor receptor , topoisomerase - 1 , v - jun , Q9Y4K3 and O14798 , and decreased Q06609 and P43351 DNA repair gene , protein phosphatase - 2A and P10415 - interacting killer mRNA levels . P00533 RT - PCR and immunohistochemistry , topoisomerase - 1 RT - PCR confirmed the chip results . CONCLUSION : Different histological alterations can be reclassified by functional , multivariate analysis using cDNA microarrays . Further studies with expanded sample number are needed for subclassification of pathological alterations .",
"Constitutive Q12888 / γ P16104 foci are increased in cells of ALL patients dependent on P11274 - P00519 and P41212 - Q01196 preleukemic gene fusions . Childhood leukemia arises from hematopoietic stem cells by induction of mutations . Quite often chromosomal translocations arise prenatally as first key event in multistage process of leukemogenesis . These translocations result in so called preleukemic gene fusions ( PGFs ) , such as P11274 - P00519 and P41212 - Q01196 , which generate hybrid proteins with altered properties . Critical DNA damage resulting in translocations are DNA double - strand breaks ( DSBs ) . P11274 - P00519 and P41212 - Q01196 were shown to be associated with increased constitutive DSBs in various model systems . We analyzed cells from peripheral blood and P28906 -/ P28906 + cells from bone marrow of pediatric acute lymphoblastic leukemia ( ALL ) patients harboring P11274 - P00519 or P41212 - Q01196 . We used sensitive technique that is based on automated enumeration of DSB co - localizing proteins γ P16104 and Q12888 , which form so called DNA repair foci . We found that level of constitutive γ P16104 / Q12888 foci is significantly higher in cells of ALL pediatric patients than in healthy subjects . There was also significant increased level of constitutive γ P16104 / Q12888 foci in cells from ALL patients harboring P11274 - P00519 or P41212 - Q01196 compared to patients without PGFs . The same increase was observed regardless cell type for both PGFs . Our data on increased DSB levels in the P11274 - P00519 / P41212 - Q01196 patient ' s cells support a model where P11274 - P00519 / P41212 - Q01196 induces DNA instability through facilitating mutagenesis and appearance of additional genetic alterations driving leukemogenesis .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK75___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .",
"Loss of P38398 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo . BACKGROUND : Previous reports suggested a central role of P38398 in DNA - damage repair mechanisms elicited by cell exposure to anti - tumor agents . Here we studied if P38398 - defective HCC1937 or P38398 - reconstituted HCC1937 /( WT ) P38398 human breast cancer xenografts ( HBCXs ) generated in SCID mice were differentially sensitive to cisplatin ( DB00515 ) in vivo and we investigated potential molecular correlates of this effect . RESULTS : DB00515 induced almost complete growth inhibition of P38398 - defective HBCXs , while P38398 - reconstituted HBCXs were only partially inhibited . Cell cycle analysis showed a significant S - and G ( 2 )/ M blockade in P38398 - defective as compared with parental P38398 - reconstituted cells . Comparative gene expression profiling of HCC1937 and HCC1937 /( WT ) P38398 showed upregulation of P43351 and Q13426 , whereas P07992 and P23921 were downregulated . Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that P38398 is mostly involved in G ( 2 )/ M but also in G ( 1 )/ S - phase checkpoints as well as in several important signaling pathways , including IGF , P15692 , estrogen receptor , PI3K / AKT and P01133 . METHODS : HCC1937 or HCC1937 /( WT ) P38398 HBCXs were generated in SCID mice . Animals were then weekly treated with 5 mg / kg DB00515 i . p . or with vehicle for 4 w . Tumor volume and mice survival were evaluated . Tumors were retrieved from animals 12 hours after the last treatment with DB00515 or vehicle treatment and the cell suspension underwent cell cycle analysis . Differential gene expression and pathway modulation between HCC1937 and HCC1937 /( WT ) P38398 cells were also studied . CONCLUSION : Our data suggest that P38398 - defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum - derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK44___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"P38936 ( Waf1 ) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate . Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential . HDAC inhibitors ( HDACI ) induce senescence and / or apoptosis in many types of tumor cells . Here , we studied the role of cyclin - kinase inhibitor P38936 ( waf1 ) ( Cdkn1n gene ) in cell cycle arrest , senescence markers ( cell hypertrophy , SA - βGal staining and accumulation of γ P16104 foci ) in P38936 ( Waf1 +/+) versus P38936 ( Waf1 -/-) mouse embryonic fibroblast cells transformed with E1A and cHa - Ras oncogenes ( mERas ) . While short treatment with the HDACI sodium butyrate ( NaB ) induced a reversible G ( 1 ) cell cycle arrest in both parental and P38936 ( Waf1 -/-) cells , long - term treatment led to dramatic changes in P38936 ( Waf1 +/+) cells only : cell cycle arrest became irreversible and cells become hypertrophic , SA - βGal - positive and accumulated γ P16104 foci associated with mTORC1 activation . The P38936 ( Waf1 +/+) cells lost their ability to migrate into the wound and through a porous membrane . Suppression of migration was accompanied by accumulation of vinculin - staining focal adhesions and Ser3 - phosphorylation of cofilin , incapable for F - actin depolymerization . In contrast , the knockout of the P38936 ( Waf1 ) abolished most of the features of NaB - induced senescence , including irreversibility of cell cycle arrest , hypertrophy , additional focal adhesions and block of migration , γ P16104 foci accumulation and SA - βGal staining . ___MASK87___ , a specific inhibitor of mTORC1 kinase , decreased cellular hypertrophy , canceled coffilin phosphorylation and partially restored cell migration in P38936 ( Waf1 +/+) cells . Taken together , our data indicate a new role of P38936 ( Waf1 ) in cell senescence , which may be connected not only with execution of cell cycle arrest , but also with the development of P42345 - dependent markers of cellular senescence .",
"Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells . Stromal cells such as myofibroblasts influence tumor progression . The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow - derived mesenchymal stromal cells ( MSCs ) which then colonize tumors . Using iTRAQ and LC - MS / MS we identified the adipokine , chemerin , as overexpressed in esophageal squamous cancer associated myofibroblasts ( CAMs ) compared with adjacent tissue myofibroblasts ( ATMs ) . The chemerin receptor , ChemR23 , is expressed by MSCs . Conditioned media ( CM ) from CAMs significantly increased O60682 cell migration compared to Q13315 - CM ; the action of P62158 - CM was significantly reduced by chemerin - neutralising antibody , pretreatment of CAMs with chemerin siRNA , pretreatment of MSCs with ChemR23 siRNA , and by a ChemR23 receptor antagonist , CCX832 . Stimulation of MSCs by chemerin increased phosphorylation of Q8NFH3 / 44 , p38 and JNK - II kinases and inhibitors of these kinases and PKC reversed chemerin - stimulated O60682 migration . Q99969 stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor ( MIF ) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations . In a xenograft model consisting of OE21 esophageal cancer cells and CAMs , homing of MSCs administered i . v . was inhibited by CCX832 . Thus , chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression .",
"Acidic pH induces topoisomerase II - mediated DNA damage . Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models . Recent studies have also implicated acidic pH in the development of preneoplastic Barrett ' s esophagus in human . However , little is known about the molecular mechanism underlying acidic pH - induced carcinogenesis . In the current study , we show that acidic pH , like the topoisomerase II ( P11388 ) poison DB00773 ( demethylepipodophyllotoxin ethylidene - beta - D - glucoside ) , induces tumors in 9 , 10 - dimethyl - 1 , 2 - benzanthracene ( DMBA )- initiated mice . The following studies in tissue culture models have suggested that acidic pH acts like a P11388 poison to induce P11388 - mediated DNA damage : ( i ) acidic pH induces P11388 - dependent DNA damage signals as evidenced by up - regulation of p53 and DB00133 - 139 phosphorylation of P16104 [ a substrate for ataxia telangiectasia mutated ( Q13315 ) Q13315 and Rad3 - related ( ATR ) kinases ] ; ( ii ) acidic pH - induced cytotoxicity in tumor cells is reduced in P11388 - deficient cells ; ( iii ) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase ( P00492 ) gene in a P11388 - dependent manner ; and ( iv ) acidic pH induces reversible P11388 - mediated DNA strand breaks in vitro . We discuss the possibility that P11388 - mediated DNA damage may contribute to acidic pH - induced carcinogenesis .",
"___MASK38___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK38___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK87___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .",
"P01236 confers resistance against cisplatin in breast cancer cells by activating glutathione - S - transferase . Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients . Given that prolactin ( PRL ) acts as an anti - apoptotic / survival factor in the breast , we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs . Treatment of breast cancer cells with PRL caused variable resistance to taxol , vinblastine , doxorubicin and cisplatin . PRL prevented cisplatin - induced G ( 2 )/ M cell cycle arrest and apoptosis . In the presence of PRL , significantly less cisplatin was bound to DNA , as determined by mass spectroscopy , and little DNA damage was seen by gamma - P16104 staining . PRL dramatically increased the activity of glutathione - S - transferase ( Q86UG4 ) , which sequesters cisplatin in the cytoplasm ; this increase was abrogated by Jak and mitogen - activated protein kinase inhibitors . PRL upregulated the expression of the GSTmu , but not the pi , isozyme . A Q86UG4 inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL . In conclusion , PRL confers resistance against cisplatin by activating a detoxification enzyme , thereby reducing drug entry into the nucleus . These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer , which is characterized by high expression of both PRL and its receptor . Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Mitoxantrone inhibits HIF - 1α expression in a topoisomerase II - independent pathway . PURPOSE : Solid tumors encounter a growth - limiting hypoxic microenvironment as they develop . Hypoxia - inducible factors ( HIF ) play important roles in hypoxia - associated tumor development and therapeutic resistance . Targeting the HIF pathway ( especially HIF - 1α ) represents a promising cancer treatment strategy . Here , we report a novel class of HIF - 1α inhibitors and the possible molecular basis of inhibition . EXPERIMENTAL DESIGN : We analyzed the inhibitory effects of clinically used topoisomerase II ( P11388 ) - targeting drugs on HIF - 1α expression with a primary focus on mitoxantrone . The potential role of P11388 in mitoxantrone - inhibited HIF - 1α expression was studied using pharmacologic inhibition , a knockdown approach , and P11388 mutant cells . Moreover , involvement of mitoxantrone in proteasome - mediated degradation , transcription , and translation of HIF - 1α was examined . RESULTS : The P11388 - targeting mitoxantrone , but neither doxorubicin nor etoposide ( DB00773 ) , strongly inhibited HIF - 1α expression under hypoxic conditions in a dose - and time - dependent manner . Surprisingly , the mitoxantrone - mediated inhibition of HIF - 1α expression was largely independent of two P11388 isozymes , proteasomal degradation , and transcription . Furthermore , mitoxantrone inhibited HIF - 1α expression and function in a similar fashion as cycloheximide , suggesting that mitoxantrone might inhibit HIF - 1α via a blockage at its translation step . In vitro translation experiments using HIF - 1α mRNA further confirmed inhibition of HIF - 1α translation by mitoxantrone . Interestingly , levels of the polysome - bound HIF - 1α and P15692 mRNA were elevated and decreased after mitoxantrone treatment , respectively . CONCLUSIONS : We have identified the P11388 - targeting compound , mitoxantrone , as an HIF - 1α inhibitor possibly through a translation inhibition mechanism , suggesting the possibility of an additional anticancer activity for mitoxantrone .",
"Effect of valproic acid through regulation of DB01221 receptor - P29323 signaling in sleep deprivation rats . Although the effect of mood stabilizer valproic acid ( DB00313 ) through multiple signaling pathways has been shown , its therapeutic mechanism is still largely unknown . We investigated the effect of DB00313 ( 200 mg / kg , every 12 h ) in sleep deprivation ( SD ) rats ( 72 h ) , the manic - like animal model , focusing on the N - methyl - D : - aspartic acid ( DB01221 ) receptor and signaling mediators of synaptic plasticity such as extracellular signal - regulated protein kinase ( P29323 ) , DB02527 response element - binding protein ( CREB ) , B cell chronic lymphocytic leukemia / lymphoma 2 ( P10415 ) , and brain - derived neurotrophic factor ( P23560 ) . SD reduced the expression of the Q13224 subunit of the DB01221 receptor in the frontal cortex and hippocampus but did not affect the expression of Q9UHB4 and Q12879 subunits . In comparison , DB00313 inhibited the SD - induced reduction of Q13224 expression in both brain regions . In addition , SD attenuated P29323 phosphorylation in the frontal cortex and hippocampus , whereas DB00313 prevented the attenuation . DB00313 also protected the SD - induced decrease of CREB phosphorylation , P10415 expression , and P23560 expression in the frontal cortex but not in the hippocampus . These results indicate that DB00313 could regulate DB01221 receptor - P29323 signaling in SD rats , preventing the SD - induced decrease of the expression of Q13224 subunit and the activation of P29323 signaling mediators such as P29323 , CREB , P10415 , and P23560 .",
"Gene expression profile of metastatic colon cancer cells resistant to cisplatin - induced apoptosis . The current chemotherapeutic modalities for advanced colorectal cancer are limited . DNA - platinating drugs such as cisplatin have poor efficacy against this malignancy . The aim of this study was to identify genes that render survival advantage after cisplatin treatment in metastatic colon cancer . Cell lines SW480 ( primary colon cancer ) and SW620 ( metastatic lesion from the same patient ) were obtained from ATCC . Apoptosis was measured by FACS analysis of cisplatin - treated ( 0 . 01 - 10 micro g / ml ) and untreated cells . Simultaneous analysis of approximately 1200 cDNAs was performed by microarray technique on untreated and treated cells from lines . Microarray results were confirmed by RT - PCR . The SW620 cell line was more resistant to apoptosis induced by cisplatin . Western blot analysis revealed equal expression of pro - caspases 3 , 8 , and 9 in both cell lines . Microarray analysis identified 15 genes and 9 expressed sequence tags ( ESTs ) significantly altered both by cell type ( metastatic vs . non - metastatic ) and treatment vs . non - treatment . Several of these transcripts are well - characterized genes including Q8IVS2 , Q99259 , P19 , P21266 , P12004 D1 , Q13315 , and CO - 029 that have been implicated in various malignancies . In the present study , we have identified a set of genes responsible for apoptosis resistance following treatment with cisplatin in the late stages of carcinogenesis . Targeting these genes may increase chemotherapy effectiveness in advanced colon cancer and reduce toxicity in normal tissue .",
"Ablation of microvessels in vivo upon dimerization of iCaspase - 9 . Anti - angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment . Inhibitors of the endothelial cell pro - survival pathway mediated by P15692 were shown to activate caspases and cause microvascular regression , but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways . Alternatively , if direct activation of an apical pro - apoptotic caspase is sufficient to disrupt microvessels in vivo , such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks . Here , we fused caspase - 9 to a mutated P62942 domain to express an inducible caspase - 9 molecule ( iCaspase - 9 ) that can be activated by a cell - permeable dimerizer drug , and transduced this construct into primary endothelial cells . We found that drug - induced dimerization of iCaspase - 9 is sufficient to activate endogenous caspase - 3 and trigger apoptosis even when endothelial cells are treated with the pro - survival factors P15692 or P09038 . A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase - 9 and elimination of human microvessels engineered in immunodeficient mice . These results demonstrate that the activation of iCaspase - 9 disrupts microvessels in vivo , and suggest a novel anti - angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells .",
"P11274 / P00519 and other kinases from chronic myeloproliferative disorders stimulate single - strand annealing , an unfaithful DNA double - strand break repair . Myeloproliferative disorders ( P53602 ) are stem cell - derived clonal diseases arising as a consequence of acquired aberrations in c - P00519 , Janus - activated kinase 2 ( O60674 ) , and platelet - derived growth factor receptor ( P09619 ) that generate oncogenic fusion tyrosine kinases ( FTK ) , including P11274 / P00519 , P41212 / P00519 , P41212 / O60674 , and P41212 / PDGFbetaR . Here , we show that FTKs stimulate the formation of reactive oxygen species and DNA double - strand breaks ( DSB ) both in hematopoietic cell lines and in P28906 (+) leukemic stem / progenitor cells from patients with chronic myelogenous leukemia ( CML ) . Single - strand annealing ( SSA ) represents a relatively rare but very unfaithful DSB repair mechanism causing chromosomal aberrations . Using a specific reporter cassette integrated into genomic DNA , we found that P11274 / P00519 and other FTKs stimulated SSA activity . Imatinib - mediated inhibition of P11274 / P00519 abrogated this effect , implicating a kinase - dependent mechanism . Y253F , E255K , T315I , and H396P mutants of P11274 / P00519 that confer imatinib resistance also stimulated SSA . Increased expression of either nonmutated or mutated P11274 / P00519 kinase , as is typical of blast phase cells and very primitive chronic phase CML cells , was associated with higher SSA activity . P11274 / P00519 - mediated stimulation of SSA was accompanied by enhanced nuclear colocalization of P43351 and P07992 , which play a key role in the repair . Taken together , these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair .",
"The dynamic alterations of P16104 complex during DNA repair detected by a proteomic approach reveal the critical roles of Ca ( 2 +)/ calmodulin in the ionizing radiation - induced cell cycle arrest . By using DNA nuclease digestion and a quantitative \" dual tagging \" proteomic approach that integrated mass spectrometry , stable isotope labeling , and affinity purification , we studied the histone P16104 - associating protein complex in chromatin in mammalian cells in response to ionizing radiation ( IR ) . In the non - irradiated control cells , calmodulin ( P62158 ) and the transcription elongation factor facilitates chromatin transcription ( FACT ) were associated with P16104 . Thirty minutes after exposing cells to IR the P62158 and FACT complexes dissociated , whereas two DNA repair proteins , poly ( ADP - ribose ) polymerase - 1 and DEAH box polypeptide 30 isoform 1 , interacted with P16104 . Two hours and 30 min after exposure , none of the above proteins were in the complex . H2B , nucleophosmin / B23 , and calreticulin were associated with P16104 in both non - irradiated and irradiated cells . The results suggest that the P16104 complex undergoes dynamic changes upon induction of DNA damage and during DNA repair . The genuine interactions between P16104 and H2B , nucleophosmin / B23 , calreticulin , poly ( ADP - ribose ) polymerase - 1 , and P62158 under each condition were validated by immunoprecipitation / Western blotting and mammalian two - hybrid assays . Because multiple Ca ( 2 +)- binding proteins were found in the P16104 complex , the roles of Ca ( 2 +) were examined . The results indicate that Ca ( 2 +)/ P62158 plays important roles in regulating IR - induced cell cycle arrest , possibly through mediating chromatin structure . The dataset presented here demonstrates that sensitive profiling of the dynamics of functional cellular protein - protein interactions can successfully lead to the dissection of important metabolic or signaling pathways .",
"Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer compared with Western countries . Epidemiological features , trends in morbidity and mortality , various age - specific incidence curves , migrant study results , and analysis of the risk factors , however , suggest that the incidence of breast cancer might be further increasing in Korea . The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis . These include older age , family history of breast cancer , early menarche , late menopause , late full - term pregnancy , and never a breast feeding . Both the establishment of high - risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer . Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea , and the five - year survival rate has been estimated as 80 - 83 % . Recent studies on the identification of susceptibility factors such as genetic polymorphisms of P09488 / T1 / P1 , P21964 , P05181 , P11511 , P05093 , P03372 , P18887 , O43542 , P43351 , TGF - alpha , P01375 , IL - 1B , IL - 1RN , P50613 etc . that predispose individuals to breast cancer by gene - environment or gene - gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy .",
"Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK44___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"Genetic analysis of expression profile involved in retinoid metabolism in non - alcoholic fatty liver disease . AIM : The patients with non - alcoholic fatty liver disease ( NAFLD ) have been reported to be at greater risk for progression to chronic liver disease including liver cirrhosis ( LC ) . To examine the mechanisms for the progression of NAFLD , a genetic analysis of hepatic expression profile in retinoid metabolism in NAFLD was performed since the loss of retinoid signaling is associated with the progression of liver disease via reactive oxygen species ( ROS ) generation . METHODS : Fifty - one genes , which are associated with retinoid metabolism and action , were examined in thirty six subjects including 17 patients with simple steatosis , 11 with non - alcoholic steatohepatitis ( NASH ) and eight controls were examined by real - time reverse transcriptase polymerase chain reaction . Immunohistochemical study was also done by 3 kinds of antibodies . RESULTS : Higher expression of P09455 O95237 , DGT1 / 2 and CES1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively . Expression of P07327 / 2 / 3 , Q92781 / 10 / 11 , O75911 and RALDH1 / 3 was increased in NAFLD , suggesting that oxidation process from retinol to all - trans retinoic acid ( DB00755 ) was enhanced . Importantly , greater expression of O43174 indicated that degradation of DB00755 was enhanced in NAFLD . Further , expression of P00441 / 2 , catalase , thioredoxin and uncoupling protein 2 was also enhanced . CONCLUSION : Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD , which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC .",
"Q13224 - containing DB01221 receptors promote glutamate synapse development in hippocampal interneurons . In postnatal development , Q13224 - containing NMDARs are critical for the functional maturation of glutamatergic synapses . Q13224 - containing NMDARs prevail until the second postnatal week when Q12879 subunits are progressively added , conferring mature properties to NMDARs . In cortical principal neurons , deletion of Q13224 results in an increase in functional AMPAR synapses , suggesting that Q13224 - containing NMDARs set a brake on glutamate synapse maturation . The function of Q13224 in the maturation of glutamatergic inputs to cortical interneurons is not known . To examine the function of Q13224 in interneurons , we generated mutant mice with conditional deletion of Q13224 in interneurons ( Q13224 ( Δ Q99259 ) ) . In Q13224 ( Δ Q99259 ) mice interneurons distributed normally in cortical brain regions . After the second postnatal week , Q13224 ( Δ Q99259 ) mice developed hippocampal seizures and died shortly thereafter . Before the onset of seizures , Q13224 - deficient hippocampal interneurons received fewer glutamatergic synaptic inputs than littermate controls , indicating that Q13224 - containing NMDARs positively regulate the maturation of glutamatergic input synapses in interneurons . These findings suggest that Q13224 - containing NMDARs keep the circuit activity under control by promoting the maturation of excitatory synapses in interneurons .",
"Topoisomerase II - mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation - associated tumorigenesis . AIMS : Both cancer - suppressing and cancer - promoting properties of reactive nitrogen and oxygen species ( RNOS ) have been suggested to play a role in tumor pathology , particularly those activities associated with chronic inflammation . Here , we address the impact of nitric oxide ( NO ) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II ( P11388 ) . We also investigate the contribution of NO to the formation of skin melanoma in mice . RESULTS : Similar to the P11388 - targeting drug , etoposide ( DB00773 ) , the NO - donor , S - nitrosoglutathione ( GSNO ) , induces skin melanomas formation in 7 , 12 - dimethyl - benz [ a ] anthracene ( DMBA ) - initiated mice . To explore the mechanism ( s ) underlying this NO - induced tumorigenesis , we use a co - culture model system to demonstrate that inflamed macrophages with inducible NO synthase ( P35228 ) expression cause γ - P16104 activation , p53 phosphorylation , and chromosome DNA breaks in the target cells . Inhibitor experiments revealed that NO and P11388 isozymes are responsible for the above described cellular phenotypes . Notably , NO , unlike DB00773 , preferentially induces the formation of TOP2β cleavable complexes ( TOP2βcc ) in cells . Moreover , GSNO induced P11388 - dependent DNA sequence rearrangements and cytotoxicity . Furthermore , the incidences of GSNO - and DB00773 - induced skin melanomas were also observed to be lower in the skin - specific top2β - knockout mice . Our results suggest that P11388 isozymes contribute to NO - induced mutagenesis and subsequent cancer development during chronic inflammation . INNOVATION AND CONCLUSIONS : We provide the first experimental evidence for the functional role of P11388 in NO - caused DNA damage , mutagenesis , and carcinogenesis . Notably , these studies contribute to our molecular understanding of the cancer - promoting actions of RNOS during chronic inflammation .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"P15692 activates Q13224 phosphorylation through Dab1 pathway . Vascular endothelial growth factor ( P15692 ) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration . Both P15692 and reelin have been shown to regulate DB01221 type glutamate receptor ( NMDAR ) activity via independent mechanisms . However , it is not known whether the above signaling pathways influence each other on NMDAR regulation . We demonstrate that Disabled 1 ( Dab1 ) , a downstream signaling molecule of reelin pathway mediates P15692 - induced regulation of NMDAR subunit Q13224 . Furthermore , P15692 treatment led to the association of P15692 receptor - 2 ( Flk1 ) and reelin receptor ( apolipoprotein E receptor 2 , ApoER2 ) , and Dab1 as well as Q13224 activation were Flk1 - dependent . Moreover , P15692 treatment could significantly rescue the deficits in phospho - Dab1 levels in reeler ( Reln -/- ) neurons . Our results suggest a major role of P15692 in the regulation of reelin signaling , and Dab1 as a key molecule in the cross talk between reelin and P15692 signaling pathways .",
"Characterization of rat P23510 by monoclonal antibody . OX40 ( CD134 ) is a member of the tumor necrosis factor ( P01375 ) receptor superfamily first identified as a rat T cell activation marker . We previously identified the rat ligand for OX40 ( P23510 ) by molecular cloning . In the present study , we newly generated an anti - rat P23510 mAb ( Q13315 - 2 ) that can inhibit the binding of OX40 to rat P23510 and thus efficiently inhibits the T cell costimulatory activity of rat P23510 . Flow cytometric analyses using Q13315 - 2 and an anti - rat OX40 mAb ( MRC OX40 ) indicated that OX40 was inducible on splenic P01730 (+) T cells by stimulation with immobilized anti - CD3 mAb , while P23510 was not expressed on resting or activated T cells . P23510 was expressed on splenic B cells after stimulation with lipopolysaccharide ( LPS ) , but not on peritoneal macrophages . Interestingly , splenic dendritic cells ( DC ) expressed P23510 constitutively , which was further upregulated by LPS stimulation . The potent costimulatory activities of splenic DC for anti - CD3 - stimulated rat P01730 (+) T cell proliferation and cytokine ( P60568 , P01579 , P22301 , and P35225 ) production were substantially inhibited by Q13315 - 2 . These results indicated that P23510 is expressed on professional antigen - presenting cells ( P25054 ) , and may be involved in humoral immune responses via T - B interaction and in cellular immune responses via T - DC interaction in the rat system .",
"Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .",
"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK33___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK33___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .",
"Dysregulated expression of death , stress and mitochondrion related genes in the sciatic nerve of presymptomatic P00441 ( G93A ) mouse model of Amyotrophic Lateral Sclerosis . Schwann cells are the main source of paracrine support to motor neurons . Oxidative stress and mitochondrial dysfunction have been correlated to motor neuron death in Amyotrophic Lateral Sclerosis ( P35858 ) . Despite the involvement of Schwann cells in early neuromuscular disruption in P35858 , detailed molecular events of a dying - back triggering are unknown . Sciatic nerves of presymptomatic ( 60 - day - old ) P00441 ( G93A ) mice were submitted to a high - density oligonucleotide microarray analysis . DAVID demonstrated the deregulated genes related to death , stress and mitochondrion , which allowed the identification of Cell cycle , ErbB signaling , DB00150 metabolism and O95057 - I - like receptor signaling as the most representative KEGG pathways . The protein - protein interaction networks based upon deregulated genes have identified the top hubs ( TRAF2 , P16104 , Q01094 , O43524 , P43246 , P08138 , P36897 ) and bottlenecks ( TRAF2 , Q01094 , P46527 , Q15672 , O43524 ) . Schwann cells were enriched from the sciatic nerve of presymptomatic mice using flow cytometry cell sorting . qPCR showed the up regulated ( Ngfr , Cdnkn1b , E2f1 , Traf2 and Erbb3 , H2afx , Cdkn1a , Hspa1 , Prdx , Mapk10 ) and down - regulated ( Foxo3 , Mtor ) genes in the enriched Schwann cells . In conclusion , molecular analyses in the presymptomatic sciatic nerve demonstrated the involvement of death , oxidative stress , and mitochondrial pathways in the Schwann cell non - autonomous mechanisms in the early stages of P35858 ."
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"P98164 is downregulated via LPS - P01375 - α - P27361 / 2 signaling pathway in proximal tubule cells . Expression and function of megalin , an endocytic receptor in proximal tubule cells ( PTCs ) , are reduced in diabetic nephropathy , involved in the development of proteinuria / albuminuria . Lipopolysaccharide ( LPS ) is chronically increased in diabetic sera , by the mechanism called metabolic endotoxemia . We investigated low - level LPS - mediated signaling that regulates megalin expression in immortalized rat PTCs ( IRPTCs ) . Incubation of the cells with LPS ( 10 ng / ml ) for 48 h suppressed megalin protein expression and its endocytic function . P01375 - α mRNA expression was increased by LPS treatment , and knockdown of the mRNA with siRNA inhibited LPS - mediated downregulation of megalin mRNA expression at the 24 - h time point . Incubation of IRPTCs with exogenous P01375 - α also suppressed megalin mRNA and protein expression at the 24 - and 48 - h time points , respectively . Q02750 inhibitor PD98059 competed partially but significantly P01375 - α - mediated downregulation of megalin mRNA expression . Collectively , low - level LPS - mediated P01375 - α - P27361 / 2 signaling pathway is involved in downregulation of megalin expression in IRPTCs .",
"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK98___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK32___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"P54252 represses transcription via chromatin binding , interaction with histone deacetylase 3 , and histone deacetylation . P54252 ( P01008 ) , the disease protein in spinocerebellar ataxia type 3 ( P54252 ) , has been associated with the ubiquitin - proteasome system and transcriptional regulation . Here we report that normal P01008 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase - 2 ( P08253 ) gene promoter and represses transcription by recruitment of the histone deacetylase 3 ( O15379 ) , the nuclear receptor corepressor ( NCoR ) , and deacetylation of histones bound to the promoter . Both normal and expanded P01008 physiologically interacted with O15379 and NCoR in a P54252 cell model and human pons tissue ; however , normal P01008 - containing protein complexes showed increased histone deacetylase activity , whereas expanded P01008 - containing complexes had reduced deacetylase activity . Consistently , histone analyses revealed an increased acetylation of total histone H3 in expanded P01008 - expressing cells and human P54252 pons . Expanded P01008 lost the repressor function and displayed altered DNA / chromatin binding that was not associated with recruitment of O15379 , NCoR , and deacetylation of the promoter , allowing aberrant P08253 transcription via the transcription factor GATA - 2 . For transcriptional repression normal P01008 cooperates with O15379 and requires its intact ubiquitin - interacting motifs ( UIMs ) , whereas aberrant transcriptional activation by expanded P01008 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain . These findings demonstrate that normal P01008 binds target promoter regions and represses transcription of a GATA - 2 - dependent target gene via formation of histone - deacetylating repressor complexes requiring its UIM - associated function . Expanded P01008 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions .",
"Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte / macrophage progenitor lineage commitment towards dendritic cell differentiation through down - regulation of receptor activator of nuclear factor - kappaB and c - Fos . Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models . To address this controversy , we used several modes of T lymphocyte activation in osteoclast differentiation -- mitogen - pulse , anti - CD3 / P10747 stimulation and in vivo and in vitro alloactivation . Osteoclast - like cells were generated from non - adherent immature haematopoietic monocyte / macrophage progenitors in murine bone - marrow in the presence of receptor activator of nuclear factor ( NF ) - kappaB ligand ( O14788 ) and monocyte - macrophage colony - stimulating factor ( P09603 ) . All modes of in vivo and in vitro T lymphocyte activation and both P01730 (+) and CD8 (+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell ( DC ) differentiation . Osteoclast - inhibitory effect was associated with T lymphocyte activation and not proliferation , and could be replaced by their culture supernatants . The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis , because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts . Inhibition was associated specifically with increased granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down - regulated Q9Y6Q6 , CD115 , c - Fos and calcitonin receptor expression , and increased differentiation towards CD11c - positive DC . An activated T lymphocyte inhibitory role in osteoclastogenesis , confirmed in vitro and in vivo , mediated through GM - P04141 release , may be used to counteract activated bone resorption mediated by T lymphocyte - derived cytokines in inflammatory and immune disorders . We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis , thereby confirming the functional link between alloreaction and bone metabolism .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"24R , 25 - dihydroxyvitamin D3 promotes the osteoblastic differentiation of human DB05914 . Although 1α , 25 - dihydroxyvitamin D3 [ 1α , 25 ( OH ) 2D3 ] is considered the most biologically active vitamin D3 metabolite , the vitamin D3 prohormone , 25 - hydroxyvitamin D3 [ DB00146 ] , is metabolized into other forms , including 24R , 25 - dihydroxyvitamin D3 [ 24R , 25 ( OH ) 2D3 ] . Herein we show that 24R , 25 ( OH ) 2D3 is fundamental for osteoblastic differentiation of human DB05914 ( hMSCs ) . Our approach involved analyses of cell proliferation , alkaline phosphatase activity , and pro - osteogenic genes ( collagen 1A1 , osteocalcin , vitamin D receptor [ P11473 ] , vitamin D3 - hydroxylating enzymes [ cytochrome P450 hydroxylases : Q6VVX0 , Q02318 , O15528 and Q07973 ] ) and assessment of Ca ( 2 +) mineralization of extracellular matrix . 24R , 25 ( OH ) 2D3 inhibited hMSC proliferation , decreased 1α - hydroxylase ( O15528 ) expression , thereby reducing the ability of hMSCs to convert DB00146 to 1α , 25 ( OH ) 2D3 , and promoted osteoblastic differentiation through increased alkaline phosphatase activity and Ca ( 2 +) mineralization . 24R , 25 ( OH ) 2D3 decreased expression of the 1α , 25 ( OH ) 2D3 receptor , P11473 . 24R , 25 ( OH ) 2D3 but not 1α , 25 ( OH ) 2D3 induced Ca ( 2 +) mineralization dependent on the absence of the glucocorticoid analog , dexamethasone . To elucidate the mechanism ( s ) for dexamethasone - independent 1α , 25 ( OH ) 2D3 inhibition / 24R , 25 ( OH ) 2D3 induction of Ca ( 2 +) mineralization , we demonstrated that 1α , 25 ( OH ) 2D3 increased whereas 24R , 25 ( OH ) 2D3 decreased reactive oxygen species ( ROS ) production . DB00146 also decreased ROS production , potentially by conversion to 24R , 25 ( OH ) 2D3 . Upon inhibition of the vitamin D3 - metabolizing enzymes ( cytochrome P450s ) , DB00146 increased ROS production , potentially due to its known ( low ) affinity for P11473 . We hypothesize that vitamin D3 actions on osteoblastic differentiation involve a regulatory relationship between 24R , 25 ( OH ) 2D3 and 1α , 25 ( OH ) 2D3 . These results implicate 24R , 25 ( OH ) 2D3 as a key player during hMSC maturation and bone development and support the concept that 24R , 25 ( OH ) 2D3 has a bioactive role in the vitamin D3 endocrine system .",
"Vitamin D up - regulates the vitamin D receptor by protecting it from proteasomal degradation in human P01730 + T cells . The active form of vitamin D3 , 1 , 25 ( OH ) 2D3 , has significant immunomodulatory properties and is an important determinant in the differentiation of P01730 + effector T cells . The biological actions of 1 , 25 ( OH ) 2D3 are mediated by the vitamin D receptor ( P11473 ) and are believed to correlate with the P11473 protein expression level in a given cell . The aim of this study was to determine if and how 1 , 25 ( OH ) 2D3 by itself regulates P11473 expression in human P01730 + T cells . We found that activated P01730 + T cells have the capacity to convert the inactive DB00146 to the active 1 , 25 ( OH ) 2D3 that subsequently up - regulates P11473 protein expression approximately 2 - fold . 1 , 25 ( OH ) 2D3 does not increase P11473 mRNA expression but increases the half - life of the P11473 protein in activated P01730 + T cells . Furthermore , 1 , 25 ( OH ) 2D3 induces a significant intracellular redistribution of the P11473 . We show that 1 , 25 ( OH ) 2D3 stabilizes the P11473 by protecting it from proteasomal degradation . Finally , we demonstrate that proteasome inhibition leads to up - regulation of P11473 protein expression and increases 1 , 25 ( OH ) 2D3 - induced gene activation . In conclusion , our study shows that activated P01730 + T cells can produce 1 , 25 ( OH ) 2D3 , and that 1 , 25 ( OH ) 2D3 induces a 2 - fold up - regulation of the P11473 protein expression in activated P01730 + T cells by protecting the P11473 against proteasomal degradation .",
"Overexpression of cytochrome P450 4F2 in mice increases 20 - hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20 - hydroxyeicosatetraenoic acid ( 20 - HETE ) . We previously found that a gain - in - function P78329 variant in a Chinese cohort was associated with elevated urinary 20 - HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen - regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his - tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20 - HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20 - HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20 - HETE levels . Our results show that increased expression of P78329 in mice enhanced 20 - HETE production and elevated blood pressure .",
"Use of fuzzy neural networks in modeling relationships of HPV infection with apoptotic and proliferation markers in potentially malignant oral lesions . To evaluate in oral leukoplakia the relationship between HPV infection and markers of apoptosis ( bcl - 2 , survivin ) and proliferation ( P12004 ) , also conditionally to age , gender , smoking and drinking habits of patients , by means of Fuzzy neural networks ( FNN ) system 21 cases of oral leukopakia , clinically and histologically diagnosed , were examined for HPV DNA presence , bcl - 2 , survivin and P12004 expression . HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR ( nPCR : MY09 - MY11 / P40197 - Q9HCN6 ) , and the HPV genotype determined by direct DNA sequencing . All markers were investigated by means of standardised immunohistochemistry procedure . Data were analysed by chi - square test , crude OR and the 95 % CI ; in blindness , FNN was applied . HPV DNA was found in 8 / 21 OL ( 38 . 1 % ) ; survivin , P12004 , and tobacco smoking were associated in univariate analysis ( p = 0 . 04 ) with HPV DNA status . HPV - 18 was the most frequently detected genotype ( 6 / 8 ) , followed by HPV - 16 ( 2 / 8 ) . FNN revealed that survivin and P12004 , both being expressed in all of OL HPV + ve , were associated with HPV infection . In conclusion , the FNN allowed to hypothesise a model of specific variables associated to HPV infection in OL . The relevance of survivin and P12004 suggest that they may be involved in HPV - mediated deregulation of epithelial maturation and , conversely , that HPV may have a role in the expression level of these two markers . FNN system seems to be an effective tool in the analysis of correlates of OL and HPV infection .",
"Immunocytochemical profile of malignant pleural effusions of small - cell lung cancer . BACKGROUND : Small - cell lung carcinoma ( SCLC ) is a highly malignant tumour of a somewhat distinctive cell type . The aim of this study was to determine the immunocytochemical profile of tumor cells and lymphoid cell in SCLC pleural fluids . METHODS : Nine cases of malignant pleural fluids of SCLC were studied using cell block preparation . In pleural effusions cytologically proven to be malignant in 9 patients with SCLC , the immunocytological features of tumor cells , together with the determination of lymphocytic subsets were documented . RESULTS : In all 9 cases , tumor cells reacted with neuron - specific enolase ( P09104 ) ( 100 % ) , whereas in 6 of 9 cases ( 66 , 66 % ) tumor cell expressed synaptophysin , thyroid transciption factor - 1 ( Q15669 - 1 ) and chromogranin A antigens . Phenotyping of the lymphocytes revealed in the majority of cases an expression of CD3 and P01730 antigens ( 8 and 7 cases , respectively ) in contrast to CD8 and P11836 expression ( 1 and 1 case , respectively ) . CONCLUSIONS : The reactivity pattern of the tumor cells with the markers used in our study is a specific for SCLC . No significant difference in the distribution of lymphocytic subpopulations is observed in correlation with other malignant and no malignant processes involving the pleural cavity .",
"Antagonistic action of novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone analogs on differentiation of human leukemia cells ( HL - 60 ) induced by 1alpha , 25 - dihydroxyvitamin D3 . We examined the effects of two novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone ( 1alpha , 25 - lactone ) analogues on human promyelocytic leukemia cell ( HL - 60 ) differentiation using the evaluation system of the vitamin D nuclear receptor ( P11473 ) / vitamin D - responsive element ( DRE ) - mediated genomic action stimulated by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) and its analogues . We found that the 1alpha , 25 - lactone analogues ( 23S ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9647 ) , and ( 23R ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9648 ) bound much more strongly to the P11473 than the natural ( 23S , 25R ) - DB00136 - 26 , 23 - lactone , but did not induce cell differentiation even at high concentrations ( 10 (- 6 ) M ) . Intriguingly , the differentiation of HL - 60 cells induced by DB00136 was inhibited by either TEI - 9647 or TEI - 9648 but not by the natural lactone . In contrast , retinoic acid or 12 - O - tetradecanoylphorbol - 13 - acetate - induced HL - 60 cell differentiation was not blocked by TEI - 9647 or TEI - 9648 . In separate studies , TEI - 9647 ( 10 (- 7 ) M ) was found to be an effective antagonist of both DB00136 ( 10 (- 8 ) M ) mediated induction of P38936 ( P38936 , CIP1 ) in HL - 60 cells and activation of the luciferase reporter assay in COS - 7 cells transfected with cDNA containing the DRE of the rat DB00146 - 24 - hydroxylase gene and cDNA of the human P11473 . Collectively the results strongly suggest that our novel 1alpha , 25 - lactone analogues , TEI - 9647 and TEI - 9648 , are specific antagonists of 1alpha , 25 ( OH ) 2D3 action , specifically P11473 / DRE - mediated genomic action . As such , they represent the first examples of antagonists , which act on the nuclear P11473 .",
"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .",
"___MASK15___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK15___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK15___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .",
"The role of cubilin gene polymorphisms and their influence on DB00146 and 1 , 25 ( OH ) 2D3 plasma levels in type 1 diabetes patients . BACKGROUND : P98164 and cubilin bind and internalize the DB00146 - DBP complex in the kidney . Once the complex is internalized , DB00146 is released and activated to 1 , 25 ( OH ) 2D3 the ligand for the vitamin D receptor ( P11473 ) . Supporting the important role of cubilin in this process recent findings showed that cubilin deficiency results in decrease of DB00146 and 1 , 25 ( OH ) 2D3 plasma levels . METHODS : Two hundred T1D patients and healthy controls ( n = 200 ) were genotyped for five polymorphisms ( rs3740168 , rs3740165 , rs1801233 , rs1801229 and rs2796835 ) within the cubilin gene . The polymorphisms were analyzed by RFLP or real time PCR . Statistic analyses were performed by using allele - wise and genotype - wise chi2 testing by using BiAS software . A p - value < 0 . 05 was considered as significant . RESULTS : We found that the genotype \" AA \" of the rs3740165 was more frequent in T1D patients compared to healthy controls ( 26 . 7 % vs . 5 . 1 % , p = 4x10 (- 7 ) ) . Nevertheless no association between the rs3740165 polymorphism and the DB00146 or 1 , 25 ( OH ) 2D3 plasma levels was found . No association with the other studied polymorphisms was observed . CONCLUSION : Thus our findings reveal a novel association of the cubilin rs3740165 polymorphism with type 1 diabetes . Nevertheless how exactly this polymorphism could increase the risk to develop type 1 diabetes is subject for further investigations .",
"DB08816 increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : DB08816 is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . DB08816 and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : DB08816 increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .",
"The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners . Mutations in the tumor suppressor genes Q92574 and P49815 , encoding hamartin and tuberin , respectively , cause the tumor syndrome tuberous sclerosis with similar phenotypes . Until now , over 50 proteins have been demonstrated to interact with hamartin and / or tuberin . Besides tuberin , the proteins Q96N67 , ezrin / radixin / moesin , Q8TDY2 , IKKbeta , Melted , P35240 , Q00994 ( p75NTR ) , P07196 , Plk1 and Q9P0N9 have been found to interact with hamartin . Whereas Plk1 and Q9P0N9 have been demonstrated not to bind to tuberin , for all the other hamartin - interacting proteins the question , whether they can also bind to tuberin , has not been studied . P49815 interacts with 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , AMPK , P62158 , Q9BUF7 / Q8NI35 , cyclin A , cyclins D1 , D2 , D3 , Dsh , ERalpha , Erk , FoxO1 , Q15751 , HPV16 E6 , HSCP - 70 , P0DMV8 , P49137 , Q96PY6 , p27KIP1 , Pam , PC1 , PP2Ac , Q15276 , Rheb , RxRalpha / P11473 and Q15796 / 3 . 14 - 3 - 3 beta , epsilon , gamma , eta , sigma , tau , zeta , Akt , Dsh , FoxO1 , Q15751 , p27KIP1 and PP2Ac are known not to bind to hamartin . For the other tuberin - interacting proteins this question remains elusive . The proteins axin , Cdk1 , cyclin B1 , O75807 , GSK3 , P42345 and Q15418 have been found to co - immunoprecipitate with both , hamartin and tuberin . The kinases Cdk1 and IKKbeta phosphorylate hamartin , Erk , Akt , P49137 , AMPK and Q15418 phosphorylate tuberin , and GSK3 phosphorylates both , hamartin and tuberin . This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin .",
"___MASK32___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK32___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Ligand - induced transrepression by P11473 through association of Q9UIG0 with acetylated histones . We have previously shown that the novel DB00171 - dependent chromatin - remodeling complex WINAC is required for the ligand - bound vitamin D receptor ( P11473 ) - mediated transrepression of the DB00146 1alpha - hydroxylase ( 1alpha ( OH ) ase ) gene . However , the molecular basis for P11473 promoter association , which does not involve its binding to specific DNA sequences , remains unclear . To address this issue , we investigated the function of Q9UIG0 in terms of the association between WINAC and chromatin for ligand - induced transrepression by P11473 . Results of in vitro experiments using chromatin templates showed that the association of unliganded P11473 with the promoter required physical interactions between Q9UIG0 and both P11473 and acetylated histones prior to P11473 association with chromatin . The acetylated histone - interacting region of Q9UIG0 was mapped to the bromodomain , and a Q9UIG0 mutant lacking the bromodomain served as a dominant - negative mutant in terms of ligand - induced transrepression of the 1alpha ( OH ) ase gene . Thus , our findings indicate that WINAC associates with chromatin through a physical interaction between the Q9UIG0 bromodomain and acetylated his tones , which appears to be indispensable for P11473 / promoter association for ligand - induced transrepression of 1alpha ( OH ) ase gene expression .",
"P98164 mediates the transport of leptin across the blood - P04141 barrier . Leptin , a peptide hormone secreted by adipose tissue , exhibits a large range of central and peripheral actions . It has been proposed that the participation of leptin in diseases such as obesity is due to , at least in part , its impaired transport across the blood - brain barrier ( BBB ) . Since , the mechanisms by which brain takes up leptin remain unclear , we set out to study how leptin may cross the BBB . We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans . We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium . Indeed , the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer ' s disease was correlated with poor entry of leptin into the brain . Moreover , amyloid beta ( Abeta ) deposits of choroid plexus could be disturbing megalin function . The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain .",
"Molecular cloning and characterization of O75197 , a novel P01130 family protein with mitogenic activity . We report molecular cloning and initial functional characterization of a novel member of the low density lipoprotein receptor ( P01130 ) gene family . The cDNA was isolated from a human osteoblast cDNA library and encoded a 1 , 615 amino acids protein designated as O75197 . It has , in the extracellular region , a cluster of three P01130 ligand binding repeats at a juxtamembrane position and four P01133 precursor homology domains separated by YWTD spacer repeats . The entire ectodomain shares the same modular organization with the middle portion of the extracellular regions of two P01130 family members , P01130 - related protein ( Q14764 ) , and P98164 / megalin . O75197 mRNA was expressed in most of the adult and fetal tissues examined . The highest expression level was seen in aorta . In human osteosarcoma cells examined , O75197 mRNA was highly enriched in TE85 cells , moderately expressed in MG63 cells and primary human osteoblasts , and undetectable in SaOS - 2 cells . NIH 3T3 cells transfected with either full length O75197 or its ectodomain showed significantly increased proliferation , whereas transfection of intracellular domain had no proliferative effect . We predict that O75197 is a multi - functional protein with potential mitogenic activity .",
"Regulatory role of promoter and 3 ' UTR variants of vitamin D receptor gene on cytokine response in pulmonary tuberculosis . Vitamin D receptor ( P11473 ) gene variants are shown to regulate immune response in tuberculosis . We studied the influence of P11473 promoter ( Cdx - 2 and A1012G ) , 3 ' untranslated region ( Apa I , Bsm I , and Taq I ) and start codon ( Fok I ) polymorphisms on 1 , 25 ( OH )( 2 ) D ( 3 )- modulated IL - 12p40 , P01579 , P22301 , and P05113 response to live Mycobacterium tuberculosis and its culture filtrate antigen ( O75347 ) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients . In peripheral blood mononuclear cell cultures with O75347 and 1 , 25 ( OH )( 2 ) D ( 3 ) , IL - 12p40 , and P01579 levels were significantly decreased ( p < 0 . 05 ) and P22301 levels were significantly increased ( p < 0 . 05 ) in patients with GG genotype . The extended genotype bbaaTT ( baT haplotype ) was associated with decreased IL - 12p40 and P01579 levels and significantly increased P22301 levels ( p < 0 . 05 ) . The Cdx - 2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased P22301 response , which suggests that 1 , 25 ( OH )( 2 ) D ( 3 ) probably through the P11473 polymorphic variants augments the anti - inflammatory response at the site of M . tuberculosis infection .",
"Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . ___MASK1___ , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5 - Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non - human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose - dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg / kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics .",
"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK15___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .",
"Integration of hormone signaling in the regulation of human DB00146 24 - hydroxylase transcription . The current study sought to define the molecular mechanisms involved in the cross talk between 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] and activators of PKC in the regulation of 25 ( OH ) D ( 3 ) 24 - hydroxlyase [ 24 ( OH ) ase ] . Transfection of the h24 ( OH ) ase promoter construct [ - 5 , 500 /- 22 luciferase ; vitamin D response elements at - 294 /- 274 and - 174 /- 151 ; AP - 1 site at - 1 , 167 /- 1 , 160 ] in vitamin D receptor ( P11473 ) - transfected COS - 7 cells resulted in strong activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . In these cells , cotreatment with the PKC activator TPA and 1 , 25 ( OH )( 2 ) D ( 3 ) yielded a 27 - fold increase in luciferase activity , which was 2 - to 3 - fold greater than activation obtained with 1 , 25 ( OH )( 2 ) D ( 3 ) alone ( P < 0 . 05 ) . Similar results were observed using LLCPK - 1 kidney cells , suggesting that the previously observed enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- induced renal 24 ( OH ) ase mRNA and activity by PKC activation occurs at the level of transcription . The functional cooperation between PKC activation and P11473 was not found to be mediated by the AP - 1 site in the h24 ( OH ) ase promoter or by enhanced binding of GRIP or Q15648 to P11473 and was also not due to PKC - mediated phosphorylation of P11473 on DB00133 ( 51 ) . Our study demonstrates that , in LLCPK - 1 kidney cells , the PKC enhancement of 1 , 25 ( OH )( 2 ) D ( 3 )- stimulated transcription may be due , in part , to an increase in P11473 concentration . In addition , inhibitors of the MAPK pathway were found to decrease the TPA enhancement ( P < 0 . 05 ) . Because activation of MAPK has been reported to result in the phosphorylation of Q15788 and in functional cooperation between Q15788 and CREB binding protein , we propose that the potentiation of P11473 - mediated transcription may also be mediated through changes in the phosphorylation of specific P11473 coregulators .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Identification of novel human Cdt1 - binding proteins by a proteomics approach : proteolytic regulation by P25054 / CCdh1 . In mammalian cells , Cdt1 activity is strictly controlled by multiple independent mechanisms , implying that it is central to the regulation of DNA replication during the cell cycle . In fact , unscheduled Cdt1 hyperfunction results in rereplication and / or chromosomal damage . Thus , it is important to understand its function and regulations precisely . We sought to comprehensively identify human Cdt1 - binding proteins by a combination of Cdt1 affinity chromatography and liquid chromatography and tandem mass spectrometry analysis . Through this approach , we could newly identify 11 proteins , including subunits of anaphase - promoting complex / cyclosome ( P25054 / C ) , O60264 and Q9UIG0 , topoisomerase I and IIalpha , Q9BQ67 / Q9BQ67 , nucleophosmin / nucleoplasmin , and importins . In vivo interactions of Cdt1 with P25054 / C ( Cdh1 ) , O60264 , topoisomerase I and IIalpha , and Q9BQ67 / Q9BQ67 were confirmed by coimmunoprecipitation assays . A further focus on P25054 / C ( Cdh1 ) indicated that this ubiquitin ligase controls the levels of Cdt1 during the cell cycle via three destruction boxes in the Cdt1 N - terminus . Notably , elimination of these destruction boxes resulted in induction of strong rereplication and chromosomal damage . Thus , in addition to P21583 ( Skp2 ) and cullin4 - based ubiquitin ligases , P25054 / C ( Cdh1 ) is a third ubiquitin ligase that plays a crucial role in proteolytic regulation of Cdt1 in mammalian cells .",
"O60603 signaling protects mice from tumor development in a mouse model of colitis - induced cancer . Inflammatory bowel disease ( Q9UKU7 ) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer . The etiology of Q9UKU7 is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host . Toll - like receptor ( TLR ) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis , innate immunity and the enhancement of intestinal epithelial cell ( IEC ) integrity . However , the role of O60603 in the development of colorectal cancer has not been studied . We utilized the AOM - DSS model for colitis - associated colorectal cancer ( CAC ) in wild type ( WT ) and O60603 (-/-) mice . Colons harvested from WT and O60603 (-/-) mice were used for histopathology , immunohistochemistry , immunofluorescence and cytokine analysis . Mice deficient in O60603 developed significantly more and larger colorectal tumors than their WT controls . We provide evidence that colonic epithelium of O60603 (-/-) mice have altered immune responses and dysregulated proliferation under steady - state conditions and during colitis , which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth . At the earliest time - points assessed , O60603 (-/-) colons exhibited a significant increase in aberrant crypt foci ( Q9NQ94 ) , resulting in tumors that developed earlier and grew larger . In addition , the intestinal microenvironment revealed significantly higher levels of P05231 and Q16552 concomitant with increased phospho - P40763 within Q9NQ94 . These observations indicate that in colitis , O60603 plays a protective role against the development of CAC .",
"Activation of the interleukin - 6 / Janus kinase / P40763 pathway in pleomorphic adenoma of the parotid gland . The interleukin - 6 ( P05231 ) / Janus kinase ( JAK ) / signal transducer and activator of transcription 3 ( P40763 ) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors , e . g . , of pleomorphic adenoma ( PA ) . In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs ( miRNAs ) regulated by this pathway in isolated duct - and myoepithelial cells in PA . 46 PAs were immunostained and 10 of these were used for in situ hybridization ( ISH ) . Six frozen specimens were analyzed using reverse transcription - polymerase chain reaction ( RT - PCR ) . Using immunohistochemistry , P05231 , P23458 , O60674 and P40763 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue . Using RT - PCR cyclin D1 , fibroblast growth factor 2 , and P38936 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland . ISH showed significant overexpression of miR - 181b in PA , while miR - 21 was undetectable in PA and normal tissue . Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs . Our findings brings us one step closer to targeted treatment of this tumor entity , although in vitro studies are warranted to confirm this .",
"Structure - activity relationships in Q9NYK1 agonistic 1H - imidazo [ 4 , 5 - c ] pyridines . Engagement of Q9NYK1 in plasmacytoid dendritic cells leads to the induction of IFN - α / β which plays essential functions in the control of adaptive immunity . We had previously examined structure - activity relationships ( SAR ) in Q9NYK1 / 8 - agonistic imidazoquinolines with a focus on substituents at the N ( 1 ) , C ( 2 ) , N ( 3 ) and N ( 4 ) positions , and we now report SAR on 1H - imidazo [ 4 , 5 - c ] pyridines . 1 - Benzyl - 2 - butyl - 1H - imidazo [ 4 , 5 - c ] pyridin - 4 - amine was found to be a pure Q9NYK1 - agonist with negligible activity on Q9NR97 . Increase in potency was observed in N ( 6 )- substituted analogues , especially in those compounds with electron - rich substituents . Direct aryl - aryl connections at P13671 abrogated activity , but Q9NYK1 agonism was reinstated in 6 - benzyl and 6 - phenethyl analogues . Consistent with the pure Q9NYK1 - agonistic behavior , prominent IFN - α induction in human PBMCs was observed with minimal proinflammatory cytokine induction . A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine . Distinct differences in N ( 6 )- substituted analogues were observed with respect to IFN - α induction in human PBMCs on the one hand , and Q07108 upregulation in lymphocytic subsets , on the other .",
"Expression of vitamin D receptor ( P11473 ) , cyclooxygenase - 2 ( P35354 ) and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) in benign and malignant ovarian tissue and DB00146 ( 25 ( OH2 ) D3 ) and prostaglandin E2 ( DB00917 ) serum level in ovarian cancer patients . Ovarian carcinomas are associated with increased inflammation which is based upon an up - regulation of inducible cyclooxygenase - 2 ( P35354 ) . Moreover , based on our previous published data , the extra - renal vitamin D metabolism seems to be dysregulated in comparison to healthy tissue . In order to gain further insight into the prostaglandin ( PG ) - and vitamin D - metabolism in ovarian carcinomas , the study aimed to evaluate the expression of the PG metabolising enzymes P35354 and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) compared to the vitamin D receptor ( P11473 ) in benign and malignant ovarian tissues . Additionally , we determined the DB00146 ( 25 ( OH2 ) D3 ) serum levels . Expression of P11473 , P35354 and P15428 was determined by Western blot analysis . Serum levels of 25 ( OH2 ) D3 and DB00917 were measured by chemiluminescence - based and colorimetric immunoassay . We detected significantly higher expressions of the PG metabolising enzymes P15428 and P35354 in malignant tissue and DB00917 serum levels were 2 - fold higher in tumour patients . Furthermore , we found an inverse correlation to the P11473 - expression which was 62 . 1 % lower in malignant tissues compared to that in benign tissues . Surprisingly , we could not detect any differences between the 25 ( OH2 ) D3 serum levels in either group ( n = 20 ) . These data suggest a correlation between PG - and vitamin D - metabolism in ovarian carcinomas .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK54___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Membrane receptors for vitamin D metabolites . Membrane - initiated signaling by steroid hormones is now widely accepted . Current debate is centered upon which protein moieties act as membrane - associated receptors . In this review , we consider evidence for the classical vitamin D receptor ( P11473 ) in this role , as well as the more recently identified 1 , 25D3 - MARRS ( membrane - associated , rapid response steroid binding ) receptor , also known as P30101 / GRp58 . The structure of the 1 , 25D3 - MARRS receptor is discussed , with emphasis on two thioredoxin domains that promote dimerization and ligand binding . We then summarize recent studies on a 24 , 25 ( OH ) 2D3 binding protein -- catalase -- and how ligand - induced decreases in enzymatic activity produce increased reactive oxygen species that target both the 1 , 25D3 - MARRS receptor -- but not the P11473 -- and the protein kinase C signaling pathway . Finally , we briefly discuss the available literature suggesting that the metabolite DB00146 may also be biologically active .",
"Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .",
"The use of the VerifyNow Q9H244 point - of - care device to monitor platelet function across a range of Q9H244 inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point - of - care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 ( VN - Q9H244 ) POC device with light transmission aggregometry ( P01374 ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 and VN - Q9H244 at baseline and after dosing . ___MASK98___ 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device - reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 showed a very similar pattern to that found with VN - Q9H244 measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 appeared to be narrower than that of P01374 . With two different thienopyridines , the VN - Q9H244 device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .",
"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .",
"Selective use of multiple vitamin D response elements underlies the 1 alpha , 25 - dihydroxyvitamin D3 - mediated negative regulation of the human O15528 gene . The human 25 - hydroxyvitamin D3 ( DB00146 ) 1alpha - hydroxylase , which is encoded by the O15528 gene , catalyzes the metabolic activation of the DB00146 into 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) , the most biologically potent vitamin D3 metabolite . The most important regulator of O15528 gene activity is DB00136 itself , which down - regulates the gene . The down - regulation of the O15528 gene has been proposed to involve a negative vitamin D response element ( nVDRE ) that is located approximately 500 bp upstream from transcription start site ( TSS ) . In this study , we reveal the existence of two new P11473 - binding regions in the distal promoter , 2 . 6 and 3 . 2 kb upstream from the TSS , that bind vitamin D receptor - retinoid X receptor complexes . Since the down regulation of the O15528 gene is tissue - and cell - type selective , a comparative study was done for the new DB00136 - responsive regions in P29320 - 293 human embryonic kidney and MCF - 7 human breast cancer cells that reflect tissues that , respectively , are permissive and non - permissive to the phenomenon of DB00136 - mediated down - regulation of this gene . We found significant differences in the composition of protein complexes associated with these O15528 promoter regions in the different cell lines , some of which reflect the capability of transcriptional repression of the O15528 gene in these different cells . In addition , chromatin architecture differed with respect to chromatin looping in the two cell lines , as the new distal regions were differentially connected with the proximal promoter . This data explains , in part , why the human O15528 gene is repressed in P29320 - 293 but not in MCF - 7 cells .",
"Vitamin D receptor - mediated suppression of RelB in antigen presenting cells : a paradigm for ligand - augmented negative transcriptional regulation . The immunological effects of vitamin D receptor ( P11473 ) ligands include inhibition of dendritic cell ( DC ) maturation , suppression of T - helper type 1 ( Th1 ) T - cell responses and facilitation of antigen - specific immune tolerance in vivo . While studying the molecular profile of DCs cultured in the presence of 1alpha , DB00146 or synthetic D3 analogs we observed that expression of the NF - kappaB family member RelB , which plays an essential role in DC differentiation and maturation , is selectively suppressed by P11473 ligands . Further in vitro and in vivo studies of P11473 - mediated RelB suppression indicated that the mechanism for this effect involves direct binding of P11473 / RXR alpha to a defined region of the relB promoter and assembly of a negative regulatory complex containing O15379 , Q13547 , Q9Y618 and , most likely , other factors . Interestingly , promoter engagement by P11473 and O15379 , but not the other identified components , is enhanced by addition of a P11473 ligand and inhibited by a pro - maturational stimulus ( LPS ) that results in RelB upregulation . Promoter assays in a panel of cell lines suggest that the P11473 ligand - dependent component of relB suppression may occur selectively in antigen presenting cells . Cell type - specific , ligand - enhanced negative transcriptional regulation represents a potentially novel paradigm for P11473 - controlled genes . In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK38___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK38___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Characterization of background anti - trinitrophenyl plaque - forming cells observed in several strains of mice . Normal mice have a large number of background anti - trinitrophenyl ( TNP ) antibody - forming cells ( AFC ) in their spleens ( about 40 - 50 anti - TNP P27918 / 10 ( 6 ) cells ) . We investigated this among several mouse strains , i . e . , C57BL / 6 , C3H / He , Balb / c , ddd , and ICR mice , and found that all strains had a similar number of anti - TNP P27918 ( plaque - forming cells ) . Developmental aspects of background anti - TNP P27918 in the ontogenic process were also investigated . The number of anti - TNP P27918 increased logari thmically during the first few days of age , reached a peak on the 13th day and attained a constant value within 30 days . Neonatal thymectomy did not decrease the number of background anti - TNP P27918 but such treatment decreased the anti - TNP P27918 response to TNP - HRBC ( horse red blood cells ) immunization . Germ - free ICR mice had a number of background anti - TNP P27918 similar to that of conventional ICR mice . Avidity of background anti - TNP P27918 was compared among mice of several ages and it was shown that there were no differences among them . These results suggest that the occurrence of these background anti - TNP P27918 is not elicited by the immune response but by the natural maturation of precursors of Q9NQ94 without antigenic stimulation .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK98___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK98___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK47___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK47___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK47___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .",
"Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid - mediated responses in the mammary glands of cycling rats . Prenatal exposure to Q03001 disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after Q03001 exposure . Our aim was to assess the effect of prenatal Q03001 exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats . Pregnant Wistar rats were exposed to either 25 or 250 g / kg / day ( 25 and 250 Q03001 , respectively ) or to vehicle . Female offspring were autopsied on postnatal day ( P01160 ) 50 or 110 . Ovarian steroid serum levels , the expression of steroid receptors and their co - regulators Q9Y6Q9 and Q9Y618 in the mammary gland , and angiogenesis were evaluated . At P01160 50 , all Q03001 - treated animals had lower serum levels of progesterone , while estradiol levels remained unchanged . The higher dose of Q03001 increased mammary ERα and decreased Q9Y6Q9 expression at P01160 50 and P01160 110 . Q9Y618 protein levels were similar among groups at P01160 50 , whereas at P01160 110 , animals exposed to 250 Q03001 showed a lower Q9Y618 expression . Interestingly , in the control and 25 Q03001 groups , Q9Y618 increased from P01160 50 to P01160 110 . At P01160 50 , an increased vascular area associated with higher P15692 expression was observed in the 250 Q03001 - treated rats . At P01160 110 , the vascular area was still increased , but P15692 expression was similar to that of control rats . The present results demonstrate that prenatal exposure to Q03001 alters the endocrine environment of the mammary gland and its angiogenic process . Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre - neoplastic lesions found later in life . This article is part of a Special Issue entitled ' Endocrine disruptors ' .",
"Comparison of human B cell activation by Q9NYK1 and Q9NR96 agonists . BACKGROUND : Human B cells and plasmacytoid dendritic cells ( pDC ) are the only cells known to express both Q9NYK1 and Q9NR96 . Plasmacytoid dendritic cells are the primary IFN - alpha producing cells in response to Q9NYK1 and Q9NR96 agonists . The direct effects of Q9NYK1 stimulation on human B cells is less understood . The objective of this study was to compare the effects of Q9NYK1 and Q9NR96 stimulation on human B cell function . RESULTS : Gene expression and protein production of cytokines , chemokines , various B cell activation markers , and immunoglobulins were evaluated . Purified human P15391 + B cells ( 99 . 9 % , containing both naïve and memory populations ) from peripheral blood were stimulated with a Q9NYK1 - selective agonist ( 852A ) , Q9NYK1 / 8 agonist ( 3M - 003 ) , or Q9NR96 selective agonist CpG ODN ( CpG2006 ) . Q9NYK1 and Q9NR96 agonists similarly modulated the expression of cytokine and chemokine genes ( P05231 , MIP1 alpha , MIP1 beta , P01375 alpha and P01374 ) , co - stimulatory molecules ( P33681 , P25942 and P19256 ) , Fc receptors ( CD23 , CD32 ) , anti - apoptotic genes ( Q07817 ) , certain transcription factors ( MYC , Q9UL49 ) , and genes critical for B cell proliferation and differentiation ( P21854 , Q9HBE5 ) . Both agonists also induced protein expression of the above cytokines and chemokines . Additionally , Q9NYK1 and Q9NR96 agonists induced the production of IgM and IgG . A Q9NR97 - selective agonist was comparatively ineffective at stimulating purified human B cells . CONCLUSION : These results demonstrate that despite their molecular differences , the Q9NYK1 and Q9NR96 agonists induce similar genes and proteins in purified human B cells .",
"Q9NR97 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1 . Toll - like receptors ( TLR ) are important in recognizing microbial pathogens and triggering host innate immune responses , including autophagy , and in the mediation of immune activation during human immunodeficiency virus type - 1 ( HIV ) infection . We report here that Q9NR97 activation in human macrophages induces the expression of the human cathelicidin microbial peptide ( CAMP ) , the vitamin D receptor ( P11473 ) and cytochrome P450 , family 27 , subfamily B , polypeptide 1 ( O15528 ) , which 1α - hydroxylates the inactive form of vitamin D , DB00146 , into its biologically active metabolite . Moreover , we demonstrate using RNA interference , chemical inhibitors and vitamin D deficient media that Q9NR97 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism . These data support an important role for vitamin D in the control of HIV infection , and provide a biological explanation for the benefits of vitamin D . These findings also provide new insights into potential novel targets to prevent and treat HIV infection .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK93___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"DB00146 attenuates experimental periodontitis through downregulation of O00206 and P23458 / P40763 signaling in diabetic mice . Vitamin D has been known to be closely associated with diabetes and periodontitis while the underlying mechanism has yet to be clarified . The present study aimed to discover the effect of 25 - hydroxyvitamin D3 ( 25 - OHD3 ) on glycemic control and periodontal health in mice with periodontitis superimposed on experimental diabetes ( known as diabetic periodontitis ) . We showed that 25 - OHD3 intraperitoneal injection attenuated diabetic periodontitis by reducing serum fasting blood glucose , glycosylated hemoglobin and P01375 - α levels , which led to decreased alveolar bone loss . Immunohistochemical staining and western blot analysis of gingival epithelia revealed that vitamin D receptor ( P11473 ) expression was enhanced upon 25 - OHD3 treatment , while toll - like receptor 4 ( O00206 ) expression was reduced . The expressions of Janus family kinase ( JAK ) 1 and signal transducer and activator of transcription ( P35610 ) 3 as well as their phosphorylation were inhibited in gingival epithelia of diabetic periodontitis mice , whereas the expression and phosphorylation of P42224 remained unchanged . These results suggest that 25 - OHD3 could improve diabetic periodontitis through downregulation of O00206 and P23458 / P40763 signaling in the gingival epithelium . Our study extends the previous findings on the regulation of diabetes with periodontitis , and may also provide a potential therapy for the patients with this disease .",
"Tumor progression in the LPB - Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status . Previous studies have suggested that 1 , 25 dihydroxyvitamin D ( 3 ) ( 1 , 25 ( OH ) 2D3 ) induces cell cycle arrest and / or apoptosis in prostate cancer cells in vitro , suggesting that vitamin D may be a useful adjuvant therapy for prostate cancer and a chemopreventive agent . Most epidemiological data however shows a weak link between serum DB00146 and risk of prostate cancer . To explore this dichotomy we have compared tumor progression in the LPB - Tag model of prostate in P11473 knock out ( VDRKO ) and wild type ( VDRWT ) mice . On the C57BL / 6 background LPB - Tag tumors progress significantly more rapidly in the VDRKO mice . VDRKO tumors show significantly higher levels of cell proliferation than VDRWT tumors . In mice supplemented with testosterone to restore the serum levels to the normal range , these differences in tumor progression , and proliferation are abrogated , suggesting that there is considerable cross - talk between the androgen receptor ( AR ) and the vitamin D axis which is reflected in significant changes in steady state mRNA levels of the AR , P12004 , cdk2 survivin and P12314 and 2 genes . These alterations may explain the differences between the in vitro data and the epidemiological studies .",
"Tumor Necrosis Factor alpha ( TNFalpha ) regulates P25942 expression through Q8N9N5 phosphorylation . P25942 plays an important role in mediating inflammatory response and is mainly induced by JAK / P35610 phosphorylation cascade . TNFalpha is the key cytokine that activates P25942 during inflammation and tumorigenesis . We have earlier shown that Q8N9N5 can repress the transcription of P12004 D1 promoter by forming a Q13547 dependent repressor complex . In this study , we show that Q8N9N5 regulates the transcription of NF - kappaB target gene P25942 . Q8N9N5 recruits Q13547 and forms a repressor complex on P25942 promoter and keeps its basal transcription in check . Further , we show that TNFalpha stimulation induces Q8N9N5 phosphorylation at DB00133 - 347 and promotes its cytoplasmic translocation , thus releasing its negative effect . Concomitantly , TNFalpha induced phosphorylation of P42224 at DB00135 - 701 by P23458 facilitates its nuclear translocation and activation of P25942 through p300 recruitment and core Histone - 3 acetylation . Thus , TNFalpha mediated regulation of P25942 expression occurs by dual phosphorylation of Q8N9N5 and P42224 .",
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK86___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK86___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK86___ .",
"Plasma membrane rafts and chaperones in cytokine / P35610 signaling . We and others have recently obtained data suggesting that cytokine - P35610 signaling in many different cell - types is a chaperoned pathway initiated at the level of specialized plasma membrane microdomains called \" rafts \" ( the \" raft - P35610 signaling hypothesis \" ) . These findings are of broad significance in that all cytokines and growth factors initiate signaling in target cells by interacting with respective cell - surface receptors . The new data suggest that raft microdomains represent the units of function at the cell - surface through which ligand - stimulated P35610 signaling is initiated . Moreover , recent evidence shows the involvement of chaperone proteins in regulating the P35610 signaling pathway . These chaperones include the human homolog of the tumorous imaginal disc 1 protein ( hTid1 ) which associates with O60674 ( O60674 ) at the level of the plasma membrane , heat shock protein 90 ( HSP90 ) which associates with P40763 and P42224 proteins in caveolin - 1 - containing raft and cytoplasmic complexes , and glucose regulated protein 58 ( P30101 / ER - 60 / P30101 ) , a thiol dependent protein - disulfide isomerase , found in association with P40763 \" statosome \" complexes in the cytosol and in the raft fraction . We suggest a function of the HSP90 chaperone system in preserving P05231 / P40763 signaling in liver cells in the context of fever . The identification and function of protein partners associated with specific P35610 species in rafts and in cytosolic complexes , and in the efficient departure of cytokine - activated STATs from the cytosolic face of rafts towards the cell nucleus are now areas of active investigation .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .",
"___MASK86___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK86___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK86___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK86___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK93___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .",
"Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case - controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . ___MASK47___ , the addictive component of cigarettes , accelerates cell proliferation through nicotinic acetylcholine receptors ( nAChR ) . In this study , we show that human BACs produce acetylcholine ( ACh ) and contain several cholinergic factors including acetylcholinesterase ( P22303 ) , choline acetyltransferase ( P28329 ) , choline transporter 1 ( Q9GZV3 , Q9GZV3 ) , vesicular acetylcholine transporter ( Q16572 , Q16572 ) , and nACh receptors ( AChRs , CHRNAs ) . ___MASK47___ increased the production of ACh in human BACs , and ACh acts as a growth factor for these cells . ___MASK47___ - induced ACh production was mediated by α7 - , α3β2 - , and β3 - nAChRs , P28329 and Q16572 pathways . We observed that nicotine upregulated P28329 and Q16572 . Therefore , we conjectured that Q16572 antagonists , such as vesamicol , may suppress the growth of human BACs . Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models . Vesamicol did not have any effect on P01133 or insulin - like growth factor - II - induced growth of human BACs . siRNA - mediated attenuation of Q16572 reversed the apoptotic activity of vesamicol . We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol . Taken together , our results suggested that disruption of nicotine - induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Increased vitamin D - driven signalling and expression of the vitamin D receptor , P35548 , and O14788 in tooth resorption in cats . Tooth resorption occurs in 20 - 75 % of cats ( Felis catus ) . The aetiology is not known , but vitamin D is suggested to be involved . Vitamin D acts through a nuclear receptor ( P11473 ) and increases the expression of receptor activator of nuclear factor - kappaB ligand ( rankl ) and muscle segment homeobox 2 ( msx2 ) genes . Mice lacking the muscle segment homeobox 2 ( msx2 ) gene show decreased levels of rankl , suggesting an interaction among P11473 , P35548 , and O14788 . Here , we investigated the expression of P11473 , P35548 , and O14788 proteins , and the activity of the P11473 - mediated signalling pathway ( using the quantitative polymerase chain reaction on P11473 target genes ) , in tooth resorption , and measured the serum levels of vitamin D metabolites in cats . Tooth resorption was categorized into either resorptive or reparative stages . In the resorptive stage , odontoclasts expressed P35548 and O14788 ( 100 % and 88 % , respectively ) and fibroblasts expressed P11473 and P35548 ( both at 100 % ) , whereas fibroblasts expressed O14788 in only 29 % of the sites analysed . In the reparative stage , cementoblasts expressed P11473 , P35548 , and O14788 , whereas fibroblasts expressed P11473 and P35548 , but not O14788 . The vitamin D status did not differ between the groups , based on the serum levels of DB00146 . However , increased expression of P11473 protein , and the relative gene expression levels of 1alpha - hydroxylase and the P11473 - target gene , 24 - hydroxylase , indicated the involvement of an active vitamin D signalling in the pathophysiology of tooth resorption in cats .",
"Expression of vitamin D receptor and 25 - hydroxyvitamin D3 - 1 { alpha }- hydroxylase in normal and malignant human colon . Considerable evidence exists to support the use of vitamin D to prevent and / or treat colorectal cancer . However , the routine use of bioactive vitamin D , 1 , 25 - dihydroxyvitamin D3 , is limited by the side effect of toxic hypercalcemia . Recent studies , however , suggest that colonic epithelial cells express 25 - hydroxyvitamin D3 - 1alpha - hydroxylase , an enzyme that converts nontoxic pro - vitamin D , DB00146 [ DB00146 ] , to its bioactive form . Yet , nothing is known as to the cellular expression of 1alpha - hydroxylase and the vitamin D receptor ( P11473 ) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci ( Q9NQ94 ) and polyps [ addressing the possibility of using nontoxic DB00146 for chemoprevention ] , nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [ relevant to using DB00146 for chemotherapy ] . In this study , we show that 1alpha - hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs , polyps , and colorectal cancer irrespective of tumor cell differentiation . In contrast , P11473 levels were low in normal colonic epithelial cells ; were increased in ACFs , polyps , and well - differentiated tumor cells ; and then declined as a function of tumor cell de - differentiation . Both 1alpha - hydroxylase and P11473 levels were negligible in tumor cells metastasizing to regional lymph nodes . Overall , these data support using DB00146 for colorectal cancer chemoprevention but suggest that pro - vitamin D is less likely to be useful for colorectal cancer chemotherapy ."
] |
[
"___MASK15___",
"___MASK1___",
"___MASK32___",
"___MASK38___",
"___MASK47___",
"___MASK54___",
"___MASK86___",
"___MASK93___",
"___MASK98___"
] |
___MASK93___
|
MH_train_396
|
interacts_with DB00120?
|
[
"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .",
"HRAS1 and P01308 genes are relocated but not structurally altered as a result of the t ( 7 ; 11 )( p15 ; p15 ) in a clone from a patient with acute myeloid leukaemia ( M4 ) . A patient whose leukaemic cells carried the rare t ( 7 ; 11 )( p15 ; p15 ) was diagnosed as having acute myelomonocytic leukaemia ( AML - M4 ) , and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation . Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the P00519 and P11274 genes . Chromosome in situ hybridization studies showed that both the HRAS1 and P01308 genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p . Neither HRAS1 nor P01308 were structurally rearranged . Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA . Because the P01308 gene , which was also translocated , is probably located proximal to HRAS1 on chromosome 11p , it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK38___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK61___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK89___ and Tissue P00747 Activator in Occluded Arteries .",
"Differential radiosensitisation by ZD1839 ( ___MASK34___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK34___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"Novel roles of Akt and P42345 in suppressing TGF - beta / P36897 - mediated P84022 activation . P01308 - like growth factor - I inhibits transforming growth factor - beta ( TGF - beta ) signaling by blocking activation of P84022 ( S3 ) , via a phosphatidylinositol 3 - kinase ( PI3K ) / Akt - dependent pathway . Here we provide the first report that the kinase activity of Akt is necessary for its ability to suppress many TGF - beta responses , including S3 activation and induction of apoptosis . Wild - type and myristoylated Akts ( Akt ( WT ) and Akt ( Myr ) ) suppress TGF - beta - induced phospho - activation of S3 but not Q15796 ( S2 ) , whereas kinase - dead Akt1 ( Akt1K179M ) or dominant - negative PI3K enhances TGF - beta - induced phospho - activation of both S2 and S3 . Using siRNA , rapamycin ( Rap ) , and adenoviral expression for P62942 - resistant and constitutively active P36897 ( P36897 ) , we demonstrate that mammalian target of Rap ( P42345 ) mediates Akt1 suppression of phospho - activation of S3 . These and further data on Akt1 - S3 binding do not support a recently proposed model that Akt blocks S3 activation through physical interaction and sequestration of S3 from TGF - beta receptors . We propose a novel model whereby Akt suppresses activation of S3 in an Akt kinase - dependent manner through P42345 , a likely route for loss of tumor suppression by TGF - beta in cancers .",
"P01308 - like growth factor - 1 receptor and ligand targeting in head and neck squamous cell carcinoma . DB01277 receptor ( IGF - 1R ) signaling is associated with increased tumorigenesis of epithelial cancers . In light of recent epidemiological studies correlating high circulating levels of DB01277 with increased risk of second primary tumors ( SPTs ) of the head and neck , we examined IGF system and epidermal growth factor receptor ( P00533 ) expression in human head and neck squamous cell carcinoma ( HNSCC ) matched pairs and a cross - section of HNSCC cell lines . Employing the latter , we demonstrated that DB01277 stimulated S - phase transition in a PI 3 - K / Akt and Erk - dependent manner in 5 of 8 cell lines , with Erk activation being dependent upon P00533 kinase activity . DB01277 stimulated thymidine incorporation was inhibited by treatment with P17936 , the IGF - 1R tyrosine kinase inhibitor DB00238 - AEW541 , or the P00533 tyrosine kinase inhibitor AG1478 . Combining P17936 with DB00238 - AEW541 or AG1478 abrogated DB01277 responses at 10 - fold lower doses than either compound alone . These results demonstrate the potential for co - targeting the IGF system and P00533 in HNSCC .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK51___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK51___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Role of - 675 4G / 5G in the plasminogen activator inhibitor - 1 gene and - 308G / A tumor necrosis factor - α gene polymorphisms in obese Argentinean patients . AIM : P00747 activator inhibitor - 1 ( P05121 ) and tumor necrosis factor - α ( P01375 - α ) are increased in the circulation of obese persons . Because a direct link between P05121 and P01375 - α in obesity has been observed , they are candidate genes for the development of obesity . We sought to evaluate the relation between the genotypic and allelic frequencies of the - 675 4G / 5G P05121 and - 308 G / A P01375 - α polymorphisms and their association with the risk for obesity in an Argentinean population . METHODS : A group of 110 consecutive obese persons and a group of 111 lean controls were recruited . Polymerase chain reaction was used to determine the frequency of P05121 and P01375 - α polymorphisms ; serum fasting glucose , insulin , and lipid levels were measured by standard methods . P01308 sensitivity was evaluated by using homeostasis model assessment . RESULTS : The - 308 P01375 - α and - 675 4G / 5G P05121 genotype distribution did not significantly differ between the groups ( p = 0 . 544 and p = 0 . 327 , respectively ) . Homeostasis model assessment was the only positive independent determinant of body mass index ( R ( 2 )= 0 . 493 ; p < 0 . 001 ) . CONCLUSION : The - 675 4G / 5G P05121 and the - 308 P01375 - α polymorphism variants tested in this study , individually or combined , were not associated with obesity in an Argentinean population .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"[ ___MASK98___ : A new drug of B - cell malignancies ] . ___MASK98___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK98___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK98___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK45___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK3___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK70___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK70___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK70___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK70___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK70___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK70___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK70___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK70___ in the treatment of changes in hypervigilance following severe stress .",
"Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .",
"P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .",
"Control of phenylalanine and tyrosine metabolism by phosphorylation mechanisms . A system for the parallel determination of enzyme phosphorylation and expressed activity in rat liver cells , and its application to studies of phenylalanine hydroxylase and tyrosine aminotransferase , is described . DB00120 hydroxylase is phosphorylated by agents which stimulate cyclic AMP - and Ca2 +- dependent protein kinase activity . The phosphorylation site ( s ) appear to be the same for both kinases . Phosphorylation is accompanied by increased metabolic flux at low , physiologically relevant , substrate concentrations . P01308 and spermine both inhibit the phosphorylation of the enzyme , possibly by increasing dephosphorylation . P17735 is phosphorylated in liver cell incubations but the rate is slow and insensitive to additions to the medium . No parallel changes in flux could be detected . Both enzymes are subject to complex regulatory mechanisms , short - and long - term . Their activities may be coordinated in vivo by control exerted at the level of the plasma membrane where both amino acids share the same transport processes . Determination of the control coefficients for the several components indicates that membrane transport may be a major limitation on flux ."
] |
[
"___MASK34___",
"___MASK38___",
"___MASK3___",
"___MASK45___",
"___MASK51___",
"___MASK61___",
"___MASK70___",
"___MASK89___",
"___MASK98___"
] |
___MASK45___
|
MH_train_397
|
interacts_with DB06148?
|
[
"Identification of multiple binding sites for [ 3H ] 5 - hydroxytryptamine in the rat CNS . Recent studies indicate that there may be multiple subtypes of [ 3H ] 5 - hydroxytryptamine ( [ 3H ] 5 - HT ) binding sites . DB06148 and spiperone inhibited the specific binding of [ 3H ] 5 - HT ( 2 - 3 nM ) to rat brain cortical membranes with shallow displacement curves . The displacement data for spiperone were best described by the presence of three independent binding sites , for which spiperone had high , medium , and low affinities . The displacement data for mianserin were best fitted by two independent , high - and low - affinity sites . The inclusion of mianserin ( 250 nM ) to inhibit [ 3H ] 5 - HT binding to the mianserin - sensitive site selectively blocked one of the sites discriminated by spiperone . These results suggest the presence of three binding sites for [ 3H ] 5 - HT , one blocked by low concentrations of spiperone ( P08908 ) , one blocked by low concentrations of mianserin ( P28335 ) , and one blocked only by high concentrations of both mianserin and spiperone ( P28222 ) . Regional differences in the relative densities of the three sites were observed . The hippocampus was rich in P08908 sites , whereas the striatum contained mainly P28222 and P28335 sites . Selective degeneration of 5 - HT - containing nerve terminals induced by the neurotoxin 5 , 7 - dihydroxytryptamine increased binding to all three sites in the cerebral cortex . Binding of [ 3H ] 5 - HT to the three sites was differentially modulated by CaCl2 and guanylimidodiphosphate . The present data suggest the presence of three independent 5 - HT1 binding sites having different affinities for mianserin and spiperone and having different regional distributions .",
"The interaction of antidepressant drugs with enteric P34969 receptors . In this study the functional interaction of the antidepressant drugs amitriptyline , mianserin , maprotiline , imipramine , fluoxetine and the putative antidepressant drug flibanserin has been studied on P34969 - mediated responses to 5 - carboxamidotryptamine ( 5 - CT ) in the guinea - pig ileum . 5 - CT induced a concentration - dependent inhibition of the contractile response to DB05875 ( 100 nM ) . Except for fluoxetine and flibanserin , all the antidepressants antagonized by different degrees the 5 - CT inhibitory response with the following rank affinity order : mianserin > maprotiline > imipramine > amitriptyline . DB06148 was the only antidepressant to show a profile of competitive antagonism at P34969 receptors in a tenfold range of concentrations ( 0 . 1 - 1 microM ) , with an affinity ( pA2 ) value of 8 . 1 +/- 0 . 6 . The antagonism of the other antidepressants was not concentration - dependent ( amitriptyline ) or was associated with slight or moderate reduction of the maximal 5 - CT response ( imipramine or maprotiline ) . The apparent affinity ( pKB ) values were : amitriptyline , 7 . 0 +/- 0 . 2 ; maprotiline , 7 . 3 +/- 0 . 6 ; imipramine , 7 . 2 +/- 0 . 4 . Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric P34969 receptors through competitive or allosteric mechanisms . This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5 - HT receptors , namely 5 - Q9H205 and Q13639 receptors .",
"Serotonin increases P27361 / 2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 ( 1 / 2 ) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5 - HT ( 2B ) receptors ( Li et al . , 2008b ) . This raises the question whether this is also the case for serotonin ( 5 - HT ) itself . In the present study serotonin was found to induce P29323 ( 1 / 2 ) phosphorylation by stimulation of 5 - HT ( 2B ) receptors with high affinity ( EC ( 50 ) : 20 - 30 pM ) , and by stimulation of 5 - HT ( 2C ) receptor with low affinity ( EC ( 50 ) : 1 microM or higher ) . P29323 ( 1 / 2 ) phosphorylation induced by stimulation of either 5 - HT ( 2B ) or 5 - HT ( 2C ) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al . , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn - dependent metalloproteinases , and thus of 5 - HT ( 2B ) receptor - mediated P01133 receptor agonist release . It is discussed that the high potency of the 5 - HT ( 2B )- mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5 - HT ( 2B ) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality - dependent increase in specific brain areas to activate 5 - HT ( 2B ) receptors . In contrast the relevance of the observed 5 - HT ( 2C ) receptors on astrocytes is questioned .",
"Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK50___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .",
"Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .",
"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK16___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK16___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK72___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK72___ who were treated with a single dose of mifepristone .",
"Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin ( Q11206 ) - induced diabetic rats . Contractile responses to serotonin ( 5 - HT ) of fundic smooth muscle strips isolated from both control and streptozotocin ( Q11206 ) - induced diabetic rats were investigated . Contrary to carbachol ( CCh ) which causes contractile hyperactivity in DM , 5 - HT response tended to decrease in DM compared to that of the control . Pindolol ( 10 (- 5 ) M ) increased the value of EC50 of the concentration - response to 5 - HT about 2 . 5 times in both the control and DM . After treatment with pindolol , the maximal tension to 5 - HT in DM significantly decreased compared to that of the control . Pindolol showed no effect on the contractile response to CCh . Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control . DB06148 ( 10 (- 5 ) M ) increased the EC50 of the response to 5 - HT about 2 - 2 . 5 times in both groups , but did not cause a significant difference between the control and DM . The Ca ( 2 +)- induced contraction caused hyperreactivity in DM in the presence of 10 (- 6 ) M CCh , but that in DM was not significantly different from the control in the presence of 10 (- 6 ) M 5 - HT . Pretreatment of phorbol 12 - myristate 13 - acetate ( PMA , 10 (- 5 ) M ) significantly attenuated the response to 5 - HT in the control , but not in DM . Results suggest that the contractile response to 5 - HT in DM is related to the altered Ca2 + signal transduction system via disturbed protein kinase C ( PKC ) activity , and that there are alterations of receptor characteristics and of the density in 5 - HT receptor subtypes , especially P08908 , during DM development .",
"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Expression of serotonergic system components during early Xenopus embryogenesis . Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function , little is known about the molecular genetic mechanisms involved . The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT - PCR , real time PCR and in situ hybridization . Transcripts encoding the serotonin receptors P28335 and P34969 , as well as the vesicular monoamine transporter Q05940 , the serotonin transporter ( P31645 ) and the serotonin synthesis enzymes tryptophan hydroxylase ( Q8IWU9 ) and aromatic amino acid decarboxylase ( AAAD ) were found to be expressed during the cleavage division stages , whereas the degradation enzyme monoamine oxidase A ( P21397 ) was absent . The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development . The embryonic transmitter mechanism , its complexity , and its variability among various species are discussed .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Comparison of the effects of aging on P34969 and P08908 receptors in discrete regions of the circadian timing system in hamsters . The circadian timekeeping system exhibits many functional changes with aging , including a loss of sensitivity to time cues such as systemic injections of the serotonergic agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) . In order to elucidate the neurochemical mechanisms responsible for this age - related loss of sensitivity of the circadian pacemaker to serotonin agonists , the present study used quantitative autoradiography to determine whether aging decreases serotonin receptor populations in male Syrian hamsters . Four neuroanatomical regions that regulate circadian timekeeping were studied ( the suprachiasmatic nuclei [ SCN ] , the lateral geniculate nuclei [ P81274 ] , and the median raphe nucleus [ MRN ] and dorsal raphe nucleus [ DRN ] ) . The specific binding of [ 3H ] 8 - OH - DPAT to serotonin7 ( P34969 ) and serotonin1A ( P08908 ) receptors was investigated by competitive inhibition with ritanserin and pindolol , respectively . The results showed that the SCN , IGL , MRN , and DRN of the male Syrian hamster exhibited specific binding of [ 3H ] 8 - OH - DPAT to both the P34969 and P08908 receptors , and that the latter receptor subtype is more abundant in all of these regions . At 17 - 19 months of age , a 50 % decrease in P34969 receptors was found in the DRN but not in any other regions . No significant age - related changes in P08908 receptors were observed in any regions examined . The finding that a marked decrease in P34969 receptors occurs in the DRN at the age previously characterized by loss of sensitivity to 8 - OH - DPAT suggests that this region and this receptor subtype play important roles in 8 - OH - DPAT induction of circadian phase shifts in vivo and that they constitute an important locus of aging in the circadian timing system .",
"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK73___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .",
"Dexamethasone potentiates serotonin - 2 receptor - mediated intracellular Ca2 + mobilization in P13671 glioma cells . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) caused a transient increase in intracellular Ca2 + in C6BU - 1 glioma cells in a concentration - dependent manner ; half maximally at 73 nM . The 5 - HT2 agonist 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane also increased the levels of intracellular Ca2 + , whereas the P28335 agonist 1 -( 3 - chlorophenyl ) piperazine and P08908 agonist 8 - hydroxy - 2 - ( di - n - propylamino ) tetralin were completely ineffective . Ketanserin and spiperone blocked the response to 5 - HT at a nanomolar concentration , but the 5 - Q9H205 antagonist MDL 72222 had no effect on it . Thus 5 - HT2 receptors are responsible for activating Ca2 + mobilization in P13671 glioma cells . Treatment of P13671 glioma cells with dexamethasone potentiated the ability of 5 - HT to cause intracellular Ca2 + mobilization in both a dose - and time - dependent manner . The dose - response curve for 5 - HT was shifted 9 - fold to the left compared to controls , and the Vmax value was also significantly enhanced . This enhanced Ca2 + mobilization was completely inhibited by ketanserin dose - dependently . In addition , the treatment with dexamethasone enhanced fluoride - activated Ca2 + mobilization , suggesting that the enhanced GTP binding protein function is one of the mechanisms responsible for the enhancement of the 5 - HT response induced by dexamethasone treatment . This enhancement of agonist activity was mediated by the type II glucocorticoid receptor ( GR ) since RU 38486 , an inhibitor of the type II GR , antagonized the dexamethasone - induced enhancement .",
"Discriminative stimulus properties of mCPP : evidence for a P28335 receptor mode of action . Previous drug discrimination studies with the serotonergic drug m - chlorophenylpiperazine ( mCPP ) showed conflicting results , with some authors concluding that the cue was mediated by P28335 receptors , but others that it was definitively not . We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data . We trained rats to discriminate mCPP ( 2 . 0 mg / kg , PO ) from water . We found that the mCPP cue generalized to m - trifluoromethyl - phenylpiperazine ( TFMPP ) and 6 - chloro - 2 -( 1 - piperazinyl )- pyrazine ( MK - 212 ) , and partially to eltoprazine , 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ( DOI ) , fenfluramine and trazodone . A moderate level of generalization was obtained with quipazine , 1 -( m - chlorophenyl ) biguanide and clonidine . No generalization was found with flesinoxan , methiothepin , idazoxan and haloperidol . DB06148 and methysergide antagonized the mCPP stimulus , whereas ketanserin antagonized it partially . Metergoline , methiothepin and clozapine only marginally antagonized the mCPP stimulus . These results show that the discriminative stimulus effects of mCPP are predominantly mediated by P28335 receptors , and to some extent by P28222 receptors . When considering our results and other research together , the substitution tests clearly point to a P28335 receptor mediated stimulus , with an additional role for P28222 receptors . Antagonism studies are less clearcut , but are also suggestive of a P28335 receptor mediated effect . A definitive answer as to whether other receptors , e . g . P41595 and P34969 , are of any importance in mCPP ' s discriminative stimulus properties has to wait for more selective ligands .",
"___MASK73___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK73___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK73___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK73___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .",
"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .",
"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .",
"Modulation of multiple sclerosis by sunlight exposure : role of cis - urocanic acid . The role of cis - urocanic acid ( UCA ) as a UV - mediated immunomodulator in MS patients was investigated . Plasma levels of cis - UCA were significantly lower in MS patients compared to controls . Stimulation of MBP - and Q16653 - specific T cells in the presence of cis - UCA , significantly increased P22301 , and inhibited IFN - γ production . PBMCs cultured in the presence of cis - UCA increased P01730 (+) CD25 (+) FoxP3 (+) regulatory T cell percentages . Dendritic cells cultured in the presence of cis - UCA significantly reduced Ag presentation capacity . Finally , cis - UCA activated the 5 - Q13049 receptor , inducing the increase in phosphorylated forms of P29323 1 / 2 and P45984 . Thus , in addition to vitamin D , cis - UCA also appears to be an additional UV - mediated immunomodulator .",
"[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK37___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .",
"Rapid desensitization of serotonin P28335 receptor - stimulated intracellular calcium mobilization in CHO cells transfected with cloned human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in Chinese hamster ovary ( CHO ) cells transfected with P28335 receptors . Fura - 2 acetoxymethyl ester was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] mesulergine binding ( KD = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from a basal level of 99 +/- 1 . 8 up to 379 +/- 18 nM , with an EC50 value for 5 - HT of 0 . 029 microM . Exposure to 5 - HT , 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ( a P28335 agonist ) , and 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ( a P28335 and 5 - Q13049 agonist ) resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . The receptor was rapidly desensitized by preexposure to 5 - HT in a time - and concentration - dependent manner . Mezerein and phorbol 12 - myristate 13 - acetate , protein kinase C activators , weakly inhibited the intracellular Ca2 + mobilization induced by 10 microM 5 - HT . Furthermore , the protein kinase C inhibitor H - 7 partially prevented the protein kinase C activator - induced inhibition of the 5 - HT - mediated increase in intracellular Ca2 + concentration . The desensitization induced by pretreatment with 5 - HT was blocked by W - 7 , added in conjunction with 5 - HT , and partially inhibited by W - 5 , a nonselective inhibitor of protein kinases and weak analogue of W - 7 . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .",
"Mediation by 5 - hydroxytryptamine2B receptors of endothelium - dependent relaxation in rat jugular vein . 1 . An ' atypical ' 5 - HT2 receptor which is located on the endothelium of rat jugular vein has been described . In the present study we have further defined the nature of the 5 - HT2 receptor subtype present in this preparation . 2 . In experiments conducted in the presence of ketanserin to preclude involvement of 5 - HT2 receptors , the mixed P41595 / 2C antagonist , SB 200646 , acted as an antagonist of 5 - HT at the endothelial 5 - HT receptor ( pA2 = 7 . 2 ) . Yohimbine , which exhibits negligible affinity for rat P28335 receptors but has high P41595 receptor affinity , acted as a potent but non - surmountable antagonist ( pA2 > or = 7 . 3 ) in rat jugular vein . Neither yohimbine nor SB 200646 affected endothelium - dependent relaxations induced by carbachol . 3 . DB06148 also acted as a surmountable antagonist ( pA2 = 7 . 3 ) and the P41595 agonist , BW 723C86 , acted as a potent partial agonist ( pEC50 [ 95 % C L ] , intrinsic activity +/- s . e . mean = 7 . 9 [ 7 . 6 - 8 . 3 ] , 0 . 84 +/- 0 . 04 ) . Responses to BW 723C86 were antagonized by SB 200646 ( 0 . 3 microM ) yielding an ' apparent ' pA2 [ 95 % CL ] of 7 . 03 [ 6 . 76 - 7 . 32 ] . 4 . These data are consistent with the presence of P41595 receptors mediating endothelium - dependent relaxation of rat jugular vein .",
"Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0 . 1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 ) , plasminogen activator inhibitor - 1 ( P05121 ) , and tissue - type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 were also measured . TF and P05121 mRNA were increased significantly in a concentration - and time - dependent manner . However , P10646 and TPA mRNA expression did not change . The inductions of TF and P05121 mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .",
"[ Moclobemide ( ___MASK36___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Thermoregulatory responses to serotonin ( 5 - HT ) receptor stimulation in the rat . Evidence for opposing roles of 5 - HT2 and P08908 receptors . The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated . The administration of the serotonin ( 5 - HT ) agonist 6 - chloro - 2 ( 1 - piperazinyl )- pyrazine ( MK - 212 ) produced a dose - related increase in body temperature . A maximal increase in body temperature of approx . 1 . 1 degrees C was observed 30 min after the administration of 3 mg / kg of MK - 212 . In contrast , administration of the putative P08908 agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) resulted in marked , dose - related hypothermic responses . Body temperatures were decreased approx . 3 degrees C 30 min after an injection of 0 . 3 mg / kg of 8 - OH - DPAT . Body temperatures were affected differentially by 5 - methoxy - N , N - dimethyltryptamine ( 5 - MeODMT ) . Large doses ( 3 - 10 mg / kg ) of 5 - MeODMT elicited hyperthermic responses , whereas small doses ( 0 . 5 - 1 . 0 mg / kg ) produced hypothermic responses . Treatment of rats with ketanserin ( 3 mg / kg ) completely prevented the hyperthermic effects of 5 - MeODMT , and , in fact , converted a hyperthermic response to 5 - MeODMT into a marked hypothermic response . Ketanserin ( 0 . 1 - 1 . 0 mg / kg ) selectively antagonized the hyperthermic response to MK - 212 but did not alter the hypothermic effect of 8 - OH - DPAT . DB06148 ( 10 mg / kg ) and pirenperone ( 0 . 03 mg / kg ) also selectively antagonized hyperthermia induced by MK - 212 . In contrast , pindolol ( 0 . 03 - 0 . 1 mg / kg ) and methiothepin ( 10 mg / kg ) selectively antagonized hypothermia induced by 8 - OH - DPAT but did not alter hyperthermia induced by MK - 212 . Spiperone ( 0 . 1 - 3 mg / kg ) and pizotifen ( 10 mg / kg ) attenuated the effects of both 8 - OH - DPAT and MK - 212 . Xylamidine , a peripheral 5 - HT antagonist , had no significant effect on hyperthermia induced by MK - 212 or hypothermia induced by 8 - OH - DPAT . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .",
"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .",
"Effect of valproic acid on serotonin - 2A receptor signaling in P13671 glioma cells . Valproic acid ( DB00313 ) , which has demonstrated efficacy in the treatment of bipolar disorder , has been shown to alter components of the phosphoinositide ( PI ) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 ( AP - 1 ) . Central serotonin - 2A ( 5 - Q13049 ) receptors , which have been implicated in the pathophysiology of manic - depressive illness , are coupled to PI hydrolysis . The promoter region of the 5 - Q13049 receptor gene contains AP - 1 binding sites . We examined in P13671 glioma cells the effect of DB00313 on 5 - Q13049 receptor signaling . Treatment of cells with DB00313 ( 100 microg / mL ) for 20 h , but not 1 . 5 h , resulted in an enhancement of 5 - Q13049 receptor - stimulated PI hydrolysis . This effect of 20 - h DB00313 exposure appeared not to be at the level of G protein or effector ( i . e . phospholipase C : P98160 ) as inositol phosphate accumulation stimulated by aluminum fluoride or the P98160 activator 2 , 4 , 6 - trimethyl - N -( m - 3 - trifluromethylphenyl ) benzenesulfonamide was not increased . The number of 5 - Q13049 receptors , as determined in saturation binding experiments using [ 3H ] ketanserin , was increased by 20 - h DB00313 treatment , with no change in affinity ( KD ) . Taken together , our data suggest that the increase in 5 - Q13049 receptor - mediated PI hydrolysis following 20 - h DB00313 exposure is not due to a general effect of DB00313 on this signaling cascade , but due to the up - regulation of 5 - Q13049 receptor number .",
"Effects of antidepressants on intracellular Ca2 + mobilization in CHO cells transfected with the human P28335 receptors . Serotonin P28335 receptor - mediated intracellular Ca2 + mobilization was investigated in P28335 receptors expressed in Chinese hamster ovary ( CHO ) cells ; and fura - 2 / AM was used to investigate the regulation of P28335 receptor function . CHO cells , transfected with a cDNA clone for the P28335 receptor , expressed 287 fmol / mg of the receptor protein as determined by mianserin - sensitive [ 3H ] - mesulergine binding ( kd = 0 . 49 nM ) . The addition of 5 - HT mobilized intracellular Ca2 + in a dose - dependent fashion , ranging from basal level of 99 +/- 1 . 8 nM up to 246 +/- 21 . 2 nM , with an EC50 value for 5 - HT of . 015 microM . Exposure to 5 - HT , a 5 - HT receptor agonist , mCPP [ 1 -( 3 - chlorophenyl ) piperazine dihydrochloride ] , a P28335 agonist , and DOI [ 1 -( 4 - iodo - 2 , 5 - dimethoxyphenyl )- 2 - aminopropane ] , a P28335 and 5 - HT2 agonist , resulted in increased intracellular Ca2 + levels . DB06148 , mesulergine , ritanserin , and ketanserin each blocked 5 - HT - mediated intracellular Ca2 + mobilization more effectively than spiperone . DB06148 and amoxapine inhibited 5 - HT - mediated intracellular Ca2 + mobilization completely ; amitriptyline , nortriptyline , and imipramine reduced it about 50 % . These results suggest that antagonism in CHO cells transfected with human P28335 receptors is a component of the serotonergic properties of a number of established antidepressants .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"Involvement of P08908 and 5 - HT2 receptor in cisplatin induced emesis in dogs . The effect of drug acting on P08908 , 5 - HT2 and 5 - Q9H205 receptors were studied against cisplatin and apomorphine induced emesis in dogs . Buspirone , P08908 receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency . DB06148 , 5 - HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency . Buspirone prevented the apomorphine induced emesis while mianserin had no effect . The antiemetic activity of buspirone may be attributable to its agonistic activity at P08908 receptor and antagonistic activity at dopamine receptors . These findings further confirm the involvement of P08908 and 5 - HT2 receptor in cytotoxic drug induced emesis , though the species difference in their antiemetic action can not be ruled out .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK59___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK17___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Presence of a P34969 receptor positively coupled to adenylate cyclase activation in human granulosa - lutein cells . Although serotonin ( 5 - HT ) has been shown to stimulate progesterone production by human granulosa - lutein cells ( hGLC ) , the receptor type and associated signaling pathway remain uncharacterized . We report here that 5 - HT receptors in these cells are positively coupled to adenylate cyclase activity . Formation of DB02527 was stimulated by 5 - HT and its agonists in a dose - and time - dependent manner . DB06148 , amoxapine , and loxapine were equipotent in antagonizing 5 - HT - induced DB02527 formation . For both DB02527 formation in cells and adenylate cyclase assay using membrane fractions , the rank order of potency for agonists of 5 - HT were : 5 - carboxy - aminotryptamine > 5 - HT > or = 5 - methoxytryptamine , consistent with a typical pharmacological profile of human 5 - ht7 ( h5 - ht7 ) receptor . Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5 - ht7 receptor complementary DNA . Northern analysis showed the presence of 2 . 8 - kb h5 - ht7 transcripts in hGLC . The three variants h5 - ht7A , h5 - ht7B , and h5 - ht7D were also detected in hGLC . Preincubation of hGLC with 5 - HT ( 10 (- 8 )- 10 (- 6 ) M ) resulted in a marked reduction in the DB02527 response when the cells were subsequently stimulated with gonadotropin , and this heterologous desensitization could be reversed by 5 - ht7 receptor antagonist clozapine . These data demonstrate that h5 - ht7 receptor is present and stimulate DB02527 formation in hGLC . In addition , the h5 - ht7 receptor seems to be implicated in the heterologous down - regulation hCG - stimulated DB02527 response in hGLC , with a possible ramification for luteal insufficiency .",
"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK15___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Activating mutations of the serotonin P28335 receptor . Site - directed mutagenesis was performed to create a mutant serotonin P28335 receptor that would mimic the active conformation of the native receptor . Structural alteration of receptor conformation was achieved by changing amino acid no . 312 from serine to phenylalanine ( S312F ) or lysine ( S312K ) . After expression in COS - 7 cells , the binding affinity of 5 - HT for [ 3H ] mesulergine - labeled P28335 receptors increased from 203 nM ( native ) to 76 nM for S312F and 6 . 6 nM for S312K mutant receptors . 5 - HT potency for stimulation of phosphatidylinositol ( PI ) hydrolysis increased from 70 nM ( native ) to 28 nM for S312F and 2 . 7 nM for S312K mutant receptors . The mutant receptors were constitutively active , stimulating PI hydrolysis in the absence of agonist . S312F and S312K mutations resulted in twofold and five - fold increases , respectively , in basal levels of PI hydrolysis . DB06148 and mesulergine displayed inverse agonist activity by decreasing basal levels of PI hydrolysis stimulated by S312K mutant receptors . [ 3H ] 5 - HT and [ 3H ] mesulergine labeled the same number of S312K mutant receptors and 5 '- guanylylimidodiphosphate had no effect on [ 3H ] 5 - HT binding . These results indicate that serine --> lysine mutation at amino acid no . 312 produces an agonist high - affinity state of the P28335 receptor that spontaneously couples to G proteins and stimulates PI hydrolysis in the absence of agonist .",
"Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .",
"Roles of E3 ubiquitin ligases in cell adhesion and migration . Recent studies have demonstrated that a number of E3 ubiquitin ligases , including Cbl , Smurf1 , Smurf2 , HDM2 , BCA2 , P21583 ( beta - TRCP ) and XRNF185 , play important roles in cell adhesion and migration . Cbl negatively regulates cell adhesion via alpha integrin and Rap1 and inhibits actin polymerization by ubiquitinating mDab1 and Q9Y6W5 . Smurf1 regulates cell migration through ubiquitination of RhoA , talin head domain and hPEM2 , while Smurf2 ubiquitinates Smurf1 , TGFbeta type I receptor and RaplB to modulate cell migration and adhesion . HDM2 negatively regulates cell migration by targeting NFAT ( a transcription factor ) for ubiquitination and degradation , while P21583 ( beta - TRCP ) ubiquitinates Snail ( a transcriptional repressor of P12830 ) to inhibit cell migration . Q13049 promotes cell migration through ubiquitination of Q9NYB9 ( Abi2 ) , a tumor suppressor . Q99942 and XRNF185 modulate cell migration by ubiquitinating paxillin . Thus , these E3 ubiquitin ligases regulate cell adhesion and ( or ) migration through ubiquitination of their specific substrates .",
"Chronic mianserin or eltoprazine treatment in rats : effects on the elevated plus - maze test and on limbic P28335 receptor levels . Rats were chronically treated with mianserin ( 10 mg / kg i . p . ) or eltoprazine ( 1 mg / kg i . p . ) and were tested in the elevated plus - maze test for anxiety . P28335 ( previously P28335 , see Humphrey et al . , 1993 , Trends Pharmacol . Sci . 14 , 223 ) binding sites and their mRNA were evaluated in limbic structures ( i . e . , amygdala , hippocampus , septum ) of a sample of these rats by autoradiographic binding studies and in situ hybridization histochemistry . DB06148 and eltoprazine displayed opposite effects in the elevated plus - maze : mianserin induced anxiolytic - like effects , while eltoprazine showed anxiogenic - like ones . Within the amygdala , but not in other structures , the quantitative autoradiographic analysis of the P28335 binding sites showed a differential effect : mianserin treatment induced a decrease in the number of these sites , while eltoprazine treatment resulted in an increase . In spite of this , neither mianserin - nor eltoprazine - treated rats displayed an alteration in the P28335 receptor mRNA levels in the brain regions examined . Our results are suggestive of a relation between anxiolytic / anxiogenic - like effects and the level of P28335 binding sites in the amygdala .",
"Effects of antidepressants on the exploration , spontaneous motor activity and isolation - induced aggressiveness in mice . OBJECTIVE : To study the role of different antidepressants on exploration , spontaneous motor activity and isolation - induced aggressiveness in mice , further to discuss different mechanisms of their anti - aggression . METHODS : With an aggressive model induced by isolation housing in mice , antagonism of different antidepressants against isolation - induced aggression was evaluated . In the group - housed mice given the same treatment as aggressive test , exploration and spontaneous motor activity were measured . RESULTS : ( 1 ) DB06148 ( 0 . 5 - 5 mg / kg - 1 ) , buspirone ( 2 . 5 - 10 mg . kg - 1 ) and meclobemide ( 2 . 5 - 10 mg . kg - 1 ) significantly inhibited the exploration in the group - housed mice , but not fluoxetine ( 2 . 5 - 10 mg . kg - 1 ) , imipramine ( 2 . 5 - 10 mg . kg - 1 ) and DOI ( 0 . 5 - 2 mg . kg - 1 ) ; ( 2 ) Both mianserin and buspirone , but not fluoxetine , imipramine , meclobemide and DOI , obviously reduced spontaneous motor activity ; ( 3 ) DB00472 , miaserin , imipramine and buspirone significantly and dose - dependently antagonized isolation - induced aggressive behavior , whereas meclobemide failed to attenuate aggression . DOI dual - regulated aggressiveness in isolation mice . CONCLUSION : Our findings suggest that the effects of fluoxetine , mianserin , buspirone , imipramine , meclobemide and DOI on exploration , spontaneous motor activity and isolation - induced aggression in mice are different , which may involve different pharmacological mechanisms underlying their anti - aggression in isolation mice . P08908 and 5 - Q13049 / 2C receptors may mediate isolation - induced aggressive behavior in mice . The involvement of 5 - HT receptor subtypes needs further clarification .",
"[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD .",
"Involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory P21554 receptors . The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia . In this review , we will firstly provide a background , brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia . We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in P21554 receptor - mediated antinociception . This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal P34969 , 5 - Q13049 and alpha - 2 adrenoceptors activation .",
"Beneficial effect of low - dose mianserin on fluvoxamine - induced akathisia in an obsessive - compulsive patient . Extrapyramidal side effects induced by some selective serotonin reuptake inhibitors ( SSRIs ) , i . e . fluoxetine and sertraline , have been previously reported in patients with depression and obsessive - compulsive disorder ( OCD ) . However , the occurrence and management of akathisia induced by fluvoxamine have not been described . In the presented case fluvoxamine - induced akathisia in an OCD patient was partially resistant to the anticholinergic agent biperiden , and was successfully treated with the 5 - Q13049 / P28335 antagonist mianserin . DB06148 ( 15 mg / day at 21 . 00 h ) was discontinued and then reinstituted ( off - on - off - on design ) . DB00810 was transiently effective in the acute akathisia , while the more persistent akathisia was alleviated by mianserin . Discontinuation of mianserin resulted in recurrence of akathisia , while full amelioration of the symptoms of akathisia was noted when mianserin was reinstituted . No aggravation of OCD symptoms was noted during mianserin administration .",
"Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells . Serotonin ( 5 - HT ) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis . In this study , we evaluated the role of 5 - HT on the functional features in neurospheres derived from adult neural stem cells ( ANSC ) . We cultured neurospheres derived from mouse hippocampus in serum - free medium containing epidermal ( P01133 ) and type - 2 fibroblast growth factor ( P09038 ) . Under these conditions ANSC expressed both isoforms of tryptophane - hydroxylase ( P17752 ) and produced 5 - HT . Blocking P17752 function by para - chlorophenylalanine ( PCPA ) reduced ANSC proliferation , which was rescued by exogenous 5 - HT . 5 - HT action on ANSC was mediated predominantly by the serotonin receptor subtype P08908 and , to a lesser extent , through the P28335 ( receptor ) subtype , as shown by selectively antagonizing these receptors . Finally , we documented a 5 - HT - induced increase of ANSC migration activity . In summary , we demonstrated a powerful serotonergic impact on ANSC functional features , which was mainly mediated by P08908 receptors .",
"Modulation of antipsychotic - induced extrapyramidal side effects by medications for mood disorders . Antipsychotic drugs are widely used not only for schizophrenia , but also for mood disorders such as bipolar disorder and depression . To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects ( EPS ) , we examined the effects of antidepressants and mood - stabilizing drugs on haloperidol ( P42357 ) - induced bradykinesia and catalepsy in mice and rats . The selective serotonin reuptake inhibitors ( SSRIs ) , fluoxetine and paroxetine , and the tricyclic antidepressant ( TCA ) clomipramine , which showed no EPS by themselves , significantly potentiated P42357 - induced bradykinesia and catalepsy in a dose - dependent manner . In contrast , the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine failed to augment , but rather attenuated P42357 - induced bradykinesia and catalepsy . DB06148 also tended to reduce the EPS induction . In addition , neither treatment with lithium , sodium valproate nor carbamazepine potentiated P42357 - induced EPS . Furthermore , treatment of animals with ritanserin ( 5 - Q13049 / 2C antagonist ) , ondansetron ( 5 - Q9H205 antagonist ) , and SB - 258585 ( P50406 antagonist ) significantly antagonized the EPS augmentation by fluoxetine . Intrastriatal injection of ritanserin or SB - 258585 , but not ondansetron , also attenuated the EPS induction . The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction . In addition , 5 - Q13049 / 2C , 5 - Q9H205 and P50406 receptors seem to be responsible for the augmentation of antipsychotic - induced EPS by serotonin reuptake inhibitors .",
"DB06148 - induced down - regulation of human 5 - hydroxytryptamine2A and 5 - hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5 - hydroxytryptamine2A ( 5 - Q13049 ) and P28335 receptors stably expressed in the human neuroblastoma cell line SH - SY5Y . Incubation of cells expressing the 5 - Q13049 receptor with mianserin ( 100 nM ) for 24 h caused a significant decrease ( 48 % ) in the binding capacity of [ 3H ] ketanserin . This receptor down - regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5 - HT but not by carbachol . Exposure of cells expressing the P28335 receptor to mianserin ( 100 nM ) for 72 h but not for 24 h similarly resulted in a significant reduction ( 44 % ) in [ 3H ] mesulergine binding . Corresponding analysis of inositol phosphate production by 5 - HT at the P28335 receptor after incubation with mianserin showed no change in maximal response after 24 h . No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h . A decrease in the binding affinity of both radioligands was also observed after mianserin treatment , but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h , and was probably due to the retention of mianserin within the tissue . We conclude that antagonist down - regulation is evident at human 5 - Q13049 and P28335 receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor .",
"DB00502 , but not clozapine , produces dramatic catalepsy in delta9 - THC - treated rats : possible clinical implications . The effect on rat catalepsy induced by Delta9 - tetrahydrocannabinol ( Delta9 - THC ) in association with haloperidol ( HP ) or clozapine ( CLOZ ) administration was investigated . Delta9 - THC dose - dependently increased HP ( 0 . 05 - 1 mg kg - 1 , s . c . ) - induced rat catalepsy , while no catalepsy was observed after CLOZ ( 1 - 20 mg kg - 1 , s . c . ) or Delta9 - THC + CLOZ administration . The P21554 antagonist SR141716A ( 0 . 5 - 5 mg kg - 1 , i . p . ) reversed the increase mediated by Delta9 - THC on HP - induced catalepsy . The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP + Delta9 - THC ; however , higher doses of quinpirole were needed in the presence of Delta9 - THC . The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP + Delta9 - THC in a similar manner . CLOZ and the 5 - Q13049 / 2C antagonists ritanserin , RS102221 and SB242084 were more effective in antagonizing HP than HP + Delta9 - THC - induced catalepsy . 7 HP and CLOZ failed to inhibit in vitro [ 3H ] CP - 55 , 940 binding , while Delta9 - THC and SR141716A did not show an appreciable affinity for the D2 receptor . It was suggested that the different effects on rat catalepsy induced by Delta9 - THC following HP or CLOZ administration may depend on the receptor - binding profiles of the two antipsychotics . The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed ."
] |
[
"___MASK15___",
"___MASK16___",
"___MASK17___",
"___MASK36___",
"___MASK37___",
"___MASK50___",
"___MASK59___",
"___MASK72___",
"___MASK73___"
] |
___MASK36___
|
MH_train_398
|
interacts_with DB00987?
|
[
"Characterization of the region of the short arm of chromosome 8 amplified in breast carcinoma . Chromosomal region 8p11 . 2 - p12 is consistently amplified in human breast cancer . We have constructed a 2 . 8 Mb YAC contig of this region , centered on the human Fibroblast Growth Factor Receptor 1 ( P11362 ) locus and encompassing the Adrenergic beta 3 Receptor ( P13945 ) locus . A smaller centromeric YAC contig spanning 1 . 4 Mb was also assembled , and included the Ankyrin 1 ( P16157 ) and Tissue - type P00747 Activator ( P00750 ) genes . Results from mapping of the contigs showed physical linkage of the P13945 and P11362 genes , which were colocalized within the same YAC clone and separated by about 900 kb , P11362 being in centromeric position . It also showed physical linkage of P16157 and P00750 genes , which appear to be separated by a maximum of 700 kb . In parallel , several loci were mapped according to their amplification status in a large panel of breast tumor samples . The overall amplification pattern suggested a continuous amplicon with a core around P11362 . Data from both the detailed physical map and the amplification status allowed to establish the following gene order , from telomere to centromere : P13945 - D8S105 - P11362 - P16157 - P00750 - P06746 . The precise localization and YAC cloning of the core of the amplicon will allow to isolate a putative oncogene involved in mammary carcinogenesis .",
"P49674 / P35222 are synthetic lethal to P04637 in colorectal cancer and are markers for prognosis . Two genes are called synthetic lethal ( SL ) if their simultaneous mutations lead to cell death , but each individual mutation does not . Targeting SL partners of mutated cancer genes can kill cancer cells specifically , but leave normal cells intact . We present an integrated approach to uncovering SL pairs in colorectal cancer ( CRC ) . Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues , we first identified potential functionally relevant ( simultaneously differentially expressed ) gene pairs . From the top - ranked pairs , ~ 20 genes were chosen for immunohistochemistry ( IHC ) staining in 171 CRC patients . To find novel SL pairs , all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features , e . g . overall survival . Of the 11 predicted SL pairs , P43246 - P06746 and P49674 - MYC were consistent with literature , and we validated the top two pairs , P49674 - P04637 and P35222 - P04637 using RNAi knockdown and small molecule inhibitors of P49674 in isogenic HCT - 116 and RKO cells . Furthermore , synthetic lethality of P49674 and P04637 was verified in mouse model . Importantly , multivariate analysis revealed that P49674 - P04637 , P35222 - P04637 , P43246 - P06400 , and P38398 - P41221 were independent prognosis markers from stage , with P49674 - P04637 applicable to early - stage and the remaining three throughout all stages . Our findings suggest that P49674 is a promising target for P04637 - mutant CRC patients which constitute ~ 40 % to 50 % of patients , while to date safety regarding inhibition of P04637 is controversial . Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics , and it is readily accessible and applicable to other cancers .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK67___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK99___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"The P06746 replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots . We have found a significant concordance between the in vitro replication errors of human P06746 and in vivo point mutations of the adenomatous polyposis coli ( P25054 ) gene that leads to colon cancer . We determined the error spectrum of P06746 in the human P25054 gene under PCR conditions and compared it with the set of mutations reported in human colon tumors . Polymerase beta created seven hotspot mutations within 141 target bp analyzed in P25054 exon 15 . Three of these polymerase beta hotspots , 2 frameshifts and a bp substitution mutation , were concordant with 3 of 13 P25054 hotspots detected in human colon cancers in the same DNA sequences . These 3 concordant hotspots accounted for some 54 % of reported in vivo P25054 hotspot mutations . Using the assumption of a hypergeometric distribution of hotspot mutations among bp of the scanned sequences , the probability of this concordance occurring by chance is < 4 x 10 (- 4 ) . These data support the hypothesis that P06746 errors are an important fraction of cancer - causing P25054 mutations .",
"Involvement of base excision repair in response to therapy targeted at thymidylate synthase . P04818 ( TS ) is an important target of several classes of chemotherapeutic agents . Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure , uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation . Base excision repair ( BER ) plays a primary role in removing damaged or modified bases from the genome , including uracil . Because of uracil misincorporation , BER is hypothesized to play a role in the cellular response to thymidylate deprivation . In this study , we used murine embryo fibroblasts wild - type or homozygous null for P06746 ( beta - pol ) , which plays a central role in BER . We found that , compared with wild - type , beta - pol null cells were resistant to the toxic effects of raltitrexed ( ___MASK84___ , ___MASK84___ ) , a folate inhibitor of TS . There was little difference in TS levels or in TS - ligand complex formation between the cell lines . Furthermore , cells deficient in P18887 , a scaffold protein for the final steps of BER , were also modestly resistant to raltitrexed compared with P18887 - proficient cells . Cell cycle analysis revealed that the responses of the wild - type and beta - pol null cells were similar during drug exposure . However , following drug removal , the beta - pol null cells appeared to resume cell cycle progression more rapidly than the wild - type cells . The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors , and that this role occurs during recovery from TS inhibition .",
"Effects of 1 - beta - D - arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by P06746 . DB00987 ( ara - C ) is an effective antileukemic agent which acts as an inhibitor of DNA synthesis . The precise mechanism responsible for this inhibitory effect , however , remains unclear . The present work has examined the effects of the triphosphate derivative , ara - P53007 , on purified P06746 . These studies were performed on M13 phage DNA templates of defined sequence . The results demonstrate that ara - C is incorporated into DNA by P06746 . The results also demonstrate that the incorporated ara - C residue acts as a relative chain terminator . Moreover , the relative chain terminating effects of ara - C are sequence specific . In this regard , DNA strand elongation was progressively slowed at sequences of two , three , and four contiguous sites for cytosine incorporation . We also demonstrate that the inhibitory effects of ara - C are reversed by competition with deoxycytidine - triphosphate for incorporation into the DNA strand . Taken together , these findings are consistent with structural differences of the incorporated arabinosyl moiety which alter reactivity of the 3 '- terminus and thereby inhibit chain elongation . These findings also provide new insights regarding the inhibitory effects of ara - C on elongation of specific DNA sequences .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK80___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Inhibition of mammalian DNA polymerases by recombinant alpha - interferon and gamma - interferon . Interferons ( IFNs ) have been shown to suppress the growth of both normal and malignant cells . We examined the effect of gene - cloned IFN - alpha and P01579 on the in vitro activities of human , calf , or rat DNA polymerases . IFN - alpha strongly inhibited the reactions of DNA polymerase alpha and beta at apparent Ki values of 1 . 25 and 0 . 35 x 10 ( 5 ) antiviral units / ml , respectively , but inhibited DNA polymerase gamma only slightly . P01579 inhibited the reaction of DNA polymerase alpha more strongly ( Ki , 1 . 2 x 10 ( 4 ) units / ml ) than IFN - alpha , but not that of P06746 . On the other hand , neither IFN - alpha nor P01579 inhibited the reactions of DNA polymerase I from Escherichia coli , Klenow fragment , T - 4 DNA polymerase , and RNA polymerase . The fact that Ki values for IFN - alpha of DNA polymerase from calf thymus , human leukemic cells , and rat liver were similar suggests the absence of species specificity among animals with regard to the inhibition of DNA polymerases by IFNs . These results indicate that DNA polymerase may be one of the targets of the action of IFNs .",
"Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant P00441 gene . Growing evidence has recently shown that mutant P00441 accumulate in the mitochondria and cause vacuolation in transgenic mice carrying mutant P00441 , an animal model of amyotrophic lateral sclerosis ( P35858 ) . In this study , the expressions of DNA repair enzymes , oxoguanine glycosylase 1 ( ogg1 ) , P06746 ( polbeta ) , and DNA polymerase gamma ( polgamma ) were examined in transgenic mice with an P35858 - linked mutant P00441 gene , a valuable model for human P35858 . In presymptomatic Tg mice , the nuclear form of ogg1 was upregulated , whereas mitochondrial ogg1 remained at the same level . DNA polymerase was selectively downregulated in the mitochondria . This study suggests an impaired protective mechanism against oxidative stress in mitochondria . The expressions of these enzymes are predominant in spinal motor neurons , suggesting a mechanism of selective motor neuron death in this animal model of P35858 .",
"Modulation of 3 - hydroxy - 3 - methylglutaryl - DB01992 reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells . The homeostasis of intracellular cholesterol in animal cells is highly regulated by a complex system in which the microsomal rate - limiting enzyme 3 - hydroxy - 3 - methylglutaryl DB01992 ( HMG - DB01992 ) reductase plays a key role in cholesterol synthesis . Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase ( P00441 ) inhibits the P04035 activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis . Although these data suggest that P00441 exerts a physiological role in cholesterol metabolism , it is still unclear whether the decrease of P04035 activity is mediated by transcriptional or by posttranscriptional events . The results of the present study , obtained by one - step RT - PCR assay , demonstrated that both P00441 and the metal - free form of enzyme ( Apo P00441 ) inhibit P04035 gene expression in hepatocarcinoma HepG2 cells , in normal human fibroblasts , and in fibroblasts of subjects affected by familiar hypercholesterolemia . Accordingly , P00441 could be used as a potential agent in the treatment of hypercholesterolemia , even in subjects lacking a functional P01130 pathway .",
"Modulation of arsenic - induced epidermal growth factor receptor pathway signalling by resveratrol . Arsenic ( As ) is both a human carcinogen and an effective anticancer drug . These aspects of arsenic toxicity develop as a consequence of arsenic - induced oxidative stress and modifications to signal pathway activity which alter gene expression . DB02709 ( RVL ) a food antioxidant found in grapes and other fruits , exhibits anti - carcinogenic properties by reducing oxidative stress and restoring signal pathway control . This study investigated the impact of RVL on arsenite [ As ( III ) ] - induced cell signalling in HaCaT keratinocytes by assaying phosphorylation status of epidermal growth factor receptor ( P00533 ) signalling intermediates and measuring changes in expression of Phase II and DNA repair biomarkers . As ( III ) exposure produced dose - dependent toxicity which was associated with increased activation of P00533 pathway intermediates , cSrc , Rac1 and extracellular signal - regulated kinases 1 and 2 ( P27361 / 2 ) . Arsenic - mediated P27361 / 2 activation negatively regulated P06746 expression and up regulated heme - oxygenase - 1 at toxic concentrations . RVL treatment modulated As ( III )- mediated P27361 / 2 activation by shifting the balance of cSrc regulatory domain phosphorylation . These effects significantly altered the response of the P00533 pathway to growth factor - induced stimulation . Our research provides evidence that treatment with pharmacologically relevant doses of RVL influences cellular responses to As ( III ) , largely due to RVL - mediated changes to Src and P27361 / 2 activation .",
"___MASK37___ enhances neurogenesis and oligodendrogenesis in ischemic brain of middle - aged mouse . Adult neural stem cells give rise to neurons , oligodendrocytes and astrocytes . Aging reduces neural stem cells . Using an inducible nestin - CreER ( P24752 )/ R26R - yellow fluorescent protein ( YFP ) mouse , we investigated the effect of ___MASK37___ , a phosphodiesterase type 5 ( O76074 ) inhibitor , on nestin lineage neural stem cells and their progeny in the ischemic brain of the middle - aged mouse . We showed that focal cerebral ischemia induced nestin lineage neural stem cells in the subventricular zone ( SVZ ) of the lateral ventricles and nestin expressing NeuN positive neurons and adenomatous polyposis coli ( P25054 ) positive mature oligodendrocytes in the ischemic striatum and corpus callosum in the aged mouse . Treatment of the ischemic middle - aged mouse with ___MASK37___ increased nestin expressing neural stem cells , mature neurons , and oligodendrocytes by 33 , 75 , and 30 % , respectively , in the ischemic brain . These data indicate that ___MASK37___ amplifies nestin expressing neural stem cells and their neuronal and oligodendrocyte progeny in the ischemic brain of the middle - aged mouse .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"Effect of pulsed estrogen therapy on hemostatic markers in comparison with oral estrogen regimen in postmenopausal women . BACKGROUND / AIMS : Hormone replacement therapy ( HRT ) is associated with an increased risk of thromboembolism dependent on the type of HRT ; therefore , we compared therapy effects of intranasal with oral estrogens on coagulation and fibrinolysis markers in postmenopausal women . METHODS : A randomized study in which 29 healthy hysterectomized women received intranasal 17beta - estradiol or oral estrogens for 3 months . RESULTS : There were no significant differences in the baseline characteristics between groups . Those women receiving intranasal estradiol showed a mild increment in plasminogen activator inhibitor - 1 ( P05121 - I ) ( from 6 . 8 +/- 3 . 5 to 9 . 6 +/- 3 . 9 U / ml , p < 0 . 01 ) ; however , fibrinogen , factor VII - tissue factor complex ( VIIa - rTF ) , antithrombin III ( P01008 ) , protein C ( PC ) activity , protein S ( PS ) activity , plasminogen ( P00747 ) , and tissue - type plasminogen activator antigen ( t - PA ) were unchanged . In contrast , oral unopposed estrogens elevated t - PA ( from 4 . 9 +/- 2 . 9 to 9 . 6 +/- 5 . 1 ng / ml , p < 0 . 01 ) in parallel with a decrement in P05121 - I ( from 5 . 2 +/- 4 . 0 to 2 . 7 +/- 1 . 7 U / ml , p < 0 . 05 ) and VIIa - rTF ( from 201 . 2 +/- 181 . 0 to 140 . 6 +/- 108 . 7 mU / ml , p < 0 . 05 ) . DB09222 , P01008 , PC , PS , and P00747 were unchanged . CONCLUSIONS : Nasal 17beta - estradiol had no effect on the coagulation markers , except a moderate increment in P05121 . In contrast , oral estrogens elicited a decrement in both VIIa - rTF and P05121 ; however , those changes did not surpass normal limits .",
"Anti - clastogenic effect of beta - glucan extracted from barley towards chemically induced DNA damage in rodent cells . beta - Glucan ( BG ) was tested in vitro to determine its potential clastogenic and / or anti - clastogenic activity , and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase . The study was carried out on cells deficient ( CHO - k1 ) and cells proficient ( HTC ) in phases I and II enzymes , and the DNA damage was assessed by the chromosomal aberration assay . BG did not show a clastogenic effect , but was anti - clastogenic in both cell lines used , and at all concentrations tested ( 2 . 5 , 5 and 10 microg / mL ) in combination with damage inducing agents ( methylmethane sulfonate in cell line CHO - k1 , and methylmethane sulfonate or 2 - aminoanthracene in cell line HTC ) . BG also showed a protective effect in the presence of a P06746 inhibitor ( cytosine arabinoside - 3 - phosphate , DB00987 ) , demonstrating that BG does not act through an anti - mutagenic mechanism of action involving P06746 .",
"[ ___MASK63___ sodium ( Photofrin - II ) ] . ___MASK63___ sodium ( ___MASK63___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK63___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Transient overexpression of mitochondrial transcription factor A ( Q00059 ) is sufficient to stimulate mitochondrial DNA transcription , but not sufficient to increase mtDNA copy number in cultured cells . Mitochondrial transcription factor A ( Q00059 ) stimulates transcription from mitochondrial DNA ( mtDNA ) promoters in vitro and in organello . To investigate whether changes of Q00059 levels also modulate transcription and replication in situ , the protein was transiently overexpressed in cultured cells . Mitochondrial mRNAs were significantly elevated at early time points , when no expansion of the Q00059 pool was yet observed , but were decreased when Q00059 levels had doubled , resemb - ling in vitro results . P29320 cells contain about 35 molecules of Q00059 per mtDNA . High levels of Q00059 were not associated with increases of full - length mtDNA , but nucleic acid species sensitive to RNAse H increased . Stimulation of transcription was more evident when Q00059 was transiently overexpressed in cells pre - treated with ethidium bromide ( EBr ) having lowered mtDNA , Q00059 and mitochondrial transcript levels . EBr rapidly inhibited mtDNA transcription , while decay of mtDNA was delayed and preferentially slowly migrating , relaxed mtDNA species were depleted . In conclusion , we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of Q00059 within the matrix is sufficient to stimulate mitochondrial transcription . Thus , this protein meets all criteria for being a key factor regulating mitochondrial transcription in vivo , but other factors are necessary for increasing mtDNA copy number , at least in cultured cells .",
"___MASK86___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK86___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .",
"Effects of DNA polymerase inhibitors on replicative and repair DNA synthesis in ultraviolet - irradiated HeLa cells . Aphidicolin specifically inhibits eukaryotic DNA polymerase alpha , while 2 ', 3 '- dideoxythymidine 5 '- triphosphate ( d2TTP ) inhibits P06746 and gamma but not alpha . DB00987 5 '- triphosphate ( araCTP ) inhibits both DNA polymerase alpha and beta although to a different extent . Here we measured the effects of these inhibitors on repair DNA synthesis of U . V .- irradiated HeLa cells by two different methods . Firstly , aphidicolin , 1 - beta - D - arabinofuranosylcytosine ( araC , a precursor of araCTP ) and 2 ', 3 '- dideoxythimidine ( d2Thd , a precursor of d2TTP ) were added directly to the culture medium . In this case , aphidicolin and araC strongly inhibited replicative DNA synthesis of HeLa cells , and they also inhibited repair synthesis after U . V .- irradiation but to a much lesser extent . In contrast , high concentrations of d2Thd inhibited repair DNA synthesis to a higher extent than replicative DNA synthesis . Secondly , the active form of inhibitor , d2TTP , was microinjection directly into cytoplasm or nuclei or U . V .- irradiated HeLa cells . Microinjection of d2TTP effectively inhibited repair synthesis . The microinjection of d2TTP , into either cytoplasm or nucleus , strongly inhibited replicative synthesis . These results might indicate that multiple DNA polymerases are involved in repair synthesis as well as in replicative synthesis .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK42___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK39___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"New features of mitochondrial DNA replication system in yeast and man . In this review , we sum up the research carried out over two decades on mitochondrial DNA ( mtDNA ) replication , primarily by comparing this system in Saccharomyces cerevisiae and Homo sapiens . Brief incursions into systems of other organisms have also been achieved when they provide new information . S . cerevisiae and H . sapiens mitochondrial DNA ( mtDNA ) have been thought for a long time to share closely related architecture and replication mechanisms . However , recent studies suggest that mitochondrial genome of S . cerevisiae may be formed , at least partially , from linear multimeric molecules , while human mtDNA is circular . Although several proteins involved in the replication of these two genomes are very similar , divergences are also now increasingly evident . As an example , the recently cloned human mitochondrial P06746 - subunit has no counterpart in yeast . Yet , yeast Abf2p and human Q00059 are probably not as closely functionally related as thought previously . Some mtDNA metabolism factors , like DNA ligases , were until recently largely uncharacterized , and have been found to be derived from alternative nuclear products . Many factors involved in the metabolism of mitochondrial DNA are linked through genetic or biochemical interconnections . These links are presented on a map . Finally , we discuss recent studies suggesting that the yeast mtDNA replication system diverges from that observed in man , and may involve recombination , possibly coupled to alternative replication mechanisms like rolling circle replication ."
] |
[
"___MASK37___",
"___MASK39___",
"___MASK42___",
"___MASK63___",
"___MASK67___",
"___MASK80___",
"___MASK84___",
"___MASK86___",
"___MASK99___"
] |
___MASK86___
|
MH_train_399
|
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